Regional Pain Syndromes That Present in the Foot, Ankle, and Lower Extremity

JEFFREY Y. F. NGEOW

MINYI TAN

Case Illustration

Patient A

S.A. is a 59-year-old woman who had a nondisplaced right 5th metatarsal fracture in October 1997. She was treated with cast stabilization for 8 weeks. She was referred to pain management consultation 5 months after the injury. S.A. reported that she had suffered from throbbing, aching, and occasional shooting pain while wearing the cast. Symptoms escalated since cast removal. Movements and weather changes aggravated the pain. She could not tolerate wearing sock and walked with a cane. Her pain score on visual analog score was 8/10. Bone scan revealed diffuse increased vascularity and uptake in the right lower leg, ankle, and foot (Fig. 12-1). The right plantar skin temperature was 29.7°C versus 28.7°C on the left. The patient’s history, symptoms, and signs were consistent with early-stage complex regional pain syndrome (CRPS). Diagnostic lumbar sympathetic nerve block (LSB) resulted in 2 to 3 days of significant pain relief. Thereafter, three more LSBs were performed with concomitant physical therapy. Gabapentin (Neurontin) was also prescribed. Within 3 weeks, she reported improvement of 70% to 80%. She could wear shoes and walk without a cane.

FIGURE 12-1. Bone scan from a patient 4 months after right 5th metatarsal fracture. Clinical CRPS developed within 8 weeks of injury.

Patient B

D.C. is a 30-year-old man who suffered a right foot and ankle injury after falling through an improperly covered manhole. There was no fracture, but he had progressive debilitation and pain in the right lower extremity. He described his pain as constant, sharp, and burning, from the tips of the toes to the groin. Physical findings included cold skin with atrophic changes, limited range of motion, and inability to bear weight. He could not tolerate wearing a shoe on the injured side. He had undergone treatments, including several kinds of medication (amitriptyline, tramadol, and gabapentin), physical therapy, and invasive treatments with LSB as well as 5 days of local anesthetic infusion with an epidural catheter. He had no long-term relief. About 20 months after the injury, a spinal cord stimulation trial (Fig. 12-2) produced immediate improvement. One week later, the permanent stimulator was implanted. D.C. continues to do well at 5-month follow-up with 70% less pain medication, and he could tolerate aggressive physical therapy.

FIGURE 12-2. Spinal cord stimulator inserted at T10-T11 with eight electrodes.

Introduction

CRPS is difficult to diagnose and treat. So it has perplexed many physicians throughout medical history. Patients with such a condition invariably complained of severe disabling pain, yet their history of present illness may often only amount to trivial injuries. Routine or even extensive investigations usually fail to reveal significant underlying causes. The baffled physicians understandably think these patients exaggerated their symptoms and sufferings. Such complainers were labeled neurotics and promptly referred to psychologists for “pain management.” Patients with CRPS affecting their lower extremities have often suffered such fates, and never had their condition treated appropriately.

Recent animal and human studies have shed light on the pathophysiology of the CRPS-related group of conditions. It is our intention to discuss some of the foot and ankle conditions that we have seen in a pain unit at an orthopedic center that have been associated with CRPS and to review their treatment in light of current understanding.

Brief Historic Review

In 1864, Mitchell and colleagues¹ first described, in victims of the American Civil War who sustained bullet injuries to their peripheral nerves, the syndrome of severe lancinating, burning pain in a limb that showed features of dystrophy. Later, Mitchell also named the condition “causalgia,” from the Greek kausis (burning) and algos (pain).² Since then, several similar conditions, not necessarily the result of penetrating injuries but sharing the common features of burning pain with dystrophy, have been recognized. In many of them, evidence of sympathetic hyperactivity such as vasospasm, hyperhidrosis, and decreased skin temperature is also present. These causalgia-like conditions were given different names such as posttraumatic pain dysfunction syndrome, shoulder-hand syndrome, reflex neurovascular dystrophy, neuroalgodystrophy, Sudeck atrophy, and others. These labels make long, interesting lists, but they merely served to emphasize differences and reflect the disagreement regarding their underlying mechanisms. There was general agreement, however, that the sympathetic nervous system was somehow involved, and excessive activity in this autonomic system brought about the dystrophic changes. This led to the gradual adoption of the term “reflex sympathetic dystrophy (RSD).”

As RSD implies, physicians are apt to believe that blocking the sympathetic pathway would result in resolution of the neuropathic symptoms and dystrophy. Sympathetic blockade, either with local anesthetics or with other means, became the preferred treatment modality. Disappointment soon set in, however, when it was found that many of the RSD cases simply did not respond to sympatholysis and, therefore, could not have been sympathetically mediated.

By 1986, the term sympathetically maintained pain (SMP) as proposed by Roberts³ was accepted for those cases labeled RSD that responded to sympathetic blockade. True RSD was naturally a member of SMP. Other cases that might not show much sympathetic overactivity but yet responded to sympathetic blockade were also included here. Conversely, pain conditions that showed features of sympathetic overactivity and even dystrophy but yet failed to respond to sympathetic blocks were labeled sympathetic independent pain (SIP). It was later recognized that SMP and SIP could represent the two ends of the spectrum for a single disease process.⁴ Despite improved nomenclature, much debate still continued as more underlying mechanisms were proposed for the SMP-SIP syndromes. Further attempts to reduce the confusion brought forth another revision in the terminology. A special Consensus Workshop in 1993 chose the umbrella name complex regional pain syndrome.⁴ To emphasize the distinction of the original causalgia, CRPS was subdivided into two categories:

1. CRPS-I covers a syndrome that develops after an initiating noxious event. Spontaneous pain or allodynia-hyperalgesia occurs. It is not limited to the territory of a single peripheral nerve and is disproportionate to the inciting event. 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. This diagnosis is excluded by the existence of conditions that would otherwise account for the degree of pain and dysfunction. RSD thus falls into this category.

2. CRPS-II is a syndrome similar to CRPS-I except that it develops after a known nerve injury. Traditionally, these injuries involve large nerves, such as the median or sciatic nerve.

Clinical Features

History of Present Illness

CRPS may present at the time of the initial injury or be delayed for weeks. CRPS-I occurs without any known nerve injury, whereas CRPS-II has an identifiable nerve lesion. CRPS-I may be associated with minor (e.g., sprains or bruises, skin irritation) or major (e.g., fractures, thermal or chemical burns, wound or joint infections, ischemic necrosis) injuries. In these conditions, involvement of peripheral nerves is common. Its association with other diseases in which direct nerve damage is not so apparent has also been reported. Such conditions include metastatic malignancy, Lyme borreliosis, diabetes, hyperthyroidism, hyperlipoproteinemia, lumbar radiculopathy resulting from lateral disc fragment, previous lumbar laminectomy, tarsal tunnel syndrome, and so on.

Without history of significant trauma, the patient may appear disproportionately disabled, frequently with startling loss of range of motion if an extremity is affected. If the patient has undergone an operation, a protracted recovery period during which the patient poorly tolerated all rehabilitative efforts is a common feature. Stories such as these when elicited should raise a high index of suspicion and should prompt the search for more specific CRPS features.

Symptoms and Signs

The outstanding feature of CRPS pain is a spontaneous superficial burning sensation superimposed on a continuous deep, often described as crushing, tearing, or throbbing pain. Exacerbation with movement is usual, but many patients notice worse pain when resting at night. There is often increased pain with weather changes as well as heat or cold intolerance. Patients usually shy away from bright sunshine and cold wind or even air conditioners. Peculiar signs in the affected parts include allodynia (pain resulting from nonpainful stimuli such as light pressure), dysesthesia (unpleasant abnormal sensation such as stinging when lightly scratched), and hyperesthesia (increased pain sensation to mild noxious stimuli such as a pinprick or a heat lamp). Other findings may be more extensive spread of pain that is not limited to the territory of a single nerve or dermatome. Vasomotor (Fig. 12-3) and sudomotor disturbances may be found in more than just the affected limb. In more advanced or chronic cases, structural changes of the skin appendages and deeper tissues may be present.

Varied symptoms and signs may be grouped according to their severity. In 1953, Bonica⁵ proposed a continuum of the RSD syndrome using stage I to III. Later, Schwartzman⁶ redefined the stages as acute, dystrophic, and atrophic, respectively.

Acute (Stage I)

This stage may occur immediately or within days of the inciting event. It is characterized by spontaneous pain with dysesthesia and warm skin with localized edema. There is a reluctance to touch and move the affected body part as a result of tenderness and muscle spasm. Increased hair and nail growth may be seen. In early stage I, the pain is usually limited to the distribution of the principal nerves involved. The skin is usually warm, dry, and red, sometimes showing vasomotor instability including areas of erythema mixed with blanching. In late stage I, however, the pain spreads beyond the involved dermatomes, and the skin becomes cyanotic or mottled resembling livedo reticularis (Fig. 12-4), cold, and clammy. In some patients, friction from clothing or light air movement on the skin may cause excruciating pain. There are usually no radiographic bone changes at this time.

FIGURE 12-3. Patient with history of CRPS caused by blunt trauma to the left foot showing vasomotor instability. Note erythematous patch over dorsum of foot that is distinct from the unaffected right foot.

Dystrophic (Stage II)

Dystrophic stage usually sets in 3 to 6 months from the onset but may appear sooner in rapidly progressing cases. This stage is heralded by a gradual increase in the area of pain, extent of the edema, degree of joint stiffness, extent of soft
tissue, and muscle wasting. The edema changes from a soft to a brawny type with glazed overlying skin. More advanced changes in the skin appendages are present. The hair becomes scant, and the nails become brittle, cracked, and grooved. Disturbance of motor functions such as tremors or dystonia may be present. Radiographic changes appear in this stage.

FIGURE 12-4. Patient with CRPS resulting from ischemic necrosis, which required toe amputation. Patchy erythema and pallor produced a mottled appearance.

Atrophic (Stage III)

This stage is characterized by advanced trophic changes that are mostly irreversible. The skin is smooth, almost glossy. It may be pale or cyanotic and feels cold as the temperature further decreases. The hair becomes sparse and coarse. Subcutaneous tissue turns brawny as it becomes atrophic with marked loss of fat. The digits are thin with severe atrophy of muscles, particularly the interossei. The interphalangeal and other joints of the extremity become stiff with decreased range of motion. They eventually result in ankylosis. Pain symptoms may have spread proximally or to other parts of the body. The affected parts are almost always aggravated by passive motion or touching. Emotional disturbance and visual or auditory stimuli can also cause marked sudden aggravation.

It should be noted that in any individual case, there is usually some overlapping of the features described in the different stages because the changes are seldom clear-cut. For example, when the initial injury includes bone or joint trauma, osteoporotic changes may appear within a few weeks in a limb that otherwise appears completely normal. Furthermore, vasomotor instability and trophic changes, disparate though they may seem, are thought to be manifestations of a progressive pathophysiologic process.⁷

Systemic Spread of CRPS

Long-standing CRPS patients suffer pain that spreads beyond the area of initial injury. It often spreads spontaneously to the contralateral or ipsilateral limb. Diagonal pattern of spread is often associated with new trauma.⁸ It was postulated that the “pathologic impulse” of CRPS is spread through the chain of sympathetic ganglia.⁹ CRPS patients often have constitutional symptoms such as lethargy, tiredness, or weakness. CRPS is a proinflammatory state where the body initiates nonspecific immune response following injury. The constitutional symptoms experienced by these patients maybe in part because of this response. Studies have shown that these patients have increased heart rate and decreased heart rate variability due to generalized autonomic imbalance related to disease duration, but not pain intensity.¹⁰ CRPS patients can develop dystonia, affecting chest wall muscles leading to restrictive lung disease.¹¹ These patients can also feel chest discomfort that may be because of irritation of the intercostobrachial nerve that innervates pectoral and intercostal muscles. This chest discomfort may be mistaken for cardiac pain or gallbladder disease.¹² These patients often suffered from bone and joint pain. It is thought that release of substance P results in activation of osteoclasts, thus forming intracortical excavation due to bone demineralization and resorption.¹³ Pathologic fractures are common and often occur in the 5th metatarsal bone. In addition to skin color changes, dermatologic manifestations include development of morbilliform rash, punched-out ulcer-like lesions, and recurrent bullous lesions, to name a few.

Pathophysiology

Despite advancement in our understanding of CRPS, its pathophysiology remains uncertain. As more knowledge is gained from the clinical observations and experimental studies, there is less agreement in a single common mechanism. The manifestation of somatosensory and motor disorders, autonomic dysfunction, and tissue structural changes makes it even more difficult for clinicians and scientists to accept a single animal model or hypothesis as the sole cause for this disorder.¹⁴

What is now generally accepted is that there is experimental evidence that suggests partial injury to a mixed peripheral nerve may be responsible for at least some of the features found in CRPS. Under normal conditions, sympathetic nerve stimulation does not excite the nociceptors (pain receptors) at the ending of an uninjured somatic nerve. Within days after partial nerve injury, however, changes occur that render the nociceptors excitable by sympathetic stimulation. The nociceptors now also respond to intra-arterially injected norepinephrine. If tissue injury and inflammation have already sensitized these nociceptors, their responses can be further augmented by sympathetic activities. Some of the proposed hypotheses that link this local event of nociceptor sensitization to the generalized manifestation of sympathetic hyperactivity are as follows.

Inflammation

Tissue and nerve injury causes the release of proinflammatory cytokines and neuropeptides, such as interleukin 6, tumor necrosis factor alpha, and substance P, in the affected area. An exaggerated localized inflammatory response is found in patients with CRPS. Studies have shown that CRPS patients have elevated levels of proinflammatory cytokines in their cerebrospinal fluid compared to healthy controls as well as those with different types of pain.¹⁵

Sympathetic Dysfunction

Local tissue factors, including sensitized nociceptors as well as neurotransmitter mediators, may activate the sympathetic system. In a vicious cycle, the noxious stimuli activate segmental and suprasegmental sympathetic discharges, producing vasoconstriction, ischemia, and further nociceptor activation. These result in impaired perfusion, which eventually leads to dystrophic changes.¹⁶ After tissue injury, abnormal connections between the sympathetic and somatic nervous systems are established. The resulting cross-talk (called ephapses)
between sympathetic efferent and somatosensory afferent nerves explains the sympathetic component of the pain in causalgia.¹⁷ In 1983, Devor¹⁸ presented finding showing that inflamed or damaged peripheral nerve twigs formed abnormal synapses in the same manner as injured nerve trunks. Such abnormal connections allowed cross-talk between the two systems, leading to increased signal input into the spinal cord, increased activity of the internuncial neuronal pool, and further stimulation of the sympathetic efferent and sensory afferents.

Spinal Mechanism

The neuronal turbulence hypothesis proposed by Sunderland¹⁹ in 1976 suggested that injury to the postganglionic sympathetic ganglia and trans-synaptic degeneration in the spinal cord would impair the function of spinal neuron groups. These groups of neurons could then form self-sustaining reverberating circuits.

Central Mechanism

In 1965, when Melzack and Wall²⁰ proposed the gate control theory of pain transmission in the spine, they also suggested a central biasing mechanism mediated through a system of descending fibers. These descending fibers arise from the brain stem reticular system, and they exert a tonic inhibition on the somatic sensory system at all levels. Reduced sensory input after somatic nerve injury (especially when the nerve is severed) would result in a decrease in the descending tonic inhibition and thus allow an increase in the transmission of the self-sustaining neuronal activities generated either in the periphery or within the spinal cord. In this situation, they postulated that prolonged pain may leave “memory traces” in the somatosensory system, making an individual more susceptible to recurrent pain. The practical application of this theory becomes relevant in the treatment of patients with phantom limb pain.²¹,²²

Neuronal Plasticity Mechanism

This proposed theory, which has become more commonly accepted, suggests that the perpetuation of abnormal firing pattern in the internuncial neuron pool in the spinal cord is responsible for abnormal pain perception. At the spinal cord level, a class of dorsal horn neurons that are multireceptive, the so-called wide dynamic range (WDR) neurons, usually do not contribute to painful sensations under normal conditions.²³ Sustained stimulation of the WDR by nociceptors, however, causes hyperexcitability and plasticity of the WDR by nociceptors, resulting in expansion of their receptive fields. This may explain why innocuous stimulations are now perceived as painful (hyperalgesia).²² Roberts and Foglesong²⁴ demonstrated that WDR neurons are the only spinal nociceptive neurons activated by sympathetic efferent activity. Therefore, WDR neurons (i.e., the high-threshold neurons) are most likely to mediate the spinal component of SMP. Sympathetic activation of WDR neurons is abolished by subcutaneous injection of local anesthetic, cooling the receptive field with ice, and intravenous injection of the α-adrenergic blocker phentolamine.

Glial Cell Activation

It has recently been hypothesized that CRPS is associated with activation of glial cells following tissue injury or inflammation. Glial cell, such as microglia and astrocytes, secretes substances that enhance pain transmission in the central nervous system once they are activated. These substances include proinflammatory cytokines, nitric oxide, and glutamate, to name a few. Animal studies have shown that activation of glial cells augments nociception. Human autopsy study of CRPS showed that long-standing CRPS patients had significant glial cell activation as well as neuronal loss in the posterior horn, predominantly at the level of the original injury.²⁵

Psychological Predisposition

Because none of the previously proposed mechanisms offer any predictability on who is more susceptible to CRPS, it is not surprising that some suggested that particular personality traits indicated predisposition toward developing CRPS. The patients’ seemingly exaggerated response to innocuous stimulations naturally led the physician to suspect psychological disorders. There is literature on both adults and children that hypothesize the presence of psychological disorders, particularly anxiety and depression, which predispose one to CRPS. Conversely, others believe that any chronic pain and suffering, in and of itself, will produce a host of psychological complications.

Diagnosis

A complete history and physical examination with high index of suspicion is crucial for diagnosis of CRPS in the early stages when disproportionate pain may be the only abnormal feature. Differentiation from other conditions may be difficult. Neuropathic pain caused by an injured or entrapped peripheral nerve or a neuroma anywhere from its root to the terminal branches may present similar symptoms, such as burning pain with hyperpathia. They are, however, usually limited to the territory of the involved nerve and associated with little sympathetic activities. Inflammatory processes not involving nerves, such as tenosynovitis and bursitis, may produce burning pain, which persists for months.⁷ They do not typically show Tinel sign, which is specific to nerves. Vascular diseases that cause decreased circulation such as Raynaud phenomenon or disseminated lupus erythematosus may mimic CRPS, although they usually affect more than one extremity at once. Therefore, the diagnosis is not infrequently made by exclusion, especially in the early stages of CRPS. For such reasons, some clinicians still do not accept CRPS as a distinctive pathologic disorder.

Several investigative tools may help to consolidate the diagnosis of CRPS:

1. Quantitative sweat test may show excessive sweating.

2. Thermography can demonstrate a disorder in heat regulation. Heat loss from the skin surface is mainly regulated by sudomotor activity on the sweat glands and the dermal microcirculation.²⁶ An affected hand or foot may at times be hyperthermic, but relative coldness is the most common finding. These changes produce the observation of vasomotor instability. They are related to sympathetic vasoconstriction and to compensatory or rebound vasodilatation of skin capillaries, which are, in turn, influenced by irritation of peripheral nerve fibers.²⁷

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