Neuromuscular pathology
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
- Clinical history, including family history.
- Laboratory studies, e.g. CK.
- Nerve conduction and electromyography studies.
- 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:
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
- Segmental demyelination - nerve/CNS abnormality.
- Axonal degeneration - nerve/CNS abnormality.
- Reinnervation - nerve injury.
- 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.
- Muscle fibre - muscle cell.
- Fascicle - surrounded by perimysium.
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.
Normal findings
- Muscle-tendon junction - myofibrils frayed + adjacent to dense connective tissue.
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.
- Image: Ragged red fibres (ouhsc.edu).
- 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. (???)
- Image: Cores (ouhsc.edu).
Approach
General:
- Size variation - in groups (neurogenic) vs. singular (myogenic).
- Shape - angulated (neurogenic) vs. round (myogenic).
- Position of nuclei - peripheral (normal); central (myogenic; centronuclear myopathy[12]).
- Necrosis - suggests myogenic.
- Fibrosis - suggests myogenic.
- Inflammation - suggest myogenic vs. systemic inflammatory.
Other:
- Obvious abnormality vs. minimal change.
- Diffuse vs. focal change.
Processing of muscle biopsies
- Formulin.
- Frozen section.
- Frozen for biochemistry.
- Fragment for electronmicroscopy (glutaraldehyde fixative).
Stains for muscle biopsies
Standard
| Stain | Comment | Image |
| H&E stain | routine | [1][13] |
| Gomori trichrome | good for nemaline rods, mitochondrial pathology (ragged red fibres - at edge of myocyte) |
[2] |
| PAS | glycogen storage disorders | [3][14] |
| Congo red | find amyloid; seen in inclusion body myositis |
[4][15] |
| 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][16] |
| NADH-TR | should have "checkerboard pattern" in normal; type 1 fibres = light blue, type 2 fibres = white |
![[1]](http://www.rvc.ac.uk/Research/Labs/NeuroLab/images/HE.jpg){kind=link}
![[2]](http://commons.wikimedia.org/wiki/File:Modified_Gomori_trichrome_stain_showing_several_ragged_red_fibers_.jpg){kind=link}
![[3]](http://neuromuscular.wustl.edu/pics/biopsy/dm/dermatopas.jpg){kind=link}
![[4]](http://neuromuscular.wustl.edu/pics/biopsy/lgd/ibmpaget/hppagetibmvaccr2.jpg){kind=link}
![[5]](http://neuromuscular.wustl.edu/pics/biopsy/dm/dermatopfatp94.jpg){kind=link}
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][17] | |
| COX | [7][17] | |
| COX-SDH |
![[6]](http://moon.ouhsc.edu/kfung/JTY1/Com04/Com04Image/Com401-3-03.gif){kind=link}
![[7]](http://moon.ouhsc.edu/kfung/JTY1/Com04/Com04Image/Com401-3-09.gif){kind=link}
Enzymatic/genetic stuff
- Phosphorylase.
- Adenylate deaminase.
- Acid phosphatase.
- Alkaline phosphatase.
Dunno:
- Toluidine blue - myopathies.
- Image: Nemaline rods (wustl.edu).[18]
IHC
- Dystrophy panel.
- Dystrophin[19] - 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:
- Polymyositis.
- Inclusion body myositis (IBM).
- Dermatomyositis.
Partial invasion of muscle fibres
DDx:[20]
- IBM.
- Polymyositis.
Images:
DDx
Neurogenic:
- Amyotrophic lateral sclerosis.
- Spinal muscular atrophy.
- Trauma.
- Vascular disease.
- Infective process.
- ?Motor neuron disease.
Myopathic:
- Inflammatory:
- Polymyositis.
- Inclusion body myositis.
- 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.[21]
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;[22] not pathognomonic - may be seen in inclusion body myositis.[23]
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.[24]
Microscopic
Features:
- Inflammation.
- Vacuolated muscle fibres (with proteineous aggregates) key feature.
- Vacuolation = "inclusion"
- Usually in the centroidal location.
- Vacuolation = "inclusion"
DDx: polymyositis.
IHC
Features:[24]
- Congo red +ve.
- APP +ve, ubiquitin +ve, tau +ve. (???)
EM
- Inclusion bodies - tubulovescicular material.[25]
Polymyositis
General
- Tx: steroids.
Microscopic
Features:
- Inflammation.
DDx: Inclusion body myositis.
Muscular dystrophy
General
- DDx: large.
A short DDx:
- Duchenne's muscular dystrophy.[26]
- Becker's muscular dystrophy.
- Limb-girdle muscular dystrophy.
- Lotsa different mutations, autosomal dominant and recessive variants.
- Myotonic dystrophy.[27][28]
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.[29]
- "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:[30]
- Wallerian degeneration.
- Axonal degeneration.
- Segmental demyelination.
Wallerian degeneration
- Digestion chamber - key feature.
Diseases
- Guillain–Barré syndrome.
- Chronic inflammatory demyelinating polyneuropathy.[31]
- Essentially chronic Guillain–Barré syndrome.
See also
References
- ↑ URL: http://moon.ouhsc.edu/kfung/jty1/NeuroHelp/ZNEWWU10.htm. Accessed on: 27 October 2010.
- ↑ 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.
- ↑ URL: http://www.gpnotebook.co.uk/simplepage.cfm?ID=1436155929. Accessed on: 27 October 2010.
- ↑ URL: http://nmdinfo.org/lectures/info.php?id=8. Accessed on: 25 October 2010.
- ↑ URL: http://neuropathology.neoucom.edu/chapter9/chapter9fALS.html. Accessed on: 25 October 2010.
- ↑ URL: http://neuromuscular.wustl.edu/lab/mbiopsy.htm#fibertype. Accessed on: 26 October 2010.
- ↑ URL: http://missinglink.ucsf.edu/lm/ids_104_musclenerve_path/student_musclenerve/musclepath.html. Accessed on: 26 October 2010.
- ↑ URL: http://moon.ouhsc.edu/kfung/JTY1/Com04/Com401-3-Diss.htm. Accessed on: 28 October 2010.
- ↑ URL: http://commons.wikimedia.org/wiki/File:Skeletal_muscle.jpg. Accessed on: 25 October 2010.
- ↑ Martini, Frederic H. (2003). Fundamentals of Anatomy & Physiology (6th ed.). Benjamin Cummings. pp. 438. ISBN 978-0805359336.
- ↑ URL: http://www.lab.anhb.uwa.edu.au/mb140/corepages/connective/connect.htm. Accessed on: 4 November 2010.
- ↑ URL: http://www.igbmc.fr/recherche/Dep_NG/Eq_JLaporte/JL3.html. Accessed on: 26 October 2010.
- ↑ URL: http://www.rvc.ac.uk/Research/Labs/NeuroLab/MuscleBiopsy.cfm. Accessed on: 26 October 2010.
- ↑ URL: http://neuromuscular.wustl.edu/pathol/dermmyo.htm. Accessed on: 26 October 2010.
- ↑ URL: http://neuromuscular.wustl.edu/pathol/ibmpaget.htm. Accessed on: 26 October 2010.
- ↑ URL: http://neuromuscular.wustl.edu/pathol/dermmyo.htm. Accessed on: 26 October 2010.
- ↑ 17.0 17.1 URL: http://moon.ouhsc.edu/kfung/JTY1/Com04/Com401-3-Diss.htm. Accessed on: 28 October 2010.
- ↑ URL: http://neuromuscular.wustl.edu/pathol/rod.htm. Accessed on: 26 October 2010.
- ↑ URL: http://www.ncbi.nlm.nih.gov/omim/310200. Accessed on: 29 October 2010.
- ↑ 20.0 20.1 URL: http://neuromuscular.wustl.edu/pathol/inflammation.htm#cellinv. Accessed on: 3 November 2010.
- ↑ 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.
- ↑ 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.
- ↑ Katzberg HD, Munoz DG (2010). "Tubuloreticular inclusions in inclusion body myositis". Clin. Neuropathol. 29 (4): 262–6. PMID 20569678.
- ↑ 24.0 24.1 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.
- ↑ URL: http://neuromuscular.wustl.edu/pathol/ibm.htm. Accessed on: 3 November 2010.
- ↑ URL: http://www.ncbi.nlm.nih.gov/omim/310200. Accessed on: 29 October 2010.
- ↑ URL: http://www.ncbi.nlm.nih.gov/omim/160900. Accessed on: 29 October 2010.
- ↑ URL: http://www.ncbi.nlm.nih.gov/omim/602668. Accessed on: 29 October 2010.
- ↑ URL: http://moon.ouhsc.edu/kfung/jty1/neurotest/Q09-Ans.htm. Accessed on: 26 October 2010.
- ↑ URL: http://missinglink.ucsf.edu/lm/ids_104_musclenerve_path/student_musclenerve/nervepath.html. Accessed on: 9 November 2010.
- ↑ URL: http://path.upmc.edu/cases/case426.html. Accessed on: 14 November 2010.
