Neuromuscular pathology

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:

• 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.
• Normal CK values:
  • 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:

• 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:
  • Nerve (surrounded by epineurium) -> Fascicle (surrounded by perineurium) -> Nerve fibre (surrounded by endoneurium).

Fibre

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:

• Myofibrils frayed + adjacent to dense connective tissue.
  • Image: Muscle-tendon junction (anhb.uwa.edu.au).

Muscle-nerve junction

Features:

• Dunno. (???)

Images:

• MN junction - crappy image (WC). (???)

Muscle spindle

Features:

• Weird looking muscle cell. (???)

Image: Muscle spindle (anhb.uwa.edu.au).

Abnormal findings

Iatrogenic

• Torn (muscle) fibres (in the process of extraction for examination):
  • Membrane intact.
  • Myofibril kaputt.
  • No inflammation.

Pathologic

• Ragged red fibres = mitochondrial pathology.
  • Image: Ragged red fibres (ouhsc.edu).
• Vacuoles
  • Acid maltase positive = lysosomal vacuoles.
  • Rimmed vacuoles = inclusion body myositis.
  • Freezing artifacts (clear).
• PAS +++ = glycogen storage disease.
• Nemaline rods = nemaline myopathy
  • Image: nemaline myopathy gomori.jpg
• Cores - central pale area along length of fibres in NADH stain = central core disease.
  • Image: core disease NADH stain.jpg.

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.

• Target fibre - "hole in middle of myofibres" = neurogenic.
  • Images: Target fibres - very high mag. (WC), 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:

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).
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. 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
Small fibres	groups ("group atrophy")	singular		group atrophy
Large fibres	no	+/-scattered	"hypercontracted fibres"	DMD (WC)
Fibre type grouping	yes (d/t chronic denervation + reinnervation)	yes (???)	based on ATPase, NADH-TR stains	ATPase 9.4, NADH-TR

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, 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]
Congo red	find amyloid; seen in inclusion body myositis	[3]
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]
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	[6], SDH (WC)
Cytochrome oxidase (COX)	stains mitochondria; usu. -ve in mitochondrial disease	[7]
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:

• Toluidine blue - myopathies.
  • Image: Nemaline rods (wustl.edu).

IHC

• Dystrophy panel.
  • Dystrophin - 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.

List of common conditions

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.

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

Partial invasion of muscle fibres

DDx:

• Polymyositis.
• Inclusion body myositis (IBM).

Images:

• Partial invasion of muscle fibres (wustl.edu).

Muscular dystrophy

General

• DDx: large.

A short DDx:

• Duchenne's muscular dystrophy.
• Becker's muscular dystrophy.
• Limb-girdle muscular dystrophy.
  • Lotsa different mutations, autosomal dominant and recessive variants.
• Myotonic dystrophy.

Microscopic

Features:

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

• 

  Becker's muscular dystrophy ([[H&E]))

• 

  Carrier status in dystrophinophathy (Dystrophin)

Images:

• Becker muscular dystrophy (upmc.edu).
• Myotonic dystrophy - several images (upmc.edu).

Limb-girdle muscular dystrophy

General

• A group of muscular dystrophies with childhood or adult onset.
• 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.
• "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.

Clinical

• If the characteristic skin lesions are absent... it is likely idiopathic inflammatory myositis and related to diabetes mellitus.

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; not pathognomonic - may be seen in inclusion body myositis.

Images:

• Tubulorecticular inclusions (ouhsc.edu).

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.

Microscopic

Features:

• Inflammation.
• Vacuolated muscle fibres (with proteineous aggregates) - key feature.
  • Vacuolation = "inclusion".
    • Usually in the centroidal location.

DDx:

• Polymyositis.

IHC

Features:

• Congo red +ve.
• APP +ve, ubiquitin +ve, tau +ve. (???)

EM

• Inclusion bodies - tubulovescicular material.

• 

  Rimmed vacuoles in inclusion body myositis (HE).

Polymyositis

General

• Tx: steroids.

Microscopic

Features:

• 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.

• 

  Polymoysitis (H&E)

• 

  Polymoysitis (H&E)

• 

  Polymoysitis (CD45)

• 

  Polymoysitis (MHC-I)

• 

  Polymoysitis (H&E)

Images:

• Focal invasion of lymphocytes (wustl.edu).

IHC

Features:

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

Granulomatous myositis

General

Etiology:

• Sarcoidosis.
• Idiopathic.
• Infectious (Tuberculosis, Syphillis, Brucellosis.
• Foreign-body reaction.
• Thymoma - myasthenia gravis.
• Lymphoma - paraneoplastic.
• Primary biliary cholangitis.

• 

  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

• 

Image centronuclear myopathy).

Drug-induced rhabdomyolysis

• AKA drug-induced acute necrotizing myopathy.

General

Clinical:

• 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:

• 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).

• 

  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

• Traumatic Neuroma
• Pacinian Neuroma
• Nerve cysts.
• Neuritis ossificans.
• Localized interdigital neuritis (Morton neuroma).

Degenerative changes

Types:

• 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:

• Digestion chambers (missinglink.ucsf.edu).
• Digestion chambers (WC).

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

• 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.
• 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.
  • 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).
• 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
  • Synovial sarcoma

See also

• Neuropathology.

External links

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