(Adapted, with permission, from Stanton-Hicks M, Jänig W, Hassenbusch S, et al. Reflex sympathetic dystrophy: Changing concepts and taxonomy. Pain. 1995;63:127–133.)

Table 23.1 International Association for the Study of Pain criteria for diagnosis of chronic regional pain syndrome (CRPS)

CRPS type I (reflex sympathetic dystrophy)

1. Type I is a syndrome that develops after an initiating noxious event

2. Spontaneous pain or allodynia/hyperalgesia occurs, is not limited to the territory of a single peripheral nerve, and is disproportionate to the inciting event

3. There is or has been evidence of edema, skin blood flow abnormality, or abnormal sudomotor activity in the region of the pain since the inciting event

4. This diagnosis is excluded by the existence of conditions that would otherwise account for the degree of pain and dysfunction

CRPS type II (causalgia)

1. Type II is a syndrome that develops after a nerve injury. Spontaneous pain or allodynia/hyperalgesia occurs and is not necessarily limited to the territory of the injured nerve

2. There is or has been evidence of edema, skin blood flow abnormality, or abnormal sudomotor activity in the region of the pain since the inciting event

3. This diagnosis is excluded by the existence of conditions that would otherwise account for the degree of pain and dysfunction

(Reproduced from Stanton-Hicks M, Janig W, Hassenbusch S, et al. Reflex sympathetic dystrophy: changing concepts and taxonomy. Pain 1995;63:127–133.)

Although multiple theories still coexist, progress is being made in rejecting convenient yet unfounded theories on the etiology of CRPS and developing research-based models that will do a better job both defining the disorder and its risk factors, and yielding more appropriate therapies.⁴ The most compelling possibility is that all cases of CRPS are caused by some form of peripheral (somatic and/or autonomic) nerve damage. The empiric observation that both forms of CRPS may have identical clinical manifestations but that type II is brought on by a recognizable nerve injury (whereas the symptoms of type I are not as closely linked to a specific cause) is suggestive of a role for nerve injury in both types. As well, there is mounting research evidence to suggest that peripheral nerve damage, whether of large recognizable nerves or of smaller distal fibers, may be the inciting incident in a cascade of events that ultimately leads to the clinical syndrome of CRPS.⁵^–⁷ This chapter will explain how CRPS is linked to nerve injury, and why this provides a logical directive for the involvement of peripheral nerve surgeons in its treatment.

Pathophysiology

There is no consensus regarding the pathophysiologic mechanisms underlying the development of CRPS. However, most pertinent to peripheral nerve surgeons is the emerging model of CRPS as the ultimate result of untreated nerve injury. We propose the three components of this model: (1) peripheral nerve injury; (2) peripheral sensitization; and (3) central sensitization (Fig. 23.3).

Fig. 23.3 Model for the development of complex regional pain syndrome (CRPS) from nerve injury. Nerve injury is followed by peripheral sensitization, which progresses to neuralgia. Via central sensitization, there is a regional spread of pain and activation of other inappropriate responses, leading to CRPS. The condition may resolve spontaneously, or with surgical treatment of the underlying nerve injury.

The two most common mechanisms of nerve injury are either from an acute trauma (including surgery), such as by crush, stretch, or transection, or from chronic compression (Fig. 23.4), as is often seen in upper and lower extremity compression syndromes like carpal, cubital, radial, or tarsal tunnel. Nerve injuries may spontaneously recover, or they may result in neuroma, or compression neuropathy – two permanent disruptions in nerve architecture that generate chronic pain. In the case of trauma, the result of nerve injury is often a painful neuroma, where the cut or crushed end of a nerve grows aberrant sprouts in an attempt to regenerate (Fig. 23.5). These sprouts become tangled in surrounding connective tissue, failing to regenerate along their normal course, and causing chronic pain. A variant of this pattern is the neuroma in continuity, where the nerve is not transected, but a crush injury disrupts the internal fascicular organization of the nerve; scar tissue then forms within the nerve, blocking the regeneration of axonal sprouts and creating a neuroma.^8,⁹ The other end point of nerve injury that causes chronic neuropathic pain is compression neuropathy (Fig. 23.4). Compression neuropathy causes nerve ischemia and degeneration by physical pressure on the nerve, which occludes blood flow as well as axonal transport. Compression neuropathy may occur in the setting of a naturally tight anatomic tunnel exacerbated by tissue edema/hypertrophy (such as occurs with overuse syndromes and trauma), or may be the result of nerve entrapment in scar tissue following trauma. Clinically recognizable neuromas or large-nerve compression neuropathies can be the basis for CRPS type II (causalgia), whereas damage to clinically undetectable small distal fibers is likely the basis of CRPS type I (RSD),^4,^5,^10,¹¹ which does not classically include a nerve injury.

Fig. 23.4 Model of nerve compression.

Fig. 23.5 Model of neuroma and neuroma in continuity. (A) Painful neuromas arise when normal neural repair/regeneration is disrupted, such as by intervening scar tissue. (B) The treatment for painful neuroma is resection of the neuroma with implantation of the proximal nerve stump into a muscle. (C) Neuroma in continuity is characterized by internal architectural derangement of an intact nerve. The segment containing neuroma can be selectively or totally resected, and then repaired using grafting or conduit.

Not all nerve injuries progress to CRPS. Some may never be painful, or may be only briefly painful. Some may cause chronic neuropathic pain in the distribution of the injured nerve, but never lead to the regional spread, dysesthesias, trophic changes, and associated dysautonomic symptoms that characterize CRPS. The first step towards the development of CRPS after nerve injury comes with the onset of peripheral sensitization, defined as a progressive increase in the response of peripheral nociceptors to repeated stimuli.¹² This increasing sensitivity of nociceptive afferents is brought about both by autosensitization, wherein activation of the receptor itself reduces its own activation threshold, and by heterosensitization, where mediators such as inflammatory cytokines (e.g., prostaglandin E₂, bradykinin) and neurotrophic factors increase excitability of the neuronal membrane without activating transducers. In both cases, transduction threshold is reduced, making it easier for an action potential to occur. Noteworthy in the case of CRPS, whose clinical features include regional spread of pain and pain in response to sympathetic stimuli, is the concept that peripheral sensitization does not only affect the injured nerve, which is often distally malfunctioning and/or incapable of producing positive signals. Instead, neighboring nerve endings are sensitized, and there is experimental evidence showing that damage to a nerve causes early and spontaneous ectopic firing of adjacent, uninjured C-fibers. These fibers also develop reduced threshold for ectopic firing; particularly, they become sensitive to alpha-adrenergic activity.^13,¹⁴

The end result of peripheral sensitization is both an increase in the pain experienced by the patient, as well as an amplification of nociceptive input entering the CNS. Left untreated, and in a chronic form, prolonged and increased nociceptive input to the CNS triggers modulation in central pain pathways, resulting in central sensitization. Central sensitization results in enhanced responsiveness of central pain transmission neurons, which either outlasts the initiating input or requires only a low-level peripheral drive to maintain it.¹² Thus, pain which began from a physical insult in the periphery can become centrally generated by the CNS even in the absence of any continued peripheral stimulus. Because the mechanisms underlying this modulation involve changes in receptor (e.g., N-methyl-d-aspartate (NMDA) receptors) expression akin to the long-term potentiation associated with memory in the hippocampus, they are long-lasting and make the disorder difficult to reverse at this point.

Taken together, this combination of nerve injury, peripheral sensitization, and central sensitization can explain many of the perplexing disease features of CRPS. Features of the syndrome that were previously assumed to be the result of abnormal sympathetic outflow can be explained by distal small-fiber loss due to nerve injury. Distal small nerve fibers are mixed in function, consisting of not only sensory (A-delta and C fibers) components, but sympathetic axons, and neuroeffector peptides (e.g., substance P, and calcitonin gene-related peptide) that regulate tissue function. Small fiber loss may cause denervation of distal limb arteriovenous shunts, with loss of resting tone and opening of the shunts.⁵ This could lead to the asymmetric limb warmth and hyperperemia associated with RSD, while causing paradoxical hypoperfusion of deeper tissues,¹⁵ contributing to deep pain. That some CRPS-affected limbs appear blue and cold rather than warm and hyperemic may be explained by eventual supersensitivity of denervated vessels to circulating catecholamines. The sudomotor instability (hypo- or hyperhidrosis) often seen in RSD/CRPS I is also explicable by nerve injury leading to denervation of sweat glands, which are normally innervated by cholinergic sympathetic small fibers. Sweat glands of CRPS I patients have been shown on pathologic examination to be denervated of these cholinergic sympathetic small fibers, but have aberrant ectopic sprouting of adrenergic innervation from nearby nervi vasorum; thus, they may both sweat insufficiently from direct neural stimulation and yet sweat excessively in response to circulating catecholamines.^5,¹⁶

Remaining disease features are accounted for by peripheral and central sensitization. As previously mentioned, the process of peripheral sensitization can reduce activation threshold as well as induce expression of adrenergic receptors on nociceptive fibers adjacent to an injured nerve ^13,¹⁴; this phenomenon helps to account for both SMP and regional spreading of pain. Spreading of pain and hypersensitivity to regions beyond the injured tissue is also accounted for by the mechanisms of central sensitization, wherein a centrally sensitized neuron can generate pain outside the distribution of the stimulating peripheral input by increasing the excitability of its synapses with multiple other central neurons.^12,¹⁷ Finally, innappropriate sensitization of both peripheral and central afferents leads to the hyperpathia and allodynia that are characteristic of the pain in CRPS.^12,¹⁸

Patient presentation

Epidemiology

CRPS occurs with an estimated incidence of 26.2 per 100 000 person-years,¹⁹ with a published range of 5.46–26.2 per 100 000 person years.^19,²⁰ Published estimates indicate that CRPS I makes up 97% of cases in the general population, with CRPS II being more common in certain subpopulations such as the military as a result of gunshot wounds and shrapnel injuries.¹⁹ However, experience in the surgical literature suggests that CRPS II may be underdiagnosed or frequently misdiagnosed as CRPS I.^6,⁷ The syndrome may occur in any age group, although the peak prevalence seems to be in middle age, suggesting that many cases actually resolve and do not progress to a chronic form with disability.^19,²⁰ Females are affected at least three times as often as men,^19,²⁰ for unclear reasons.

Precipitating events

The most common precipitating events for CRPS I are extremity fractures (e.g., distal radius fractures) and sprains, although surgery, tendon injuries, and crush injuries are also common causes. Seemingly minor or innocuous events, such as phlebotomy, can also be causes, as can nontraumatic insults such as tumors, infarctions, and vasculitis with mononeuropathy multiplex. For known cases of CRPS II, nerve compression syndromes and penetrating injuries (including surgery) are common causes. For both types of CRPS, the upper extremity is more often involved than the lower extremity (60% versus 40%), although as a group, CRPS of the extremities make up the vast majority of cases, with head, trunk, and visceral involvement being possible but rare.^21,²² This distribution is in keeping with an underlying etiology of nerve injury, since the axial pattern and proximity to hard tissues of extremity nerves make them more vulnerable to injury than trunk nerves. Upper extremity involvement may be more frequent than lower extremity involvement due to the smaller receptive fields and greater density of innervation in the arm than the leg.

Patient characteristics

The only high-powered study to examine medical history prior to the onset of CRPS found an association between a history of migraines, asthma, neuropathies, osteoporosis, and menstrual cycle-related problems and the later development of CRPS.²³ Although the cryptogenic nature of the disease as well as the emotional changes it may produce in patients have caused suspicion for a hysterical or psychological underpinning in CRPS, multiple studies have studied the association of psychological factors with CRPS onset and found no evidence in support of CRPS as a psychologically mediated disease, or of the idea that certain psychological profiles are predisposed to its development.²³^–²⁵ With this being said, it is important to keep in mind that emotional and psychological changes such as anxiety and depression do develop in chronic CRPS as a consequence of central sensitization, and therefore may be a presenting feature of the disease.

Diagnosis

CRPS is a clinical diagnosis that should be made based on history and physical examination findings. There are several proposed diagnostic criteria, with the 1994 International Association for the Study of Pain (IASP) criteria (Table 23.1) being most frequently cited. Several modifications of these criteria have been proposed in an attempt to improve specificity.²⁶

For the peripheral nerve surgeon, the question of whether or not a patient meets certain CRPS criteria is far less important than the question of whether the patient’s pain will respond to surgical intervention. Evaluation by the peripheral nerve surgeon should consist of a thorough search for the presence of an underlying nerve injury (compression or neuroma) that may have initiated the syndrome, and then an assessment of whether surgical treatment of the nerve injury is likely to improve that patient’s symptoms.

Nerve injuries are identified by the combination of history, physical exam, and electrodiagnostic testing. History should be focused on whether or not the patient recalls a traumatic or surgical event in the area that may have caused a nerve injury. If the pain began after a previous surgery, the operative note should be requested and reviewed for mention of nerve injuries. The history should also clarify exactly the type of pain and the distribution of pain; every attempt should be made to clarify whether the pain rests in the distribution of one or more peripheral nerves, or whether regional spread outside of specific nerve distributions has occurred. Associated symptoms such as the presence of edema, vasodysregulation, sudomotor instability, and weakness or dystonia may also be inventoried, although their significance to the peripheral nerve surgeon is somewhat less. Finally, it is crucial to elicit an account of the time passed since the initial insult, and the length of time that the full syndrome of CRPS, if present, has been active. Patients with newer-onset CRPS (less than 3–6 months) who are still in the process of nerve injury and peripheral sensitization are much more likely to benefit from surgical repair of peripheral pain generators than those with chronic CRPS whose pain has become centrally generated. Other factors in the history that favor a good response to surgery are a discrete traumatic event responsible for the initiation of pain, and a well-localized source of pain.

Physical examination should be performed concurrently with the history to augment the identification of nerve injuries. Physical exam begins with a search for outward scars or signs of trauma to the painful region. The presence of any of the typical inflammatory, dysautonomic, or atrophic features of CRPS should be noted (Figs 23.6 and 23.7). The location of the patient’s pain as described in the history should then be mapped on to the surface of the body, and this region should be scrutinized by the examiner for a correlation to specific peripheral nerve distributions. When the distribution of the pain does not match a known peripheral nerve distribution, either multiple overlapping nerve territories may be implicated, or the regional spread of pain via sensitization may have occurred. Once the region of pain has been clarified on physical exam, the presence of a Tinel’s sign in nerves within the region should be tested for by tapping over any known anatomical compression points, obvious scars, or suspected sites of painful neuromas. The presence of a positive Tinel’s sign (a tingling sensation radiating distally from the site of percussion) helps to localize cutaneous neuromas, and signals a greater likelihood of response to surgery for nerve compression injuries, presumably by indicating the presence of surviving neurons distal to the point of injury.