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.

Micrograph of a nerve biopsy. Toluidine blue stain.

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

Macroscopic to microscopic

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 - fibre types

Type 1 - AKA slow twitch:

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

Type 2 - AKA fast twitch:

  • Predominantly glycolytic metabolism.

Mnemonic for type I fibres slow fat red ox:

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

Table - fibre types

Parameter Type I Type II
Twitch speed slow fast
Colour red white
Fat content higher lower
ATP production oxidative anaerobic
glycoloysis
Glycogen higher lower
Resistance to fatigue higher lower
ATPase quality lower higher
Myoglobin higher lower
Mitochondria higher lower

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

Others:

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. Formalin fixed (formalin fixed-paraffin embedded).
  2. Frozen tissue for histology.
  3. Frozen tissue for biochemistry.
  4. Fragment for electron microscopy (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] vs. toluidine blue. (???)
    • Thin sections: 0.1 - 1 micrometres.
  • 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.

  • Groups of atrophic fibers (HE)

  • Angulated atrophic fibers (HE)

  • Fiber type grouping and targetoid fibers in neurogenic atrophy (ATPase)

  • Type 2 fiber atrophy (HE)

  • Type 2 fiber atrophy (ATPase)

Myogenic:

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

  • Basophilic fibers and nuclear internalization in muscular dystropy (HE).

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 H&E[15], H&E (WC)
Gomori trichrome good for nemaline rods,
mitochondrial pathology
(ragged red fibres - at edge
of myocyte) 		RRF (WC)
PAS glycogen storage disorders [1][16]
Congo red find amyloid; seen in
inclusion body myositis 		[2][17]
Oil red O lipid more in
type 1 fibres 		ORO
ATPase pH4.2
ATPase pH9.4 		should have "checkerboard
pattern" in normal; see table below 		[3][16]
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) 		stains mitochondria;
usu. +ve in mitochondrial disease[18] 		[4][19], SDH (WC)
Cytochrome oxidase (COX) stains mitochondria;
usu. -ve in mitochondrial disease 		[5][19]
COX-SDH used to look for mitochondrial disease

Enzymatic/genetic stuff

Stain Comment Image
Phosphorylase
Adenylate deaminase
Acid phosphatase (ACPH) necrosis (red)
Alkaline phosphatase (ALPH) regeneration (punctate - black)

Dunno:

IHC

  • Dystrophy panel.
    • Dystrophin[21] - Duchenne muscular dystrophy (onset usu. <3 years), Becker's muscular dystrophy (onset usu. 20s or 30s).
      • Membranous staining is normal. Loss of membranous staining = pathologic.
        • Tested with three antibodies -- as the protein is hueuge.
    • 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.
  • TDP-43 (also TDP43) - cytoplasmic staining in IBM.

List of common conditions

Neurogenic:

Myopathic:

Other:

Groups of disorders

Inflammatory myopathy

DDx:

  1. Polymyositis.
    • Disease of adults.
  2. Inclusion body myositis (IBM).
    • Distal weakness.
    • Can be sporadic or hereditary.
  3. Dermatomyositis.
    • Acute development.
    • May be associated with malignancy.
  4. Granulomatous myositis.
  5. Graft-versus-host disease.
  6. Infectious myositis.
    • Rare.


Quick overview:

Dermatomyositis Polymyositis sporadic Inclusion body myositis
Myositis type Perifascicular Diffuse Diffuse (limited inflammation)
Histology Perivascular inflammation, Perifascicular damage. Endomysial inflammation and damage. Endomysial inflammation, rimmed vacuoles withe eosinophilic inclusions, neurogenic changes.
Immunostaining CD4+ B-cell lymphocytes predominate, C5b9 complement complex deposits in capillaries. CD8+ lymphocytes invading non-necrotic fibers. Mainly CD8-positive lymphocytes.
Electron microscopy Tubulovesicular inclusions. Nothing special. Filamentous inclusions.
Exemplary image
 
 
 

Partial invasion of muscle fibres

DDx:[22]

Images:

Muscular dystrophy

General

  • DDx: large.

A short DDx:

  • Duchenne's muscular dystrophy.[21]
  • Becker's muscular dystrophy.
  • Limb-girdle muscular dystrophy.
    • Lotsa different mutations, autosomal dominant and recessive variants.
  • Myotonic dystrophy.[23][24]

Microscopic

Features:

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

  • Becker's muscular dystrophy ([[H&E]))

  • Carrier status in dystrophinophathy (Dystrophin)

Images:

Limb-girdle muscular dystrophy

General

  • A group of muscular dystrophies with childhood or adult onset.[25]
  • 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.

  • Loss of alpha sarcocglycan in LGMD2D (WC).


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.[26]
  • "Ballooned" mitochondria; loss of cristae -- loss of membranous folds within mitochrondrion.

  • ragged red fibers (Gomöri Trichrom)

  • Cox-deficient fibers (blue) in mitochondrial myopathy (COX-SDH stain)

  • Crystalline inclusions in the mitochondria (Electron microscopy)

Type 2 fibre atrophy

General

DDx:

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

Microscopic

Features:

  • Atrophy for type 2 atrophy.

Images

  • Denervation atrophy - high mag. (WC)

  • Type 2 fibre atrophy - ATPase pH 9.4 - intermed. mag. (WC)

  • Type 2 fibre atrophy - ATPase pH 9.4 - high mag. (WC)

Specific entities

Amyotrophic lateral sclerosis

Main article: Amyotrophic lateral sclerosis
  • Abbreviated ALS.

General

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

Microscopic

Features:

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

Dermatomyositis

For the skin manifestations see: Inflammatory_skin_disorders#Dermatomyositis.

General

  • Complement mediated disease - membrane attack complex.
  • Usually middle age.
  • Associated skin rash is common.
    • May precede or follow muscle pathology.
  • Associated with malignancy in approximately 10% of cases.[27]

Clinical

  • If the characteristic skin lesions are absent... it is likely idiopathic inflammatory myositis and related to diabetes mellitus.[28]

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.

Images

  • Dermatomyositis - intermed. mag. (WC)

  • Dermatomyositis - high mag. (WC)

  • Dermatomyositis - low mag. (WC)

  • Dermatomyostits (WC/jensflorian)

  • C5b9 complex deposits in dermatomyositis (WC)

EM

  • Endothelial tubuloreticular inclusions (abbrev. TRIs) - undulating tubules in the smooth ER, usu. perinuclear;[29] not pathognomonic - may be seen in inclusion body myositis.[30]

Images:

DDx:

  • Anti-Jo1 myositis
  • Paraneoplastic myositis

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.[31]

Microscopic

Features:

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

DDx:

IHC

Features:[31]

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

EM

  • Inclusion bodies - tubulovescicular material.[32]

  • Rimmed vacuoles in inclusion body myositis (HE).

Polymyositis

General

  • Tx: steroids.

Microscopic

Features:[33]

  • Lymphocytes - may be in large clusters.
    • "Partial invasion" - lymphocytes within the muscle fibres - key feature.
  • Regenerating fibres with enlarged nuclei.

DDx:

  • Polymoysitis (H&E)

  • Polymoysitis (H&E)

  • Polymoysitis (CD45)

  • Polymoysitis (MHC-I)

  • Polymoysitis (H&E)

Images:

IHC

Features:[33]

  • T cells > B cells.
    • Endomysial - T cells.
    • Perimysial - B cells.


Granulomatous myositis

General

Etiology:[34]

  • Sarcoidosis (H&E)

  • Granulomatous myositis (H&E)

Metabolic myopathy

Microscopic

Fetures:

  • Intramuscular storage deposits.
    • PAS positive stain in glycogen storage disease.

  • Glycogen storage (PAS).

  • Glycogen storage (Trichrom).

  • Type V glocogenosis (McArdle, HE).

Myotonic dystrophy

Microscopic

Features:

  • Internal nuclei/central nuclei.

Nemaline myopathy

General

  • A type of congenital myopathy.
  • Paediatric thingy.
  • Rods are seen in trichrome stain

  • Nemaline rods (Trichrom Gomöri).

Centronuclear myopathy

  • AKA myotubular myopathy
  • Several types
    • X-chromosomal recessive: floppy infant
    • austosmal dominant: late onset with proximal involvement, ptosis, opthalmoplegia

Image centronuclear myopathy[35]).

Drug-induced rhabdomyolysis

  • AKA drug-induced acute necrotizing myopathy.

General

Clinical:[36]

  • Myalgias.
  • Myoglobinuria.
  • Increased elevated serum creatine kinase (CK).

Causes:

  • Ecstasy (MDMA).
  • Statins.

Microscopic

Features:

  • Muscle necrosis.
    • Fibre collapse = increased staining on H&E, HPS.
    • Karyolysis - loss of nuclei.
    • Macrophage (phagocytosis) clean-up = pale moth-eaten appearance (seen well on PAS).
  • No inflammation.
  • No perifascicular atrophy.

Images:

Stains

  • PAS +ve fibres (macrophages).

IHC

  • CD45 -ve (no lymphocytes).

EM

Trichinosis

See Microorganisms.

Parasitic disease classically associated with consumption of uncooked pork.

Nerve stuff

General

  • Most common biopsy: sural nerve.

Stains

Myelin stain:

  • Blue = myelin.

Gomori trichrome:

  • Axon = green.
  • Myelin = red.


Degenerative changes

Types:[37]

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

Wallerian degeneration

  • Digestion chambers - key feature.

Images:

Segmental demyelination

  • Onion bulb formations - key feature.

  • Onion bulbs in toluidine blue stain.

  • Onion bulbs in HSMN type I.


Diseases

  • Guillain–Barré syndrome.
  • Chronic inflammatory demyelinating polyneuropathy (CIDP).[38]
    • Essentially chronic Guillain–Barré syndrome.
  • Toxic polyneuropathy (drug toxicity).[39]

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. ↑ 16.0 16.1 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://moon.ouhsc.edu/kfung/jty1/neurohelp/ZNEWWU10.htm. Accessed on: 2 March 2011.
  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. ↑ 21.0 21.1 Online 'Mendelian Inheritance in Man' (OMIM) 310200
  22. ↑ 22.0 22.1 URL: http://neuromuscular.wustl.edu/pathol/inflammation.htm#cellinv. Accessed on: 3 November 2010.
  23. ↑ Online 'Mendelian Inheritance in Man' (OMIM) 160900
  24. ↑ Online 'Mendelian Inheritance in Man' (OMIM) 602668
  25. ↑ URL: http://www.ncbi.nlm.nih.gov/books/NBK1408/. Accessed on: 25 November 2010.
  26. ↑ URL: http://moon.ouhsc.edu/kfung/jty1/neurotest/Q09-Ans.htm. Accessed on: 26 October 2010.
  27. ↑ Chen YJ, Wu CY, Huang YL, Wang CB, Shen JL, Chang YT (2010). "Cancer risks of dermatomyositis and polymyositis: a nationwide cohort study in Taiwan". Arthritis Res. Ther. 12 (2): R70. doi:10.1186/ar2987. PMC 2888225. PMID 20398365. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2888225/.
  28. ↑ 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.
  29. ↑ 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.
  30. ↑ Katzberg HD, Munoz DG (2010). "Tubuloreticular inclusions in inclusion body myositis". Clin. Neuropathol. 29 (4): 262–6. PMID 20569678.
  31. ↑ 31.0 31.1 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.
  32. ↑ URL: http://neuromuscular.wustl.edu/pathol/ibm.htm. Accessed on: 3 November 2010.
  33. ↑ 33.0 33.1 URL: http://moon.ouhsc.edu/kfung/jty1/neurohelp/ZNN0TA01.htm. Accessed on: 25 February 2012.
  34. ↑ Prieto-González, S.; Grau, JM.. "Diagnosis and classification of granulomatous myositis.". Autoimmun Rev 13 (4-5): 372-4. doi:10.1016/j.autrev.2014.01.017. PMID 24424169.
  35. ↑ URL: http://www.igbmc.fr/recherche/Dep_NG/Eq_JLaporte/JL3.html. Accessed on: 26 October 2010.
  36. ↑ Coco, TJ.; Klasner, AE. (Apr 2004). "Drug-induced rhabdomyolysis.". Curr Opin Pediatr 16 (2): 206-10. PMID 15021204.
  37. ↑ URL: http://missinglink.ucsf.edu/lm/ids_104_musclenerve_path/student_musclenerve/nervepath.html. Accessed on: 9 November 2010.
  38. ↑ URL: http://path.upmc.edu/cases/case426.html. Accessed on: 14 November 2010.
  39. ↑ URL: http://path.upmc.edu/cases/case173.html. Accessed on: 8 January 2012.

External links

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