Clinical evidence.pmd

Pain Physician, Volume 5, Number 3, pp 260-265 2002, American Society of Interventional Pain Physicians®ISSN 1533-3159 Clinical Evidence of Chemical Radiculopathy
Curtis W. Slipman, MD*, Zacharia Isaac, MD**, David A. Lenrow, MD#, Larry H. Chou, MD##,
Russel V. Gilchrist, DO
and Edward J. Vresilovic, MD, PhD
It is universally accepted that an anatomic abnormality greater than axial pain, examination findings demonstrating such as a herniated disc or spinal stenosis can lead to a new myotomal deficit that correlates with the root level radicular leg pain. There is some controversy as to whether predicted by the dermatomal pain distribution, and failure radicular pain can be caused by a non-structural, solely to improve after at least 4 weeks of active physical therapy.
biochemical disorder. Prior studies using biochemical Magnetic resonance imaging void of local nerve root analysis of inflammatory mediators of the disc or pathology as per review by the first author and the surrounding structures have enumerated many possible interpreting radiologist was required. Each patient had to biochemical mediators of radicular pain. However, such have a positive electromyographic study for an acute studies have not definitively demonstrated whether these radiculopathy. Each patient had to have a positive inflammatory mediators are the causes of radicular pain or fluoroscopically guided diagnostic selective nerve root whether these mediators are simply products of the In summary, this paper provides clinical evidence that The purpose of this paper is to report upon patients who anatomic abnormalities are not required to cause satisfy strict criteria affirming a diagnosis of radiculopathy radiculopathy, thus implying that a biochemical etiology in the presence of normal imaging studies. The study was is likely to play a significant role in radiculopathy and designed as a prospective case series of patients fulfilling inclusion and exclusion criteria at a university hospitaloutpatient physiatric spine practice.
Keywords: Radiculitis, radiculopathy, radicular pain,
chemical, biochemical, electromyography
Inclusion criteria consisted of symptoms of extremity pain There are numerous causes of leg pain which have a spinal
was popularized by Mixter and Barr in 1934 (1). In contrast, etiology. These can be classified into radicular or somatic there is some controversy as to whether radicular pain (previously termed sclerotomal) etiologies. It is can be caused by a non-structural, solely biochemical universally accepted that an anatomic abnormality such disorder. A few authors have postulated this latter scenario as a herniated disc or spinal stenosis can lead to radicular can occur, but there has been no definitive proof offered.
leg pain. This biomechanical paradigm for radicular pain Prior studies using biochemical analysis of inflammatorymediators of the disc or surrounding structures haveenumerated many possible biochemical mediators of From the Department of Rehabilitation Medicine and radicular pain (2-15). However, such studies have not Orthopedic Surgery, the Penn Spine Center, and Hospital definitively demonstrated whether these inflammatory of the University of Pennsylvania, Philadelphia, Pennsyl- mediators are the causes of radicular pain or whether they vania. *Dr. Slipman is the director and associate profes- are simply products of the degenerative cascade.
sor, **Dr. Isaac is a fellow, #Dr. Lenrow is an assistant Theoretically, these inflammatory mediators, found near professor and ♦Dr. Gilchrist is a fellow at the Penn Spine degenerative discs, can be “innocent bystanders” or Center, Hospital of the University of Pennsylvania, ##Dr.
“tombstones” in the process that produces pain and Chou is the director of PM&R Services and assistant pro- radiculopathy. Hence, they could be markers of fessor of the Department of Rehabilitation Medicine, and degeneration rather than provocateurs of the degenerative ♣Dr. Vresilovic is chief of Orthopaedic Spinal Disorders cascade. If this were true, structural abnormalities would at the Penn Spine Center and assistant professor of the always have to be present to produce radiculopathy, and Department of Orthopaedic Surgery at the Hospital of the anti-inflammatory medications injected locally should University of Pennsylvania. Address correspondence: Curtis W. Slipman, MD, 3400 Spruce Street, Philadel-phia, PA 19104. E-mail: [email protected] A basic requisite for a biochemical basis of radicular pain Pain Physician Vol. 5, No. 3, 2002
is the ability of structures spatially contiguous with the injury such as history of chemotherapy, radiation therapy, dorsal root ganglion (DRG) to generate chemical diabetes mellitus, HIV, lymphoma, antecedent viral illness, inflammatory mediators. There is a plethora of literature, history of alcoholism, heavy metal exposure, etc; history in animal and human models, that demonstrates the ability of prior spine surgery, or an abnormal MRI of the thoracic of the intervertebral disc to generate inflammatory inlet or pelvis for those complaining of arm or leg pain, mediators (2-15). Given this inflammatory potential, one must assume that such chemicals can reach the DRG,thereby sensitizing it to mechanical stimulation. If this The technique for diagnostic selective nerve root block assumption is accurate, then there must be instances in utilizes no sedation. Fluoroscopic guidance was always which patients present with radicular pain without used. For diagnostic cervical procedures, the needle tip discernible structural pathology. Identifying patients with position and perineural flow was confirmed with the these findings would provide irrefutable evidence that infusion of 0.5 mL of Omnipaque®. Afterward, 0.8 mL inflammatory mediators have the ability to reach and of 2% Xylocaine® was injected. For diagnostic initiate an inflammatory response in the nerve root. The lumbosacral procedures, the needle tip position and purpose of this paper is to report upon such patients; perineural flow was confirmed by the injection of 1.0 mL individuals who satisfy strict criteria affirming a diagnosis of Omnipaque. Subsequently, 1.0 mL of 2% Xylocaine of radiculopathy in the presence of normal imaging studies.
Each patient completed a 100 mm visual analogue scale(VAS) and pain drawing immediately prior to and 30 Patients were enrolled in this study on a prospective basis minutes after a diagnostic selective nerve root block. An if they met specific inclusion and exclusion criteria.
independent trained medical professional administered the Inclusion criteria consisted of symptoms of extremity pain pre- and post-injection assessments to insure objectivity.
greater than axial pain, examination findings A threshold of 80% reduction on the VAS defined a demonstrating a new myotomal deficit that correlates with the root level predicted by the dermatomal paindistribution, and failure to improve after at least 4 weeks Although not part of the diagnostic assessment, as part of of active physical therapy. A high quality closed magnetic the treatment plan, patients with a diagnostic positive block resonance imaging void of local nerve root pathology as received a subsequent therapeutic selective nerve root per review by the first author and the interpreting block. For cervical therapeutic injections, a mixture of radiologist was required. The MRI had to reveal no 1.0 mL of Celestone Soluspan® and 0.5 mL of 1% evidence of spinal stenosis, herniated disc, tumor, synovial Xylocaine was infused around the nerve root. For lumbar cyst, foraminal stenosis, lateral recess stenosis, or other therapeutic injections, a mixture of 2.0 mL of Celestone intradural or extradural lesion. Flexion/extension Soluspan and 1.0 mL of 1% Xylocaine was infused. A radiographs had to reveal no evidence of segmental range of 2 to 4 injections per patient was used. Patients instability. Each patient had to have a positive participated in a stabilization physical therapy program electromyographic study for an acute radiculopathy that and strengthening exercises for the muscles of the affected corresponded with the distribution of pain and the myotomal deficit. Criteria established by the the AmericanAcademy of Electrodiagnostic Medicine (AAEM) for the All data collection, analysis, and telephone interviews were electromyographic definition of radiculopathy was used.
performed by an independent reviewer. Fourteen variables Electrodiagnostic evidence of nerve root involvement were recorded for each patient when treatment was included the presence of positive sharp waves, fibrillation initiated; they were: age, sex, symptom duration, pain potentials, or complex repetitive discharges observed in location, 100 mm VAS pain score, 10 point verbal pain the associated lumbar paraspinal musculature and in at rating, medication usage (adjuvant analgesics included least two muscles with similar myotomal, but different anti-epileptics or oral steroid tapers), employment status, peripheral nerve innervation (16). Finally, each patient smoking history, electrodiagnostic abnormalities, motor had to have a positive diagnostic selective nerve root block.
exam abnormalities, sensory exam abnormalities, reflex Exclusion criteria consisted of a history of trauma or work abnormalities, and provocative maneuver response.
related injury; peripheral neuropathy; any illness or Provocative maneuvers performed included Spurling’s medication known to cause peripheral nervous system maneuver and upper extremity root tension signs for Pain Physician Vol. 5, No. 3, 2002
cervical radiculopathy. For lumbar radiculopathy, had completed an oral steroid taper.
provocative maneuvers included straight leg raise, crossedstraight leg raise, reverse straight leg raise, sitting root Follow-up data collection occurred at 1, 3, 6 and 12 tension sign, and Braggard’s maneuver. For suspected L5 months. The average final follow-up interval occurred at and S1 radiculopathies, if reproduction of similar pain 14.5 months (range: 12 to 20 months) after discharge from symptoms below the knee was produced with straight leg treatment. An average of 3 therapeutic injections (range: raise, crossed straight leg raise, or Braggard’s maneuver 2 to 4) was administered to each symptomatic level.
then the provocative maneuver was considered positive.
For suspected L4 radiculopathy, the reverse straight leg The average recorded follow up verbal score at the 1 month raise was considered positive if anterior thigh and medial and final follow-up was 1.5 (range: 0 to 3). There was no calf pain similar to the patient’s complaints were elicited appreciable change in the pain rating score during the entire with knee flexion with the patient laying prone.
follow-up interval. Two patients were working full time,one part time, and one was not eligible for employment.
Follow-up data were collected by an independent reviewer No change in employment status was observed over time.
during a phone interview with each patient. Variables Two patients were using over-the-counter medications, and recorded included present medication usage, employment one was using prescription NSAIDs. None were using status, and a verbal pain rating using a 10 point scale.
Verbal pain ratings represented each patients’ currentaverage daily pain level rated from 0 to 10. Patients were DISCUSSION
followed at 1, 3, 6 and 12 months following discharge.
All patients were reassessed when the last patient enrolled Chemical radiculitis is an inflammatory condition of the nerve root, which may result following the rupture of theannulus fibrosus and dissemination of disc fluid along the nerve root sheath (2). The concept of radiculitis was firstdescribed by Lewin (17) in 1943, when he discussed the Four patients, 2 men and 2 women with a mean age of condition of irritation of the lumbar and sacral nerve roots.
46.3 years (range: 28 to 59 years old) were included.
In 1946, Holmes and Sworn (18) reported 5 cases of Patients’ average symptom duration at initial presentation lumbosacral root pain without any identifiable mechanical was 17.5 months (range: 3 to 48 months). One patient cause. A decade later, Walk (19) evaluated 200 clinical was a smoker. As per our exclusion criteria, none of the cases of discography assessing 310 lumbar intervertebral patients’ symptoms arose from a work or accident related discs. Walk (19) hypothesized that 2 neurological injury. The level of root involvement for each patient is syndromes may be caused by intervertebral discs; listed in table 1. The initial clinical characteristics of the compression of the nerve root by the disc or irritation of the nerve by the perineural spread of the contents of thenucleus pulposus occurring through a disc rupture.
The average VAS score at initial presentation was 73 Subsequently, it has been demonstrated that when nucleus (range: 60 to 90). Two patients were working full time, pulposus material is exposed to the vascular space an one part time, and one patient was retired. At the time of immune response with subsequent antibody formation presentation, all four patients were using prescription results (20). Gertzbein (20) evaluated 10 patients with nonsteroidal anti-inflammatory drugs (NSAIDs), two were sequestered discs or disc protrusion contained by annulus using opioids, one was using adjuvant analgesics, and one Table 2. Clinical characteristics of patient
Table 1. Level of nerve root involved
population at initial presentation Pain Physician Vol. 5, No. 3, 2002
or posterior longitudinal ligament. He showed that an cartilaginous endplate, but the precise role in discogenic increase in the cellular immune response existed by low back pain is unclear. In a recent study, Roberts et al demonstrating an elevation in the lymphocyte (11) demonstrated that the degree of matrix transformation test of these patients. Marshall performed metalloproteinase activity was proportional to the degree immunological research on 9 patients with severe acute back strain and lower extremity pain (20). He found that6 of the 9 subjects possessed an IgM response to increased Various neuropeptides have been found in disc specimens.
titers of glycoprotein liberated from the intervertebral disc, Ashton et al (12) identified elevated levels of calcitonin- further supporting the hypothesis of chemical induced gene related peptide (CGRP) and substance P (SP) in the outer annulus fibrosus. Nerve fibers immunoreactive tovasoactive intestinal peptide (VIP) and c-flanking peptide A variety of studies have been performed to understand of neuropeptide (CPON) were also found in the majority the role of inflammation in radicular pain. Leukocytes, of annulus fibrosus specimens. VIP is involved in macrophages and lymphocytes have been found at the site vasodilation and possibly in sensory transmission. CGRP of surgically created porcine disc protrusions in vivo (3).
is involved in nociception, while CPON is a Saal and co-investigators (4) found elevated levels of vasoconstrictor. In addition to its role in nociception, SP phospholipase A (PLA ), the rate limiting enzyme in the increases prostaglandins, IL-1, collagenase, and tissue chemical cascade that liberates arachidonic acid, necrosis factor. SP and CGRP were also found in the prostaglandins, and leukotrienes, in disc material obtained annulus and posterior longitudinal ligament in rats and from patients surgically treated for radiculopathy due to a human specimens obtained at the time of surgery (13, 14).
herniation (5). Subsequently, Ozaktay et al (6) SP and VIP were analyzed by radioimmunoassay to demonstrated that PLA can produce electrophysiologic determine their concentration in experimentally induced and histologic changes in neural tissue. Further research chronic nerve root compression (15). Elevated levels of by Chen et al (7) showed that PLA promotes loss of SP but not VIP were noted in the DRG of the porcine myelin, breakdown of myelin sheaths, and vacuolar compressed nerve root. In an earlier study, Weinstein et degeneration ultimately creating hypersensitive regions al (22) demonstrated elevated levels of SP and VIP in the where ectopic discharges may be elicited. Matrix DRG of dogs who underwent discography. The authors metalloproteinases are known to be responsible for normal postulated compressive forces applied to disc can pump extracellular matrix remodeling and can degrade all the fluids into vertebral body, annulus, or posterior known matrix components of the intervertebral disc.
longitudinal ligaments with stimulation of nociceptive Several studies have shown the liberation of these cytokines during disc degeneration. Kang et al (8) obtainedand assayed disc material from patients undergoing surgery Given the assumption that radicular pain manifests for herniated disc or scoliosis. Herniated disc material consequent to an inflammatory process, it is reasonable demonstrated statistically elevated levels of matrix to assume that providing an antiinflammatory agent would metalloproteinase activity, nitric oxide, PGE2, and be an appropriate treatment choice (23-27).
interleukin-6 (IL-6) when compared to the scoliotic discs.
Glucocorticoids are known to be the most potent In a follow-up study, Kang et al (9) also demonstrated antiinflammatory agents. It has also been demonstrated that interleukin-1 beta stimulated the production of matrix that methylprednisolone reduces the electrophysiologic metalloproteinase, nitric oxide, and interleukin-6 in the dysfunction associated with nucleus pulposus induced cells of intervertebral discs. Kanemoto et al (10) nerve root injury, but questions remain about the performed immunohistologic staining of 100 human subcellular mechanisms behind this corticosteroid effect intervertebral disc specimens collected at the time of (28). More recent literature (29) identifying a reduced surgery to evaluate the disc degeneration cytokines matrix PLA activity level in injured nerves follow the metalloproteinase-3 (MMP-3) and tissue inhibitor of administration of epidural betamethasone, suggests that metalloproteinase-1 (TIMP-1). In 78% of the surgical the anti-inflammatory properties of these agents may be specimens, immunohistological staining demonstrated the responsible for their ability to preserve nerve conduction.
presence of MMP-3 and the absence of TIMP-1. These Relief of sensory radicular symptoms may also result from findings may suggest that intervertebral disc degeneration an ability of corticosteroids to stabilize neural membranes, is caused by a disturbance in the equilibrium of MMP-3 thus suppressing ectopic discharges within the dorsal root and TIMP-1. MMP-3 contributes to degeneration of the ganglion (DRG) and injured nerve fibers, which are Pain Physician Vol. 5, No. 3, 2002
believed to lead to pain and paresthesias (30, 31).
Additionally, corticosteroids may have a direct anestheticeffect on small unmyelinated nociceptive C-fibers within This paper provides clinical evidence that anatomic irritated neural tissue (22, 30). Although glucocorticoids abnormalities are not required to cause radiculopathy. The are the primary agent used to mitigate radicular symptoms, obvious implication is that a biochemical etiology can it must be emphasized that local anesthetics are used initiate radiculopathy and/or radicular pain. This may simultaneously. These agents have been shown to exhibit suggest, but in no way proves, a role for selective injections properties that may be helpful in treating radicular pain.
of anti-inflammatory agents for patients with radicular pain In particular, lidocaine may offer a therapeutic effect through its ability to improve blood flow (32) and reduceneural dysfunction (33) in injured nerve roots.
The results of this study provide confirmatory clinical Mixter WJ, Barr JS. Rupture of the intervertebral evidence and support the existence of a non-structural, disc with involvement of the spinal canal. N Engl J biochemical mechanism by which radiculopathy can occur.
Marshall LL, Trethewie ER, Curtain CC. Chemical We chose a highly selected population with irrefutable radiculitis: A clinical, physiological and clinical evidence of radiculopathy and no discernible immunological study. Clin Ortho Rel Res 1977; anatomic explanation. Since we only included patients with motor abnormalities, a normal MRI, a positive EMG, Habtemariam A, Virri J, Gronblad M et al.
and a positive diagnostic selective nerve root block, we Inflammatory cells in full thickness annulus injury in necessarily excluded individuals with radicular pain pigs. An experimental disc herniation animal model.
without each of these inclusion criteria. We believe by using such strict criteria we have been able to provide the Saal JS, Franson RC, Dobrow R et al. High levels of first report of radiculopathy without concurrent anatomic inflammatory phospholipase A2 activity in lumbardisc herniations. Spine 1990; 15:674-678.
pathology. In clinical practice, we frequently treat patients with radicular pain without obvious anatomic pathology.
phospholipase A2 is inflammatory. Spine 1992; We must emphasize that although these patients present commonly, they are not suitable to be included in this Ozaktay AC, Cavanaugh JM, Blagoev DC et al .
paper. Various reasons precluding using these patients Phospholipase A2 induced electrophysiologic and such as the presence of a nondermatomal pain pattern, histologic changes in rabbit dorsal lumbar spine absence of a motor deficit, or a normal EMG. In these tissues. Spine 1995; 20:2659-2668.
circumstances, a normal EMG study can occur despite the Chen C, Cavanaugh JM, Ozaktay AC et al. Effects of phospholipase A2 on lumbar nerve root structures andfunction. Spine 1997; 22:1057-1064.
Kang JD, Gergescu HI, McIntyre-Larkin L et al.
We need to emphasize that the presence of a myotomal Herniated lumbar intervertebral discs spontaneously deficit when radicular symptoms are solely precipitated produce matrix metalloproteinases, nitric oxide, by a biochemical process is rare; we interviewed over 1500 interleukin-6, and prostaglandin E2. Spine 1996; new patients to enlist the 4 who are included in this report.
The fact that the full clinical manifestation of pain, Kang JD, Stefanovic-Racic M, McIntyre LA et al.
weakness, and a neurophysiologic abnormality is Toward a biochemical understanding of human uncommon does not diminish the importance of its intervertebral disc degeneration and herniation: occurrence. Such patients also provide at a minimum, the Contributions of nitric oxide, interleukins,prostaglandin E2, and matrix metalloproteinases.
suggestion, that there are individuals whose symptoms do not include motor deficits. In our view, that group of Kanemoto M, Hukuda S, Komiya Y et al.
patients is more common. They tend to describe pain that travels in a radicular distribution, but have no corroborative metalloproteinase-3 and tissue inhibitor of imaging or neurophysiologic study. Often, the only metalloproteinase-1 in human intervertebral discs.
confirmatory tool is a diagnostic nerve root block.
Pain Physician Vol. 5, No. 3, 2002
Roberts S, Caterson B, Menage J et al. Matrix steroids and their effects on phospholipase A : An metalloproteinases and aggrecanase. Spine 2000; animal model of radiculopathy. Spine 1998; 23:1191- Ashton IK, Roberts S, Jaffray DC et al. Neuropeptides Riew KD, Yin Y, Gilula L et al. The effect of nerve in the human intervertebral disc. J Orthop Res 1994; root injections on the need for operative treatment of lumbar radicular pain. A prospective, randomized, Konttinen YT, Gronblad M, Antti-Poika I et al.
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Vad V, Bhat A, Lutz GE et al. Transforaminal epidural Imai S, Konttinen Y, Tokunaga Y et al. An steroid injections in lumbosacral radiculopathy. Spine ultrastructural study of calcitonin gene related peptide immunoreactive nerve fibers innervating the rat Kraemer J, Ludwig J, Bickert U et al. Lumbar epidural posterior longitudinal ligament: A morphologic basis perineural injection: A new technique. Eur Spine J for their possible efferent actions. Spine 1997; Olmarker K, Byrod G, Cornefjord M et al. Effects of Cornefjord M, Olmarker K, Farley DB et al.
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Lee HM, Weinstein JN, Meller ST et al. The role of Wilbourn AJ, Aminoff MJ. AAEM Minimonograh steroids and their effects on phospholipase A : An 32: The electrodiagnostic examination in patients with animal model of radiculopathy. Spine 1998; 23:1191- radiculopathies. Muscle Nerve 1998; 21:1612-1631.
Lewin P. Backache and Sciatic Neuritis. Lea and Corticosteroids suppress ectopic neural discharge Holmes JM, Sworn BR. Lumbosacral root pain. Br originating in experimental neuromas. Pain 1985; Walk L. Clinical significance of discography. Acta Johansson A, Hao J, Skolund B. Local corticosteroid application blocks transmission in normal nociceptor Gertzbein SD. Degeneration disk disease of the C-fibers. Acta Scand 1990; 34:335-338.
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Tullberg T, Svanborg E, Isaccsson J et al. A Olmarker K, Byrod G, Cornefjord M et al. Effects of preoperative and postoperative study of the accuracy methylprednisolone on nucleus pulposus induced and value of electrodiagnosis in patients with nerve root injury. Spine 1994; 19:1803-1808.
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Lee HM, Weinstein JN, Meller ST et al. The role of Pain Physician Vol. 5, No. 3, 2002


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