Difference between revisions of "Neuromuscular pathology"

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Neuromuscular pathology (view source)

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#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===
===Clinical===
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**Men: 24-195 unit/litre.
**Men: 24-195 unit/litre.
**Women: 24-170 units/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=
=Muscle structure/histology=
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**Nerve (surrounded by ''epineurium'') -> Fascicle (surrounded by ''perineurium'') -> Nerve fibre (surrounded by ''endoneurium'').
**Nerve (surrounded by ''epineurium'') -> Fascicle (surrounded by ''perineurium'') -> Nerve fibre (surrounded by ''endoneurium'').


===Fibre types===
===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/start}}
{{familytree | | | |A11| | | | |A11 =Types          }}
{{familytree | | | |A11| | | | |A11 =Types          }}
Line 47: Line 86:
{{familytree/end}}
{{familytree/end}}


====List - fibre types====
Type 1 - [[AKA]] slow twitch:
Type 1 - [[AKA]] slow twitch:
*Predominantly oxidative metabolism, i.e. have lots of mitochondria.
*Predominantly oxidative metabolism, i.e. have lots of mitochondria.
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| higher
| higher
| lower
| lower
|-
| ATPase pH 9.4 stain
| light brown
| dark brown
|}
|}
</center>
</center>
*Check for fibre type grouping or fibre type predominance.


===Normal findings===
===Normal findings===
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*Ragged red fibres = mitochondrial pathology.
*Ragged red fibres = mitochondrial pathology.
**Image: [http://moon.ouhsc.edu/kfung/jty1/NeuroTest/Q71-Ans.htm Ragged red fibres (ouhsc.edu)].
**Image: [http://moon.ouhsc.edu/kfung/jty1/NeuroTest/Q71-Ans.htm Ragged red fibres (ouhsc.edu)].
*Rimmed vacuoles = [[inclusion body myositis]].
*Vacuoles
**Acid maltase positive = lysosomal vacuoles.
**Rimmed vacuoles = [[inclusion body myositis]].
**Freezing artifacts (clear).
*PAS +++ = [[glycogen storage disease]].
*PAS +++ = [[glycogen storage disease]].
*Regenerative fibres = large nuclei, basophilic cytoplasm (incr. protein synthesis, incr. RNA).
*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:
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.
*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)].
**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)].
*Cores - central pale area along length of fibres = myopathic. (???)
*Regenerative fibres = large nuclei, basophilic cytoplasm (incr. protein synthesis, incr. RNA).
**Image: [http://moon.ouhsc.edu/kfung/jty1/Composites/FNN0IE08-core-NADHb.htm Cores (ouhsc.edu)].


===Approach===
===Approach===
General:
General:
#Size variation - in groups (neurogenic) vs. singular (myogenic).  
*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).
#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>).
#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]] - suggests myogenic.
#[[Necrosis]] & regeneration - suggests acute myogenic.
#Fibrosis - suggests myogenic.
#Fibrosis - suggests chronic myogenic.
#Inflammation - suggest myogenic vs. systemic inflammatory.
#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:
Other:
#Obvious abnormality vs. minimal change.
#Obvious abnormality vs. minimal change.
#Diffuse vs. focal change.
#Diffuse vs. focal change.
#Pathology in adjacent vessels or connective tissue.


==Processing of muscle biopsies==
==Processing of muscle biopsies==
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|-
|-
| H&E stain
| H&E stain
| routine
| routine, fibre size, shape, nuclei
| [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)]
| [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)]
|-
|-
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|-
|-
| NADH-TR  
| NADH-TR  
| should have "checkerboard <br>pattern" in normal; <br>type 1 fibres = light blue, <br>type 2 fibres = white
| good for cores or tubular aggregates, should have "checkerboard <br>pattern" in normal; <br>type 1 fibres = light blue, <br>type 2 fibres = white
|  
| [https://commons.wikimedia.org/wiki/File:Cell_sample_of_muscle_tissue_with_central_core_disease_(stained_for_contrast).jpg]
|-
| Myoadenylate deaminase
| Normal: positive, AMPDA deficiency: negative
| [https://commons.wikimedia.org/wiki/File:MAD_deficiency_enzymatic.jpg MAD deficiency]
|-
| Acid phosphatase
| Histiocytes/Macrophages, Lysosomal storage, Lipofuscin
|
|-
| Cytochrome oxidase
| Mitochondrial pathology
| [https://commons.wikimedia.org/wiki/File:Cox-deficient_fibers_in_mitochondrial_myopathy.jpg COX deficiency]
|}
|}


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===General===
===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>
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]]
* [[Sarcoidosis]].
* Idiopathic
* Idiopathic.
* Infectious ([[Tuberculosis]], Syphillis, Brucellosis
* Infectious ([[Tuberculosis]], Syphillis, Brucellosis.
* Foreign-body reaction
* Foreign-body reaction.
* [[Thymoma]] - myasthenia gravis
* [[Thymoma]] - myasthenia gravis.
* [[Lymphoma]] - paraneoplastic
* [[Lymphoma]] - paraneoplastic.
* [[Primary biliary cirrhosis]]
* [[Primary biliary cholangitis]].


<gallery>
<gallery>
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File:Granulomatous myositis.jpg | Granulomatous myositis ([[H&E]])
File:Granulomatous myositis.jpg | Granulomatous myositis ([[H&E]])
</gallery>
</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==
==Metabolic myopathy==
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*A type of congenital myopathy.
*A type of congenital myopathy.
*Paediatric thingy.
*Paediatric thingy.
*May appear secondary in other lesions.
*Rods are seen in trichrome stain
*Rods are seen in trichrome stain
<gallery>
<gallery>
File:Biopsy nemaline myopathy gomori.jpg | Nemaline rods (Trichrom Gomöri).
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>
</gallery>


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===General===
===General===
*Most common biopsy: sural nerve.
*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===
===Stains===
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*Myelin = red.
*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===
===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>
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>
*Wallerian degeneration.
*Axonal degeneration.
*Axonal degeneration.  
*Wallerian degeneration.  
*Segmental demyelination.  
*Segmental demyelination.  
====Axonal degeneration====
*Axonal swelling.
*Intra-axonal filamentous aggregates.
*Mitochondrial abnormalities.
*Aggregation of organelles and dense bodies.


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


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</gallery>
</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.


===Diseases===
 
*Guillain–Barré syndrome.
<gallery>
*Chronic inflammatory demyelinating polyneuropathy (CIDP).<ref>URL: [http://path.upmc.edu/cases/case426.html http://path.upmc.edu/cases/case426.html]. Accessed on: 14 November 2010.</ref>
File:Leprosy with perineural invasion 3.jpg | leprosy with perineural invasion. H&E stain (WC/Kozhikode)
**Essentially chronic Guillain–Barré syndrome.
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>
*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=
=See also=
Michael
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