Nerve Anatomy and Physiology

Connective Tissue Layers

Epineurium:

• Composition: Loose areolar connective tissue, type I and III collagen, fibroblasts
• Thickness: Comprises 30-75% of nerve cross-sectional area
• Vascularity: Contains vasa nervorum (longitudinal vessels) and lymphatics
• Function: Mechanical protection, allows gliding, nutrient supply
• Clinical: Provides strength for suturing during repair

Perineurium:

• Composition: 7-15 concentric layers of flattened cells with tight junctions
• Function: Blood-nerve barrier (selective permeability), maintains endoneurial microenvironment
• Pressure: Maintains endoneurial fluid pressure at 2-8 mmHg
• Clinical: Critical for regeneration - intact perineurium guides axons to correct targets (Sunderland I-II vs III)
• Resistance: High electrical resistance prevents current leakage

Endoneurium:

• Composition: Type III collagen fibrils, Schwann cells, capillaries
• Structure: Forms tubes around individual axons (diameter 0.4-14 micrometers)
• Function: Mechanical support for axons, ion regulation, regeneration scaffold
• Clinical: Intact endoneurial tubes (Bands of Büngner) are critical for successful regeneration
• Fluid: Contains endoneurial fluid (nutrient transport)

Understanding the three layers explains why injury severity affects prognosis.

Internal Nerve Architecture

Fascicular patterns:

• Monofascicular: Single large fascicle (e.g., digital nerves distally)
• Oligofascicular: Few large fascicles (2-10 fascicles)
• Polyfascicular: Many small fascicles (e.g., median nerve at wrist has 15-20 fascicles)
• Plexiform: Fascicles branch and rejoin along length

Topographic organization:

• Proximal nerves: Mixed fascicles (motor and sensory intermixed)
• Distal nerves: Segregated fascicles (motor and sensory separate)
• Example: Median nerve motor fascicle (recurrent branch) is distinct at wrist but mixed proximally
• Clinical: Group fascicular repair possible distally; epineural repair used proximally

Intraneural topography:

• Fascicles to specific targets occupy consistent positions within nerve
• Sciatic nerve: Tibial division posteromedial, peroneal division anterolateral
• Ulnar nerve: Motor fascicles to intrinsics are dorsal at wrist
• Clinical: Allows selective fascicular repair and internal neurolysis

Fascicular organization determines surgical repair strategy.

Vascular Anatomy of Nerves

Extrinsic blood supply (vasa nervorum):

• Segmental vessels: Enter epineurium at regular intervals (regional arteries)
• Longitudinal anastomoses: Form extensive network in epineurium and perineurium
• Redundancy: Allows nerve mobilization without devascularization (up to 15 cm safe)

Intrinsic blood supply:

• Perineurial plexus: Rich capillary network in perineurium
• Endoneurial capillaries: Continuous capillaries with tight junctions (blood-nerve barrier)
• Watershed zones: Areas vulnerable to ischemia (e.g., ulnar nerve at cubital tunnel)

Clinical implications:

• Nerve mobilization: Can mobilize 10-15 cm without devascularization due to intrinsic supply
• Tension: Excessive tension impairs intraneural blood flow, impeding regeneration
• Compartment syndrome: Increased pressure reduces endoneurial perfusion
• Diabetes: Microangiopathy affects vasa nervorum, contributing to neuropathy

Understanding vascular anatomy prevents iatrogenic injury during nerve repair.

Classification by Diameter and Speed

Key principles:

• Diameter determines speed: Larger diameter = faster conduction (less resistance)
• Myelination increases speed: Saltatory conduction 50x faster than continuous
• Clinical testing: Large fibers (vibration, proprioception) lost first in compression; small fibers (pain) lost last
• Regeneration: Large myelinated fibers regenerate faster than small unmyelinated fibers

Fiber classification explains differential susceptibility to injury and recovery patterns.

Lloyd Classification for Sensory Afferents

Clinical correlation:

• Ia/Ib loss: Absent deep tendon reflexes, loss of proprioception
• II loss: Loss of light touch and vibration (impaired hand function)
• III/IV preservation: Pain sensation intact despite motor and proprioceptive loss
• Recovery sequence: Large fibers (Ia/Ib/II) recover before small fibers (III/IV)

Understanding sensory classification explains examination findings after nerve injury.

Why Fibers Respond Differently to Injury

Compression injury (neuropraxia):

• Most vulnerable: Large myelinated A-alpha and A-beta (proprioception, vibration)
• Mechanism: Demyelination at nodes of Ranvier, impaired saltatory conduction
• Spared: Small C fibers (pain) relatively resistant
• Clinical: Early carpal tunnel has vibration loss before pain loss

Ischemic injury:

• Most vulnerable: Large motor fibers (high metabolic demand)
• Mechanism: ATP depletion, Na/K-ATPase failure, depolarization
• Clinical: Compartment syndrome causes motor loss before sensory loss

Axonal injury (axonotmesis):

• Wallerian degeneration: Affects all fiber types distal to injury
• Regeneration rate: A-alpha/beta regenerate at 1-3 mm/day; C fibers slower
• Clinical: Motor and large sensory recovery precedes pain fiber recovery

Differential vulnerability explains clinical presentations and guides examination.

Membrane Potential at Rest

Resting membrane potential: -70 mV (inside negative relative to outside)

Ionic basis:

• Sodium (Na+): High outside (140 mM), low inside (10 mM)
• Potassium (K+): High inside (140 mM), low outside (5 mM)
• Chloride (Cl-): High outside (110 mM), low inside (10 mM)
• Intracellular anions: Negatively charged proteins trapped inside

Maintenance mechanisms:

1. Na+/K+-ATPase pump: Actively transports 3 Na+ out, 2 K+ in (uses ATP)
2. Selective permeability: Membrane more permeable to K+ than Na+ at rest
3. Potassium leak channels: Allow K+ to exit, creating negative inside
4. Equilibrium potentials: ENa = +60 mV, EK = -90 mV, resting is between

Nernst equation (equilibrium potential for ion):

• E = (RT/zF) times ln([ion outside]/[ion inside])
• At body temperature: E = 61 mV times log([outside]/[inside]) / z
• Predicts voltage where ion flux is zero

Goldman-Hodgkin-Katz equation (membrane potential):

• Accounts for permeability to multiple ions (primarily K+, Na+, Cl-)
• Resting state: dominated by K+ permeability (Em approaches EK = -90 mV)

Understanding resting potential is fundamental to action potential generation.

Depolarization and Repolarization

All-or-none principle:

• Below threshold: No action potential (stimulus dissipates)
• At or above threshold: Full action potential (amplitude constant)
• Intensity coding: Frequency of action potentials (rate coding), not amplitude

Refractory periods limit firing rate:

• Absolute refractory: Cannot fire (Na+ channels inactivated)
• Relative refractory: Can fire with larger stimulus
• Maximum firing rate: approximately 1000 Hz (limited by absolute refractory period)

Action potential propagation allows rapid signal transmission over long distances.

Myelination and Speed

Myelin structure:

• Schwann cells: Wrap around axon (up to 100 times) in peripheral nerves
• Oligodendrocytes: Myelinate multiple axons in CNS
• Myelin composition: 70% lipid (sphingomyelin, cholesterol), 30% protein (P0, MBP, PMP22)
• Function: Electrical insulation (high resistance, low capacitance)

Nodes of Ranvier:

• Unmyelinated gaps: 1-2 micrometer intervals along axon (every 1-3 mm)
• Ion channel density: High concentration of voltage-gated Na+ channels at nodes
• Function: Action potentials regenerate at nodes only (saltatory conduction)

Saltatory conduction mechanism:

1. Action potential generated at node
2. Local current flows under myelin to next node (passive spread)
3. Depolarization at next node triggers new action potential
4. Process repeats (action potential "jumps" from node to node)

Advantages of myelination:

• Speed increase: 50-fold faster than unmyelinated fibers (120 m/s vs 2 m/s)
• Energy efficiency: Fewer Na+/K+-ATPase pumps needed (only at nodes)
• Allows large diameter: Unmyelinated fibers would need 100x larger diameter for same speed

Saltatory conduction explains why myelinated fibers conduct signals rapidly and efficiently.

Clinical Three-Grade System

Neuropraxia:

• Mechanism: Focal demyelination (compression, ischemia, mild traction)
• Pathology: Myelin damaged, axon continuity preserved
• Electrophysiology: Conduction block at injury site; normal distal to block
• Recovery: Remyelination over days to weeks (Schwann cells repair)
• Example: Saturday night palsy (radial nerve compression)

Axonotmesis:

• Mechanism: Severe crush or traction (axon torn, sheath intact)
• Pathology: Wallerian degeneration distal to injury; endoneurium preserved
• Electrophysiology: No conduction distal after 3-5 days (degeneration complete)
• Recovery: Axonal regeneration at 1-3 mm/day through intact endoneurial tubes
• Outcome: Good recovery if target not too distant (reinnervation before atrophy)
• Example: Closed humeral shaft fracture with radial nerve palsy

Neurotmesis:

• Mechanism: Laceration, severe traction, high-energy trauma
• Pathology: Complete disruption of axons and connective tissue sheaths
• Electrophysiology: No recovery potential without surgical intervention
• Recovery: None unless surgically repaired (primary or secondary repair)
• Outcome: Incomplete recovery even with repair (misdirected axons, target muscle atrophy)
• Example: Open fracture with nerve transection, iatrogenic nerve laceration

Seddon classification guides initial clinical management decisions.

Surgical Five-Grade System

Grade I (Seddon neuropraxia):

• Conduction block only, axon intact, complete recovery

Grade II (Seddon axonotmesis - best case):

• Axon disrupted, endoneurium intact
• Axons regenerate through intact tubes to correct targets
• Excellent recovery (minimal misdirection)

Grade III (Critical distinction):

• Axon and endoneurium disrupted, perineurium intact
• Nerve appears in continuity (can be misleading)
• Intrafascicular scarring disrupts endoneurial tubes
• Variable recovery: Some axons reach targets, others form neuromas
• May benefit from neurolysis (removing scar) or grafting

Grade IV:

• Only epineurium intact (perineurium disrupted)
• Severe intraneural scarring, neuroma in continuity
• Poor recovery without surgery (axons misdirected)
• Requires resection and nerve grafting

Grade V:

• Complete transection (all layers severed)
• No recovery without surgical repair
• Requires primary repair (if gap less than 2 cm) or grafting

Sunderland classification predicts recovery and guides surgical decision-making.

Six-Grade System (Adds Mixed Injury)

Mackinnon Grade VI: Combination injury (different Sunderland grades in different fascicles)

Clinical scenario:

• Common in partial nerve lacerations, stretch injuries, high-energy trauma
• Some fascicles intact (Grade I-II), others transected (Grade V)
• Examination: Partial motor/sensory function preserved
• Management: Selective repair of injured fascicles, preserve intact ones

Surgical challenges:

• Difficult to distinguish intact from injured fascicles intraoperatively
• Nerve action potentials (NAPs): Electrical stimulation proximal, record distal (if NAP present, fascicle intact)
• Histological assessment: Frozen section to assess fascicular injury
• Risk: Repairing intact fascicles worsens outcome (iatrogenic injury)

Mackinnon's modification recognizes the complexity of mixed injuries.

Distal Axon Degeneration After Injury

Molecular mechanisms:

• Calcium influx: Activates calpains (proteases) causing axonal breakdown
• Ubiquitin-proteasome system: Degrades cytoskeletal proteins (neurofilaments, tubulin)
• Schwann cell dedifferentiation: Lose myelin phenotype, acquire repair phenotype
• Upregulation of c-Jun: Master transcription factor in Schwann cells for repair program
• Neurotrophic factors: NGF, BDNF, GDNF support regenerating axons

Clinical significance:

• Electrical conduction preserved: Distal axon conducts for 24-48 hours (useful for intraoperative nerve stimulation)
• Denervation changes on EMG: Appear at 2-3 weeks (fibrillations, positive sharp waves)
• Window for repair: Schwann cell support optimal for 12-18 months; declines thereafter (endoneurial tubes collapse)

Understanding Wallerian degeneration explains the timing of nerve repair and recovery.

Proximal Axon Regeneration Process

Proximal stump response:

1. Chromatolysis (24-48 hours): Neuronal cell body swells, Nissl substance disperses, nucleus moves peripherally (protein synthesis increases)
2. Gene expression changes: Upregulate growth-associated proteins (GAP-43), tubulin, actin
3. Growth cone formation: Axon tip forms growth cone (motile structure with filopodia)
4. Sprouting: Multiple sprouts emerge from proximal stump (5-50 per axon)

Growth cone navigation:

• Chemotaxis: Neurotrophic factors (NGF, BDNF) create gradient
• Contact guidance: Growth cone follows Schwann cells (Bands of Büngner) within endoneurial tubes
• Adhesion molecules: N-CAM, L1, laminin on Schwann cells guide axons
• Topographic specificity: Motor axons prefer motor pathways, sensory prefer sensory (partial selectivity)

Regeneration rate:

• Fast transport rate: 1-3 mm/day (average 1 mm/day clinically)
• Delay at repair site: Initial delay of 3-4 weeks (growth cone formation, crossing scar)
• Tinel's sign: Percussion over regenerating axons causes tingling (tracks advancement)
• Distance matters: Long distances (brachial plexus to hand) may take 12-18 months

Myelination of regenerating axons:

• Schwann cells remyelinate regenerated axons
• Internodal distance shorter than original (10-20% of normal)
• Conduction velocity 60-80% of original (thinner myelin, shorter internodes)

Axonal regeneration is slow and often incomplete - understanding the process guides realistic expectations.

Variables Influencing Nerve Regeneration

Patient factors:

• Age: Children regenerate better than adults (faster rate, more plasticity)
• Diabetes: Microangiopathy and neuropathy impair regeneration
• Smoking: Nicotine reduces blood flow to nerves
• Nutrition: Vitamin deficiencies (B12, folate) impair regeneration

Injury factors:

• Mechanism: Clean laceration better than crush or avulsion
• Level: Distal injuries better than proximal (shorter distance, less time for muscle atrophy)
• Nerve type: Pure sensory better than pure motor; motor better than mixed
• Associated injury: Vascular injury, soft tissue loss worsen prognosis

Surgical factors:

• Timing: Early repair (less than 3 months) better than delayed
• Tension: Tension-free repair critical (tension impairs blood flow and regeneration)
• Coaptation: Precise fascicular alignment reduces misdirection
• Gap: Direct repair better than graft; autograft better than conduit

Biological factors:

• Distance to target: Short distances (digital nerves) have excellent recovery; long distances (brachial plexus) have poor motor recovery
• Muscle denervation time: Motor endplates degenerate after 12-18 months (irreversible)
• Misdirection: Axons may reach wrong targets (motor to sensory, vice versa)
• Neuroma formation: Axons blocked by scar form neuromas (painful)

Multiple factors interact to determine final functional outcome.