The painful neuroma

Understanding, diagnosing, and treating a painful neuroma should no longer be a mystery or a problem. The response of the peripheral nerve to injury has been defined, the factors that thwart neural regeneration so that a neuroma does not form have been defined, and techniques to treat the painful neuroma have been developed.

A peripheral nerve is covered with a myelin sheath produced by a Schwann cell.

The cell body for a sensory neuron of the peripheral nervous system lies in a dorsal root ganglion and from the exit of this nerve from the vertebral foramen it is covered with Schwann cells (Fig. 6.1). This is in contrast to the true cranial nerves with sensory function, like the optic and olfactory nerves, which are extensions of the central nervous system, and do not regenerate successfully to the distal target organ.⁶ When a peripheral nerve is injured, for example by a complete transection, the distal portion of the nerve degenerates (Wallerian degeneration).⁷ Since the Schwann cell is a single cell living along the length of the degenerating axon of the peripheral nerve, the Schwann cell remains alive. Ultimately, all that will remain of the nerve is the basement membrane that was elaborated by the Schwann cell. When the interaction between the axon and the Schwann cell is lost, the Schwann cell up-regulates and produces nerve growth factor.⁸ The proximal end of the peripheral nerve will produce axon sprouts within 24 hours of the nerve transection, which will begin to regenerate distally. The sprouts are lured by the nerve growth factor, and will track preferentially along the basement membrane, for whose negatively charged laminin and type IV collagen the sprouts have an affinity (Fig. 6.2).^9–11 The regeneration will proceed along the distal pathway towards the appropriate target end-organ.¹²

Fig. 6.1 The spinal nerve is formed from a ventral (motor) root and a dorsal (sensory) root of the spinal cord. Note that the dorsal root is joined to dorsal ganglia that contain the cell bodies of the sensory neurons, whereas the cell bodies of the motor neurons are contained within the spinal cord itself. When the spinal nerve exits the vertebral foramen it becomes ensheathed by Schwann cells and is termed a peripheral nerve. This particular peripheral nerve is illustrated as arising from the thoracic spine region, in which region its sensory branches directly innervate the skin without formation of a plexus, as occurs for the lower extremity from the lumbosacral plexus. Note that the dorsal ramus of the spinal nerve can be entrapped in its passage to the lower back, causing symptoms of chronic nerve entrapment termed “notalgia paraesthetica.”

Fig. 6.2 (A) A transection injury to a peripheral nerve results in degeneration of the axon distal to the site of transection (wallerian degeneration). (B) The Schwann cells along this distal segment of the axon survive, up-regulate, and produce nerve growth factor, while the axons of the proximal segment produce sprouts for distal regeneration. (C) When neural regeneration proceeds unimpeded, the axons will return to their distal target organ, with the creation of an in-continuity neuroma. (D) When neural regeneration is impeded by scar tissue from the injury, distal regeneration does not occur and an end-bulb neuroma forms.

If this process is thwarted at the site of neural regeneration, a neuroma will form. A neuroma is a benign tumor created by axon sprouts becoming encased in collagen. A neuroma will become painful if it is located in an area that subjects these sprouts to stimulation. Such sites include locations that are superficial, next to joints, adherent to moving tendons, and subjacent to weight-bearing surfaces. The common denominator for all of these is tension. The tension causes the fibroblasts in the region of the axon sprouts to produce the collagen that results in the growth of the neuroma and the adherence of the neuroma to surrounding structures.¹³

Within this evolving mass of axon sprouts and fibroblasts, abnormal communications or synapse-like structures may form between nerves that normally do not communicate with each other. These are the source of ephaptic conduction, which has been shown to be the origin of pain signals from the small myelinated group A-delta and unmyelinated group C fibers. Spontaneous origin of signals from these pain and temperature fibers have been recorded by single-unit neurophysiologic techniques from neuromas of the radial sensory nerve in the baboon.¹⁴ For example, that study found that 10% of more than 200 fibers that were studied had spontaneous activity in a 2-month neuroma, and this percentage increased to 18% in a 7-month neuroma, which was twice the activity found in the same-diameter intact (control) nerves. That study also demonstrated that the neuroma was mechanosensitive; just touching it generated signals, which did not occur from the control nerves. These findings provide the basis for the author’s current treatment strategy that involves resecting the end-bulb neuroma, instead of the traditional approach that involved just moving the “mature end-bulb neuroma” to a new place that was “quiet.”^15–17

Chronic nerve compression

The pathophysiology of chronic nerve compression implies that the evaluation of nerve function must be based upon the knowledge that there will be a progressive loss of peripheral nerve function. Therefore, the diagnosis and treatment of chronic nerve compression are based upon an understanding of this pathophysiology. The structure and function of the peripheral nerve, and how these are altered with increasing degrees of pressure and with increasing lengths of time, have been investigated in rat, rabbit, and monkey animal models,^18–28 and many of these models have used the sciatic nerve. Therefore, the disease process is the same for the better-known upper extremity nerve compressions as it is for the lesser-known lower extremity peripheral nerve compressions.

A review of this literature indicates that if there is a constriction of greater than 20% placed upon the diameter of the peripheral nerve, then acute axonal degeneration will occur. If there is a pressure of greater than 20 mmHg applied to the peripheral nerve, there will be a decrease in blood flow. In the acute situation, these conditions produce pain. If this degree of compression comes on over a gradual period of time, and over a length of the peripheral nerve that is several times the diameter of the nerve, then the conditions produce chronic nerve compression. After about 2 months of compression by a silicone tube that does not constrict the diameter of the nerve, the first changes in the pathophysiology occur. These are a weakening of the tight junctions of the endothelial cells in the perineurium, and this results in serum entering the endoneurial space. This creates endoneurial edema. When this occurs in the relatively tight confines of the perineurium, there is an increase in pressure that will decrease blood flow. The conscious perception of this is paresthesia. At this point in time, the only clinical findings will be related to the cutaneous sensory threshold for touch, which will first become elevated for static two-point discrimination, or will manifest itself as a change in perception of vibratory stimuli applied with a tuning fork or a vibrometer.^29,30 These pathophysiologic concepts provide a basis for staging chronic nerve compression (Tables 6.1–6.4).

Table 6.1 Numerical grading scale for any peripheral nerve³²

Table 6.2 Numerical grading scale for the median nerve at the wrist level³²

Table 6.3 Numerical grading scale for the ulnar nerve at the elbow level³²

Table 6.4 Numerical grading scale for the tibial nerve at ankle level

After about 6 months of this degree of compression, the first histologic changes in myelin can be observed. This consists of thinning of the myelin. With progressive compression, there will be increasing loss of myelin, so that under slides in which a myelin stain has been used, it appears as if there has been a loss of the large myelinated, touch, fibers. They will not actually have begun to degenerate yet, as demonstrated by electron microscopy, in which the unmyelinated large fibers can be demonstrated still to be present. At this stage, the patient will have weakness in the motor system related to the muscles supplied by that nerve, and increasing numbness in the territory (fingers) related to the sensory supply of that nerve. Pinch and grip strength can be measured directly. There will be no atrophy, because without true loss of the motor axons, there will be no decrease in bulk of the muscles. At this stage of compression, the cutaneous pressure thresholds will be elevated increasingly for the quickly adapting fibers, measured either with vibrometry or with moving two-point discrimination with the Pressure-Specified Sensory Device (PSSD),³¹ and for the slowly adapting fibers, measured with static two-point discrimination with the PSSD. Although no longitudinal study using the Semmes–Weinstein nylon monofilaments has been published in patients with chronic nerve compression,³³ the analogous measurement, made with the PSSD, which is one-point static touch, is still normal at this stage of compression.¹² Two-point discrimination, measured in millimeters, is still normal, because no nerve fibers have died. At this stage in chronic nerve compression, with myelin thinning, traditional electrodiagnostic testing may begin to detect increases in the distal sensory latency. Amplitudes will still be normal because no nerve fibers have died yet. In general, quantitative neurosensory testing is more sensitive than traditional electrodiagnostic testing (nerve conduction study/electromyogram), so it is more likely to detect this stage of nerve compression. Neurosensory testing is less expensive than nerve conduction study/electromyogram, and will not cause the patient any pain.^34,35

If either the length of time is increased for this degree of compression, or if the degree of compression increases, whether due to work, metabolic or rheumatologic disease, then neural degeneration occurs. As suggested in the preceding paragraph, this will be detected in the motor system by muscle wasting and in the sensory system by abnormal distance at which one from two points can be distinguished. Examples of these changes are given in Table 6.2 for median nerve compression at the wrist, Table 6.3 for ulnar nerve compression at the elbow, and Table 6.4 for tibial nerve compression in the tarsal tunnel.^27,29 Using the PSSD, this change occurs first for static two-point discrimination and then for moving two-point discrimination. This was demonstrated in a retrospective analysis of patients with carpal and cubital tunnel syndrome. The one-point static touch measurement will become abnormal some time after the change in two-point discrimination distance, and is therefore a relatively insensitive tool for detecting the onset of this stage. Vibrometry and tuning fork use can identify this stage, but does not permit the therapist to identify correctly which nerve is being compressed without additional testing. It must be remembered that the vibratory stimulus travels as a wave, whereas the pressure stimulus remains localized to the applied test site.^23,24,31 For example, if the involved nerve is the tibial nerve, and the hallux pulp is tested, there may still be relatively preserved sensation mediated by the peroneal nerve. Testing of both the dorsum of the foot and hallux pulp and medial heel may permit distinction of which nerve is involved.

If there is some limitation on the gliding of the peripheral nerve through its site of anatomic narrowing, then, when the adjacent joint moves, there will an increase in tension along the length of the nerve which may manifest itself as a further increase in pressure upon the nerve. This limitation of gliding may come from some injury or anatomic variant that limits excursion of the nerves. This subject will be discussed in detail related to individual nerve compression syndromes.

Statistical evaluation of the results of the treatment of nerve compression has been difficult due to the failure of most reports to distinguish the degree of nerve compression among the patients in the study. An entire group of patients with nerve compression is usually described following surgery as having results that are excellent, good, fair, or poor. In comparing one published study to another, it would be helpful to be able to know the degree of severity of nerve compression in the patients being reported. It would be useful in a given study to know how patients with different degrees of nerve compression responded to the same operation. Even if this is recognized as a goal, without a numerical grading system the author is left only with the choice of indicating what percentage of people who had a mild degree of nerve compression improved, and what percentage of patients with a severe degree of nerve compression improved. With a numerical grading system, as outlined above, a unique number, representing the pathophysiologic condition of the compressed nerve as manifested by its functional impairment can be assigned to each patient, and these numbers can be treated statistically. Finally, treatment strategies and outcome analysis for the peripheral nerve can be analyzed mathematically. When this is done, it should be remembered to use nonparametric statistics.

The painful neuroma

The patient with a painful neuroma will complain of an area of skin or a joint that causes pain either at rest, or, more commonly, when the part is touched or moved. When an area of pain relates to the territory of a peripheral nerve, and the patient has had an injury or an operation in that area, then consideration must be given to the presence of a painful neuroma of that peripheral nerve. In earlier times, this would have been called “causalgia,” but today, if the pain persists for more than 6 months, it is termed “complex regional pain syndrome I.” If movement of the ankle or knee creates pain, then consideration must be given to the presence of a neuroma of the nerve that innervates that joint. Anatomy books do not show nerves innervating joints, and this knowledge required cadaver dissections, which have been published for the knee (Fig. 6.3 B and C)³⁶ and for the ankle (Fig. 6.3A).³⁷ Clinical approaches and results for the lower extremity were reviewed in 2009.⁵ Beginning with the knee, and then extending this approach to the ankle, anatomical dissections were performed to identify joint innervation, With this knowledge routes for the administration of local anesthetic were identified. Demonstrating that pain relief is possible by anesthetic blockade in patients who failed traditional musculoskeletal approaches led to the creation of surgical approaches to resect involved nerve(s).

Fig. 6.3 Illustrations of the innervation of lower extremity joints. (A) The sinus tarsi is innervated by branches of the deep peroneal nerve that arise proximal to the lateral mallelous, just before the branch to the extensor digitorum brevis. (B) The medial aspect of the knee joint is innervated by a branch of the femoral nerve. After the femoral nerve innervates the vastus medialis, at which point anatomy books show the nerve terminating, the nerve continues distally and past the end of the muscle to innervate the medial knee structures. (C) The lateral aspect of the knee joint is innervated by a branch of the sciatic nerve, which, after it innervates the posterior knee capsule, travels anterior, deep to the biceps tendon, and then innervates the lateral knee structures. The medial and lateral retinacular nerves likely overlap anteriorly, although this has not been proven.

(Reproduced with permission from Dellon.com.)

When pain is outside the territory of a single peripheral nerve, and the pain has been present for more than 6 months, and especially if there is an associated change in skin color or temperature, or sweating (sympathetic activity), this syndrome was called reflex sympathetic dystrophy. Today this is called complex regional pain syndrome II. This condition is usually managed by the anesthesia pain management doctor with lumbar sympathetic blocks, and neuropathic pain medication. Ultimately, an implanted spinal nerve stimulator (dorsal column stimulator) or a peripheral nerve stimulator may be implanted. There is often more than one peripheral nerve involved: there may be a true cutaneous neuroma, neuroma of the joint afferent, and nerve entrapment or a second peripheral nerve with a neuroma that accounts for the wide distribution of pain. This is a critical diagnostic concept, because it means that the nerve block should be applied to more than one nerve if a single nerve block has not been successful and that the block may also be necessary for the joint afferent. Furthermore, if this approach is successful, spinal stimulators will be unnecessary.

Motor function should be normal physiologically with the exception of two considerations. Firstly, if there is ankle pain, then the patient may not use muscles that cause ankle movement, leading to disuse atrophy of the muscles. Secondly, there is often wasting of the extensor digitorum brevis associated with ankle pain, since the nerve that innervates this muscle, the deep peroneal nerve, has been injured, usually with the stretch/traction associated with an inversion sprain.

Chronic nerve compression

The patient with chronic compression of a peripheral nerve will complain of numbness or paresthesias in the skin territory innervated by that nerve. The patient will complain of weakness in the muscles innervated by that nerve. If both the peroneal and tibial nerves have chronic compression at the same time, the patient will have numbness over the dorsal and plantar aspects of the foot and arising proximal to the ankle. This will give the same appearance as if the patient had a peripheral neuropathy, especially if the problem occurs in both legs. This type of situation occurs in patients who have sports injuries, or other injuries. As a contrast in etiology, but with the same clinical presentation, will be patients who do have a metabolic neuropathy, for example, those with diabetes, or chemotherapy-induced neuropathy, who have secondary chronic nerve compressions. These patients with present with a history of neuropathy, and frequently will not have been examined to identify the presence of a chronic nerve compression.³⁸ If the nerve compression is diagnosed and treated in such patients, they will frequently experience sensory recovery despite the presence of diabetic neuropathy.

The pathognomonic feature of chronic nerve compression on physical examination is the presence of a positive Hoffman–Tinel sign. With an understanding of the pathophysiology of chronic nerve compression (see above), it becomes clear that in the earliest stage there will be intermittent symptoms and there will be no physical findings present. This is often the situation with musicians, such as the pianist or violinist who complains of numbness in the little finger, from playing with the elbow bent, but has no Hoffman–Tinel sign over the ulnar nerve at the cubital tunnel. In the lower extremity, an analogous situation occurs with the soccer player whose leg may seem to give out, who has received many a blunt trauma to the outside of the knee or repeated ankle inversion sprains, and who has compression of the common peroneal nerve at the fibular neck. With further time and a greater degree of compression, axons will demyelinate and there will be an increase in the threshold required to produce a sensory response; a higher degree of vibration with the tuning fork, or a greater pressure required to discriminate one from two points touching the big-toe pulp with the PSSD while two-point discrimination distance remains normal. In the motor system, this will correspond to weakness on manual muscle testing. At this point, the Hoffman–Tinel sign will become positive. With further time and degree of compression, axons will die, and there will be a decrease in two-point static touch discrimination (the distance before two points can be distinguished will increase), and muscle atrophy will occur. The Hoffman–Tinel sign will remain positive. With a very advanced degree of compression, the peripheral nerve seems to stop its attempt to remyelinate and regenerate, and the Hoffman–Tinel sign becomes negative. This variation in the presence of the Hoffman–Tinel sign over time is understandable in terms of progression of compression and changes within the peripheral nerve, and should not be interpreted as a failure of the Hoffman–Tinel sign to be a valuable clinical examination technique.^39,40

The painful neuroma

Selection of the patient for surgical treatment of the painful neuroma begins after the first 6 months of pain. During the first 6 months of the patient’s pain, management will usually be done by the primary care physician and/or the original treating surgeon, often in conjunction with a therapist. Most often, the patient will have tried opiates, nonsteroidal anti-inflammatory drugs, massage, ultrasound, and steroid injection. Once the pain has lasted 6 months, the patient enters the phase of chronic pain, and is now traditionally referred to a pain management physician. At this point, the patient will usually be tried on neuropathic pain medication, such as nortriptyline, Neurontin, Cymbalta, or Lyrica, and often a combination of these.

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