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.

Clinical

  • Fasciculations - small involuntary muscle contraction, imply lower motor neuron lesion.
  • Reflexes - see physical examination.
  • Strength.

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.

Muscle structure/histology

Macro to micro

Organization:[4]

  • 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:[5]
    • 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.

Normal findings

Muscle-tendon junction

Features:

Muscle-nerve junction

Features:

  • Dunno. (???)

Images:

Muscle spindle

Features:

  • Weird looking muscle cell. (???)

Image: Muscle spindle (anhb.uwa.edu.au).[7]

Abnormal findings

Iatrogenic

  • Torn (muscle) fibres (in the process of extraction for examination):
    • Membrane intact.
    • Myofibril kaputt.
    • No inflammation.

Pathologic

  • 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[8]).
  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 fixed (formulin fixed-paraffin embedded).
  2. Frozen tissue for histology.
  3. Frozen tissue for biochemistry.
  4. Fragment for electronmicroscopy (glutaraldehyde fixed).

SMH labeling

  • "E" = "frozens"; done on frozen tissue.
    • IHC done on these.
    • May have the label "2" ... even though there is no part 2.
  • Blue slides = "plastics", i.e. plastic embedded.
    • Stained with methylene blue.[9] (???)
  • Normal SMH numbering = "paraffin".

Patterns (pathologic)

Overview

 
 
 
 
 
 
 
 
Neuromuscular
pathology
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurogenic
 
 
Myogenic
 
 
Other/Mixed
Neurogenic Myogenic Notes Image
Shape of fibres angulated round round fibres[10]
Small fibres groups
("group atrophy") 		singular group atrophy[11]
Large fibres
 no +/-scattered "hypercontracted
fibres" 		DMD (WC)
Fibre type
grouping 		yes (d/t chronic
denervation +
reinnervation)[12] 		yes (???) based on ATPase,
NADH-TR stains 		ATPase 9.4[13], NADH-TR[14]

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.

Stains for muscle biopsies

Standard

Stain Comment Image
H&E stain routine [1][15]
Gomori trichrome good for nemaline rods,
mitochondrial pathology
(ragged red fibres - at edge
of myocyte) 		[2]
PAS glycogen storage disorders [3][16]
Congo red find amyloid; seen in
inclusion body myositis 		[4][17]
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][18]
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][19]
COX [7][19]
COX-SDH

Enzymatic/genetic stuff

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

Dunno:

IHC

  • Dystrophy panel.
    • Dystrophin[21] - 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 (?), axonal swellings.
  • Ubquitin - inclusion body myositis.
  • TDP43 - cytoplasmic staining in IBM.
    • Normally stain the nucleus.

Inflammatory myopathy

DDx:

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

Partial invasion of muscle fibres

DDx:[22]

  • 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.[23]

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

  • Endothelial tubuloreticular inclusions (abbrev. TRIs) - undulating tubules in the smooth ER, usu. perinuclear;[24] not pathognomonic - may be seen in inclusion body myositis.[25]

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.[26]

Microscopic

Features:

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

DDx: polymyositis.

IHC

Features:[26]

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

EM

  • Inclusion bodies - tubulovescicular material.[27]

Polymyositis

General

  • Tx: steroids.

Microscopic

Features:

  • Inflammation.

DDx: Inclusion body myositis.

Muscular dystrophy

General

  • DDx: large.

A short DDx:

  • Duchenne's muscular dystrophy.[28]
  • Becker's muscular dystrophy.
  • Limb-girdle muscular dystrophy.
    • Lotsa different mutations, autosomal dominant and recessive variants.
  • Myotonic dystrophy.[29][30]

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.

Limb-Girdle Muscular Dystrophy

General

  • A group of muscular dystrophies with childhood or adult onset.[31]
  • Rare.
  • Usually autosomal recessive.
  • Treatment: none; supportive only.

Subtypes

  • Sarcoglycanopathy.
  • Calpainopahty.
  • Dysferlinopathy.

Notes:

  • Can be demonstrated with IHC.

DDx

  • DMD gene associated MDs (Duchenne MD, Becker MD).
  • Facioscapulohumeral muscular dystrophy (FSHD).
  • Emery-Dreifuss MD (EDMD).
  • Congenital MD (CMD).
  • Inflammatory myopathies.

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.[32]
  • "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

  • Most common biopsy: sural nerve.

Stains

Myelin stain:

  • Blue = myelin.

Gomori trichrome:

  • Axon = green.
  • Myelin = red.

Degenerative changes

Types:[33]

  • Wallerian degeneration.
  • Axonal degeneration.
  • Segmental demyelination.

Wallerian degeneration

Diseases

  • Guillain–Barré syndrome.
  • Chronic inflammatory demyelinating polyneuropathy (CIDP).[34]
    • Essentially chronic Guillain–Barré syndrome.

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://commons.wikimedia.org/wiki/File:Skeletal_muscle.jpg. Accessed on: 25 October 2010.
  5. ↑ Martini, Frederic H. (2003). Fundamentals of Anatomy & Physiology (6th ed.). Benjamin Cummings. pp. 438. ISBN 978-0805359336.
  6. ↑ URL: http://www.lab.anhb.uwa.edu.au/mb140/corepages/connective/connect.htm. Accessed on: 4 November 2010.
  7. ↑ URL: http://www.lab.anhb.uwa.edu.au/mb140/corepages/muscle/muscle.htm. Accessed on: 28 November 2010.
  8. ↑ URL: http://www.igbmc.fr/recherche/Dep_NG/Eq_JLaporte/JL3.html. Accessed on: 26 October 2010.
  9. ↑ URL: http://www.nature.com/modpathol/journal/v18/n5/full/3800344a.html. Accessed on: 26 November 2010.
  10. ↑ URL: http://nmdinfo.org/lectures/info.php?id=8. Accessed on: 25 October 2010.
  11. ↑ URL: http://neuropathology.neoucom.edu/chapter9/chapter9fALS.html. Accessed on: 25 October 2010.
  12. ↑ URL: http://neuromuscular.wustl.edu/lab/mbiopsy.htm#fibertype. Accessed on: 26 October 2010.
  13. ↑ URL: http://missinglink.ucsf.edu/lm/ids_104_musclenerve_path/student_musclenerve/musclepath.html. Accessed on: 26 October 2010.
  14. ↑ URL: http://moon.ouhsc.edu/kfung/JTY1/Com04/Com401-3-Diss.htm. Accessed on: 28 October 2010.
  15. ↑ URL: http://www.rvc.ac.uk/Research/Labs/NeuroLab/MuscleBiopsy.cfm. Accessed on: 26 October 2010.
  16. ↑ URL: http://neuromuscular.wustl.edu/pathol/dermmyo.htm. Accessed on: 26 October 2010.
  17. ↑ URL: http://neuromuscular.wustl.edu/pathol/ibmpaget.htm. Accessed on: 26 October 2010.
  18. ↑ URL: http://neuromuscular.wustl.edu/pathol/dermmyo.htm. Accessed on: 26 October 2010.
  19. ↑ 19.0 19.1 URL: http://moon.ouhsc.edu/kfung/JTY1/Com04/Com401-3-Diss.htm. Accessed on: 28 October 2010.
  20. ↑ URL: http://neuromuscular.wustl.edu/pathol/rod.htm. Accessed on: 26 October 2010.
  21. ↑ URL: http://www.ncbi.nlm.nih.gov/omim/310200. Accessed on: 29 October 2010.
  22. ↑ 22.0 22.1 URL: http://neuromuscular.wustl.edu/pathol/inflammation.htm#cellinv. Accessed on: 3 November 2010.
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ Katzberg HD, Munoz DG (2010). "Tubuloreticular inclusions in inclusion body myositis". Clin. Neuropathol. 29 (4): 262–6. PMID 20569678.
  26. ↑ 26.0 26.1 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.
  27. ↑ URL: http://neuromuscular.wustl.edu/pathol/ibm.htm. Accessed on: 3 November 2010.
  28. ↑ URL: http://www.ncbi.nlm.nih.gov/omim/310200. Accessed on: 29 October 2010.
  29. ↑ URL: http://www.ncbi.nlm.nih.gov/omim/160900. Accessed on: 29 October 2010.
  30. ↑ URL: http://www.ncbi.nlm.nih.gov/omim/602668. Accessed on: 29 October 2010.
  31. ↑ URL: http://www.ncbi.nlm.nih.gov/books/NBK1408/. Accessed on: 25 November 2010.
  32. ↑ URL: http://moon.ouhsc.edu/kfung/jty1/neurotest/Q09-Ans.htm. Accessed on: 26 October 2010.
  33. ↑ URL: http://missinglink.ucsf.edu/lm/ids_104_musclenerve_path/student_musclenerve/nervepath.html. Accessed on: 9 November 2010.
  34. ↑ URL: http://path.upmc.edu/cases/case426.html. Accessed on: 14 November 2010.

External links

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