Nerve Anatomy and Physiology

Peripheral nerves transmit electrical signals between the central nervous system and the peripheral tissues. Understanding their anatomy and physiology is fundamental to managing nerve injuries and to understanding neurological deficits in orthopaedic surgery.

Scope. This page covers the structure, conduction and fibre-type basic science. The injury and repair biology that builds on it - the Seddon and Sunderland classifications, Wallerian degeneration, chromatolysis, Schwann-cell reprogramming and axonal regeneration - is covered in depth on the Nerve Injury and Regeneration page; the two are companion reads.

Why it matters. Peripheral nerve injury is an uncommon but disabling complication of limb trauma. In a large European trauma registry an associated peripheral nerve injury was recorded in approximately 3.3% of severely injured patients with upper-extremity involvement, clustering in young men after high-energy mechanisms (notably motorcycle trauma) and with humeral or forearm fractures. Accurate classification with the Seddon and Sunderland systems guides prognosis, the decision to observe versus explore, and the timing of repair.

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The three connective-tissue layers

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Epineurium. The outermost sheath is loose areolar connective tissue of type I and III collagen and fibroblasts, and makes up 30-75% of the nerve's cross-sectional area. It carries the vasa nervorum (longitudinal vessels) and the lymphatics, protects the fascicles mechanically, lets the nerve glide and supplies nutrients; Sunderland described it as the cushion against compression. Surgically it is the layer preserved in neurolysis and the layer that gives suture purchase in a repair.

Perineurium. Each fascicle is bounded by 7-15 concentric layers of flattened cells joined by tight junctions. This is the blood-nerve barrier: selectively permeable, it maintains the endoneurial microenvironment and its ionic composition, holds the endoneurial fluid pressure at 2-8 mmHg, and its high electrical resistance prevents current leakage. It is a tough, tension-resistant sheath, and the nerve's tensile strength and capacity to resist traction reside in it.

Endoneurium. Within each fascicle, type III collagen fibrils, Schwann cells and capillaries surround the individual axons, forming tubes (0.4-14 micrometres in diameter, lined by the Schwann cell basement membrane) that contain endoneurial fluid for nutrient transport. The endoneurium supports the axons mechanically, regulates their ionic environment and is the scaffold for regeneration: after injury the tubes persist and fill with Schwann cell columns, the Bands of Büngner, along which regenerating axons travel.

Why the layers matter. Injury severity is graded by how many of the sheaths are lost, and the sheaths decide the prognosis. Axons regenerating within intact endoneurial tubes (Sunderland I-II) reach their correct targets and recover spontaneously; once the endoneurium is disrupted (Sunderland III) regeneration is misdirected and recovery variable, and once the perineurium goes as well (Sunderland IV) intraneural scarring and a neuroma in continuity leave a nerve that is in continuity but recovers poorly. The layering also explains the repair options, epineurial versus fascicular, set out under fascicular organisation below.

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Fascicular organisation

Fascicular patterns. Nerves differ in how their fibres are bundled:

• Monofascicular - a single large fascicle (digital nerves distally)
• Oligofascicular - a few large fascicles (2-10)
• Polyfascicular - many small fascicles (the median nerve at the wrist has 15-20)
• Plexiform - fascicles branch and rejoin along the length of the nerve

Topography. Proximally the fascicles are mixed, with motor and sensory fibres intermingled; distally they segregate, so the median nerve's motor fascicle to the recurrent branch is distinct at the wrist but mixed further up. Fascicles to particular targets also occupy consistent positions within the trunk: in the sciatic nerve the tibial division lies posteromedial and the peroneal division anterolateral, and in the ulnar nerve at the wrist the motor fascicles to the intrinsics lie dorsal. Knowing the map is what allows selective fascicular repair and internal neurolysis.

What it means for repair. Distal nerves, monofascicular or oligofascicular with segregated fibres, allow group fascicular repair with better coaptation. Proximal nerves, polyfascicular and plexiform, need an epineurial repair because fascicular matching is impossible, and attempting fascicular dissection proximally risks additional injury.

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Blood supply

Extrinsic supply. Segmental regional vessels enter the epineurium at regular intervals and form extensive longitudinal anastomoses in the epineurium and perineurium: the vasa nervorum. That redundancy, together with the intrinsic supply, is why 10-15 cm of nerve can be mobilised without devascularising it.

Intrinsic supply. A rich capillary plexus lies in the perineurium, and the endoneurial capillaries are continuous capillaries with tight junctions, which is the vascular side of the blood-nerve barrier. There are watershed zones vulnerable to ischaemia, the ulnar nerve at the cubital tunnel among them.

Clinical consequences. Excessive tension impairs intraneural blood flow and impedes regeneration. Compartment syndrome raises pressure and reduces endoneurial perfusion, and diabetic microangiopathy affects the vasa nervorum and contributes to neuropathy. Respecting the vascular anatomy is what prevents iatrogenic injury during nerve repair.

Fibres are classified two ways: Erlanger and Gasser by diameter and conduction speed (A, B, C, with the A group subdivided), and Lloyd by a numeric grouping of the sensory afferents (I-IV). The Lloyd groups correspond to Erlanger-Gasser types, and in both schemes size predicts speed and vulnerability.

Erlanger-Gasser classification

Diameter and myelin set the speed. A larger axon offers less internal resistance and conducts faster; myelination adds saltatory conduction, which is about 50 times faster than continuous conduction. The same size gradient governs regeneration, as large myelinated fibres regenerate faster than small unmyelinated ones.

Lloyd classification of sensory afferents

Reading the examination. Loss of Ia and Ib fibres abolishes the deep tendon reflexes and proprioception; loss of group II removes light touch and vibration, and with them useful hand function. When groups III and IV are preserved, pain sensation is intact despite motor and proprioceptive loss. On recovery the large fibres (Ia, Ib, II) return before the small ones (III, IV).

Why fibres respond differently to injury

Compression. The large myelinated A-alpha and A-beta fibres, carrying proprioception and vibration, are the most vulnerable: the lesion is demyelination at the nodes of Ranvier with failure of saltatory conduction, a neuropraxia. The small C fibres carrying pain are relatively resistant, which is why early carpal tunnel syndrome loses vibration sense before pain.

Ischaemia. The large motor fibres, with the highest metabolic demand, fail first as ATP is depleted, the Na+/K+-ATPase stops and the membrane depolarises. Clinically, compartment syndrome causes motor loss before sensory loss.

Axonal injury. In an axonotmesis Wallerian degeneration takes every fibre type distal to the lesion. On the way back the A-alpha and A-beta fibres regenerate at 1-3 mm/day and the C fibres more slowly, so motor and large-fibre sensory recovery precede the return of pain fibres.

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Resting potential

The resting membrane potential is -70 mV, inside negative relative to outside. It exists because the ions are distributed unevenly across the membrane and the membrane does not treat them equally:

• Sodium - high outside (140 mM), low inside (10 mM)
• Potassium - high inside (140 mM), low outside (5 mM)
• Chloride - high outside (110 mM), low inside (10 mM)
• Intracellular anions - negatively charged proteins trapped inside the cell

How it is maintained. The Na+/K+-ATPase pumps 3 Na+ out for 2 K+ in, consuming ATP, and at rest the membrane is far more permeable to K+ than to Na+ because of the potassium leak channels. K+ therefore leaks out down its gradient and leaves the inside negative. The equilibrium potentials are ENa = +60 mV and EK = -90 mV, and the resting potential sits between them, much closer to EK.

Nernst and Goldman-Hodgkin-Katz. The Nernst equation, E = (RT/zF) times ln([ion outside]/[ion inside]), gives the voltage at which the net flux of a single ion is zero; at body temperature it simplifies to E = 61 mV times log([outside]/[inside]) divided by z. The Goldman-Hodgkin-Katz equation extends this to the real membrane by weighting several ions (chiefly K+, Na+ and Cl-) by their permeability, and at rest, dominated by K+ permeability, it predicts a membrane potential approaching EK.

The action potential

All or none. A stimulus below threshold dissipates and produces nothing; at or above threshold the full action potential fires with a constant amplitude. Stimulus intensity is therefore encoded in the frequency of action potentials, rate coding, and not in their size.

The refractory periods set the ceiling. Nothing can fire during the absolute refractory period, while the Na+ channels are inactivated, and only a larger stimulus fires during the relative period. The absolute period limits the maximum firing rate to approximately 1000 Hz.

Saltatory conduction

Myelin. In the peripheral nervous system a Schwann cell wraps around the axon up to 100 times; in the central nervous system one oligodendrocyte myelinates several axons. Myelin is about 70% lipid (sphingomyelin, cholesterol) and 30% protein (P0, MBP, PMP22), and its job is electrical insulation: high resistance, low capacitance.

Nodes of Ranvier. The myelin is interrupted by unmyelinated gaps of 1-2 micrometres every 1-3 mm along the axon, and the voltage-gated Na+ channels are concentrated there. Action potentials regenerate only at the nodes:

1. An action potential is generated at a node
2. Local current flows passively under the myelin to the next node
3. Depolarisation at that node triggers a new action potential
4. The process repeats, so the impulse "jumps" from node to node

The pay-off. Conduction is about 50-fold faster than in an unmyelinated fibre (120 m/s against 2 m/s), fewer Na+/K+-ATPase pumps are needed because they work only at the nodes, and the fibre can stay small: an unmyelinated axon would need a diameter 100 times larger to reach the same speed.

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Two systems are in use and they map onto each other. Seddon's three grades are clinical, assigned from the mechanism and the examination, and guide the initial decision; Sunderland's five degrees are anatomical, defined by which sheaths are disrupted, and predict recovery and the need for surgery. Mackinnon added a sixth degree for the mixed injury.

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Seddon classification

Neuropraxia. Compression, ischaemia or mild traction damages the myelin focally while the axon remains in continuity. There is a conduction block at the injury with normal conduction distal to it, and the Schwann cells remyelinate the segment over days to weeks. Saturday night palsy, a radial nerve compression, is the standard example.

Axonotmesis. A severe crush or traction tears the axon but leaves the sheath intact, so Wallerian degeneration follows distal to the injury while the endoneurium is preserved. Distal conduction is lost by 3-5 days, and recovery is by axonal regeneration at 1-3 mm/day through the intact endoneurial tubes: good, provided the target is not so distant that the muscle atrophies before the axons arrive. The closed humeral shaft fracture with a radial nerve palsy is the example.

Neurotmesis. A laceration, severe traction or high-energy trauma disrupts axons and connective tissue sheaths together. There is no recovery without surgical repair, primary or secondary, and even after repair recovery is incomplete because axons are misdirected and target muscles atrophy. An open fracture with nerve transection, or an iatrogenic nerve laceration, is the example.

Sunderland classification

Grades I and II. Grade I is Seddon's neuropraxia: a conduction block with the axon intact and complete recovery. Grade II is the best case of axonotmesis: the axon is disrupted but the endoneurium intact, so the axons regenerate through their own tubes to the correct targets with minimal misdirection and excellent recovery.

Grade III. The axon and the endoneurium are disrupted but the perineurium is intact, so the nerve appears in continuity and can mislead. Intrafascicular scarring disrupts the endoneurial tubes; some axons reach their targets and others form neuromas, so recovery is variable, and the nerve may benefit from neurolysis to remove the scar, or from grafting.

Grades IV and V. In grade IV only the epineurium is intact: severe intraneural scarring produces a neuroma in continuity, the misdirected axons recover poorly without surgery, and the segment needs resection and nerve grafting. Grade V is complete transection of every layer, with no recovery without surgical repair: primary repair if the gap is under 2 cm, otherwise grafting.

Mackinnon modification

Grade VI is the mixed injury, with different Sunderland grades in different fascicles. It is common in partial lacerations, stretch injuries and high-energy trauma: some fascicles are intact or grade I-II while others are transected, so on examination partial motor and sensory function is preserved. Management is selective repair of the injured fascicles while preserving the intact ones.

The surgical difficulty is telling intact from injured fascicles on the table. A nerve action potential is recorded by stimulating proximal to the injury and recording distal to it, and a fascicle that conducts one is intact; frozen section can assess fascicular injury histologically. The risk is that repairing an intact fascicle worsens the outcome by adding iatrogenic injury.

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Wallerian degeneration

The molecular programme. Calcium influx activates calpains, the proteases that break the axon down, and the ubiquitin-proteasome system degrades the cytoskeletal proteins, neurofilaments and tubulin. The Schwann cells dedifferentiate, losing the myelin phenotype for a repair phenotype under the control of c-Jun, the master transcription factor of the repair programme, and their neurotrophic factors (NGF, BDNF, GDNF) support the regenerating axons.

What the clinician sees. The distal axon goes on conducting for 24-48 hours after the injury, which is useful for intra-operative nerve stimulation. Denervation changes on EMG, fibrillation potentials and positive sharp waves, appear at 2-3 weeks: the time it takes for Wallerian degeneration to complete and for the muscle fibre membrane to become unstable as acetylcholine receptors are upregulated. Do not expect EMG changes in the first week.

Axonal regeneration

The proximal stump. The neuron's response to losing its axon runs in sequence:

1. Chromatolysis (24-48 hours): the cell body swells, the Nissl substance disperses and the nucleus moves to the periphery as protein synthesis increases
2. Gene expression changes: growth-associated proteins (GAP-43), tubulin and actin are upregulated
3. Growth cone formation: the axon tip forms a motile growth cone with filopodia
4. Sprouting: multiple sprouts, 5-50 per axon, emerge from the proximal stump

Finding the way. The growth cone follows a chemotactic gradient of neurotrophic factors (NGF, BDNF), and by contact guidance follows the Schwann cells of the Bands of Büngner within the endoneurial tubes, adhering to N-CAM, L1 and laminin on their surface. Guidance is partially selective: motor axons prefer motor pathways and sensory axons sensory pathways.

The rate. Axons advance at 1-3 mm/day, on average 1 mm/day clinically, after an initial delay of 3-4 weeks for growth cone formation and crossing the scar at the repair site. Percussion over the regenerating axons produces tingling, Tinel's sign, which tracks the advancing front; over long distances, brachial plexus to hand, regeneration may take 12-18 months.

The regenerated fibre is not the original. Schwann cells remyelinate the regenerated axons, but the internodes are shorter than before (10-20% of normal) and the myelin thinner, so conduction velocity recovers to only 60-80% of the original.

Factors affecting recovery

Patient factors. Children regenerate better than adults, with a faster rate and more plasticity. Diabetes impairs regeneration through microangiopathy and neuropathy, nicotine reduces blood flow to the nerve, and vitamin deficiencies (B12, folate) impair regeneration.

Injury factors. A clean laceration does better than a crush or avulsion, a pure sensory nerve better than a pure motor one and a motor nerve better than a mixed one, and an associated vascular injury or soft-tissue loss worsens the prognosis. Distal injuries do better than proximal ones, for the reasons in the pearl below.

Surgical factors. Early repair, within 3 months, beats delayed repair. The repair must be tension-free, because tension impairs blood flow and regeneration; precise fascicular alignment reduces misdirection; and a direct repair beats a graft, as an autograft beats a conduit.

Biology. Short distances (digital nerves) recover excellently and long distances (brachial plexus) give poor motor recovery; motor endplates degenerate irreversibly after 12-18 months of denervation. Axons may reach the wrong targets, motor to sensory and vice versa, and axons blocked by scar form painful neuromas.

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A focal peripheral nerve lesion maps to a single named-nerve territory and is confirmed electrodiagnostically; the critical step is to exclude compartment syndrome and acute arterial ischaemia, which are limb-threatening and demand emergency intervention rather than expectant nerve management.

Global Epidemiology

• Peripheral nerve injury (PNI) is an uncommon complication of limb trauma. In the European TraumaRegister DGU cohort of 49,382 severely injured patients with upper-extremity involvement, an associated nerve injury was present in approximately 3.3%.
• PNI clusters in young males (mean age approximately 40 years, around 79% male) and after high-energy mechanisms, with motorcycle accidents the single most common cause in that registry.
• Typical concomitant lesions are humeral (approximately 37%) and ulnar (approximately 20%) fractures, vascular laceration, and extensive soft-tissue damage; PNI roughly doubles inpatient rehabilitation need and lengthens hospital stay.
• In penetrating and ballistic trauma, nerve deficits are common (around 30% of upper-extremity gunshot injuries in one Level 1 trauma series) but are frequently neuropraxic or axonotmetic, with more than half improving spontaneously, supporting initial expectant management of nerve-in-continuity ballistic injuries.
• In limited-resource and conflict settings, blast and gunshot mechanisms predominate and the ulnar nerve is the most frequently injured peripheral nerve.

Classification and Decision Frameworks (Side by Side)

Evidence-Based Reconstruction Principles (Global Consensus)

• Timing: clean, sharp transections are repaired primarily and early; closed fracture-associated palsies (e.g. radial nerve palsy with humeral shaft fracture) are usually observed because most are neuropraxia or axonotmesis that recover. Reconstruction should ideally occur within the 12-18 month window before motor endplates and repair Schwann cells degenerate.
• Repair ladder by gap: direct tension-free coaptation is preferred; hollow conduits are reserved for short sensory gaps (typically under 25 mm) in low-demand nerves; processed nerve allograft has registry support for digital nerve gaps of 25-50 mm (around 86% meaningful sensory recovery); autograft (sural nerve) remains the reference standard for longer or critical motor/mixed nerves.
• Nerve transfers (e.g. double fascicular Oberlin-type transfer for elbow flexion, spinal accessory to suprascapular nerve) shorten the distance from coaptation to target muscle and have improved outcomes in proximal and brachial plexus injuries.
• Electrodiagnostics: nerve conduction studies and needle EMG are timed at 2-3 weeks or later after injury, when denervation changes (fibrillations, positive sharp waves) appear; intraoperative nerve action potentials help decide between neurolysis and resection-grafting for a nerve-in-continuity.

Practice Variation and Resource Setting

• High-resource settings: ready access to microsurgery, intraoperative neuromonitoring, processed allograft and conduits, and specialist peripheral-nerve and brachial-plexus units; increasing use of nerve transfers.
• Limited-resource and conflict settings: predominance of blast/gunshot injuries, delayed presentation, reliance on autograft and tendon transfers rather than commercial conduits/allograft, and emphasis on rehabilitation and protective sensory retraining.
• Across all settings, hand therapy and structured rehabilitation (sensory re-education, prevention of contracture, protective sensation education) are integral to functional outcome.

Exam Relevance (All Boards)

• Nerve anatomy and physiology is a core basic-science topic for fellowship candidates worldwide.
• Examiners commonly test the three-layer architecture, the ionic basis of the action potential and saltatory conduction, and the Seddon/Sunderland classifications with their clinical implications.
• The highest-yield distinction is Sunderland degree II (good prognosis) versus degree III (poor prognosis) in a nerve that appears in continuity, and the use of intraoperative nerve action potentials to resolve it.