Nerve entrapment involves a cascade of physiological changes caused by compression and tension. Some of these changes are irreversible. The magnitude and duration of the forces determines the extent of injury. In the acute form, mechanical injury and metabolic blocks impede nerve function. In the chronic form, there is a sequence of changes starting with a breakdown of the blood-nerve-barrier, followed by edema with connective tissue changes, followed by diffuse demyelination, and finally followed by axonmetesis. The injury will often be a mixed lesion where mild/moderate compression is a combination of a metabolic block and neuropraxia, while severe compression combines elements of neuropraxia and axonmetesis.

Nerve cells comprise a small cell body and a very long segment called the axon. The cell body resides in the spinal cord and the axon extends all the way to the innervation target of the nerve. Peripheral nerve axons can be longer than 100 cm as they may need to travel along the full length of a limb to reach their innervation target, while the cell body is only 100 micrometers long. Nerves may be myelinated or unmyelinated. Myelinated nerves have the axon covered by segments of schwann cells, which are short and concentrically wrapped around the diameter of an axon to give the appearance of a sausage-like mass and called a myelin sheath. The schwann cells are arranged in pattern such all parts of the axon are wrapped in schwann cells and successive schwann cells are separated by a very small distance. This separation gap is called a node of Ranvier. Unmyelinated nerves are also surrounded by schwann cells but the schwann cells are not wrapped around the axon multiple times to form a myelin sheath.

The axons of nerve cells are surrounded by various connective tissue layers and bundled together in a structure called a nerve fiber. At the surface of a nerve fiber is a tissue layer called the epineurium or sometimes external epineurium. Within the epineurium there is a connective tissue matrix called the internal epineurium and fascicles. The internal epineurium acts as soft cushion for the fascicles. A nerve fiber may have a variable number of fascicles, but there will be at least one (otherwise there would be no nerve cells). Fascicles are surrounded by a tissue layer called the perineurium which is a protective sheath that acts as a barrier. Inside the fascicles is the endoneurium, a tissue matrix analogous to the internal epineurium, and the nerve cells. The endoneurium has many small blood capillaries (endoneurial microvessels) which directly supply the nerves themselves. These capillaries have tight junctions to prevent the free flow of materials between cells and instead require substances to pass through the endothelial cells.

The peripheral blood nerve barrier is analogous to the blood brain barrier. Like the blood brain barrier, the blood nerve barrier creates a stable, privileged environment where certain substances cannot pass through due to tight junctions. The blood nerve barrier is made up of inner cells of the perineurium and the endothelial cells of the endoneurial microvessels.

Nerve entrapment is caused primarily by two physical forces on soft tissue: compression and tension. Compression will squeeze the nerve and impair its local microcirculatory environment which commonly happens in anatomic tunnels. Tension is a pulling force, often caused by scarring which impedes nerve mobility during limb movements. Both the magnitude and duration of these forces can determine the extent of injury.

Pressure can interrupt or arrest the microcirculatory environment of the nerve starting a pathophysiological cascade. As the heart beats, it pushes blood through arteries/arterioles/capillaries. Blood also travels through veins though more passively via valves and the assistance of muscles to squeeze veins. If there is localized pressure high enough, it can interrupt the normal flow of blood.

For compression to affect nerve function, pressure needs to be applied non-uniformly. For example, frogs can survive in isolated pressure chambers at high pressures but much lower local compression can block conduction of the nerve. Scuba divers can dive to tens of meters of water depth and will not experience any form of nerve compression, but the same pressure divers experience under 1 meter of water (pressure under 1m of water is 10k Pascal ~ 80mmHg) applied locally can completely arrest nerve function.

Compression is especially likely in anatomic tunnels or fibro-osseous spaces where there may be a conflict with the amount of free space available and the volume of the contents. If the tunnel narrows or if the contents of the tunnel expand, there will be an increase in pressure. Examples of tunnels are the carpal tunnel, tarsal tunnel, and cubital tunnel. Sometimes compression occurs in areas that are not considered tunnels and where a nerve passes between two mechanically stiffer tissue types that can squeeze or pinch the soft nerve. Examples include the lateral femoral cutaneous nerve at the inguinal ligament and the middle cluneal nerves at the long posterior sacroiliac ligament. The compression even be dynamic, where compression may only be present during certain activities and positions. In deep gluteal syndrome, patients often have sciatic radiculopathy when sitting but not standing.