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Chronic Regional Pain Syndrome (CRPS) and Reflex Sympathetic Dystrophy (RSD) for Primary Care Professionals. How to Diagnose and When to Refer to a Pain Specialist

Background

Complex Regional Pain Syndrome (CRPS) is a chronic condition characterized by burning pain and abnormalities in the sensory, motor and autonomic nervous systems. [1] This chronic pain condition is believed to be the result of dysfunction in the central, sympathetic, or peripheral nervous systems. [1] When “C” fiber type pain is present and objective evidence of vasomotor (skin temperature) or sudomotor (skin sweating) signs are evident a special form of CRPS called Reflex Sympathetic Dystrophy (RSD) exits.

(Figure 1)

The sympathetic nervous system supplies all of the body structures — including muscle, tendon, ligament, dura, disk, synovium, bone, and even the internal organs. When one of these tissues becomes injured, it is the sympathetic nervous system's job to monitor the injury and tell the spinal cord or the brain about it. Sometimes, however, the sympathetic nerves forget to stop monitoring the injury. When this happens it is abnormal, or dystrophic.

Dystrophy can be compared to a car engine that keeps on running (or dieseling), even after being turned off. Since no one really understands what triggers this aberration it is referred to as a reflexive response. While Chronic Regional Pain syndrome (CRPS) is another term that is often used to describe RSD, not all cases of CRPS involve the sympathetic system. As a result despite attempts to improve nomenclature, the two are not necessarily the same thing. RSD is anything but simple. Anyone afflicted with sympathetic pain should obtain a medical opinion and consult a doctor with specialized interest or training in this disorder.

Introduction

After spraining an ankle the first thing someone feels is sharp electric pain that is later followed by burning pain. While the sharp pain comes from the fast pain fibers, the burning pain comes from the sympathetic nerve fibers. Normally the burning pain stops over time [2, 3]. Sometimes however, the burning does not stop. In addition the painful part may feel cold and develop sensitivity to cold temperature, falling barometric pressure or precipitation. If the condition progresses the skin can change colors and become sweaty while remaining cool at the same time. Patients also develop a natural tendency to avoid being touched by anything or anyone. This is referred to as allodynia.

Once signs and symptoms progress beyond simple cold sensitivity the condition is referred to as RSD Stage 1. With sympathetic over activity there is a decrease in blood flow to the injury site (especially the structures in the surrounding skin). If the condition is allowed to persist then a loss of range of motion or muscle mass can occur. Once this occurs the condition is referred to as RSD Stage 2. In Stage 3 the bones become thin as well (Sudek’s Atrophy). While most physicians familiar with RSD still cite these classically described stages more recently other forms of RSD have become recognized as well [4].

RSD almost always begins after an identifiable event such as a crush injury, torn ligament, or fracture [5]. The initial injury can be minor, or more severe. Since RSD can be a progressive disorder anyone with persistent weather sensitive pain after an injury should be looked at with an index of suspicion.

(Figure 2)

Diagnosis

One of the most important roles for diagnostic testing is to help rule out other more easily treatable conditions. Often there are several. For example there may be associated ligamentous strain, peripheral vascular disease or occult infection. Depending upon the case, Electrodiagnostic studies, Diagnostic Musculoskeletal Ultrasound, Physiologic and Duplex Vascular examinations, MRI, and laboratory can all be important.

Interpreting objective studies that are used for RSD requires special expertise. As a result many doctors rely on clinical response to treatment to make the diagnosis. One commonly employed method is to perform sympathetic blocks and then look for pain relief. The block is supposed to stop the dystrophic nerve fibers from firing excessively or incessantly and lead to decreased pain and increased blood flow [6, 7].

Using sympathetic block as the sole diagnostic criteria for RSD however leaves a lot to be desired. For example relying upon sympathetic block alone ignores the presence of false negative responses. Many people suspected of having RSD still complain of pain, even after a “successful” block has been performed. When this happens doctors have a tendency to blame psychological factors, even when a patient has obvious physical signs of injury and has persisted with their complaints in a consistently reliable manner over time.

One way to circumvent this problem is to employ sympathetic skin response studies (such as Medical Infrared Thermography) to monitor the intended effect of block. Other then pain score response (which is subjectively obtained) in the absence of skin temperature monitoring there often is no objective evidence that the intended block was successfully accomplished to begin with.

Infrared Thermography and three phase bone scans and two studies commonly referenced to when making a diagnoses of RSD. Three phase bone scans are felt to be more specific but not very sensitive. For example three phase bone scans require up to 30% bone loss to be positive. On the other hand Medical Thermography is much more sensitive but not as specific (hence interpretation of test results requires additional medical education that addresses the same).

Cold stress thermal imaging maps sympathetic skin response by measuring skin temperature with an infrared camera. Skin Temperature is not supposed vary greater then one degree centigrade on mirror sides of the body. When variance from side to side is greater then one degree centigrade an “asymmetric” pattern exists and the test is said to be positive. While a positive Thermogram only means that there is an abnormal physiologic response in skin temperature regulation the distribution of the abnormality can provide information as to the generator of the abnormality and the quality of the findings can provide insight into the subtype of RSD [8].

As with all objective physiological studies thermal imaging studies only provide indirect evidence into which structures might be involved or may be generating the observed physiologic response [9-12]. While training is required to understand the constellation of pathology that correlates to any given thermal asymmetry pattern the basis for the association has been repeatedly validated [13-15] Due to the wide diversity of sympathetic pain syndromes that exist it should not be assumed that there is a singular profile that is characteristic for all forms of CRPS or RSD [4].

Quantitative sensory testing (QST) can also provide information about thermal, pain and vibratory thresholds. Inherent limits to QST include limited distribution of measurement and patient response participation. There are also no QST profiles that are characteristic for any particular generator of CRPS [4]. Only infrared thermal imaging allows the examiner to map sympathetic skin response to cold stress throughout the entire distribution of skin temperature change associated with underlying pathology.

Treatments

Because there is no singular cure for CRPS/RSD doctors frequently focus treatment on patient symptoms rather then trying to address the root cause of the disorder. Since CRPS/RSD patients have chronic, complex pain that involves the immune, vascular and neurologic systems a diagnosis based approach is the only way to potentially arrest or manage progression of the disorder. As a result of the morbidity and mortality associated a pharmacologic approach that only addresses pain control through chronic opiate use other avenues of treatment should also be employed. No singular approach will likely impact all of the systems involved. Typical non opiate pharmacologic treatments that have been used successfully in CRPS/RSD patients include: [16, 17]

  • Topical analgesics
  • Antidepressants
  • Corticosteroids
  • Antiepileptics
  • Antihypertensives & other cardiovascular related medications
  • Hormonal agents
  • Anti infectives
  • Immunomodulating medications
  • Atypicals


In addition, other non-pharmacologic treatments may include (but are not limited to):

  • Sympathetic nerve block – anesthetics to block receptors or restore sympathetic nerve function
  • Peripheral nerve block – for localized pain relief
  • Trigger Point Injection- to relieve muscle related pain
  • Joint Injection- to reduce intra articular sources of “C” fiber response
  • Prolotherapy- to restore underlying ligamentous or tendon injury
  • Platelet Rich Plasma (PRP) grafting – to induce an intensified, local wound healing reaction that may both restore normal anatomy and sympathetic physiology
  • Physical therapy – to restore ROM and function to the afflicted limb or body part and reduce Hyperalgesia
  • Acupuncture – when properly employed to balance sympathetic and parasympathetic tone
  • Psychotherapy – cognitive treatments that address the whole patient


As a last resort even more aggressive (and more controversial) treatments have included:

  • Spinal cord stimulation
  • Intrathecal drug pumps
  • Surgical sympathectomy
  • Ketamine coma induction


A group of Dutch researchers in their quest to develop multidisciplinary guidelines for the treatment of CRPS [18] found insufficient evidence that NSAIDS, oral opioids, morphine injection, local anesthetics, some anti¬convulsants, anti-depressants, capsaicin, muscle relaxants, Botox, sympathetic block, amputation, TENS, multidisciplinary treatment or psychological treatment work. The same group then proposed that there is Level 3 evidence for other treatments that are not commonly employed, including:

  • IV ketamine or corticosteroids might work
  • Two months of daily DMSO or NAC cream might help
  • Surgical sympathectomy can help some patients


There is no singular approach for the treatment of CRPS/RSD that has been universally accepted.

Sympathetic Pain vs. RSD

The job of the sympathetic system is to provide an independent neural network for functions that are intended to occur automatically and to provide the central nervous system with a mechanism of feedback outside of the normal somato-sensory network. Not unlike patients with diabetes that are sometimes diet controlled and at other times require implantable insulin infusion pumps just because someone may have sympathetic pain does not mean that they have RSD or that it will progress through the classical stages of RSD.

In addition since the sympathetic “C” fiber and "A delta" nerve fibers share similar physiologic characteristics many patients with sympathetic pain are also sensitive to vibration. White Finger Vibration Syndrome is one such example. As a result both groups of patients many complain that driving or operating machinery makes them worse.

Whether someone has a sympathetic pain syndrome or more classically defined RSD the vast majority of afflicted patients will report cold, weather and barometric pressure sensitivity. It seems empirical that since regulation of normal homeostasis is impaired with dystrophy the more extreme the stimulus (for example, excessive cold temperature) the less the aberrant sympathetic system can adapt. While for the most part this holds true when addressing RSD patient complaints, clinical presentation and severity of objective signs do not always correlate. This is no different then any other disease process.

There is also no correlation between patient complaints about sensitivity to environmental stimuli or severity of pain and the stage or subtype of RSD that they may have. None the less, it is helpful to keep in mind that for the most part milder cases may only report weather sensitivity when it is very cold or when major fronts come through while more severe cases are more likely to complain about smaller shifts in barometric pressure, sometime even several days away.

RSD Variants

Not all cases of RSD are alike; subsets exist. For example in on variant vasodilatation instead of vasoconstriction of the involved part occurs. This presentation has been referred to as the Angry Backfiring C (ABC) Syndrome. It occurs when the “C” fiber backfires and spits out excess histamines and other inflammatory cytokines. It is felt to be due to a back firing calcium dependant potassium channel. Thermographic studies show localized areas of warm, vasodilated skin.

In addition to burning allodynia the ABC syndrome also has its own special signs and symptoms. These include:

  1. Erythralgia - redness of the skin.
  2. Warm hyperalgesia - warm hurts.
  3. Cold abolishes the pain.


There are other variants as well. With the Triple C Syndrome (CCC) the patient presents with cold hypesthesia (they cannot readily differentiate between cold and pain), cold hyperalgesia, and cold skin. This is likely a consequence of excess vasospasm due to sympathetic denervation supersensitivity caused by dropout of sympathetic efferents associated with small caliber nerve fiber insult [19]. A hyperexcitable, fast potassium voltage gate has also been implicated. Thermographic studies show regional areas of hyper-intense cold skin.

(Figure 3)

Medical Thermology studies are read by looking for temperature asymmetry patterns. Each color in the palette represents a one degree centigrade change from its neighbor on the color palette. The top of the tool bar is warmest and the bottom is coldest. CCC syndrome patients demonstrate obvious, localized regions of relatively cold skin temperature.

Differentiating between subsets of RSD is important. For example, sympathetic block may not work or may even make pain worse when the ABC (vasodilated) subset is present. Traditional sympathetic blockade is also less likely to be effective with CCC patients. In this case the vasoconstricted area is usually farther from the trunk (in the foot or hand) so any block is less likely to be as effective.

The CCC variant is also associated with aberrant nerve membrane pathology that cannot accommodate to change. This means a more deeply penetrating and complete block must be performed to influence the dystrophic site. When RSD variants exist electroceutical applications of sympathetic block that target the actual voltage gate or channel involved may prove more effective then chemical block [20, 21].

In addition to sympathetic ganglion blockade when variants exist anesthetic injection directed toward peripheral nerves that are rich in “C” fibers and are also closer to the injury site should be considered. These blocks should still be performed proximal to the injury site and within the distribution of vasomotor asymmetry measured on thermal imaging. It also stands to reason that different pharmacologic regimens should be employed depending upon which variant the patient has.

Fortunately there is now awareness that not all sympathetic pain patients have classical RSD and not all CRPS cases are due to RSD. There is also greater understanding of how to use diagnostic studies to categorize what type of sympathetic pain exists [22]. Some patients may present with both classical RSD and regional variant pathology. An awareness of RSD variants readily explains why diagnosing patients with sympathetic pain syndromes by their response to sympathetic block alone has by in large been a failure.

RSD with Dystonic Features

RSD with dystonic features is a special category of RSD. In this case the patient develops dystonia of the involved part. The dystonia usually manifests with increased tone however spontaneous movement can occur as well. In mild cases there may be only a complaint of decreased balance or dexterity. In moderate cases there may be visible contractions of a single muscle (focal dystonia) and in more severe cases an entire limb may move about uncontrollably. These movements can be paroxysmal or continuous.

While no one really knows what causes dystonia, or why RSD patients get motor form of dystrophy. Possible explanations include C fiber over-activity that results in "cross talk" to neighboring motor nerve fibers, the creation of peripheral muscle spindle/sympathetic efferent fiber reflex arcs (a feedback loop between muscle and nerve), defects in the brainstem routing that allows reflex arc formation between peripheral muscle spindle and sympathetic nerve fibers, and central biasing that creates overflow of central activity and improper routing [23, 24].

Sympathetic blockade rarely offers relief in patients with motor form of dystonia. Treatment must first be directed toward stopping the movement disorder (which itself causes further vasoconstriction, fatigue, and pain in the involved limb). Anti-Parkinson drugs, muscle relaxers, non-steroidal anti-inflammatory medicines, and Botulinum (denatured botulinum toxin) are best suited for this. When motor form of dystrophy is present electromyographic (EMG) examination is helpful to identify which muscles are firing abnormally. Once the movement has been controlled sympathetic block followed by treatment of the underlying generator is more likely to be successful [15].

RSD and Spread

It is not uncommon for patients with RSD to report that their symptoms have spread to other body parts. They often attribute these new symptoms to RSD rather then due to some other cause. While more often then not these new symptoms are from a different cause, the physician should keep in mind that RSD can spread from within the same body part or to other body parts [6, 1].

Whenever spread of RSD is suspected an aggressive clinical approach is warranted. It is as important to stop RSD from spreading as it is to stop it from progressing through stages 1-3. The physician should looks for objective findings of spread such as vasomotor or sudomotor instability, edema, contracture, hyperalgesia and weather sensitive pain [24, 25]. In those cases where co-morbid medical disease or other pain syndromes are found they should be treated in the typical fashion for that diagnosis.

RSD and Fibromyalgia

While RSD and fibromyalgia are clearly distinct syndromes, there can be overlap between the two. In mild cases of RSD (or sympathetically mediated pain) confusion as to the diagnosis can occur but at the extremes the two diagnoses are rarely confused.

The RSD patient’s chief complaint centers on abnormal pain and excessive response to cold, changes in barometric pressure and moving weather fronts. RSD patients may share certain symptoms found in fibromyalgia patients including “brain fog”, difficultly sleeping, somato visceral complaints but their chief compliant still centers on cold sensitivity due to abnormally functioning “C” fibers.

In contrast weather sensitivity is only one feature of fibromyalgia patients. They may not be able to even clearly state that they have weather sensitive pain. Other differentiators include the absence of an inciting event (that is almost universally present in the RSD patient), sleep disorders, under lying immune-inflammatory related complaints, associated visceral symptoms and confounding emotional issues. The fact that overlap between RSD & fibromyalgia exists is simply another good reason to aggressively evaluate RSD patients that complain of spread for a change in condition, even when only have mild disease has been previously proven.

RSD Like Syndromes

There are still other special sympathetic pain syndromes that have their own unique clinical presentation. For example cluster headache is a commonly recognized form of autonomic pathology. The literature is filled with references that implicate vasoactive peptides at the arteriole in multiple forms of headache. Due to its diffuse nature the humeral neuro-immuno-endocrine system has been implicated.

The Posterior Cervical Sympathetic Syndrome of Barre-Lieou is associated with headache, atypical facial pain and neck pain. In this instance a traction injury of the posterior cervical sympathetic chain results in complaints of pain, dizziness, tinnitus, blurred vision and nausea. While traction injuries (as in whiplash) to the posterior cervical chain are the most common etiology, other causes include local trauma, chronic infection and coagulopathy. In some cases the sphenopalatine or the superior cervical sympathetic ganglia may be involved instead of the posterior cervical chain.

Hoffman’s zones (regions of aberrantly behaving sympathetically innervated venous valves) may also be involved in patients with phlebitis, reflux or dependant rubor. Post mastectomy and head and neck cancer patients who have had lymph node dissection should be fully evaluated for sympathetically derived vascular or third space associated pathology.

Thoracic outlet syndrome (TOS) is yet another RSD like syndrome. The vast majority of TOS cases are not due to a cervical rib or a result of structurally verifiable arterial or venous occlusion. Electrodiagnostic, X-Ray, and vascular contrast studies are frequently normal. Sympathetic skin response on thermal imaging however is commonly abnormal in the medial aspect of the arm and forearm in TOS patients. Numerous examples exist in the literature where sympathetic block has been used successfully to afford relief to this population.

RSD & Visceral Involvement

It has been postulated that musculoskeletal RSD can affect the internal organs [26]. While it is generally accepted that internal organs can refer pain to the musculoskeletal system not everyone agrees that the musculoskeletal system can affect the internal organs. Despite this difference of opinion the presence of somato-visceral interaction is not a new concept as direct interaction between the two systems exists through the autonomic nervous system (ANS).

Since the ANS is ubiquitous and is responsive to hormones, immune factors, and neurotransmitters distant forms of feedback exist as well. Other then distant communication capability this interaction offers a third level of higher communication. Examples include hypothalamic biasing (like cloud based computing) and hormone/neuro-transmitter interactions at the autonomic nervous system level (as with Wi-Fi to cellular bridges).

By accepting that the somatic system can affect the viscera, pathology in internal organs in dystrophy patients is easily explained. That is not to say that all visceral disease should be attributed to RSD. Rather distinct and separate pathology should be ruled out first. The most commonly reported organs involved in RSD patients include the heart and eyes.

Due to the autonomic innervation of the eye, patients with RSD may complain of difficulty with dry eyes or blurred vision. In some instances accommodation is impaired. In other cases the tearing mechanism is altered and pupillary function can become sluggish. These symptoms may or may not wax and wane in concert with exacerbations of pain.

Cardiac abnormalities include arrhythmias (due to the dependency of the heart on the autonomic system for proper pacing and rhythm) and low ejection fraction. This should not be surprising as the sympathetic system modulates heart contractility, left ventricular wall tension, vascular tone, and impacts left ventricular remodeling or hypertrophy.

Heart failure in patients without RSD is associated with prolonged or abnormal amounts of circulating neurotransmitter and reduced norepinephrine responsiveness. Furthermore it responds to treatment with Carvedilol, a medication that prevents the release of norepinephrine. The mechanism of action for congestive heart failure and its response to therapeutic intervention are both consistent with a visceral autonomic dystrophy.

While kidney and adrenal disease have not been implicated in RSD patients the sympathetic system does have feedback loops with the Renin-¬Angiotensin system, sex hormones, and the pituitary-hypothalamic axis. It stands to reason that complaints of fatigue, decreased libido, and diminished ability to deal with stress occur in patients with RSD.

Many patients with RSD are worried about having dental procedures performed. Most dentists use epinephrine with local anesthetic, so they fear that their dystrophy may flare due to associated vasoconstriction. Judicious use of epinephrine should be considered. Other oral related factors associated with RSD include altered saliva viscosity, volume and content.

(Figure 4)

Whenever an organ system becomes problematic typical diagnostic conditions should be considered. If answers are not forthcoming then somato-visceral autonomic aberrations should be given serious consideration. This is especially true with ophthalmic, cardiac, hormonal, and dental system involvement.

Prognosis

While spontaneous remission can occur in certain individuals, most experience unremitting, crippling, and irreversible pain. Patients should be counseled that the goals of treatment include improving quality of life, aggressive intervention to prevent a worsening of condition or spread, and a hopeful eye toward reversing the lasting effects of chronic pain. Having said that as with most medical conditions intervention directed toward underlying pathology as opposed to symptom management offers a greater likelihood of improving patient health.

Once the distribution and type of RSD is determined sympathetic block above, and treatment below, can lead to remarkable improvement. Prognosis is further enhanced by having an understanding of which underlying structures might be a generator of any particular presentation.

Mobility should always be encouraged. Success in controlling internal organ system symptoms has also been accomplished through sympathetic block of the ganglion that impacts the affected organ, through the use of medications that help stabilize autonomic function and correcting neurotransmitter imbalance, hormonal regulation or co-morbid immuno-inflammatory disease.

Conclusion:

Treatment of an RSD with its variants is difficult. Physicians should consider various, nerve membrane stabilizing medications that make use of a voltage gated receptor pharmacology approach rather then relying solely upon analgesics for symptom management. Prognosis is enhanced when the underlying pathology is addressed.

Not all cases of CRPS have RSD and not all cases of RSD are the same. There are different stages, types, variants, and subsets of sympathetic pain. The physician should work toward identifying these differences and tailor care toward the individual needs of the patient. With this approach reversal of RSD, improved functional outcome, better quality of life, or RSD in remission are all possible.

References
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