Difference between revisions of "Neuromuscular pathology"

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'''Neuromuscular pathology''' is the study of muscle and neural-muscle pathologies.   
[[Image:Vasculitic neuropathy - plastics - low mag.jpg|thumb|right|[[Micrograph]] of a nerve biopsy. [[Toluidine blue stain]].]]
'''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 after not infrequently not possible to definitely distinguish.
Muscle pathology is dealt together with neurologic disease as, at the presentation, they are not infrequently impossible to definitely distinguish.


==Work-up==
=Work-up=
===General===
#Clinical history, including family history.
#Clinical history, including family history.
#Laboratory studies, e.g. CK.
#Laboratory studies, e.g. CK.
#Nerve conduction and electromyography studies.
#Nerve conduction and electromyography studies.
#Muscle biopsy.
#Muscle / nerve 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:<ref>URL: [http://moon.ouhsc.edu/kfung/jty1/NeuroHelp/ZNEWWU10.htm http://moon.ouhsc.edu/kfung/jty1/NeuroHelp/ZNEWWU10.htm]. Accessed on: 27 October 2010.</ref>
*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.<ref name=pmid17224570>{{cite journal |author=Filosto M, Tonin P, Vattemi G, ''et al.'' |title=The role of muscle biopsy in investigating isolated muscle pain |journal=Neurology |volume=68 |issue=3 |pages=181–6 |year=2007 |month=January |pmid=17224570 |doi=10.1212/01.wnl.0000252252.29532.cc |url=}}</ref>
*Normal CK values:<ref>URL: [http://www.gpnotebook.co.uk/simplepage.cfm?ID=1436155929 http://www.gpnotebook.co.uk/simplepage.cfm?ID=1436155929]. Accessed on: 27 October 2010.</ref>
**Men: 24-195 unit/litre.
**Women: 24-170 units/litre.
 
===Biopsy===
====Muscle biopsies====
Indications:
* Weakness, Fatigue, Cramps
* Myopathic EMG
* Elevated CK
Not indicated: Myasthenia gravis, myotonia
 
* MRI to select ideal spots for biopsy.
* In chronic diseases, select a '''moderately''' affected muscle.
** Best specific muscles: Deltoid, Biceps, Quadriceps.
** Avoid areas with previous EMG analysis.
 
* Tissue should be sent fresh or frozen for analysis.
** Freeze most tissue in isopentane (-160°C) immersed in liquid nitrogen.
** Ultrastructural analyis might be required in some cases -> save something in 4% glutaraldehyde.
* [[FFPE]] specimens unsuitable for enzymatic stains.
** Useful for morphology of inflammatory cells.
 
====Nerve biopsies====
* Nerve procession: 3 pieces
** Frozen -> useful for acid phosphatase, congo etc..
** Formalin -> for IHC.
** 4% Glutaraldehyde fixed -> for electron microscopy.
 
====Skin biopsies====
* Punch biopsies (3mm) for small fiber neuropathy.
** Paraformaldehyde-lysine-periodate -> for PGP9.5 immunofluorescence.
 
=Muscle structure/histology=
===Macroscopic to microscopic===
Organization:<ref>URL: [http://commons.wikimedia.org/wiki/File:Skeletal_muscle.jpg http://commons.wikimedia.org/wiki/File:Skeletal_muscle.jpg]. Accessed on: 25 October 2010.</ref>
*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:<ref>{{Ref Martini6|438}}</ref>
**Nerve (surrounded by ''epineurium'') -> Fascicle (surrounded by ''perineurium'') -> Nerve fibre (surrounded by ''endoneurium'').
 
===Fibre===
[[File:1022 Muscle Fibers (small).jpg|500px|right]]
====Fibre morphology====
*Small or large?
**Related to age?  Birth 15µm, 6yrs: 25-30µm, 12yrs: 45µm, adult: 50-60µm.
*Round or angular?
*Architecture: Normal, inclusions, nuclear internalization?
*Pathology distribution: Absent, focal, uniform?
**Pathologic material: Amyloid, Glycogen, Lipid?
====Fibre types====
{{familytree/start}}
{{familytree | | | |A11| | | | |A11 =Types          }}
{{familytree | |,|-|-|^|-|-|.|}}
{{familytree | B11 | | | | B12 |B11=Type 1<br>slow twitch|B12=Type 2<br>fast twitch }}
{{familytree/end}}
 
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====
<center>
{| class="wikitable sortable"
! Parameter
! Type I
! Type II
|-
| Twitch speed
| slow
| fast
|-
| Colour
| red
| white
|-
| Fat content
| higher
| lower
|-
| ATP production
| oxidative
| anaerobic <br>glycoloysis
|-
| Glycogen
| higher
| lower
|-
| Resistance to fatigue
| higher
| lower
|-
| ATPase quality
| lower
| higher
|-
| Myoglobin
| higher
| lower
|-
| Mitochondria
| higher
| lower
|-
| ATPase pH 9.4 stain
| light brown
| dark brown
|}
 
</center>
 
*Check for fibre type grouping or fibre type predominance.
 
===Normal findings===
====Muscle-tendon junction====
Features:
*Myofibrils frayed + adjacent to dense connective tissue.
**Image: [http://www.lab.anhb.uwa.edu.au/mb140/corepages/connective/Images/mtj040vg.jpg Muscle-tendon junction (anhb.uwa.edu.au)].<ref>URL: [http://www.lab.anhb.uwa.edu.au/mb140/corepages/connective/connect.htm http://www.lab.anhb.uwa.edu.au/mb140/corepages/connective/connect.htm]. Accessed on: 4 November 2010.</ref>
 
====Muscle-nerve junction====
Features:
*Dunno. (???)


==Patterns==
Images:
*[http://commons.wikimedia.org/wiki/File:Skeletal_muscle_-_cross_section,_nerve_bundle.jpg MN junction - crappy image (WC)]. (???)
 
====Muscle spindle====
Features:
*Weird looking muscle cell. (???)
 
Image: [http://www.lab.anhb.uwa.edu.au/mb140/corepages/muscle/Images/mspindle041he.jpg Muscle spindle (anhb.uwa.edu.au)].<ref>URL: [http://www.lab.anhb.uwa.edu.au/mb140/corepages/muscle/muscle.htm http://www.lab.anhb.uwa.edu.au/mb140/corepages/muscle/muscle.htm]. Accessed on: 28 November 2010.</ref>
 
===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: [http://moon.ouhsc.edu/kfung/jty1/NeuroTest/Q71-Ans.htm Ragged red fibres (ouhsc.edu)].
*Vacuoles
**Acid maltase positive = lysosomal vacuoles.
**Rimmed vacuoles = [[inclusion body myositis]].
**Freezing artifacts (clear).
*PAS +++ = [[glycogen storage disease]].
*Nemaline rods = [[nemaline myopathy]]
**Image: [http://commons.wikimedia.org/w/index.php?title=File:Biopsy nemaline myopathy gomori.jpg]
*Cores - central pale area along length of fibres in NADH stain = central core disease.
**Image: [http://commons.wikimedia.org/w/index.php?title=File:Central core disease NADH stain.jpg].
 
Others:
*Annular myofibrils ("ringbinden") = myopathic: Regeneration, myotonic dystrophy, tenotomy. Found in approx. 3% of unselected cases.
Images: [http://frontalcortex.com/?page=image&topic=1&qid=987] - HE, NADH or MAD stains are useful.
*Target fibre - "hole in middle of myofibres" = neurogenic.
**Images: [http://commons.wikimedia.org/w/index.php?title=File:Denervation_atrophy_-_very_high_mag.jpg Target fibres - very high mag. (WC)], [http://commons.wikimedia.org/wiki/File:Denervation_atrophy_-_sdh_-_very_high_mag.jpg Target fibres - SDH stain - very high mag. (WC)].
*Regenerative fibres = large nuclei, basophilic cytoplasm (incr. protein synthesis, incr. RNA).
 
===Approach===
General:
*Neurogenic or myopathic?
*Acute or chronic?
Check:
#Size variation - in groups (neurogenic, Dystrophinopathies) vs. singular scattered (myogenic, acute neurogenic).
#Shape - angulated (neurogenic) vs. round (myogenic).
#Position of nuclei - peripheral (normal); central (myogenic; centronuclear myopathy<ref>URL: [http://www.igbmc.fr/recherche/Dep_NG/Eq_JLaporte/JL3.html http://www.igbmc.fr/recherche/Dep_NG/Eq_JLaporte/JL3.html]. Accessed on: 26 October 2010.</ref>).
#[[Necrosis]] & regeneration - suggests acute myogenic.
#Fibrosis - suggests chronic myogenic.
#Inflammation - suggest myogenic vs. systemic inflammatory.
#*Lymphocytes, macrophages, eosinophils - or even neoplastic?
#Fibre type predominance - suggest congenital myopathy (esp. in small type 1 fibres), demyelinating neuropathy.
Other:
#Obvious abnormality vs. minimal change.
#Diffuse vs. focal change.
#Pathology in adjacent vessels or connective tissue.
 
==Processing of muscle biopsies==
#[[Formalin]] fixed (formalin fixed-paraffin embedded).
#Frozen tissue for histology.
#Frozen tissue for biochemistry.
#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.<ref>URL: [http://www.nature.com/modpathol/journal/v18/n5/full/3800344a.html http://www.nature.com/modpathol/journal/v18/n5/full/3800344a.html]. Accessed on: 26 November 2010.</ref> vs. toluidine blue. (???)
**Thin sections: 0.1 - 1 micrometres.
*Normal SMH numbering = "paraffin".
 
==Patterns (pathologic)==
===Overview===
===Overview===
{{familytree/start}}
{{familytree/start}}
Line 21: Line 238:
| '''Neurogenic'''
| '''Neurogenic'''
| '''Myogenic'''
| '''Myogenic'''
| '''Notes'''
| Notes
| '''Image'''
| Image
|-
|-
| Shape of fibres  
| Shape of fibres  
Line 33: Line 250:
| groups <br>("group atrophy")
| groups <br>("group atrophy")
| singular
| singular
|
|  
| [http://neuropathology.neoucom.edu/chapter9/images9/13-7.jpg group atrophy]<ref>URL: [http://neuropathology.neoucom.edu/chapter9/chapter9fALS.html http://neuropathology.neoucom.edu/chapter9/chapter9fALS.html]. Accessed on: 25 October 2010.</ref>
| [http://neuropathology.neoucom.edu/chapter9/images9/13-7.jpg group atrophy]<ref>URL: [http://neuropathology.neoucom.edu/chapter9/chapter9fALS.html http://neuropathology.neoucom.edu/chapter9/chapter9fALS.html]. Accessed on: 25 October 2010.</ref>
|-
|-
| Large fibres<br>
| Large fibres<br>
| No
| no
| +/-Scattered
| +/-scattered
| "hypercontracted fibres"
| "hypercontracted<br>fibres"
| [http://commons.wikimedia.org/wiki/File:Duchenne-muscular-dystrophy.jpg DMD (WC)]
| [http://commons.wikimedia.org/wiki/File:Duchenne-muscular-dystrophy.jpg DMD (WC)]
|-
| Fibre type<br>grouping
| yes (d/t chronic <br>denervation + <br>reinnervation)<ref>URL: [http://neuromuscular.wustl.edu/lab/mbiopsy.htm#fibertype http://neuromuscular.wustl.edu/lab/mbiopsy.htm#fibertype]. Accessed on: 26 October 2010.</ref>
| yes (???)
| based on ATPase, <br>NADH-TR stains
| [http://missinglink.ucsf.edu/lm/ids_104_musclenerve_path/student_musclenerve/subpages/ng.atp.9.4.1.html ATPase 9.4]<ref>URL: [http://missinglink.ucsf.edu/lm/ids_104_musclenerve_path/student_musclenerve/musclepath.html http://missinglink.ucsf.edu/lm/ids_104_musclenerve_path/student_musclenerve/musclepath.html]. Accessed on: 26 October 2010.</ref>, [http://moon.ouhsc.edu/kfung/JTY1/Com04/Com04Image/Com401-3-12.gif NADH-TR]<ref>URL: [http://moon.ouhsc.edu/kfung/JTY1/Com04/Com401-3-Diss.htm http://moon.ouhsc.edu/kfung/JTY1/Com04/Com401-3-Diss.htm]. Accessed on: 28 October 2010.</ref>
|}
|}


Line 48: Line 271:
*Groups of small fibres.
*Groups of small fibres.
*Apparent increase of nuclei.
*Apparent increase of nuclei.
<gallery>
File:Neurogenic atrophy muscle biopsy HE x100.jpg | Groups of atrophic fibers (HE)
File:Muscle angular atrophic fibers.jpg | Angulated atrophic fibers (HE)
File:ATPase targetoid fibers neurogenic muscle atrophy.jpg | Fiber type grouping and targetoid fibers in neurogenic atrophy (ATPase)
File:Denervation atrophy - very high mag.jpg | Type 2 fiber atrophy (HE)
File:Denervation atrophy - atp94 - high mag.jpg | Type 2 fiber atrophy (ATPase)
</gallery>


Myogenic:
Myogenic:
Line 53: Line 284:
*+/-Intense (darker) cytoplasm.
*+/-Intense (darker) cytoplasm.
*+/-Fibrosis (between fibres).
*+/-Fibrosis (between fibres).
*+/-Nuclear internalization.
*+/-Necrosis.
*+/-Necrosis.
<gallery>
File:BMD histology.jpg | Basophilic fibers and nuclear internalization in muscular dystropy (HE).
</gallery>


===Detail===
===Detail===
Line 61: Line 297:
#Myopathy - something is wrong with the muscle fibres.
#Myopathy - something is wrong with the muscle fibres.


==Muscle structure/histology==
=Stains for muscle biopsies=
===Macro to micro===
===Standard===
Organization:<ref>URL: [http://commons.wikimedia.org/wiki/File:Skeletal_muscle.jpg http://commons.wikimedia.org/wiki/File:Skeletal_muscle.jpg]. Accessed on: 25 October 2010.</ref>
{| class="wikitable"
*Muscle - surrounded by epimysium.
| '''Stain'''
**Fascicle - surrounded by perimysium.
| '''Comment'''
***Muscle fibre - muscle cell.
| '''Image'''
****Myofibrils - contractile elements within the muscle cell.
|-
 
| H&E stain
===Fibre types===
| routine, fibre size, shape, nuclei
{{familytree/start}}
| [http://www.rvc.ac.uk/Research/Labs/NeuroLab/images/HE.jpg H&E]<ref>URL: [http://www.rvc.ac.uk/Research/Labs/NeuroLab/MuscleBiopsy.cfm http://www.rvc.ac.uk/Research/Labs/NeuroLab/MuscleBiopsy.cfm]. Accessed on: 26 October 2010.</ref>, [http://commons.wikimedia.org/wiki/File:Denervation_atrophy_-_very_high_mag.jpg H&E (WC)]
{{familytree | | | |A11| | | | |A11 =Types          }}
|-
{{familytree | |,|-|-|^|-|-|.|}}
| Gomori trichrome
{{familytree | B11 | | | | B12 |B11=Type 1<br>slow twitch|B12=Type 2<br>fast twitch }}
| good for nemaline rods, <br>mitochondrial pathology<br>(ragged red fibres - at edge <br>of myocyte)
{{familytree/end}}
| [http://commons.wikimedia.org/wiki/File:Modified_Gomori_trichrome_stain_showing_several_ragged_red_fibers_.jpg RRF (WC)]
 
|-
====List====
| PAS
Type 1 - [[AKA]] slow twitch:
| glycogen storage disorders
*Predominantly oxidative metabolism, i.e. have lots of mitochondria.
| [http://neuromuscular.wustl.edu/pics/biopsy/dm/dermatopas.jpg]<ref name=dermmyo>URL: [http://neuromuscular.wustl.edu/pathol/dermmyo.htm http://neuromuscular.wustl.edu/pathol/dermmyo.htm]. Accessed on: 26 October 2010.</ref>
 
|-
Type 2 - AKA fast twitch:
| Congo red  
*Predominantly glycolytic metabolism.
| find [[amyloid]]; seen in<br>inclusion body myositis
 
| [http://neuromuscular.wustl.edu/pics/biopsy/lgd/ibmpaget/hppagetibmvaccr2.jpg]<ref name=ibmpaget>URL: [http://neuromuscular.wustl.edu/pathol/ibmpaget.htm http://neuromuscular.wustl.edu/pathol/ibmpaget.htm]. Accessed on: 26 October 2010.</ref>
Mnemonic ''Slow red fat ox'': '''Slow''' twitch fibres are (grossly) more '''red''' (due to mitochondria),
|-
lipid rich ('''fat''') and primarily have '''oxidative''' metabolism.
| Oil red O  
 
| lipid more in<br> type 1 fibres
===Abnormal findings===
| [http://moon.ouhsc.edu/kfung/jty1/Composites/FNEWWU10-lipid-storage.htm ORO]
*Ragged red fibres = mitochondrial pathology.
|-
*Rimmed vacuoles = inclusion body myositis.
| ATPase pH4.2<br>ATPase pH9.4
*PAS +++ = glycogen storage disease.
| should have "checkerboard <br>pattern" in normal; see table below
 
| [http://neuromuscular.wustl.edu/pics/biopsy/dm/dermatopfatp94.jpg]<ref name=dermmyo>URL: [http://neuromuscular.wustl.edu/pathol/dermmyo.htm http://neuromuscular.wustl.edu/pathol/dermmyo.htm]. Accessed on: 26 October 2010.</ref>
===Approach===
|-
General:
| NADH-TR  
#Size variation - in groups (neurogenic) vs. singular (myogenic).  
| good for cores or tubular aggregates, should have "checkerboard <br>pattern" in normal; <br>type 1 fibres = light blue, <br>type 2 fibres = white
#Shape - angulated (neurogenic) vs. round (myogenic).
| [https://commons.wikimedia.org/wiki/File:Cell_sample_of_muscle_tissue_with_central_core_disease_(stained_for_contrast).jpg]
#Position of nuclei.
|-
#Necrosis - suggests myogenic.
| Myoadenylate deaminase
#Fibrosis - suggests myogenic.
| Normal: positive, AMPDA deficiency: negative
#Inflammation.
| [https://commons.wikimedia.org/wiki/File:MAD_deficiency_enzymatic.jpg MAD deficiency]
Other:
|-
#Obvious abnormality vs. minimal change.
| Acid phosphatase
#Diffuse vs. focal change.
| Histiocytes/Macrophages, Lysosomal storage, Lipofuscin
 
|
==Processing of muscle biopsies==
|-
#Formulin.
| Cytochrome oxidase
#Frozen section.
| Mitochondrial pathology
#Frozen for biochemistry.
| [https://commons.wikimedia.org/wiki/File:Cox-deficient_fibers_in_mitochondrial_myopathy.jpg COX deficiency]
#Fragment for electronmicroscopy (glutaraldehyde fixative).
|}
 
==Stains for muscle biopsies==
Common/standard:
*H&E stain.
*Gomori trichrome - Good for nemaline rods, mitochondrial pathology (red).
*PAS.
*Congo red - find [[amyloid]]; seen in inclusion body myositis.
*Oil Red O - type 1 more lipid.
*ATPase - should have checkerboard pattern in normal.
*NADH-TR - should have checkerboard pattern in normal.
 
Special - mitochondrial pathology.:
*SDH.
*COX.
*COX-SDH.
 
Enzymatic/genetic stuff:
*Phosphorylase.
*Adenylate deaminase.
*Acid phosphatase.
*Alkaline phosphatase.
 
Dunno:
*Toluidine blue.
 
IHC:
*Dystrophy panel.
*Lymphocytic markers (CD45, CD3, CD4, CD8, CD20).
*MAC - inclusion body myositis.
*APP - inclusion body myositis.
*Ubquitin - inclusion body myositis.


===ATPase stain pattern/fibre type===
===ATPase stain pattern/fibre type===
Line 155: Line 360:
|}
|}


==Inflammatory myopathy==
===Special - mitochondrial pathology===
DDx:
{| class="wikitable"
#Polymyositis.
| '''Stain'''
#Inclusion body myositis.
| '''Comment'''
#Dermatomyositis.
| '''Image'''
|-
|[[Succinate dehydrogenase|Succinate <br>dehydrogenase (SDH)]]
| stains mitochondria; <br>usu. +ve in mitochondrial disease<ref>URL: [http://moon.ouhsc.edu/kfung/jty1/neurohelp/ZNEWWU10.htm http://moon.ouhsc.edu/kfung/jty1/neurohelp/ZNEWWU10.htm]. Accessed on: 2 March 2011.</ref>
| [http://moon.ouhsc.edu/kfung/JTY1/Com04/Com04Image/Com401-3-03.gif]<ref name=ouhsc1>URL: [http://moon.ouhsc.edu/kfung/JTY1/Com04/Com401-3-Diss.htm http://moon.ouhsc.edu/kfung/JTY1/Com04/Com401-3-Diss.htm]. Accessed on: 28 October 2010.</ref>, [http://commons.wikimedia.org/wiki/File:Denervation_atrophy_-_sdh_-_high_mag.jpg SDH (WC)]
|-
| Cytochrome oxidase (COX)
| stains mitochondria; <br>usu. -ve in mitochondrial disease
| [http://moon.ouhsc.edu/kfung/JTY1/Com04/Com04Image/Com401-3-09.gif]<ref name=ouhsc1>URL: [http://moon.ouhsc.edu/kfung/JTY1/Com04/Com401-3-Diss.htm http://moon.ouhsc.edu/kfung/JTY1/Com04/Com401-3-Diss.htm]. Accessed on: 28 October 2010.</ref>
|-
|COX-SDH
| used to look for mitochondrial disease
|
|}
 
===Enzymatic/genetic stuff===
{| class="wikitable"
| '''Stain'''
| '''Comment'''
| '''Image'''
|-
| Phosphorylase
|
|
|-
| Adenylate deaminase
|
|
|-
| Acid phosphatase (ACPH)
| necrosis (red)
|
|-
| Alkaline phosphatase (ALPH)
| regeneration (punctate - black)
|
|}
 
Dunno:
*Toluidine blue - myopathies.  
**Image: [http://neuromuscular.wustl.edu/pics/biopsy/rods/rodhptb2.jpg Nemaline rods (wustl.edu)].<ref>URL: [http://neuromuscular.wustl.edu/pathol/rod.htm http://neuromuscular.wustl.edu/pathol/rod.htm]. Accessed on: 26 October 2010.</ref>
 
===IHC===
*Dystrophy panel.
**Dystrophin<ref name=omim310200>{{OMIM|310200}}</ref> - 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.
**Normally stains the nucleus.
***Same protein that that in implicated in [[ALS]] and [[frontotemporal dementia]].


==DDx==
=List of common conditions=
Neurogenic:
Neurogenic:
*Amyotrophic lateral sclerosis.
*[[Amyotrophic lateral sclerosis]].
*Spinal muscular atrophy.  
*Spinal muscular atrophy.  
*Trauma.
*Trauma.
Line 172: Line 432:
Myopathic:
Myopathic:
*Inflammatory:
*Inflammatory:
*#Polymyositis.
*#[[Polymyositis]].
*#Inclusion body myositis.
*#[[Inclusion body myositis]].
*#Dermatomyositis.
*#[[Dermatomyositis]].
*Duchenne muscular dystrophy.
*Duchenne muscular dystrophy.
*Becker muscular dystrophy.
*Becker muscular dystrophy.
*Limb-girdle muscular dystrophy.
*[[Limb-girdle muscular dystrophy]].
*Myotonic dystrophy.
*[[Myotonic dystrophy]].
*Metabolic - glycogen storage disease.
*Metabolic - [[glycogen storage disease]].


Other:
Other:
*Myasthenia gravis.
*Myasthenia gravis.
*Mitochondrial myopathy.
*[[Mitochondrial myopathy]].
*Congenital fibre type disproportion.
*Congenital fibre type disproportion.
*Periodic paralysis.
*Periodic paralysis.


=Groups of disorders=
==Inflammatory myopathy==
DDx:
#[[Polymyositis]].
#*Disease of adults.
#[[Inclusion body myositis]] (IBM).
#*Distal weakness.
#*Can be sporadic or hereditary.
#[[Dermatomyositis]].
#*Acute development.
#*May be associated with malignancy.
#[[Granulomatous myositis]].
#Graft-versus-host disease.
#Infectious myositis.
#*Rare.
'''Quick overview:'''
{| class="wikitable"
|
| '''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
|[[File:Dermatomyositis_muscle_biopsy_HE.jpg | center | thumb]]
|[[File:Polymyositis_muscle_biopsy_HE.jpg | center | thumb]]
|[[File:IBM rimmed vacuoles HE x200.jpg | center | thumb]]
|}
===Partial invasion of muscle fibres===
DDx:<ref name=inflam_wustledu>URL: [http://neuromuscular.wustl.edu/pathol/inflammation.htm#cellinv http://neuromuscular.wustl.edu/pathol/inflammation.htm#cellinv]. Accessed on: 3 November 2010.</ref>
*[[Polymyositis]].
*[[Inclusion body myositis]] (IBM).
Images:
*[http://neuromuscular.wustl.edu/pathol/inflammation.htm#cellinv Partial invasion of muscle fibres (wustl.edu)].<ref name=inflam_wustledu>URL: [http://neuromuscular.wustl.edu/pathol/inflammation.htm#cellinv http://neuromuscular.wustl.edu/pathol/inflammation.htm#cellinv]. Accessed on: 3 November 2010.</ref>
==Muscular dystrophy==
===General===
*DDx: large.
A short DDx:
*Duchenne's muscular dystrophy.<ref name=omim310200>{{OMIM|310200}}</ref>
*Becker's muscular dystrophy.
*Limb-girdle muscular dystrophy.
**Lotsa different mutations, autosomal dominant and recessive variants.
*Myotonic dystrophy.<ref name=omim160900>{{OMIM|160900}}</ref><ref name=omim602668>{{OMIM|602668}}</ref>
===Microscopic===
Features:
*Endomysial fibrosis.
*Hypercontracted fibres (large muscle fibres).
<gallery>
File:BMD histology.jpg | Becker's muscular dystrophy ([[H&E]))
File:Dys1 Dystrophinopathy carrier.jpg | Carrier status in dystrophinophathy (Dystrophin)
</gallery>
Images:
*[http://path.upmc.edu/cases/case161.html Becker muscular dystrophy (upmc.edu)].
*[http://path.upmc.edu/cases/case234/micro.html Myotonic dystrophy - several images (upmc.edu)].
==Limb-girdle muscular dystrophy==
===General===
*A group of muscular dystrophies with childhood or adult onset.<ref>URL: [http://www.ncbi.nlm.nih.gov/books/NBK1408/ http://www.ncbi.nlm.nih.gov/books/NBK1408/]. Accessed on: 25 November 2010.</ref>
*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.
<gallery>
File:LGMD2D alpha sarcoglycan.jpg | Loss of alpha sarcocglycan in LGMD2D (WC).
</gallery>
==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.<ref>URL: [http://moon.ouhsc.edu/kfung/jty1/neurotest/Q09-Ans.htm http://moon.ouhsc.edu/kfung/jty1/neurotest/Q09-Ans.htm]. Accessed on: 26 October 2010.</ref>
*"Ballooned" mitochondria; loss of cristae -- loss of membranous folds within mitochrondrion.
<gallery>
File:Ragged red fibres - gtc - very high mag.jpg | ragged red fibers (Gomöri Trichrom)
Cox-deficient_fibers_in_mitochondrial_myopathy.jpg | Cox-deficient fibers (blue) in mitochondrial myopathy (COX-SDH stain)
File:Mitochondrial_myopathy_crystalline_inclusions.jpg | Crystalline inclusions in the mitochondria (Electron microscopy)
</gallery>
==Type 2 fibre atrophy==
===General===
DDx:
*Disuse.
*Space travel.
*Steroids.
*Others.
===Microscopic===
Features:
*Atrophy for type 2 atrophy.
====Images====
<gallery>
Image:Denervation_atrophy_-_high_mag.jpg | Denervation atrophy - high mag. (WC)
Image:Denervation_atrophy_-_atp94_-_intermed_mag.jpg | Type 2 fibre atrophy - ATPase pH 9.4 - intermed. mag. (WC)
Image:Denervation_atrophy_-_atp94_-_high_mag.jpg | Type 2 fibre atrophy - ATPase pH 9.4 - high mag. (WC)
</gallery>
=Specific entities=
==Amyotrophic lateral sclerosis==
==Amyotrophic lateral sclerosis==
{{Main|Amyotrophic lateral sclerosis}}
*Abbreviated ''ALS''.
===General===
===General===
*Abbreviated ''ALS''.
*Abbreviated ''ALS''.
Line 196: Line 611:
*Neurogenic pattern:
*Neurogenic pattern:
**Group atrophy.
**Group atrophy.
**+/-Target fibre.
**+/-Target fibres.


==Dermatomyositis==
==Dermatomyositis==
:''For the skin manifestations see: [[Inflammatory_skin_disorders#Dermatomyositis]]''.
===General===
===General===
*Complement mediated disease... membrane attach complex.
*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.<ref name=pmid20398365>{{cite journal |author=Chen YJ, Wu CY, Huang YL, Wang CB, Shen JL, Chang YT |title=Cancer risks of dermatomyositis and polymyositis: a nationwide cohort study in Taiwan |journal=Arthritis Res. Ther. |volume=12 |issue=2 |pages=R70 |year=2010 |pmid=20398365 |pmc=2888225 |doi=10.1186/ar2987 |url=}}</ref>
 
====Clinical====
*If the characteristic skin lesions are absent... it is likely ''idiopathic inflammatory myositis'' and related to ''[[diabetes mellitus]]''.<ref name=pmid20536597>{{cite journal |author=Limaye VS, Lester S, Blumbergs P, Roberts-Thomson PJ |title=Idiopathic inflammatory myositis is associated with a high incidence of hypertension and diabetes mellitus |journal=Int J Rheum Dis |volume=13 |issue=2 |pages=132–7 |year=2010 |month=May |pmid=20536597 |doi=10.1111/j.1756-185X.2010.01470.x |url=}}</ref>
 
===Microscopic===
===Microscopic===
Features:
Features:
*Perifascicular inflammation with perifascicular atrophy - '''key feature'''.
*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====
<gallery>
Image:Dermatomyositis_-_intermed_mag.jpg | Dermatomyositis - intermed. mag. (WC)
Image:Dermatomyositis_-_high_mag.jpg | Dermatomyositis - high mag. (WC)
File:Dermatomyositis HE x40.jpg | Dermatomyositis - low mag. (WC)
File:NP MGMT 0252.jpg | Dermatomyostits (WC/jensflorian)
File:Dermatomyositis c5b9.jpg | C5b9 complex deposits in dermatomyositis (WC)
</gallery>
===EM===
*Endothelial tubuloreticular inclusions (abbrev. ''TRIs'') - undulating tubules in the smooth ER, usu. perinuclear;<ref name=pmid19330338>{{cite journal |author=Stoltenburg-Didinger G, Genth E |title=[Dermatomyositis] |language=German |journal=Z Rheumatol |volume=68 |issue=4 |pages=287–94 |year=2009 |month=June |pmid=19330338 |doi=10.1007/s00393-008-0398-y |url=}}</ref> not pathognomonic - may be seen in inclusion body myositis.<ref name=pmid20569678>{{cite journal |author=Katzberg HD, Munoz DG |title=Tubuloreticular inclusions in inclusion body myositis |journal=Clin. Neuropathol. |volume=29 |issue=4 |pages=262–6 |year=2010 |pmid=20569678 |doi= |url=}}</ref>
Images:
*[http://moon.ouhsc.edu/kfung/jty1/Com/Com310-1-Diss.htm Tubulorecticular inclusions (ouhsc.edu)].
====DDx:====
* Anti-Jo1 myositis
* Paraneoplastic myositis


==Inclusion body 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.<ref name=pmid8579968>{{cite journal |author=Askanas V, Engel WK |title=New advances in the understanding of sporadic inclusion-body myositis and hereditary inclusion-body myopathies |journal=Curr Opin Rheumatol |volume=7 |issue=6 |pages=486–96 |year=1995 |month=November |pmid=8579968 |doi= |url=}}</ref>
===Microscopic===
===Microscopic===
Features:
Features:
*Inflammation.
*Inflammation.
*Vacuolated fibres (with proteineous aggregates) - '''key feature'''.
*Vacuolated muscle fibres (with proteineous aggregates) - '''key feature'''.
**Vacuolation = "inclusion".
***Usually in the centroidal location.


DDx: polymyositis.
DDx:  
*[[Polymyositis]].


IHC: APP +ve, ubiquitin +ve, tau +ve.
===IHC===
Features:<ref name=pmid8579968/>
*Congo red +ve.
*APP +ve, ubiquitin +ve, tau +ve. (???)
 
===EM===
*Inclusion bodies - tubulovescicular material.<ref>URL: [http://neuromuscular.wustl.edu/pathol/ibm.htm http://neuromuscular.wustl.edu/pathol/ibm.htm]. Accessed on: 3 November 2010.</ref>
 
<gallery>
File:IBM rimmed vacuoles HE x200.jpg | Rimmed vacuoles in inclusion body myositis (HE).
</gallery>


==Polymyositis==
==Polymyositis==
===General===
===General===
*Tx: steroids.
*Tx: steroids.
===Microscopic===
Features:<ref name=ouhsc_znn>URL: [http://moon.ouhsc.edu/kfung/jty1/neurohelp/ZNN0TA01.htm http://moon.ouhsc.edu/kfung/jty1/neurohelp/ZNN0TA01.htm]. Accessed on: 25 February 2012.</ref>
*Lymphocytes - may be in large clusters.
**"Partial invasion" - lymphocytes within the muscle fibres - '''key feature'''.
*Regenerating fibres with enlarged nuclei.
DDx:
*[[Inclusion body myositis]].
*[[Dermatomyositis]].
<gallery>
File:Neuropathology case XII 01.jpg | Polymoysitis ([[H&E]])
File:Neuropathology case XII 02.jpg | Polymoysitis ([[H&E]])
File:Neuropathology case XII 03.jpg | Polymoysitis (CD45)
File:Neuropathology case XII 04.jpg | Polymoysitis (MHC-I)
File:Polymyositis_HE.jpg | Polymoysitis ([[H&E]])
</gallery>
Images:
*[http://neuromuscular.wustl.edu/pathol/inflammation.htm#cellinv Focal invasion of lymphocytes (wustl.edu)].
===IHC===
Features:<ref name=ouhsc_znn>URL: [http://moon.ouhsc.edu/kfung/jty1/neurohelp/ZNN0TA01.htm http://moon.ouhsc.edu/kfung/jty1/neurohelp/ZNN0TA01.htm]. Accessed on: 25 February 2012.</ref>
*T cells > B cells.
**Endomysial - T cells.
**Perimysial - B cells.
==Granulomatous myositis==
===General===
Etiology:<ref>{{Cite journal  | last1 = Prieto-González | first1 = S. | last2 = Grau | first2 = JM. | title = Diagnosis and classification of granulomatous myositis. | journal = Autoimmun Rev | volume = 13 | issue = 4-5 | pages = 372-4 | month =  | year =  | doi = 10.1016/j.autrev.2014.01.017 | PMID = 24424169 }}</ref>
* [[Sarcoidosis]].
* Idiopathic.
* Infectious ([[Tuberculosis]], Syphillis, Brucellosis.
* Foreign-body reaction.
* [[Thymoma]] - myasthenia gravis.
* [[Lymphoma]] - paraneoplastic.
* [[Primary biliary cholangitis]].
<gallery>
File:Sarkoidosis muscle.jpg | Sarcoidosis ([[H&E]])
File:Granulomatous myositis.jpg | Granulomatous myositis ([[H&E]])
</gallery>
==Spinal muscular atrophy==
* Autosomal recessive disease by SMN1 gene deletion on chromosome 5q.
* Centromeric gene copy (SMN2) whose product can mitigate disease severity.
* Variability in severity and age of onset of disease (SMA type 1-4).
* Neurogenic muscle atrophy, weakness, loss of reflexes, tongue fasciculation and tremor.
** Usu. groups of atrophic fibers.
** Few compensatorirc hypertrophic fibers.
===Diagnostic relevance===
* Antisense-oligonucleotide that increase full-length protein product derived from SMN2 (Nusinersen).
* Gene transfer with scAAV9-SMN (Zolgensma).
==Metabolic myopathy==
===Microscopic===
Fetures:
*Intramuscular storage deposits.
** PAS positive stain in glycogen storage disease.
<gallery>
File:PAS glycogen storage disease intermed mag.jpg | Glycogen storage (PAS).
File:Trichrom glycogen storage disease intermed mag..jpg | Glycogen storage (Trichrom).
File:Vacuolar myopathy mcArdle type V glcogenosis.jpg | Type V glocogenosis (McArdle, HE).
</gallery>
==Myotonic dystrophy==
===Microscopic===
===Microscopic===
Features:
Features:
*Inflammation.
*Internal nuclei/central nuclei.
 
==Nemaline myopathy==
===General===
*A type of congenital myopathy.
*Paediatric thingy.
*May appear secondary in other lesions.
*Rods are seen in trichrome stain
<gallery>
File:Biopsy nemaline myopathy gomori.jpg | Nemaline rods (Trichrom Gomöri).
File:Congenital nemaline myopathy.jpg | Congenital nemaline myopathy (Trichrom Gomöri).
</gallery>
 
 
==Central core myopathy==
===General===
*Floppy infant, but stable clinial course.
*Autosomal dominant inheritance.
**Mutation in RYR1
**Predisposition for malignant hyperthermia.
*Normal CK levels.
*Non-pathologic EMG.
 
*Cores visile in NADH staining.
**Mostly centrally, but can be eccentric.
 
<gallery>
File:Central core disease NADH stain.jpg | Cores (NADH stain).
File:Cell sample of muscle tissue with central core disease (stained for contrast).jpg | Cores (NADH TR stain).
</gallery>
 
==Centronuclear myopathy==
*AKA myotubular myopathy
*Several types
** X-chromosomal recessive: floppy infant
** austosmal dominant: late onset with proximal involvement, ptosis, opthalmoplegia
 
<gallery>
File:Biopsy centronuclear myopathy HE.jpg
</gallery>
 
Image centronuclear myopathy<ref>URL: [http://www.igbmc.fr/recherche/Dep_NG/Eq_JLaporte/JL3.html http://www.igbmc.fr/recherche/Dep_NG/Eq_JLaporte/JL3.html]. Accessed on: 26 October 2010.</ref>).


DDx: Inclusion body myositis.
==Drug-induced rhabdomyolysis==
*AKA ''drug-induced acute necrotizing myopathy''.


==Muscular dystrophy==
===General===
===General===
*DDx: lots.
Clinical:<ref name=pmid15021204>{{Cite journal  | last1 = Coco | first1 = TJ. | last2 = Klasner | first2 = AE. | title = Drug-induced rhabdomyolysis. | journal = Curr Opin Pediatr | volume = 16 | issue = 2 | pages = 206-10 | month = Apr | year = 2004 | doi =  | PMID = 15021204 }}</ref>
*Myalgias.
*Myoglobinuria.
*Increased elevated serum creatine kinase (CK).
 
Causes:
*Ecstasy (MDMA).
*Statins.


===Microscopic===
===Microscopic===
Features:
Features:
*Endomysial fibrosis.
*Muscle [[necrosis]].
*Hypercontracted fibres (large muscle fibres).
**Fibre collapse = increased staining on [[H&E stain|H&E]], [[HPS stain|HPS]].
**Karyolysis - loss of nuclei.
**Macrophage (phagocytosis) clean-up = pale moth-eaten appearance (seen well on [[PAS stain|PAS]]).
*No inflammation.
*No perifascicular atrophy.
 
Images:
*[http://path.upmc.edu/cases/case184/micro.html Drug-induced rhabdomyolysis - several images (upmc.edu)].
 
===Stains===
*PAS +ve fibres (macrophages).
 
===IHC===
*CD45 -ve (no lymphocytes).
 
===EM===
*Negative for [[tubuloreticular inclusions]].
 
==Trichinosis==
:See ''[[Microorganisms]]''.
Parasitic disease classically associated with consumption of uncooked pork.
 
=Nerve stuff=
===General===
*Most common biopsy: sural nerve.
**Approx. 20-30% of the biopsies are diagnostic or may alter treatment decisions.
** Far less common: Superficial peroneal nerve.
*Metabolic, toxic and nutritional causes account for 50% of neuropathies.
*Inflammatory neuropathies (mostly GBS, CIDP or vasculitis): 10-20%.
*Familial neuropathy: 10-20%.
*Neoplasm-associated neuropathy: 5-10%.
 
===Nerve structure===
*Nerve (surrounded by epineurium).
*Fascicle (surrounded by perineurium).
** Usu 6-15 fascicles in sural nerve.
*Nerve fibre (surrounded by endoneurium).
**Myelinated axons.
**Unmyelinated axons and their Schwann cells together are called Remak bundles.
 
Epineurium:
* Capillaries, arterioles and venules.
* Fibroblasts (CD34+/-ve, EMA-ve, S100-ve).
* Macrophages (CD68+ve, CD168+ve).
* Mast cells (metachromatic granules).
* Leukocytes (usu. less than 10 CD3+ve Lymphocytes/mm²).
* Pacinian corpuscles (no pathological relevance).
 
Perineurium:
* Fascicles may separated by perineurial septae.
*Occasional perineurial calcifications (no pathological relevance).
*Renaut bodies (subperineurial whorled structures consisting of fibroblasts).
 
<gallery>
Image:N_renaut_body_semithin.jpg|Renaut body in a fascicle.
File:Pacinian Corpuscle (36298105211).jpg|Pacinian corpuscle.
</gallery>
 
===Stains===
Myelin stain:
*Blue = myelin.
 
Gomori trichrome:
*Axon = green.
*Myelin = red.
 
Toluidine blue staion:
*Plastic embedded semithin sections (1µm).
 
===Artifacts===
*Myelin splits: stretching.
*Neurokeratin: Formalin fixation (longitudinal: "herringbone", cross section: "wagon-wheels").
*Dark staining myelin: crushing.
*Pale expanding myelin sheets: delayed fixation.
*Uneven myelin staining: osmication problems.
*Shrunken crescentic fascicles: Hyperosmolarity.
 
===Reactive changes===
* Traumatic [[Peripheral_nerve_sheath_tumours#Traumatic_neuroma|Neuroma]]
* Pacinian [[Neuroma]]
* Nerve cysts.
* Neuritis ossificans.
* Localized interdigital neuritis ([[Morton neuroma]]).
 
===Degenerative changes===
Types:<ref>URL: [http://missinglink.ucsf.edu/lm/ids_104_musclenerve_path/student_musclenerve/nervepath.html http://missinglink.ucsf.edu/lm/ids_104_musclenerve_path/student_musclenerve/nervepath.html]. Accessed on: 9 November 2010.</ref>
*Axonal degeneration.
*Wallerian degeneration.
*Segmental demyelination.
 
====Axonal degeneration====
*Axonal swelling.
*Intra-axonal filamentous aggregates.
*Mitochondrial abnormalities.
*Aggregation of organelles and dense bodies.
 
====Wallerian degeneration====
*Watery axon and granular disintegration (distal).
*Macrophage accumulation (3-4d after transsection).
*Many lysosomes (CD68+ve).
*Endoneurial proliferation.
*Digestion chambers - '''key feature'''.
 
Images:
*[http://missinglink.ucsf.edu/lm/ids_104_musclenerve_path/student_musclenerve/subpages/digchamb1.html Digestion chambers (missinglink.ucsf.edu)].
*[http://commons.wikimedia.org/wiki/File:Digestion_chambers_--_very_high_mag_-_cropped.jpg Digestion chambers (WC)].
 
====Segmental demyelination====
*Onion bulb formations - '''key feature'''.
<gallery>
File:Onion bulbs semi thin nerve biopsy.jpg | Onion bulbs in toluidine blue stain.
File:Onion bulb formation HMSN.jpg | Onion bulbs in HSMN type I.
</gallery>
 
===Regeneration===
*Axon sprouts (regenerating clusters): Three or more closely apposed myelinated axons.
*Thin myelin sheaths.
 
===Inflammation===
*[[Inflammatory pseudotumour]].
*[[Leprosy]] (Leprous neuropathy).
*[[Sarcoidosis]].
*CMV neuritis in immuncompromised patients.
*[[Vasculitis]].
*Paraprotein-associated neuropathy.
*Neuropathy with macrophage-induced demyelination (CIDP, GBS).
 
====Guillain–Barré syndrome====
*Acute inflammatory demyelinating polyneuropathy (AIDP)
*Preceding infection (RSV, EBV, CMV, HIV, Mycoplasma).
*Monophasic course of motor / sensory deficits.
*Hours to 4 weeks.
*Elevated CSF protein but normal cell count.
*Mononuclear ednoneurial perivascular inflammatory infiltrate (mostly CD4+ve).
*Destructive myelin stripping by macrophages.
*Reduced fiber density.
*Uncompacted myelin / Widely spaced myelin.
 
====Chronic inflammatory demyelinating polyneuropathy (CIDP)====
*Progredient course longer than 8 weeks.<ref>URL: [http://path.upmc.edu/cases/case426.html http://path.upmc.edu/cases/case426.html]. Accessed on: 14
November 2010.</ref>
*Progressive or relapsing and remitting course.
*Multifocal affections of proximal nerves (motor and sensory symptoms).
*Responsive to steroids.
*Enlargement of affected nerve.
*Variation of fiber density between fascicles / reduced axon numbers.
*CD4+ve/CD8+ve inflammatory infiltrates(approx. 65% cases).
*Demyelination (thinly myelinated axons, macrophages).
*Onion-bulb formations (15-40%, chronic recurrent demyelination and remyelination).
DDx: Familial hypertrophic neuropathy.
 
====Neurosarcoidosis====
*Neurological symptoms in 5% of sarcoidosis cases.
*Granulomas may be endoneurial or epineurial.
*Compact mass of epitheloid cells.
*Perilesional fibrosis and lymphocytic infiltrates.
*Axonal loss and regenerating fibers.
*Segmental demyelination and remyelination.
 
====Vasculitic neuropathy====
*Endoneurial and epineurial mircrovessels, arterioles and venules.
*Ischemia of nerve: thrombosis and fibrinoid necrosis.
*Signs of previous vasculitis: Vessel narrowing, fragmentation of elastica, fibrous obliteration and recanalization.
*Often nerve involvement in systemic vasculitis:
**Medium-sized epineurial vessels: mostly classic polyarteritis nodosa.
**Small and medium-sized vessels and eosinophilia: Churg-Strauss angitis.
**Small vessels and necrotizing: ANCA-associated microscopic polyangitis.
 
 
<gallery>
File:Leprosy with perineural invasion 3.jpg | leprosy with perineural invasion. H&E stain (WC/Kozhikode)
File:Granulomatous_nerve_inflammation.jpg | Granulomatous inflammation of peripheral nerve in sarcoidosis (WC/jensflorian)
</gallery>
 
===Other Diseases===
*Amyloid neuropathy: Amorphic endoneurial deposits.
**TTR amyloidosis is of specific interest, because treatment options exist.<ref>{{Cite journal  | last1 = Adams | first1 = D. | last2 = Koike | first2 = H. | last3 = Slama | first3 = M. | last4 = Coelho | first4 = T. | title = Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease. | journal = Nat Rev Neurol | volume = 15 | issue = 7 | pages = 387-404 | month = Jul | year = 2019 | doi = 10.1038/s41582-019-0210-4 | PMID = 31209302 }}</ref>
**Example of amyloid deposits [https://www.nature.com/articles/s41582-019-0210-4/figures/3 here]
*Neuropathy associated with paraproteinemia: Alterations in myelin periodicity, nerve fiber loss.
**[[MGUS]] - Monoclonal gammopathy of unknown significance.
** Multiple myeloma.
**[[POEMS]] syndrome.
**[[LCDD]] - light chain deposition diesease.
*Toxic polyneuropathy (drug toxicity).<ref>URL: [http://path.upmc.edu/cases/case173.html http://path.upmc.edu/cases/case173.html]. Accessed on: 8 January 2012.</ref>
*Polyglucosan body disease.
 
===Neoplasms===
 
''Main article: [[Peripheral nerve sheath tumours]]''
 
*Nerve sheath tumors:
**[[Schwannoma]]
**[[Neurofibroma]]
**[[Perineurioma]]
**[[Nerve sheath myxoma]]
**[[Malignant peripheral nerve sheath tumour]]
*Non neurogenic-tumors of the nerve:
**[[Paraganglioma]]
**[[Lipoma]]
**[[Hemangioblastoma]] <ref>{{Cite journal  | last1 = Gläsker | first1 = S. | last2 = Berlis | first2 = A. | last3 = Pagenstecher | first3 = A. | last4 = Vougioukas | first4 = VI. | last5 = Van Velthoven | first5 = V. | title = Characterization of hemangioblastomas of spinal nerves. | journal = Neurosurgery | volume = 56 | issue = 3 | pages = 503-9; discussion 503-9 | month = Mar | year = 2005 | doi =  | PMID = 15730575 }}</ref>
**[[Synovial sarcoma]] <ref>{{Cite journal  | last1 = Scheithauer | first1 = BW. | last2 = Amrami | first2 = KK. | last3 = Folpe | first3 = AL. | last4 = Silva | first4 = AI. | last5 = Edgar | first5 = MA. | last6 = Woodruff | first6 = JM. | last7 = Levi | first7 = AD. | last8 = Spinner | first8 = RJ. | title = Synovial sarcoma of nerve. | journal = Hum Pathol | volume = 42 | issue = 4 | pages = 568-77 | month = Apr | year = 2011 | doi = 10.1016/j.humpath.2010.08.019 | PMID = 21295819 }}</ref>
 
=See also=
*[[Neuropathology]].


==References==
=References=
{{reflist|2}}
{{reflist|2}}
=External links=
*[http://moon.ouhsc.edu/kfung/jty1/NeuroHelp/ZNEWWU10.htm How to work up a muscle biopsy (ouhsc.edu)].
*[http://neuromuscular.wustl.edu/lab/mbiopsy.htm Muscle biopsies (wustl.edu)].


[[Category:Neuropathology]]
[[Category:Neuropathology]]

Latest revision as of 21:03, 30 September 2021

Micrograph of a nerve biopsy. Toluidine blue stain.

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 / nerve 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.

Biopsy

Muscle biopsies

Indications:

  • Weakness, Fatigue, Cramps
  • Myopathic EMG
  • Elevated CK

Not indicated: Myasthenia gravis, myotonia

  • MRI to select ideal spots for biopsy.
  • In chronic diseases, select a moderately affected muscle.
    • Best specific muscles: Deltoid, Biceps, Quadriceps.
    • Avoid areas with previous EMG analysis.
  • Tissue should be sent fresh or frozen for analysis.
    • Freeze most tissue in isopentane (-160°C) immersed in liquid nitrogen.
    • Ultrastructural analyis might be required in some cases -> save something in 4% glutaraldehyde.
  • FFPE specimens unsuitable for enzymatic stains.
    • Useful for morphology of inflammatory cells.

Nerve biopsies

  • Nerve procession: 3 pieces
    • Frozen -> useful for acid phosphatase, congo etc..
    • Formalin -> for IHC.
    • 4% Glutaraldehyde fixed -> for electron microscopy.

Skin biopsies

  • Punch biopsies (3mm) for small fiber neuropathy.
    • Paraformaldehyde-lysine-periodate -> for PGP9.5 immunofluorescence.

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

1022 Muscle Fibers (small).jpg

Fibre morphology

  • Small or large?
    • Related to age? Birth 15µm, 6yrs: 25-30µm, 12yrs: 45µm, adult: 50-60µm.
  • Round or angular?
  • Architecture: Normal, inclusions, nuclear internalization?
  • Pathology distribution: Absent, focal, uniform?
    • Pathologic material: Amyloid, Glycogen, Lipid?

Fibre types

 
 
 
Types
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Type 1
slow twitch
 
 
 
Type 2
fast twitch

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
ATPase pH 9.4 stain light brown dark brown
  • Check for fibre type grouping or fibre type predominance.

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:

  • Annular myofibrils ("ringbinden") = myopathic: Regeneration, myotonic dystrophy, tenotomy. Found in approx. 3% of unselected cases.

Images: [1] - HE, NADH or MAD stains are useful.

Approach

General:

  • Neurogenic or myopathic?
  • Acute or chronic?

Check:

  1. Size variation - in groups (neurogenic, Dystrophinopathies) vs. singular scattered (myogenic, acute neurogenic).
  2. Shape - angulated (neurogenic) vs. round (myogenic).
  3. Position of nuclei - peripheral (normal); central (myogenic; centronuclear myopathy[8]).
  4. Necrosis & regeneration - suggests acute myogenic.
  5. Fibrosis - suggests chronic myogenic.
  6. Inflammation - suggest myogenic vs. systemic inflammatory.
    • Lymphocytes, macrophages, eosinophils - or even neoplastic?
  7. Fibre type predominance - suggest congenital myopathy (esp. in small type 1 fibres), demyelinating neuropathy.

Other:

  1. Obvious abnormality vs. minimal change.
  2. Diffuse vs. focal change.
  3. Pathology in adjacent vessels or connective tissue.

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, fibre size, shape, nuclei 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 [2][16]
Congo red find amyloid; seen in
inclusion body myositis 		[3][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 		[4][16]
NADH-TR good for cores or tubular aggregates, should have "checkerboard
pattern" in normal;
type 1 fibres = light blue,
type 2 fibres = white 		[5]
Myoadenylate deaminase Normal: positive, AMPDA deficiency: negative MAD deficiency
Acid phosphatase Histiocytes/Macrophages, Lysosomal storage, Lipofuscin
Cytochrome oxidase Mitochondrial pathology COX deficiency

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] 		[6][19], SDH (WC)
Cytochrome oxidase (COX) stains mitochondria;
usu. -ve in mitochondrial disease 		[7][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
Dermatomyositis muscle biopsy HE.jpg
Polymyositis muscle biopsy HE.jpg
IBM rimmed vacuoles HE x200.jpg

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)


Spinal muscular atrophy

  • Autosomal recessive disease by SMN1 gene deletion on chromosome 5q.
  • Centromeric gene copy (SMN2) whose product can mitigate disease severity.
  • Variability in severity and age of onset of disease (SMA type 1-4).
  • Neurogenic muscle atrophy, weakness, loss of reflexes, tongue fasciculation and tremor.
    • Usu. groups of atrophic fibers.
    • Few compensatorirc hypertrophic fibers.

Diagnostic relevance

  • Antisense-oligonucleotide that increase full-length protein product derived from SMN2 (Nusinersen).
  • Gene transfer with scAAV9-SMN (Zolgensma).

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.
  • May appear secondary in other lesions.
  • Rods are seen in trichrome stain

  • Nemaline rods (Trichrom Gomöri).

  • Congenital nemaline myopathy (Trichrom Gomöri).


Central core myopathy

General

  • Floppy infant, but stable clinial course.
  • Autosomal dominant inheritance.
    • Mutation in RYR1
    • Predisposition for malignant hyperthermia.
  • Normal CK levels.
  • Non-pathologic EMG.
  • Cores visile in NADH staining.
    • Mostly centrally, but can be eccentric.

  • Cores (NADH stain).

  • Cores (NADH TR stain).

Centronuclear myopathy

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

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.
    • Approx. 20-30% of the biopsies are diagnostic or may alter treatment decisions.
    • Far less common: Superficial peroneal nerve.
  • Metabolic, toxic and nutritional causes account for 50% of neuropathies.
  • Inflammatory neuropathies (mostly GBS, CIDP or vasculitis): 10-20%.
  • Familial neuropathy: 10-20%.
  • Neoplasm-associated neuropathy: 5-10%.

Nerve structure

  • Nerve (surrounded by epineurium).
  • Fascicle (surrounded by perineurium).
    • Usu 6-15 fascicles in sural nerve.
  • Nerve fibre (surrounded by endoneurium).
    • Myelinated axons.
    • Unmyelinated axons and their Schwann cells together are called Remak bundles.

Epineurium:

  • Capillaries, arterioles and venules.
  • Fibroblasts (CD34+/-ve, EMA-ve, S100-ve).
  • Macrophages (CD68+ve, CD168+ve).
  • Mast cells (metachromatic granules).
  • Leukocytes (usu. less than 10 CD3+ve Lymphocytes/mm²).
  • Pacinian corpuscles (no pathological relevance).

Perineurium:

  • Fascicles may separated by perineurial septae.
  • Occasional perineurial calcifications (no pathological relevance).
  • Renaut bodies (subperineurial whorled structures consisting of fibroblasts).

  • Renaut body in a fascicle.

  • Pacinian corpuscle.

Stains

Myelin stain:

  • Blue = myelin.

Gomori trichrome:

  • Axon = green.
  • Myelin = red.

Toluidine blue staion:

  • Plastic embedded semithin sections (1µm).

Artifacts

  • Myelin splits: stretching.
  • Neurokeratin: Formalin fixation (longitudinal: "herringbone", cross section: "wagon-wheels").
  • Dark staining myelin: crushing.
  • Pale expanding myelin sheets: delayed fixation.
  • Uneven myelin staining: osmication problems.
  • Shrunken crescentic fascicles: Hyperosmolarity.

Reactive changes

Degenerative changes

Types:[37]

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

Axonal degeneration

  • Axonal swelling.
  • Intra-axonal filamentous aggregates.
  • Mitochondrial abnormalities.
  • Aggregation of organelles and dense bodies.

Wallerian degeneration

  • Watery axon and granular disintegration (distal).
  • Macrophage accumulation (3-4d after transsection).
  • Many lysosomes (CD68+ve).
  • Endoneurial proliferation.
  • Digestion chambers - key feature.

Images:

Segmental demyelination

  • Onion bulb formations - key feature.

  • Onion bulbs in toluidine blue stain.

  • Onion bulbs in HSMN type I.

Regeneration

  • Axon sprouts (regenerating clusters): Three or more closely apposed myelinated axons.
  • Thin myelin sheaths.

Inflammation

Guillain–Barré syndrome

  • Acute inflammatory demyelinating polyneuropathy (AIDP)
  • Preceding infection (RSV, EBV, CMV, HIV, Mycoplasma).
  • Monophasic course of motor / sensory deficits.
  • Hours to 4 weeks.
  • Elevated CSF protein but normal cell count.
  • Mononuclear ednoneurial perivascular inflammatory infiltrate (mostly CD4+ve).
  • Destructive myelin stripping by macrophages.
  • Reduced fiber density.
  • Uncompacted myelin / Widely spaced myelin.

Chronic inflammatory demyelinating polyneuropathy (CIDP)

  • Progredient course longer than 8 weeks.[38]
  • Progressive or relapsing and remitting course.
  • Multifocal affections of proximal nerves (motor and sensory symptoms).
  • Responsive to steroids.
  • Enlargement of affected nerve.
  • Variation of fiber density between fascicles / reduced axon numbers.
  • CD4+ve/CD8+ve inflammatory infiltrates(approx. 65% cases).
  • Demyelination (thinly myelinated axons, macrophages).
  • Onion-bulb formations (15-40%, chronic recurrent demyelination and remyelination).

DDx: Familial hypertrophic neuropathy.

Neurosarcoidosis

  • Neurological symptoms in 5% of sarcoidosis cases.
  • Granulomas may be endoneurial or epineurial.
  • Compact mass of epitheloid cells.
  • Perilesional fibrosis and lymphocytic infiltrates.
  • Axonal loss and regenerating fibers.
  • Segmental demyelination and remyelination.

Vasculitic neuropathy

  • Endoneurial and epineurial mircrovessels, arterioles and venules.
  • Ischemia of nerve: thrombosis and fibrinoid necrosis.
  • Signs of previous vasculitis: Vessel narrowing, fragmentation of elastica, fibrous obliteration and recanalization.
  • Often nerve involvement in systemic vasculitis:
    • Medium-sized epineurial vessels: mostly classic polyarteritis nodosa.
    • Small and medium-sized vessels and eosinophilia: Churg-Strauss angitis.
    • Small vessels and necrotizing: ANCA-associated microscopic polyangitis.


  • leprosy with perineural invasion. H&E stain (WC/Kozhikode)

  • Granulomatous inflammation of peripheral nerve in sarcoidosis (WC/jensflorian)

Other Diseases

  • Amyloid neuropathy: Amorphic endoneurial deposits.
    • TTR amyloidosis is of specific interest, because treatment options exist.[39]
    • Example of amyloid deposits here
  • Neuropathy associated with paraproteinemia: Alterations in myelin periodicity, nerve fiber loss.
    • MGUS - Monoclonal gammopathy of unknown significance.
    • Multiple myeloma.
    • POEMS syndrome.
    • LCDD - light chain deposition diesease.
  • Toxic polyneuropathy (drug toxicity).[40]
  • Polyglucosan body disease.

Neoplasms

Main article: Peripheral nerve sheath tumours

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. ↑ Adams, D.; Koike, H.; Slama, M.; Coelho, T. (Jul 2019). "Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease.". Nat Rev Neurol 15 (7): 387-404. doi:10.1038/s41582-019-0210-4. PMID 31209302.
  40. ↑ URL: http://path.upmc.edu/cases/case173.html. Accessed on: 8 January 2012.
  41. ↑ Gläsker, S.; Berlis, A.; Pagenstecher, A.; Vougioukas, VI.; Van Velthoven, V. (Mar 2005). "Characterization of hemangioblastomas of spinal nerves.". Neurosurgery 56 (3): 503-9; discussion 503-9. PMID 15730575.
  42. ↑ Scheithauer, BW.; Amrami, KK.; Folpe, AL.; Silva, AI.; Edgar, MA.; Woodruff, JM.; Levi, AD.; Spinner, RJ. (Apr 2011). "Synovial sarcoma of nerve.". Hum Pathol 42 (4): 568-77. doi:10.1016/j.humpath.2010.08.019. PMID 21295819.

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