Neuromuscular pathology

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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.

Myogenic:

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

Detail

  1. Segmental demyelination - nerve/CNS abnormality.
  2. Axonal degeneration - nerve/CNS abnormality.
  3. Reinnervation - nerve injury.
  4. Myopathy - something is wrong with the muscle fibres.

Stains for muscle biopsies

Standard

Stain Comment Image
H&E stain routine, 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).

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.


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.

Type 2 fibre atrophy

General

DDx:

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

Microscopic

Features:

  • Atrophy for type 2 atrophy.

Images

Specific entities

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

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]

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:

Images:

IHC

Features:[33]

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


Granulomatous myositis

General

Etiology:[34]


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.

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


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.

Centronuclear myopathy

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

Image centronuclear myopathy[35]).

Drug-induced rhabdomyolysis

  • AKA drug-induced acute necrotizing myopathy.

General

Clinical:[36]

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

Causes:

  • Ecstasy (MDMA).
  • Statins.

Microscopic

Features:

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

Images:

Stains

  • PAS +ve fibres (macrophages).

IHC

  • CD45 -ve (no lymphocytes).

EM

Trichinosis

See Microorganisms.

Parasitic disease classically associated with consumption of uncooked pork.

Nerve stuff

General

  • Most common biopsy: sural nerve.
    • 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).

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.

Regeneration

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

Inflammation

  • Inflammatory pseudotumour.
  • Leprosy (Leprous neuropathy).
  • Sarcoidosis.
  • Neuropathy with macrophage-induced demyelination (CIDP, GBS).
    • Guillain–Barré syndrome.
    • Chronic inflammatory demyelinating polyneuropathy (CIDP).[38]
      • Destructive myelin stripping by macrophages.
      • Uncompacted myelin / Widely spaced myelin.
  • CMV neuritis in immuncompromised patients.
  • Vasculitis.

Other Diseases

  • Toxic polyneuropathy (drug toxicity).[39]
  • Polyglucosan body disease.

Neoplasms

Main article: Peripheral nerve sheath tumours

See also

References

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