Neuromuscular pathology

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Neuromuscular pathology is the study of muscle and neurologic disease associated with muscle dysfunction. It is a part of neuropathology.

Muscle pathology is dealt together with neurologic disease as, at the presentation, they are not infrequently impossible to definitely distinguish.

Work-up

General

  1. Clinical history, including family history.
  2. Laboratory studies, e.g. CK.
  3. Nerve conduction and electromyography studies.
  4. Muscle biopsy.

Laboratory studies

The CK suggest the type of disorder:[1]

  • High ~200-300X normal -- suggests myogenic.
  • Intermedidate ~20-30X normal -- possibly inflammatory.
  • Low ~2-5X normal -- possibly neurogenic.

Notes:

  • The CK value is most useful when it is very high.[2]
  • Normal CK values:[3]
    • Men: 24-195 unit/litre.
    • Women: 24-170 units/litre.

Patterns

Overview

 
 
 
 
 
 
 
 
Neuromuscular
pathology
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurogenic
 
 
Myogenic
 
 
Other/Mixed
Neurogenic Myogenic Notes Image
Shape of fibres angulated round round fibres[4]
Small fibres groups
("group atrophy") 		singular group atrophy[5]
Large fibres
 no +/-scattered "hypercontracted
fibres" 		DMD (WC)
Fibre type
grouping 		yes (d/t chronic
denervation +
reinnervation)[6] 		yes (???) based on ATPase,
NADH-TR stains 		ATPase 9.4[7], NADH-TR[8]

List

Neurogenic:

  • Angulated myocytes.
  • Groups of small fibres.
  • Apparent increase of nuclei.

Myogenic:

  • Round myocytes.
  • +/-Intense (darker) cytoplasm.
  • +/-Fibrosis (between fibres).
  • +/-Necrosis.

Detail

  1. Segmental demyelination - nerve/CNS abnormality.
  2. Axonal degeneration - nerve/CNS abnormality.
  3. Reinnervation - nerve injury.
  4. Myopathy - something is wrong with the muscle fibres.

Muscle structure/histology

Macro to micro

Organization:[9]

  • Muscle - surrounded by epimysium.
    • Fascicle - surrounded by perimysium.
      • Muscle fibre - muscle cell.
        • Myofibrils - contractile elements within the muscle cell.

Notes:

  • This is similar for nerves:[10]
    • Nerve (surrounded by epineurium) -> Fascicle (surrounded by perineurium) -> Nerve fibre (surrounded by endoneurium).

Fibre types

 
 
 
Types
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Type 1
slow twitch
 
 
 
Type 2
fast twitch

List

Type 1 - AKA slow twitch:

  • Predominantly oxidative metabolism, i.e. have lots of mitochondria.

Type 2 - AKA fast twitch:

  • Predominantly glycolytic metabolism.

Mnemonic Slow red fat ox: Slow twitch fibres are (grossly) more red (due to mitochondria), lipid rich (fat) and primarily have oxidative metabolism.

Abnormal findings

  • Ragged red fibres = mitochondrial pathology.
  • Rimmed vacuoles = inclusion body myositis.
  • PAS +++ = glycogen storage disease.
  • Regenerative fibres = large nuclei, basophilic cytoplasm (incr. protein synthesis, incr. RNA).

Others:

  • Target fibre - "hole in middle of myofibres" = neurogenic. (???)
  • Cores - central pale area along length of fibres = myopathic. (???)

Approach

General:

  1. Size variation - in groups (neurogenic) vs. singular (myogenic).
  2. Shape - angulated (neurogenic) vs. round (myogenic).
  3. Position of nuclei - peripheral (normal); central (myogenic; centronuclear myopathy[11]).
  4. Necrosis - suggests myogenic.
  5. Fibrosis - suggests myogenic.
  6. Inflammation - suggest myogenic vs. systemic inflammatory.

Other:

  1. Obvious abnormality vs. minimal change.
  2. Diffuse vs. focal change.

Processing of muscle biopsies

  1. Formulin.
  2. Frozen section.
  3. Frozen for biochemistry.
  4. Fragment for electronmicroscopy (glutaraldehyde fixative).

Stains for muscle biopsies

Standard

Stain Comment Image
H&E stain routine [1][12]
Gomori trichrome good for nemaline rods,
mitochondrial pathology
(ragged red fibres - at edge
of myocyte) 		[2]
PAS glycogen storage disorders [3][13]
Congo red find amyloid; seen in
inclusion body myositis 		[4][14]
Oil red O lipid more in
type 1 fibres
ATPase pH4.2
ATPase pH9.4 		should have "checkerboard
pattern" in normal; see table below 		[5][15]
NADH-TR should have "checkerboard
pattern" in normal;
type 1 fibres = light blue,
type 2 fibres = white

ATPase stain pattern/fibre type

Type 1
slow twitch 		Type 2
fast twitch
pH 4.2 dark light
pH 9.4 light dark

Special - mitochondrial pathology

Stain Comment Image
Succinate
dehydrogenase (SDH) 		[6][16]
COX [7][16]
COX-SDH

Enzymatic/genetic stuff

  • Phosphorylase.
  • Adenylate deaminase.
  • Acid phosphatase.
  • Alkaline phosphatase.

Dunno:

IHC

  • Dystrophy panel.
    • Dystrophin[18] - Duchenne muscular dystrophy (onset <3 years), Becker's muscular dystrophy (onset 20s or 30s).
    • Spectrin - a cause of long QT syndrome. (???)
  • Lymphocytic markers (CD45, CD3, CD4, CD8, CD20).
  • MAC - inclusion body myositis.
  • APP - inclusion body myositis.
  • Ubquitin - inclusion body myositis.

Inflammatory myopathy

DDx:

  1. Polymyositis.
  2. Inclusion body myositis (IBM).
  3. Dermatomyositis.

Partial invasion of muscle fibres

DDx:[19]

  • IBM.
  • Polymyositis.

Images:

DDx

Neurogenic:

  • Amyotrophic lateral sclerosis.
  • Spinal muscular atrophy.
  • Trauma.
  • Vascular disease.
  • Infective process.
  • ?Motor neuron disease.

Myopathic:

  • Inflammatory:
    1. Polymyositis.
    2. Inclusion body myositis.
    3. Dermatomyositis.
  • Duchenne muscular dystrophy.
  • Becker muscular dystrophy.
  • Limb-girdle muscular dystrophy.
  • Myotonic dystrophy.
  • Metabolic - glycogen storage disease.

Other:

  • Myasthenia gravis.
  • Mitochondrial myopathy.
  • Congenital fibre type disproportion.
  • Periodic paralysis.

Amyotrophic lateral sclerosis

General

  • Abbreviated ALS.
  • Affects - corticospinal tract - gliosis.

Microscopic

Features:

  • Neurogenic pattern:
    • Group atrophy.
    • +/-Target fibres.

Dermatomyositis

General

  • Complement mediated disease - membrane attack complex.
  • Usually middle age.
  • Associated skin rash is common.

Clinical

  • If the characteristic skin lesions are absent... it is likely idiopathic inflammatory myositis and related to diabetes mellitus.[20]

Microscopic

Features:

  • Perifascicular inflammation with perifascicular atrophy - key feature.
  • Loss of vessels around muscle fibres.
    • Vessels should be where more than 3 or more fibres are opposed to one another.

EM

  • Tubuloreticular inclusions - undulating tubules in the smooth ER, usu. perinuclear;[21] not pathognomonic - may be seen in inclusion body myositis.[22]

Images:

Inclusion body myositis

General

  • Usually elderly.
  • Thought to be related to Alzheimer's disease due to similar staining with congo red and several IHC stains.[23]

Microscopic

Features:

  • Inflammation.
  • Vacuolated muscle fibres (with proteineous aggregates) key feature.
    • Vacuolation = "inclusion"
      • Usually in the centroidal location.

DDx: polymyositis.

IHC

Features:[23]

  • Congo red +ve.
  • APP +ve, ubiquitin +ve, tau +ve. (???)

Polymyositis

General

  • Tx: steroids.

Microscopic

Features:

  • Inflammation.

DDx: Inclusion body myositis.

Muscular dystrophy

General

  • DDx: large.

A short DDx:

  • Duchenne's muscular dystrophy.[24]
  • Becker's muscular dystrophy.
  • Limb-girdle muscular dystrophy.
    • Lotsa different mutations, autosomal dominant and recessive variants.
  • Myotonic dystrophy.[25][26]

Microscopic

Features:

  • Endomysial fibrosis.
  • Hypercontracted fibres (large muscle fibres).

Myotonic dystrophy

Microscopic

Features:

  • Internal nuclei/central nuclei.

Nemaline myopathy

General

  • A type of congenital myopathy.
  • Paediatric thingy.


Mitochondrial disorders

General

  • Onset childhood to adulthood.
  • Heteroplasmy - variable distribution of badness within affected individuals.
    • Leads to "threshold effect".

Microscopic

  • Trichrome most useful - find the ragged red fibres - usu. at the cell periphery.
  • COX-SDH:
    • Non-staining (???).
    • Peripheral blue accumulation in occasional cells.

EM

Features:

  • Crystalloid inclusions.[27]
  • "Ballooned" mitochondria; loss of cristae -- loss of membranous folds within mitochrondrion.

Trichinosis

See Microorganisms.

Parasitic disease classically associated with consumption of uncooked pork.

Type 2 fibre atrophy

DDx:

  • Disuse.
  • Space travel.
  • Steroids.
  • Others.

Nerve stuff

General

  • Biopsy: sural nerve.
  • Myelin stain: blue = myelin.
  • Gomori trichrome: axon = green, myelin = red.

See also

References

  1. ↑ URL: http://moon.ouhsc.edu/kfung/jty1/NeuroHelp/ZNEWWU10.htm. Accessed on: 27 October 2010.
  2. ↑ Filosto M, Tonin P, Vattemi G, et al. (January 2007). "The role of muscle biopsy in investigating isolated muscle pain". Neurology 68 (3): 181–6. doi:10.1212/01.wnl.0000252252.29532.cc. PMID 17224570.
  3. ↑ URL: http://www.gpnotebook.co.uk/simplepage.cfm?ID=1436155929. Accessed on: 27 October 2010.
  4. ↑ URL: http://nmdinfo.org/lectures/info.php?id=8. Accessed on: 25 October 2010.
  5. ↑ URL: http://neuropathology.neoucom.edu/chapter9/chapter9fALS.html. Accessed on: 25 October 2010.
  6. ↑ URL: http://neuromuscular.wustl.edu/lab/mbiopsy.htm#fibertype. Accessed on: 26 October 2010.
  7. ↑ URL: http://missinglink.ucsf.edu/lm/ids_104_musclenerve_path/student_musclenerve/musclepath.html. Accessed on: 26 October 2010.
  8. ↑ URL: http://moon.ouhsc.edu/kfung/JTY1/Com04/Com401-3-Diss.htm. Accessed on: 28 October 2010.
  9. ↑ URL: http://commons.wikimedia.org/wiki/File:Skeletal_muscle.jpg. Accessed on: 25 October 2010.
  10. ↑ Martini, Frederic H. (2003). Fundamentals of Anatomy & Physiology (6th ed.). Benjamin Cummings. pp. 438. ISBN 978-0805359336.
  11. ↑ URL: http://www.igbmc.fr/recherche/Dep_NG/Eq_JLaporte/JL3.html. Accessed on: 26 October 2010.
  12. ↑ URL: http://www.rvc.ac.uk/Research/Labs/NeuroLab/MuscleBiopsy.cfm. Accessed on: 26 October 2010.
  13. ↑ URL: http://neuromuscular.wustl.edu/pathol/dermmyo.htm. Accessed on: 26 October 2010.
  14. ↑ URL: http://neuromuscular.wustl.edu/pathol/ibmpaget.htm. Accessed on: 26 October 2010.
  15. ↑ URL: http://neuromuscular.wustl.edu/pathol/dermmyo.htm. Accessed on: 26 October 2010.
  16. ↑ 16.0 16.1 URL: http://moon.ouhsc.edu/kfung/JTY1/Com04/Com401-3-Diss.htm. Accessed on: 28 October 2010.
  17. ↑ URL: http://neuromuscular.wustl.edu/pathol/rod.htm. Accessed on: 26 October 2010.
  18. ↑ URL: http://www.ncbi.nlm.nih.gov/omim/310200. Accessed on: 29 October 2010.
  19. ↑ 19.0 19.1 URL: http://neuromuscular.wustl.edu/pathol/inflammation.htm#cellinv. Accessed on: 3 November 2010.
  20. ↑ Limaye VS, Lester S, Blumbergs P, Roberts-Thomson PJ (May 2010). "Idiopathic inflammatory myositis is associated with a high incidence of hypertension and diabetes mellitus". Int J Rheum Dis 13 (2): 132–7. doi:10.1111/j.1756-185X.2010.01470.x. PMID 20536597.
  21. ↑ Stoltenburg-Didinger G, Genth E (June 2009). "[Dermatomyositis]" (in German). Z Rheumatol 68 (4): 287–94. doi:10.1007/s00393-008-0398-y. PMID 19330338.
  22. ↑ Katzberg HD, Munoz DG (2010). "Tubuloreticular inclusions in inclusion body myositis". Clin. Neuropathol. 29 (4): 262–6. PMID 20569678.
  23. ↑ 23.0 23.1 Askanas V, Engel WK (November 1995). "New advances in the understanding of sporadic inclusion-body myositis and hereditary inclusion-body myopathies". Curr Opin Rheumatol 7 (6): 486–96. PMID 8579968.
  24. ↑ URL: http://www.ncbi.nlm.nih.gov/omim/310200. Accessed on: 29 October 2010.
  25. ↑ URL: http://www.ncbi.nlm.nih.gov/omim/160900. Accessed on: 29 October 2010.
  26. ↑ URL: http://www.ncbi.nlm.nih.gov/omim/602668. Accessed on: 29 October 2010.
  27. ↑ URL: http://moon.ouhsc.edu/kfung/jty1/neurotest/Q09-Ans.htm. Accessed on: 26 October 2010.

External links

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