Neuromuscular pathology

Neuromuscular pathology is the study of muscle and neurologic disease associated with muscle dysfunction. It is a part of neuropathology.

Muscle pathology is dealt together with neurologic disease as, at the presentation, they are not infrequently impossible to definitely distinguish.

Work-up

1. Clinical history, including family history.
2. Laboratory studies, e.g. CK.
3. Nerve conduction and electromyography studies.
4. Muscle biopsy.

Patterns

Overview

Neuromuscular pathology

Neurogenic

Myogenic

Other/Mixed

	Neurogenic	Myogenic	Notes	Image
Shape of fibres	angulated	round		round fibres
Small fibres	groups ("group atrophy")	singular		group atrophy
Large fibres	No	+/-Scattered	"hypercontracted fibres"	DMD (WC)

List

Neurogenic:

• Angulated myocytes.
• Groups of small fibres.
• Apparent increase of nuclei.

Myogenic:

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

Muscle structure/histology

Macro to micro

Organization:

• Muscle - surrounded by epimysium.
  • Fascicle - surrounded by perimysium.
    • Muscle fibre - muscle cell.
      • Myofibrils - contractile elements within the muscle cell.

Fibre types

Types

Type 1 slow twitch

Type 2 fast twitch

List

Type 1 - AKA slow twitch:

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

Type 2 - AKA fast twitch:

• Predominantly glycolytic metabolism.

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

Abnormal findings

• Ragged red fibres = mitochondrial pathology.
  • Image: Ragged red fibres (ouhsc.edu).
• Rimmed vacuoles = inclusion body myositis.
• PAS +++ = glycogen storage disease.
• Regenerative fibres = large nuclei, basophilic cytoplasm (incr. protein synthesis, incr. RNA).

Others:

• Target fibre - "hole in middle of myofibres" = neurogenic. (???)
• Cores - central pale area along length of fibres = myopathic. (???)
  • Image: Cores (ouhsc.edu).

Approach

General:

1. Size variation - in groups (neurogenic) vs. singular (myogenic).
2. Shape - angulated (neurogenic) vs. round (myogenic).
3. Position of nuclei.
4. Necrosis - suggests myogenic.
5. Fibrosis - suggests myogenic.
6. Inflammation.

Other:

1. Obvious abnormality vs. minimal change.
2. Diffuse vs. focal change.

Processing of muscle biopsies

1. Formulin.
2. Frozen section.
3. Frozen for biochemistry.
4. 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

	Type 1 slow twitch	Type 2 fast twitch
pH 4.2	dark	light
pH 9.4	light	dark

Inflammatory myopathy

DDx:

1. Polymyositis.
2. Inclusion body myositis.
3. Dermatomyositis.

DDx

Neurogenic:

• Amyotrophic lateral sclerosis.
• Spinal muscular atrophy.
• Trauma.
• Vascular disease.
• Infective process.
• ?Motor neuron disease.

Myopathic:

• Inflammatory:
  1. Polymyositis.
  2. Inclusion body myositis.
  3. Dermatomyositis.
• Duchenne muscular dystrophy.
• Becker muscular dystrophy.
• Limb-girdle muscular dystrophy.
• Myotonic dystrophy.
• Metabolic - glycogen storage disease.

Other:

• Myasthenia gravis.
• Mitochondrial myopathy.
• Congenital fibre type disproportion.
• Periodic paralysis.

Amyotrophic lateral sclerosis

General

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

Microscopic

Features:

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

Dermatomyositis

General

• Complement mediated disease... membrane attach complex.
• Usually middle age. (???)
• Associated skin rash is common. (???)

Microscopic

Features:

• Perifascicular inflammation with perifascicular atrophy - key feature.

Inclusion body myositis

General

• Usually elderly.

Microscopic

Features:

• Inflammation.
• Vacuolated fibres (with proteineous aggregates) - key feature.

DDx: polymyositis.

IHC: APP +ve, ubiquitin +ve, tau +ve.

Polymyositis

General

• Tx: steroids.

Microscopic

Features:

• Inflammation.

DDx: Inclusion body myositis.

Muscular dystrophy

General

• DDx: large.

Microscopic

Features:

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

Myotonic dystrophy

Microscopic

Features:

• Internal nuclei/central nuclei.

Nemaline myopathy

General

• A type of congenital myopathy.
• Paediatric thingy.

Mitochondrial disorders

General

• Onset childhood to adulthood.
• Heteroplasmy - variable distribution of badness within affected individuals.
  • Leads to "threshold effect".

Microscopic

• Trichrome most useful - find the ragged red fibres - usu. at the cell periphery.
• COX-SDH - non-staining.

EM

Features:

• Crystalloid inclusions

Type 2 fibre atrophy

DDx:

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

Nerve stuff

General

• Biopsy: sural nerve.
• Myelin stain: blue = myelin.
• Gomori trichrome: axon = green, myelin = red.

See also

• Neuropathology.

External links

• How to work up a muscle biopsy (ouhsc.edu).