There are many different factors that cause formation of a neuroma.

The surgical classification used by Guégan sets out in a pragmatic way by dividing traumatic nerve injuries into three levels of anatomical severity, each of which has a different probability of forming a scar neuroma [18].

Sunderland details five levels of anatomo-functional severity in traumatic nerve trunk injury [37]: (1) temporary conduction block without axonal injury; (2) endoneural bundle intact but loss of axonal continuity, followed by Wallerian degeneration of the distal end and, in parallel with this, satisfactory regeneration of the proximal ends; (3) intra-fascicular injury with loss of continuity of nerve fibres, causing oedema and intra-trunk inflammation, followed by Wallerian degeneration and scar fibrosis distally, regeneration with intra-trunk progression of the proximal axons which are impeded by the formation of intra-trunk fibrous blocks; (4) fascicular structure of the nerve destroyed but axis of the trunk preserved by the perineurial connective tissue; (5) complete sectioning of a nerve.

Where a nerve fibre is sectioned, axonal degeneration begins at the distal extremity, characterised by granular fatty involution of axons and their myelin sheaths along the entire length of the peripheral segment as far as the terminal branches: this is classic retrograde Wallerian degeneration. Once the reabsorption processes are complete, only empty perineurial connective tissue sheaths remain. At the proximal end, after a phase of early and often partial retrograde degeneration, processes of anterograde axonal regeneration occur rapidly. This regeneration results from the growth of axonal fibres from the central end of the sectioned nerve: the proximal end of each sectioned axon gives off a variable number of very fine newly formed axons. If penetration and recolonisation of the empty sheaths in the distal extremity do not occur due to anatomical factors hampering their progress (poor end-to-end anatomical apposition, fibrous blockages), axonal proliferation may result in the formation of excess axonal fascicles that do not connect with their potential peripheral target. Alternatively, if the perineurial sheaths are not interrupted, the newly formed fibres may penetrate the connective tissue sheaths that have been left empty by the process of degeneration. The metabolic activity of Schwann cells within the connective tissue sheaths then increases and tubes form around the axons: these are Bungner’s bands. Neurotrophic factors are also produced locally, such as neurotrophins, neuropoietic cytokines, interleukins and fibroblast growth factor [27]. NGF (nerve growth factor) is specifically needed for the survival of sensory neurons and regulates the excitability of nociceptive fibres [1]. It is transported retrogradely along the axon towards the cell body of the sensitive nerve fibres. The increase in the local concentration of NGF after nerve section seems to be initiated by interleukin 1β, which is secreted by macrophages that have migrated into the injured tissue. The NGF membrane receptors present along the Bungner’s bands are activated after a nerve injury, permitting the axons to progress along these tubes, sending out microspicules towards the bands to orient the direction of their progress. It is only later, once the axon is stabilised in its location within the fascicle, that the myelin sheath is reformed from the perineural Schwann cells.

The functional quality of the axonal bud depends above all on whether the axons are in contact with Schwann cells and the probability of satisfactory anatomical regeneration of a nerve fascicle is higher if a larger number of intact connective tissue sheaths have been left totally empty after degeneration. Overall the speed of regeneration of nerve fibres in man is between 1 and 3 mm per day under optimal conditions.

When a connective tissue scar is formed between the budding end of the axon and the empty connective tissue sheaths, the proximal end of the axon stops its progress at the obstacle and forms a nodular thickening which is classified in anatomo-functional terms as a neuroma. The size of the neuroma depends on several factors, such as the amount of abnormal axonal regrowth, the number of fibroblasts making up the scar, the number of residual perineurial Schwann cells and the number and quality of perineural blood vessels. It also depends on whether or not infection is also present and whether or not microscopic foreign bodies are present which have not been or cannot be removed. Complete section of a nerve is therefore not a necessary condition for formation of a neuroma, if the surgical repair is satisfactory in micro-anatomical terms.

Not all neuromas are likely to cause severe, chronic and disabling pain. During axonal regeneration within a sensory nerve trunk that has previously been injured, the progression of nerve fibres may involve type C fibres, which are small calibre, non-myelinated fibres that transmit nociceptive-type information. If a neuroma is formed that consists at least partly of fibres of this type, several processes may take place [10, 20]: (1) abnormal contact between fibres may promote the formation of ephapses, areas where non-physiological transmission of electrical signals occur between fibres giving rise to true short-circuits; (2) the neuroma may become hyperexcitable due to the presence of inflammatory mediators or catecholamines which are released locally either by fibroblasts and macrophages that are still present or by small type B fibres from the autonomic nervous system which are also regenerating; (3) transitory spontaneous electrical activity may occur at budding axonal ends; (4) electrical activity is initiated by any mechanical or thermal stimulation of axonal ends within the nodular thickening. These processes cumulatively contribute towards the formation of a painful neuroma.

Based on studies carried out in animals, several biological mechanisms involving various nerve fibres but mainly C fibres, have been shown to account for these phenomena.