Muscle pathology and diseases are a high-yield topic for neurology examinations as many of these disorders have characteristic or pathognomonic findings that allow for easy test question writing! For this topic, pathology slide interpretation will be a great skill to have! Luckily this chapter has dozens of high-quality images with which to practice.

Author: Brian Hanrahan MD

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Acquired Myopathies

Idiopathic inflammatory myopathies

Polymyositis

  • A female-predominant disease seen in one’s adult years that presents with subacute symmetric proximal weakness and pain.
  • Can be associated with rheumatoid arthritis, HIV, or underlying malignancy.
  • Muscle biopsy shows endomysial and perivascular monocytic inflammation and necrosis with regeneration.

Dermatomyositis

  • A female-predominant disease which presents with subacute proximal weakness and pain.
  • Dermatologic manifestations include a heliotrope rash on eyelids and an erythematous rash of the face or neck.
  • Can be associated with connective tissue disease, malignancy, and interstitial lung disease.
  • Muscle biopsy shows perifascicular inflammation and atrophy with sparing of the central fascicle.

Inclusion body myositis (IBM)

  • A male-predominant slowly progressive idiopathic inflammatory condition of patients over the age of 50.

  • Clinical features include asymmetric weakness of the finger flexors and the quadriceps muscles.

Treatment

  • Polymyositis and dermatomyositis are responsive to immunosuppressive therapies (steroids, methotrexate, azathioprine, mycophenolate, etc.) while IBM is not.

Table 1: Idiopathic Inflammatory myopathies

Table of inflammatory myopathies

Toxic myopathies

Steroid myopathy

  • Occurs in the setting of chronic exposure.
  • Patients present with progressive proximal muscle weakness with normal CK levels.

  • EMG testing is typically normal.
  • Discontinuation of steroid therapy leads to resolution of symptoms.

Statin-induced myopathy

  • Less common than statin-induced myalgias, which can occur in as much as 20% of users.
  • Pathogenesis is thought to be secondary to inhibition of mevalonic acid synthesis via inhibition of HMG-CoA reductase.
  • Higher doses of statins and concurrent medications such as fibrates, niacin, calcium channel blockers, antiretrovirals, and cyclosporine can increase the risk of statin-induced myopathy.

Hydroxychloroquine-related myopathy

  • Occurs in the setting of treatment for malaria or rheumatologic disease with hydroxychloroquine or chloroquine.

  • Symptoms resolve with discontinuation of the medication.

Inherited (non-channel) Myopathies

Muscular dystrophies

Duchenne muscular dystrophy (DMD)

  • Due to an X-linked out-of-frame mutation of the dystrophin gene resulting in complete loss of dystrophin.
    • Dystrophin anchors the cellular cytoskeleton to actin, contributing to the stability of the plasma membrane.
  • Symptoms of weakness, cramping, and fatigue begin at 3-5 years of age with loss of ambulation by 13 years. Death secondary to respiratory or cardiac failure typically occurs in the second to third decade of life.
    • Exam on initial presentation will show pseudohypertrophy in calf muscles, a waddling gait, toe walking, and Gower’s sign.
  • Pathology: Degenerating fibers of various sizes undergoing phagocytosis, excessive fibrosis, and connective tissue.
    • Immunohistochemical staining for dystrophin will show a complete lack of staining.
Muscle pathology Dystrophin staining of normal muscle compared to a muscle of patient with DMD
(Left) Dystrophin staining (brown) of normal muscle compared to a muscle of a patient with DMD (Right)
Muscle pathology Mosaic Pattern in Female Duchenne Muscular Dystrophy Carrier
Mosaic Pattern in Female Duchenne Muscular Dystrophy Carrier
  • Treatment:
    • Corticosteroids slow the progression of the disease.
    • Eteplirsen, which works by exon skipping of dystrophin mRNA, was recently FDA-approved for a subset of patients with DMD who have out-of-frame mutations on exon 51 of the dystrophin gene.

Becker muscular dystrophy

  • Patients present similarly to DMD but will do so later in life due to the partial function of dystrophin via an in-frame mutation of the dystrophin gene.
  • Immunohistochemical staining for dystrophin will show partial staining.
  • Treatment: corticosteroids
Muscle Pathology Becker Muscular Dystrophy
(Left) Dystrophin staining (brown) of normal muscle compared to the muscle of a patient with BMD (Right)

Myotonic dystrophy (MD)

  • The most common muscular dystrophy in adults.
    • Type 1 MD is an autosomal dominant disorder due to a CTG repeat of the myotonic dystrophy protein kinase (DMPK) gene that anticipates with successive generations.
    • Type 2 MD is also autosomal dominant, but due to a CCTG repeat of the CNBP gene.
  • Patients present with myotonia as well as weakness of the face, neck, and intrinsic hand muscles.
    • Myotonia can be treated with sodium channel blockers (mexiletine, phenytoin, and carbamazepine) and tricyclic antidepressants (amitriptyline, clomipramine, and imipramine).
    • Other symptoms include excessive daytime sleepiness, conduction defects, cataracts, frontal balding, ptosis, and endocrine dysfunction.
    • Patients with MD need to have interval EKGs for cardiac arrhythmias.

  • EMG will show myotonic discharges (spontaneous potentials with waxing and waning amplitude and frequency) on needle EMG.

Fukuyama muscular dystrophy

  • Presents in the neonatal period with hypotonia, contractures, and gross motor delays
  • Cerebral dysgenesis and intellectual disability are often seen as well.
  • Associated with mutations to fukutin (putative glycosyltransferase) gene.

EMG findings in muscular dystrophies:

  • Fibrillation potentials, positive sharp waves, and short, small, polyphasic MUAPs with early recruitment.

Congenital myopathies

Myotubular/centronuclear myopathy

  • A disease that presents with hypotonia, weakness involving the cranial nerve innervated muscles, and cognitive changes.
  • Pathology:
    • Muscle biopsy will show centrally-located nuclei with a perinuclear sarcoplasmic reticulum extending radially in a “halo” formation.
Muscle Pathology Centronuclear Myotubular Myopathy
Muscle biopsy showing centrally located nuclei in muscle fibers

Nemaline myopathy

  • Presents with infantile hypotonia.
  • Pathology:
    • Muscle biopsy will show a finding of rod- or thread-like eosinophilic structures on Gomori trichrome stain.
    • Electron microscopy shows rod-like or oval, electron-dense bodies radiating from the sarcomeric Z-line.

Central core disease

  • An autosomal dominant disease that presents with neonatal hypotonia and weakness secondary to mutations to the ryanodine calcium channel (RYR1).
  • Pathology:
    • Muscle biopsy will show lucent central cores on NADH stain with variably sized fibers with internalized nuclei.
  • Patients are at a higher risk to develop malignant hyperthermia.

Inherited Myopathic Channelopathies

Hyperkalemic periodic paralysis

  • An autosomal dominant disorder due to a mutation in an alpha subunit of SCN4A voltage-gated sodium channel.

  • Presents with episodic weakness before the age of 10.

  • Attacks last less than a few hours and are triggered by resting after exercise, steroids, fasting, or potassium-rich foods.

  • Potassium levels can be elevated during an attack but may be normal.

  • Acute attacks can be managed with decreasing serum potassium levels: IV glucose or insulin, IV calcium gluconate, oral carbohydrates, furosemide, and/or inhaled beta-agonists.

  • Prophylactic therapy includes acetazolamide or thiazides.

Hypokalemic periodic paralysis

  • An autosomal dominant disorder due to a mutation in the gene CACNA1S, which encodes L-type voltage-gated calcium channels.

  • Presents with episodes of weakness that last hours to days triggered by rest after exercise, large carbohydrate meals, insulin, and steroids.

    • Potassium levels can be low during an attack.

  • Onset is usually later than those with hyperkalemic periodic paralysis, occurring in the second to third decade of life.

  • Prophylactic therapy includes acetazolamide or potassium-sparing diuretics.

Myotonia congenita

  • Due to a mutation of the chloride channel (CLCN1) gene.
  • Presents with normal muscle strength, myotonia, and muscle stiffness between 2-3 years of age.
  • Patients will have normal or increased bulk, and muscle stiffness will improve with exercise.

Paramyotonia congenita

  • Due to mutation in the alpha subunit of SCN4A voltage-gated sodium channel.
    • Recall, this is the same channel involved in hyperkalemic periodic paralysis.
  • Presents with muscle stiffness provoked by cold, exercise, or hypokalemia. Unlike myotonia congenita, muscle stiffness worsens with activity.

Table 2: Inherited channel myopathies

Table of Channelopathy Myopathies

Metabolic Myopathies

Lipid storage disorders

Glycogen storage diseases

  • Symptoms in glycogen storage diseases depend on the tissue distribution of the missing enzyme.

Pompe disease (alpha-glucosidase (GAA) deficiency)

  • Can be appreciated early in life with hypotonia, macroglossia, and hepatomegaly. Patients will have progressive heart and skeletal muscle weakness, and eventually respiratory failure.
  •  Treatment:
    • Enzyme replacement therapy with intravenous alglucosidase alfa can improve motor, cardiac, and respiratory function.

McArdle disease (myophosphorylase deficiency)

  • Affects skeletal muscle while sparing cardiac tissue.
  • Presents with rapid onset fatigue with exercise that improves with continued activity.
  • Myophosphorylase can also be called glycogen phosphorylase.

EMG findings in glycogen storage diseases

    • Pompe disease: Fibrillations, positive sharp waves, complex repetitive discharges, and myotonic discharges.
    • Metabolic myopathies with an exercise-induced component (i.e. McArdle disease/myophosphorylase deficiency ) will typically have normal EMG studies if not performed during acute exacerbations.

Mitochondrial myopathies

  • An umbrella term that includes several syndromes such as myoclonic epilepsy with ragged red fibers (MERRF), mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) .
  • Pathology:
    • Ragged red fibers are typically seen on muscle biopsy. Other findings include increased subsarcolemmal staining on succinate dehydrogenase (SDH) stains (ragged blue fibers).

MELAS

  • “Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes”
  • The name alone gives you most of the facts needed for neurology examinations.
  • Associated with mutations related to mitochondrial MT-TL1.

MERRF

  • “Myoclonic epilepsy with ragged red fibers”
  • The name alone gives you most of the facts needed for neurology examinations.

References

  1. Amato AA, Barohn RJ. Evaluation and treatment of inflammatory myopathies. Journal of Neurology, Neurosurgery & Psychiatry 2009;80:1060-1068.
  2. Amato, Anthony A., and John T. Kissel. “Inflammatory Myopathies.” Swaiman’s Pediatric Neurology, 2017, pp. 1141–1147., doi:10.1016/b978-0-323-37101-8.00150-8.
  3. Benjamin Larman, H., et al. (2013). “Cytosolic 5′-nucleotidase 1A autoimmunity in sporadic inclusion body myositis.” 73(3): 408-418.
  4. Dimauro, Salvatore, et al. “Mitochondrial Myopathies.” Annals of Neurology, vol. 17, no. 6, 1985, pp. 521–538., doi:10.1002/ana.410170602.
  5. Emery, Alan Eh. “The Muscular Dystrophies.” The Lancet, vol. 359, no. 9307, 2002, pp. 687–695., doi:10.1016/s0140-6736(02)07815-7.
  6. Franc, Sylvia, et al. “A Comprehensive Description of Muscle Symptoms Associated with Lipid-Lowering Drugs.” Cardiovascular Drugs and Therapy, vol. 17, no. 5/6, 2003, pp. 459–465., doi:10.1023/b:card.0000015861.26111.ab.
  7. Mammen, Andrew L. “Toxic Myopathies.” CONTINUUM: Lifelong Learning in Neurology, vol. 19, 2013, pp. 1634–1649., doi:10.1212/01.con.0000440663.26427.f4.
  8. Mcclatchey, Andrea I., et al. “Temperature-Sensitive Mutations in the III–IV Cytoplasmic Loop Region of the Skeletal Muscle Sodium Channel Gene in Paramyotonia Congenita.” Cell, vol. 68, no. 4, 1992, pp. 769–774., doi:10.1016/0092-8674(92)90151-2.
  9. Muchir, A. and H. J. Worman (2007). “Emery-Dreifuss muscular dystrophy.” Current Neurology and Neuroscience Reports 7(1): 78-83.
  10. Saperstein, David S. “Muscle Channelopathies.” CONTINUUM: Lifelong Learning in Neurology, vol. 12, 2006, pp. 121–139., doi:10.1212/01.con.0000290465.34703.fd.
  11. Tarnopolsky, M. A. (2016). “Metabolic Myopathies.” Continuum (Minneap Minn) 22(6, Muscle and Neuromuscular Junction Disorders): 1829-1851.
  12. Birnkrant, David J., et al. “Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management.” The Lancet Neurology, vol. 17, no. 4, 2018, pp. 347

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