Epidural steroid injections: Complications and management

Techniques in Regional Anesthesia and Pain Management (2009) 13, 236-250

Epidural steroid injections: Complications and management Esther M. Benedetti, MD, Rapipen Siriwetchadarak, MD, John Stanec, MD, Richard W. Rosenquist, MD From the Department of Anesthesia, The University of Iowa, Iowa City, Iowa. KEYWORDS: Epidural steroid injection; Acute spinal and radicular pain; Chronic spinal and radicular pain

Epidural steroid injections (ESIs) are a form of interventional therapy broadly used worldwide for the treatment of pain. Although generally considered a safe treatment, with a low incidence of complications, these may range from very mild and transient symptoms to truly catastrophic events, including brain damage, spinal cord injury and death. Even when proper technique is used, sufficient training in interventional pain medicine is obtained, and adequate safety measures are taken, fatal events can occur. The purpose of this review article is to examine the reported complications of ESIs and suggested negative outcome management. © 2009 Elsevier Inc. All rights reserved.

Epidural steroid injections (ESIs) are a common form of treatment for acute and chronic spinal and radicular pain. Although widely used throughout the USA and the world, and reputed to be a safe form of treatment, complication rates for this procedure have been estimated to be up to 9.6%.1 In a study by Derby, the incidence of minor complications following epidural steroids was estimated to be 5 per 1000 cases.2 The overall complication rate in patients undergoing epidural injections under fluoroscopy in a large case series (n ⫽ 5334) was reported to be 0.07%.3 However, the range of complications associated with performance of this technique may be as simple as minor bruising or soreness at the needle insertion site, to those that are much more serious, such as permanent neurologic injury, brain damage, and death. In recent years, claims related to pain management have increased, going from 2% to 3% in the 1970s to 10% in the 1990s, of which 40% were related to complications following epidural injections.4

Address reprint requests and correspondence: Esther M. Benedetti, MD, Department of Anesthesia, The University of Iowa, 200 Hawkins Drive, 6 JCP, Iowa City, IA 52242. E-mail address: [email protected].

1084-208X/$ -see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1053/j.trap.2009.06.011

Risk factors Several risk factors have been identified as general potential hazards to patient safety during epidural injections. 1. Sedation. The use of sedation during epidural injections remains controversial, especially when performed in the cervical spine. It is left up to the clinician’s judgment as to the level of consciousness desired. Some physicians provide intravenous sedation to improve the level of comfort and decrease anxiety from the procedure; however, even light sedation may impair the ability of the patient to report pain or paresthesias—symptoms that may,5-7 or may not8,9 precede permanent severe and even deadly complications.10 2. Anatomy. A thorough knowledge of the neuraxial anatomy is paramount to perform safe epidural injections. For instance, because cervical epidural injectate is capable of traveling up to four spaces from the site of injection, it has been recommended that interlaminar cervical epidural injections be performed at the lowest possible level to take advantage of the largest posterior epidural space. The epidural space at C7-T1 is the largest in the cervical spine, measuring 1.5-2 mm compared with higher levels where it progressively decreases in size, approaching 0 mm. Addi-

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tionally, patients who have undergone spinal surgery may no longer have normal anatomy, as in the case of patients who have undergone laminectomies (but not anterior fusion).11 In fact, most case reports of spinal cord infarction after lumbar transforaminal ESIs involve patients with previous surgery of the lumbar spine.12-14 3. Technique. Both interlaminar and transforaminal techniques have been linked with catastrophic complications, and prospective studies are required to compare the efficacy and safety of each approach.15 The cord is at risk of puncture with interlaminar cervical epidural steroid injection (CESI) as the ligamentum flavum in the cervical region can be deficient in the midline in half of specimens.16 Use of the transforaminal approach, initially advocated due to its perceived therapeutic superiority over the interlaminar approach, has been under much scrutiny in the past years because of the frequency and severity of associated complications, and consequently, this technique has lost much popularity. In addition, some authors believe that the potential risks associated with the performance of the cervical transforaminal technique far outweigh the potential benefit and longevity of the therapeutic injection.17 4. Positioning. Several cases of spinal cord injury have been attributed to unanticipated patient movement. Some practitioners advocate the use of prone positioning as this may provide greater positional stability. 5. Level of training. Although major complications occur even in expert hands, the significant increase in the number of serious complications after epidural injections in the past several years (particularly following cervical transforaminal steroid injections) may be related to the growing numbers of interventional pain procedures and the wide variety of specialists performing these procedures. These include anesthesiologists, physiatrists, neurologists, radiologists, and others. Furthermore, there is wide variability in the level of formal training and supervision preceding the independent practice of pain medicine for many of those performing interventional pain procedures.

Complications directly related to the procedure Psychogenic reactions

237 complication, such as diabetes mellitus, obesity, and hypertension, all of which have a potential effect on ophthalmic vasculature. The premorbid state associated with a rapid increase in ICP may result in the potential for retinal venous hypertension and subsequent hemorrhage. Of these 10 cases, 9 were in female patients. The lone male patient was also significant for the development of diabetes mellitus 3 weeks after the injection of epidural steroids.18 Over time, visual loss improved in all cases reported.

Vasovagal episodes Vasovagal reactions are defined as episodes involving a spectrum of symptoms and signs that may include lightheadedness, profuse sweating, nausea, bradycardia, hypotension, and loss of consciousness. Some reports have quoted an incidence of vasovagal reaction of ⬍1% to 1.7% after CESI,11 and other authors have reported vasovagal reactions of 0% to 4%.19 In a recent publication by Trentman and coworkers, the author states that vasovagal reactions are seven times more frequent after a CESI than a lumbar ESI (8% vs 1%, respectively). Although the reason for the higher rate of vasovagal episodes in cervical epidurals compared with lumbar remains unclear, it may be due to the combination of anxiety, flexed neck in the prone position, drapes, and the direct stimulus from a cervical procedure.20

Miscellaneous Facial flushing and fever each have a 9.3% incidence21; transient postprocedure insomnia has been reported to occur in 4.7% of patients22; nonpositional headache has an incidence of 3.5%.22 Mood swings, depression, agitation, and even psychosis23 have been described after repeated steroid injections. Symptoms may be delayed in appearance (up to 1 week) and resolve spontaneously over the course of several days. Exacerbation of neck pain and radicular pain has been documented, with an incidence as high as 13.2%.21 The pain may be related to the injection of large volumes of therapeutic agents into an epidural space already compromised by disc herniation, spinal stenosis, or epidural fibrosis. It is postulated that this symptom may be avoided by injecting slowly.24

Patients may experience fear, anxiety, and apprehension in anticipation of an interventional procedure.

Drug-related complications

Transient blindness

Steroids

Ten case reports in the English literature were found on this rare complication. The pathophysiology is not well understood, although it is believed to be secondary to a significant increase in intracranial pressure (ICP) related to both the volume and speed of injection. Certain risk factors have also been associated with the development of this

Common synthetic corticosteroids used in spinal injection procedures are derivatives of prednisolone, which is an analogue of cortisol. All have anti-inflammatory potency somewhat greater than cortisol per dosage unit.17,25 Methylprednisolone is the methyl derivative of prednisolone, whereas betamethasone, dexamethasone, and triamcinolone

Triamcinolone Acetonide

Dexamethasone* sodium phosphate Decadron (American Regent Laboratories, Shirley, NY) Solution Yes 7.5-10.5 Yes 0.75 mg 30 0 100 min-5 h 36-72 h

Solution No ⬃8.5 Yes 0.6 mg 25 0 100 min-5 h 36-72 h

Betamethasone* sodium phosphate

are all fluorinated derivatives of prednisolone. Additionally, betamethasone is an isomer of dexamethasone. The sodium phosphate moiety renders the steroidal compounds watersoluble in the case of betamethasone and dexamethasone, rendering both appropriate for parenteral use25 and possibly safer in epidural procedures given the risk of inadvertent intravascular injection.17 All synthetic corticosteroids have long (36- to 72-hour) biological half-lives with resultant long duration of action. Particulate suspensions (methylprednisolone acetate, triamcinolone acetonide, betamethasone sodium phosphate, betamethasone acetate) would theoretically offer the advantage of additional duration of action based on a tissue depot of large, slowly absorbing particles. There are no safety studies advocating the use of one corticosteroid formulation over another. Similarly, there are no clinical outcome studies comparing one method of epidural administration over another. Methylprednisolone, triamcinolone, and betamethasone have all been associated with ischemic complications reported in the American literature, whereas dexamethasone has not.26,27 Table 1 illustrates properties of compounds commonly used for spinal injections.17

Dosage form Benzyl alcohol pH IV administration Equivalent dose Anti-inflammatory potency† Sodium-retaining potency‡ Pharmacokinetic t-1/2§ Biological t-1/2§

Brand name

Table 1

Epidural lipomatosis. Hypertrophy of fatty tissue in the epidural space can cause symptomatic spinal stenosis and direct compression of neural structures in addition to epidural blood vessels. It is an uncommon, but well known, complication of chronic systemic steroid exposure and has been described both in Cushing’s syndrome as well as in Cushing’s disease, adrenal tumors, and anabolic steroid users. The exact pathophysiology is unknown, but it has been hypothesized that glucocorticoids induce selective hypertrophy in certain fat deposits in the body and that insulin levels elevated by steroids induce deposition of lipid tissue in adipose tissue. Two case reports have appeared in the literature identifying epidural steroid administration as the sole cause of this entity. Documentation of these cases was carried out with pre- and postepidural steroid lumbar spine imaging (computed tomography [CT] and magnetic resonance imaging [MRI]).29,30

Corticosteroid properties17

Local (at site of administration)

Generic name

Chorioretinopathy. Serous detachment of the neurosensory retina has been associated with steroid therapy. The epidural route of steroid administration has been implicated in playing a causative role. Pizzimenti describes two cases of central serous chorioretinopathy after triamcinolone or methylprednisolone use in the epidural space.28 The prognosis of this entity is good with most cases reaching full or near-complete recovery.

Betamethasone sodium phosphate/betamethasone acetate Celestone Soluspan (ScheringPlough, Kenilworth, NJ) Suspension No 6.8-7.2 No Not available 25 0 Not available Not available

Methylpred-nisolone acetate Depo-Medrol (Pharm & Upjohn, Kalamazoo, MI) Suspension Yes 3.5-7 No 4 mg (sodium succinate) 5 (sodium succinate) 0 3 h [sodium succinate] 12-36 h [sodium succinate]

Ophthalmologic

*Betamethasone is identical to dexamethasone but has a 16-betamethyl group instead of a 16-alphamethyl group. They are considered “stereoisomers.” † As a point of reference, the anti-inflammatory potency of hydrocortisone is 1 and prednisolone is 4. ‡ As a point of reference, the sodium-retaining potency of hydrocortisone is 2 and prednisone or prednisolone is 1. § t-1/2 ⫽ half-life; half-life (biological vs pharmacokinetic) is variable because of patient-specific physiological parameters, site and method of administration, water/lipid solubility of the agent, and dosage form (suspension vs solution).

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Kenalog-40 (Bristol-Myers Squibb, Princeton, NJ) Suspension Yes 5-7.5 No 4 mg 5 0 5h 12-36 h

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Systemic Increased blood pressure. Small increases in systolic blood pressure may be seen after a single ESI. This may be due to mineralocorticoid effects inducing water and sodium retention. Larger blood pressure increases may be seen in patients with preexisting hypertension.31 Hyperglycemia. A single ESI may lead to loss of glycemic control in diabetic patients for 2 weeks following administration.32 Postprandial blood glucose levels tend to be higher and last longer after steroid administration in diabetic patients with poor glycemic control.33 Therefore, it should be recommended that HbA1c levels be ⬍7% before initiation of steroid therapy. Fluid retention. This may result in mild peripheral edema or can produce significant fluid retention with resultant clinical consequences. Goebert described a case of congestive heart failure secondary to fluid retention after a single ESI.34 Suppression of the hypothalamic pituitary adrenal axis. Epidural administration of steroids may be associated with longer hypothalamic pituitary adrenal axis suppression than intra-articular injections—possibly related to greater bloodstream penetration. Duration of suppression is unpredictable and varies widely depending on the steroid administered. Most studies quote 1-3 weeks.33,35 One case occurred following two epidural injections (each with 80 mg of methylprednisolone) separated by 1 week. Serum cortisol levels have been shown to be depressed for 1-2 weeks after epidural injection but return to normal after 3 weeks.11,36 In most cases, these abnormalities resolved within several weeks, but in one case they persisted for 12 months.37 Cushing’s syndrome. Cushingoid side effects, including facial edema, buffalo hump, supraclavicular fat pads, skin bruising, and scaly skin lesions, have been reported following epidural steroid administration.37-40 This has usually resulted from exceptionally high doses of corticosteroid given over a short period.36 Musculoskeletal Myopathy. One case report was found in the literature in which a 74-year-old female patient received one 60-mg triamcinolone lumbar epidural injection for the treatment of spinal stenosis with radicular pain. She developed, over the course of the following 2-4 weeks, progressive proximal muscle weakness (especially at the pelvic girdle) in association with cushingoid features (ie, moonlike face, buffalo hump, and truncal obesity). Although she did not have any specific laboratory abnormalities, she did present with increased urinary creatinine excretion and decreased serum cortisol and urinary free-cortisol. This patient was followed for 16 weeks, after which she regained complete motor strength but retained partial cushingoid features. All corti-

239 costeroids have been implied as causative agents in steroid myopathy; however, fluorinated steroids (triamcinolone, bethamethasone, and dexamethasone) are more likely to do so.41 Neurologic Chemical meningitis. A case of aseptic meningitis was reported by Morris in which symptoms began 48 hours after an epidural injection of methylprednisolone acetate without local anesthetic.42 Arachnoiditis. The epidural route of steroid administration has not been directly implicated in the appearance of arachnoiditis; however, there does exist a strong link between intrathecal steroid delivery and its development.38 Unrecognized dural puncture, which occurs in 5% to 6% of epidurals,43 may result in accidental intrathecal administration of steroids, which have been reported to cause adhesive arachnoiditis, sclerosing pachymeningitis, and calcific arachnoiditis.44-46

Local anesthetics Transient motor weakness This is related to the pharmacologic effect produced by local anesthetics. One case report was presented by Mount in which the inadvertent intrathecal administration of local anesthetics resulted in spinal anesthesia.47 Cerebrospinal fluid (CSF) lavage with normal saline and Lactated Ringer’s has been proposed as a possible therapeutic strategy that could reduce morbidity and mortality, as well as permanent neurologic injury, after an unintentional or accidental intrathecal administration of large doses of local anesthetics that result in a total spinal anesthetic, by removing and diluting the injected drug.48 Cauda equina This is a rare complication of lumbar spinal and epidural anesthesia and is secondary to injury (trauma, ischemia, or neurotoxicity) of sacral roots. Bilir49 presents a case report of a transient cauda equina syndrome after a lumbar interlaminar ESI. Symptoms (perineal anesthesia and lower extremity weakness) appeared 3 hours post administration of triamcinolone and bupivacaine. However, symptoms completely resolved after 8 hours, and the patient was discharged home. Likewise, McLain presented one case report in which, after an ESI, the patient developed transient neurological deficit (paralysis), having demonstrated via MRI the existence of a loculation of the injectate at a level that corresponded with her neurological deficit. The explanation offered was that of compression of nerve roots. Two additional case reports were found where, after epidural administration of local anesthetics, the patients experienced symptoms consistent with a cauda equina syndrome that later completely resolved.50

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Persistent hiccups This is defined as hiccups that persist for longer than 48 hours, and intractable are those that persist for more than 2 months.51 Very few cases have been reported in the literature pertaining to this particularly bothersome and potentially severe complication. Slipman reported a patient who, after two separate thoracic epidural steroid and local anesthetic injections, developed persistemt hiccups for 15-18 hours after the procedure.52 McAllister presents a case of a 65-year-old man who received three lumbar epidural injections with triamcinolone (80 mg) with dilute bupivacaine (0.08%) injections (11 cc total volume each injection), and one with triamcinolone (80 mg) diluted in normal saline (10 cc total volume). One year after the last steroid injection, the patient was taken to surgery and received an epidural bupivacaine infusion for postoperative pain management. Each time the patient received the epidural local anesthetic, he developed persistent hiccups that would last anywhere from 5 to 7 days postadministration. This, however, did not occur when the steroid was withdrawn from the preparation injected.53 Allergic reactions Allergic reaction to local anesthetics, although rare, may occur either from the local anesthetic agent itself or, if present, from the methylparaben used as a preservative. True idiosyncratic reactions (anaphylaxis hypersensitivity) are extremely rare. This may occur even with a properly chosen and administered anesthetic. It can cause sudden cardiovascular and respiratory collapse followed rapidly by death. Systemic toxicity This may occur after the epidural injection of an excessive dosage or by the accidental vascular administration of all, or part, of a therapeutic epidural dose. An abnormal rate of absorption and biotransformation of the anesthetic can also lead to such a systemic reaction. Systemic toxicity may be mild, moderate, or severe. In a mild reaction, the patient may experience light-headedness, headache, vertigo, tinnitus, metallic taste, hypertension, tachycardia, nausea, and slight muscle cramps. A moderate reaction can result in loss of consciousness and/or convulsions, whereas a severe toxic reaction due to massive overdosage may result in coma, cardiorespiratory depression, and death. To prevent such complications, the lowest concentration and volume of the local anesthetic drug should be used, and care taken to avoid unintentional intravascular injection. Blood pressure, oxygen saturation, and ECG monitoring must be undertaken, and all necessary resuscitation equipment should be present at the time of the procedure.

Contrast dye Anaphylaxis Patients with a known sensitivity to iodine, prior reactions to dye, food allergies, asthma, or hay fever have a

higher incidence of anaphylactic reactions to contrast media. Premedication with antihistamines or corticosteroids may reduce the incidence and severity of life-threatening reactions in such patients. Currently, the recommended contrast dye used in myelography and fluoroscopic injections is nonionic, either iso- or hypo-osmolar. The largest study to compare the effects of intrathecal nonionic (Iopamidol, Bracco Diagnostics, Princeton, NJ) to ionic (Metrizamide, Sanofi Winthrop, New York, NY) contrast found that substantially fewer systemic reactions occurred in the nonionic group.54 The reported risk of anaphylactic reactions using iso-osmolar contrast is extremely low, about 0.04%.55 In 337,647 cases in which iso-osmolar contrast was used, only 1 death occurred.56 Controlled studies on nonionic contrast agents used intrathecally in myelography have shown diverse adverse reactions, including headache (18%), nausea (7.3%), muscular pain (3.7%), and hypotension (1.1%).57 These studies were performed by using 10-15 mL of injected contrast, which is well above the 1-3 mL used in fluoroscopic epidural injections.

Drug combinations The ASA Closed Claims Project demonstrates that serious injuries, such as death or brain injury, have occurred after ESIs when these have been administered concurrently with local anesthetics with or without opioids.4

Needle-related injuries As the needle is advanced on to the epidural space, it encounters different tissues, which may be damaged from the cutting edge of the instrument or minor mechanical tissue displacement (noncoring bevels) that may produce either transient (generally minor) or permanent injury (usually catastrophic) to the affected structure.

Local Some patienxts (3.1%) complain of increased back pain at the needle entry site following epidural injections.22 This may be related to procedural trauma, resulting in bruising or paraspinal muscle spasm.

Dural puncture Dural puncture is a common complication of the interlaminar approach, with a reported incidence between 5% and 17%.24 During transforaminal epidural injections, the target for needle tip placement is lateral to the end of the dural sheath. Despite this, there are reported cases of dural puncture during lumbar transforaminal steroid injections58; however, the literature regarding this complication is scant and the real incidence is unknown.

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Postdural puncture headache Postdural puncture headache is a well-known complication of dural puncture and tends to be self-limited, as most cases resolve without intervention. The incidence of headache following dural puncture has been reported to be between 7.5% and 75% depending on technique, practitioner experience, and needle size.26 The incidence of headaches has been reported to be 1.4% to 6% following lumbar interlaminar epidural injections,59 3.1% following lumbar transforaminal epidural injections,1 2.6% following thoracic interlaminar epidural injections,60 and up to 21% after caudal epidural injections.61 The headaches may be caused by either unrecognized dural puncture causing CSF leakage or inadvertent injection of air into the subarachnoid space.62,63 Pneumoencephalus This is an uncommon complication of epidural steroid injections and has been reported following injections and multiple sites in the spine.64-66 Subdural injection Reported incidence of dural puncture and subdural neural blockade during interlaminar epidural injections is estimated to be 0.82%.67 Intradiscal injection The transforaminal epidural approach has the potential risk of entering the intervertebral disc. Finn reported a case of intradiscal dye spread using the transforaminal approach in a patient with disc herniation despite the use of proper technique.68 Although no grave consequence was reported in this case, recommendations made by the authors include the mandatory use of fluoroscopy to document adequate needle placement as well as prophylactic IV antibiotics should the disc be inadvertently entered.

Direct neurologic injury The ASA Closed Claims Project in 2004 identified significant serious nerve injury claims after ESIs (28/114 claims) and found that 7 of these 28 cases resulted in quadriplegia/paraplegia.4 Spinal cord trauma Lee and coworkers69 reported a case of direct spinal cord needle penetration after a C6-C7 transforaminal ESI under fluoroscopic guidance. Strategies suggested to minimize the risk of inappropriate needle placement during the cervical transforaminal approach include the following. (1) Correct position should be confirmed in anteroposterior, lateral, and oblique planes, using real-time fluoroscopy before proceeding to inject through the needle. (2) The needle tip should be placed in the posterior aspect of the neural foramen on an oblique plane and no further than halfway across the width of the articular pillar in an anteroposterior view. (3) Upon

241 any complaint of lancinating pain during the insertion, needle position should be reassessed and considered as a clear signal to immediately stop further needle advancement. Needle puncture itself is believed to induce far less damage than subsequent injection into the substance of the cord itself. The use of contrast medium should allow assessment of appropriate epidural and/or perineural dye spread and lack of vascular uptake using real-time fluoroscopy with or without digital subtraction angiography. If the injected contrast does not show appropriate outlining of the dural sleeve or vascular uptake is identified, the injection should be discontinued immediately. The use of blunt needles or pencil point tip needles might minimize the risk of spinal cord or vascular penetration.17,26,69 Nerve injury One case report of acute monoplegia after caudal lysis of adhesions using 10 cc Omnipaque, 5 cc of hyaluronidase 750 UI in saline, and 5 cc of 0.1% bupivacaine with 4 mg dexamethasone at each L5 nerve root (30 cc total volume) has been identified. The patient developed immediate paralysis and complete sensory loss of the right lower extremity, while maintaining perianal sensation as well as bladder and bowel control. Imaging studies discarded a mass effect from a bleed as the cause of the deficit. After 5 weeks postprocedure, she demonstrated full recovery. This transitory neural deficit was postulated to have occurred secondary to a large volume of injectate causing increased pressure and nerve compression.70 Neuropathic pain has been reported after CESI, possibly secondary to spinal cord or nerve root needle trauma or neurotoxicity secondary to polyethylene glycol used in methylprednisolone suspension.71

Infectious complications Spinal infectious complications after epidural steroid administration are rare. Spontaneous cases in the general population have been quoted to occur in approximately 0.33196 cases per 10,000 hospital admissions each year.72 The ASA Closed Claims revision in 2004 found serious infectious complications in 20 of 114 epidural steroid claims.4 Diabetes mellitus has been identified as the major risk factor for the development of spinal infections.73 Systemic diseases, such as chronic renal insufficiency (dialysis),74 Crohn’s disease,75 and cancer,76 have been linked to spinal infections as they reduce immunocompetence. Additionally, repeated IV medications, the use of immune suppressing drugs, such as chemotherapeutic drugs,77 immune compromise, or IV drug abuse have also been implicated in neuraxial infections. Contaminated equipment usage is one of the main reasons for the increased incidence of infections among the IV drug-abusing population.78 It is well established that heroin users exhibit cellular as well as humoral immune system dysfunction,79 predisposing them to infec-

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tious disorders. Alcohol abuse is also a risk factor for the development of spinal infections. It is thought that dietary deficiencies (protein) contribute to this increased risk.80 Yet another causative factor that has a large impact on the development of a neuraxial infection is spine surgery; 13% to 21% of patients present with clinical signs of infection 8 weeks postprocedure.81 Possible mechanisms implicated in seeding infectious agents (viral, bacterial, fungal, or protozoal) are translocation from needle entry site at skin, hematogenous spread, introduction via the injectate, or catheter colonization into the epidural, subdural, intradural, or subarachnoid space.82,83 Staphylococcus aureus, followed by Streptococcus species and Staphylococcus epidermidis have been identified as the most common agents involved in all types of infections in the spine. Steroids interfere with cytokine production in addition to suppressing the hypothalamic–pituitary–adrenocortical axis, which may lead to immune suppression predisposing patients to pathologic infectious processes. Spinal tissue infections rarely occur independent of one another; rather, multiple different tissues tend to present infected simultaneously.

Epidural–intradural abscess The first case report of epidural abscesses found in the literature dates back to 1761 in Venice, Italy. An epidural abscess is generally a pyogenic, bacterial infection. The most common pathogens identified are Gram-positive cocci. Since the beginning of the 20th century, Staphylococcus aureus has been known as the primary etiologic agent in epidural infections, followed by Streptococcus species. Gram-negative bacteria have increased in incidence in the last 15 years.84 This may well represent a worldwide trend in an age of increased IV drug abuse,85 especially in the United States. Epidural parasitic infections are an extremely rare form of spinal infection, but there are a few case reports finding Dracunculus medinensis86 and Echinococcus granulosus as the causative agents.87,88 Fungal infections are rare in the spine. One case of intradural abscess resulting from Aspergillus fumigatus colonization has been reported. This patient developed discitis, osteomyelitis, and neurologic deterioration requiring surgical debridement and 6 months of IV antifungal therapy, after which she fully recovered.89 At present, the overall incidence of epidural abscess is approximately 0.2-2 cases per 10,000 admissions.73,90 Waldman reported in a large case series of 790 CESIs, no cases of epidural abscesses.91 Trauma represents a large risk factor for epidural infections. Tissue disruption can predispose to hematogenous spread of microorganisms both by breaking anatomic barriers as well as seeding infectious agents into the epidural space.92 Several cases of neuraxial abscesses have been described not only after ESIs,93,94 but also to other invasive procedures, such as trigger point injections,95 stellate ganglion block,96 and acupuncture.97

Some clinicians have recommended the direct application of epidural steroids during closure of microdiscectomies to relieve postoperative nerve root irritation. However, after several case reports of postoperative infection, this practice has been discouraged.

Discitis Very few cases of discitis have been reported in the literature following epidural (interlaminar, caudal, or transforaminal) steroid injections. Median time to onset of infectious symptoms has been quoted to be approximately 7 days postprocedure.98

Osteomyelitis Osteomyelitis usually occurs simultaneously with epidural abscesses. However, in the case presented by Simopoulos, a 77-year-old male diabetic patient with low back pain secondary to lumbar spinal stenosis received an epidural methylprednisolone injection under aseptic technique following skin prep with 10% povidone iodine solution. He presented to the clinic 20 days postprocedure with increased back pain, but without fever, malaise, or neurologic dysfunction. He was found to have developed a soft tissue MRSA abscess and osteomyelitis without colonization of the epidural space. He was treated with surgical incision and drainage, and received a 45-day course of IV vancomycin with complete resolution of the infection.99 Chlorhexidine-based solutions have been found to decrease the number of positive skin cultures and should be considered in patients with increased risk for infection.100,101

Meningitis Bacterial meningitis is a rare complication of ESIs. Several case reports have been cited in the literature, some with Staphylococcus aureus as the pathogen.102 Lumbar punctures have been discouraged by some clinicians as a diagnostic tool for meningitis as the procedure may increase bacterial spread from the epidural space into the subarachnoid space. Diagnosis Laboratory findings may help with the diagnosis of infectious processes. Most patients will present with an elevated erythrocyte sedimentation rate (ESR) and creatine protein (CRP), having been reported as normal only in one asplenic diabetic patient.103 Diagnostic imaging is the gold standard in diagnosing spinal infection. Plain x-ray is not reliable for this purpose unless it is a long-standing infection resulting in sclerotic changes and erosion of the vertebral end plates.104 The diagnostic value of CT is limited and may only serve to plan surgical procedures (biopsies of the epidural abscess or of bone in case of osteomyelitis). How-

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ever, in the case of patients with contraindications to MRI, it remains the best alternative. Myelography has traditionally been the study of choice for making the diagnosis of epidural abscess as blockage of contrast occurs at the level of the abscess. Recently, however, MRI has taken the central role in the diagnosis of infection, as it provides excellent sensitivity, lacks the invasive nature of needle sampling, and saves the patient from exposure to radiation as in CT. Use of gadolinium contrast during MRI may allow improved delineation of the infectious process.105 Treatment A combination of conservative and surgical measures is generally considered the best approach to management. The use of antibiotics is paramount, and the following criteria for antibiotic choice described by Leys and coworkers106 should be fulfilled: (1) an agent must be chosen that covers S. aureus as this is the most common agent identified, (2) toxicity of the agent should be kept low to allow for prolonged treatment (several weeks), and (3) the agent selected must have the ability to penetrate osseous tissue (also mandatory when treating spondylo discitis). While waiting for definitive confirmation of the causative agent, combined antibiotic therapy should be considered. Negative cultures (CSF, blood) have been reported and attributed to the early use of antibiotics before obtaining culture material.107 The duration of antibiotic treatment should be from 4 to 6 weeks but may require up to 12 weeks. Antibiotic treatment must be started IV but may be followed with oral formulations.108 Choice of antibiotic therapy relies on clinician and institutional preference as well as on resistance testing and geographic location. Surgical decompression is usually reserved for patients who develop neurologic deficits. Anterior decompression, combined or not with corpectomy, for the treatment of anterior epidural space infection is the procedure of choice.109 More commonly, the abscess is located in the posterior epidural space, and the surgical treatment of choice is an emergent decompressive laminectomy with debridement (with or without spinal stabilization).110 Percutaneous fluoroscopically guided drainage is also an option if the epidural infectious mass is well delineated111 and accessible via a posterior approach. Despite adequately chosen medical and surgical treatment, more than half of patients do not recover entirely, and immunocompromised patients have a much higher risk of death.98

Vascular-related injuries Hemorrhagic Spontaneous idiopathic epidural hematomas are rare, having first been described in 1869 by Jackson.112 Most reported cases are found in adults 50-80 years of age,113

243 with only a few cases reported in children.114 Several conditions, such as hypertension, coagulopathies, systemic disease and neoplasms, AV malformations or valsalva maneuvers (coughing, vomiting, or sneezing), have been quoted as potential risk factors.115,116 A 30-year review of the literature reported 326 patients who suffered spontaneous spinal subdural or epidural hematomas.117 Additionally, Groen and Ponssen118 reported 199 patients with spontaneous spinal epidural hematomas. In more than 25% of these cases, a coagulopathy, drug-induced, acquired, or congenital abnormality was present. Presenting symptoms are those of acute radicular pain followed by progressive neurologic dysfunction, characteristic of spinal cord compression. Rarely full recovery occurs, and some neurologic sequelae are seen even after prompt identification of the hematoma and appropriate surgical decompression is performed.119 Recurrence of spontaneous spinal hematomas has been reported as well.120 Spinal epidural hematomas are the most common form of bleeding in the spinal canal, probably because of the prominent epidural venous plexus,121 whereas spinal subarachnoid hematomas are the rarest of the intraspinal hematomas because of the diluting and redistributing effect of the cerebrospinal fluid. Vandermeulen and coworkers122 presents a review of 61 cases of epidural/subdural hematomas after neuraxial procedures, and a clotting anomaly or use of anticoagulant therapy was present in 42/61. Acute intracranial subdural hematoma Persistent headache with neurologic findings after an epidural injection is clinically important as it may be the presenting symptom of a subdural intracranial hematoma. The mechanism proposed for this occurrence is decreased intracranial pressure secondary to a CSF leak inducing a downward displacement of the brain, and subsequent tearing of bridging veins resulting in a subdural hematoma. Typically, it is treated with strict bed rest, hydration and analgesics, as well as an epidural blood patch; however, in patients with progressive neurologic deficits or loss of consciousness, surgical decompression may be necessary.123 Few isolated cases have been reported in the literature.124,125 Cervical subdural hematoma Very few cases of subdural hematomas have been reported in the literature, but most are associated with an underlying coagulopathy. In one such case report, this complication was found in a 62-year-old female who underwent a CESI for the treatment of a right-sided radiculopathy.126 She had received a previous CESI with symptomatic relief. Four weeks after the first injection, her symptoms returned, and she was scheduled for a repeat injection. This procedure was delayed for 1 week due to the patient’s use of Fiorinal (Novartis, East Hanover, NJ), an aspirin-containing compound used to treat her chronic migraine headaches. According to the report, she underwent an “uncomplicated right-sided, posterior ESI at C4-C5,” and was discharged home in good condition. Within a few hours of discharge, she noted weak-

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ness in the right upper extremity and presented to her local emergency department. A CT scan at that time demonstrated displacement of the cord from anterior to posterior in the C3-C5 region. She was transferred to another facility for evaluation and ultimately taken to the operating room for emergency posterior decompression. When the surgery started, 11 hours post-CESI, the patient’s neurologic function had deteriorated to near quadriparesis. She underwent posterior cervical decompression from C1-C7 and was found to have a large subdural hematoma, emanating from C4-C5 with extension to C2 and C7. During the surgical approach, the CESI needle tract was followed into the epidural space, and no evidence of dural puncture was found. Over the next week, her neurologic function gradually improved with complete resolution of left-sided symptoms and residual right-sided weakness. One to two days later, she exhibited an acute decline in neurologic function with findings consistent with meningitis. CSF cultures grew both pseudomonas and staphylococcus. After 2 weeks in the ICU, she ultimately died from cardiac arrest secondary to sepsis. Epidural hematoma Epidural bleeding is quite common after a needle puncture; however, the amount of blood is usually clinically insignificant and the hemorrhage is self-limited.127 Wulf cites an incidence of 1 epidural hematoma in 190,000 epidural anesthetics128; and, even though it is considered in general to be a rare complication, it is indeed the most common form of spinal bleeding. Risk factors identified for the development of epidural hematoma are anticoagulation therapy, coagulopathies, thrombocytopenia, traumatic procedure, traumatic catheter insertion, spinal cord pathology, and chronic renal failure.129 One case report of a lumbar epidural hematoma with profound neurologic sequelae was encountered in a patient with unrecognized idiopathic thrombocytopenic purpura that received a single lumbar ESI.130 Another case report of epidural hematoma after a cervical ESI was found in a patient with several previous uneventful ESIs. This last patient was receiving treatment with indomethacin, 75 mg b.i.d., a known platelet inhibitor, at the time of injection.131 Previously repeated administration of steroids in the epidural space may predispose to increased blood vessel wall fragility resulting in easier traumatic injury and subsequent bleeding.132 Subarachnoid hematoma Subarachnoid hematoma differs from subarachnoid hemorrhage by the formation of a clot within the subarachnoid space rather than free blood suspended in CSF as found in the latter. It is presumed that copious bleeding and/or diminished CSF flow prevents the extravascular blood from being washed away and therefore forms a clot.133 Some believe that this occurs when radicular vessels (arteries or veins) rupture, especially implicated in subarachnoid hematomas which follow interventional neuraxial procedures.134

In most cases reported following lumbar puncture, most involved a preexisting coagulopathy. Interestingly, no case reports of subarachnoid hematomas have been reported following epidural injections.135 Retroperitoneal hematoma Only one retroperitoneal hematoma has been reported in a patient on anticoagulant therapy who received a fluoroscopically guided lumbar transforaminal injection of steroids.136,137

Ischemic injuries of the brain and spinal cord The increased use of targeted ESIs using fluoroscopic guidance has been accompanied by a range of new complications. Most notable among these has been a significant number of ischemic injuries involving the brain and spinal cord. A growing body of evidence supports an embolic mechanism for these injuries, whereby inadvertent intraarterial injection of particulate corticosteroid causes a distal infarct. Emboli injected into the distal basilar artery region can cause midbrain, pons, cerebellum, thalamus, temporal, and occipital lobe infarctions. A prospective study of 504 cervical transforaminal ESIs demonstrated a 19.4% incidence of fluoroscopically confirmed intravascular contrast injections, over half of which had a negative aspiration.26,138 Another potential mechanism of infarction includes vertebral artery perforation producing dissection/ thrombosis of the vessel and needle-induced vasospasm. The occurrence of ischemic complications does not depend on the imaging modality used to guide the injection, ie, fluoroscopy139-141 or CT.142 Previous injection of contrast medium through the needle resulting in no vascular opacification is not a guarantee against ischemic complication, because both the operator and the technician may easily miss a fleeting fluoroscopic image. Furthermore, subtle displacement of the needle may occur between the injection of the contrast medium and that of the corticosteroid.138 Intravascular administration of particulate steroid A 2004 survey from the University of California, San Diego27 attempted to characterize neurologic infarctions following cervical transforaminal ESIs. Anonymous surveys were sent to 1340 physician members of the American Pain Society, and 287 (21%) responded. Seventy-eight complications were reported, of which 30 were cases of spinal cord or brain infarction (16 brain, 12 cervical spinal cord, and 2 combined brain/spinal cord infarcts). Of these 30 infarction cases, 6 were fatal. Of the 4 infarction cases involving the use of corticosteroid alone (without local anesthetic), all had used methylprednisolone. This is the strongest association to date between particulate corticosteroids and brain/ spinal cord infarctions. Vascular precipitation of injectate or arterial embolism by an inadvertent intravascular injection of steroid into a radicular artery or vertebral artery, and mechanically in-

92.59% 6.48% 0.93% 14.81% 14.81% 66.67% 3.70% 37.04% 28.40% 30.86% 3.70% 47.73% 28.41% 22.73% 1.14%

Particle sizes

1-10 ␮m 10-20 ␮m 20-50 ␮m ⬎50 ␮m

48.57% 11.43% 31.43% 8.57%

Dexamethasone sodium phosphate (Decadron; Am. Regent Laboratories, Shirley, NJ) Triamcinolone acetonide (Kenalog-40; Bristol-Myers Squibb, Princeton, NJ) Methylprednisolone acetate (Depo-Medrol; Pharmacia & Upjohn, Kalamazoo, MI) Betamethasone sodium phosphate/ betamethasone acetate (Celestone Soluspan; Schering-Plough, Kenilworth, NJ)

Particle sizes of various corticosteroid compounds145

duced vasospasm of blood vessels, have been implicated as possible causes for cerebellar and spinal cord infarction, although the exact mechanism is still poorly understood. Accuracy in identifying vascular contrast patterns declines when static images are taken during the injection of dye (sensitivity of 50%) and is significantly worse when vascular injections occurred simultaneous to the expected contrast flow seen in epidural injections.143 Therefore, live fluoroscopy has been recommended during contrast injection to minimize accidental intravascular uptake while performing lumbosacral transforaminal ESIs.143,144 The incidence of simultaneous epidural and vascular injection during lumbosacral transforaminal epidural injection is reported to be 8.9%.143 The complex blood supply to the spinal cord is partially derived from the spinal branch of a local artery that then divides into anterior and posterior radicular arteries. Local arteries supplying corresponding radicular arteries consist of the vertebral, deep cervical, ascending cervical, posterior intercostal, lumbar, or lateral sacral arteries. The arteria radicularis magna (artery of Adamkiewicz) is an enlargement of a lumbar anterior radicular artery supplying much of the blood supply to the lower two-thirds of the spinal cord. It has been implicated in paraplegia after lumbar transforaminal block. The vertebral artery travels up the spinal column to the foramina transversaria within each cervical transverse process. It lies anterior and adjacent to the cervical neural foramen. Accordingly, unintended penetration is possible during selective cervical transforaminal blockade. Methylprednisolone, triamcinolone, and betamethasone have all been associated with ischemic complications reported in the American literature, whereas dexamethasone has not (Table 2).26,27 Particles in dexamethasone and betamethasone tend to be rod-like and lucent, whereas particles of methylprednisolone and triamcinolone tend to be opaque and amorphous. As shown, triamcinolone and methylprednisolone contain a relatively greater percentage of large particles when compared with dexamethasone. This may represent a factor contributing to vascular occlusion/infarction. Additionally, over time, particles of triamcinolone and methylprednisolone tend to coalesce into large aggregates far in excess of 100 ␮m. Aggregate particles of this size can potentially place large blocks of neural tissue at risk for injury or infarction. Kaplan and coworkers146 reported four cases of venous uptake of contrast material during fluoroscopically guided cervical interlaminar ESI at the C6-C7 level. The blood vessel involved is most likely the posterior internal vertebral venous plexus, which drains the interlaminar space and returns blood to the right atrium via the vertebral and brachiocephalic veins. In all four cases, intravascular uptake occurred despite negative aspiration of blood before injection of contrast material. All patients were injected at the C7-T1 level. Because of this study, the authors recommended using fluoroscopic imaging to guide needle placement, as well as live fluoroscopic imaging of contrast administration to detect intravascular injection. Advanced

245 Betamethasone sodium phosphate

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Table 2

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imaging techniques, such as a digital subtraction, may be helpful in reducing these potentially devastating complications. The incidence of intravascular injection was 19.4% in cervical transforaminal ESIs,138 11.2% in transforaminal lumbar ESI (8.1% in lumbar transforaminal ESIs and 21.3% in S1 transforaminal ESI),138 and 9.2% in caudal ESI.147 The higher intravascular injection rate at S1 may be attributed to increased vascularity present in the sacral foraminal region. Although this has been observed by spine surgeons, it is not described in surgical anatomy texts or publications.148 Observed blood in the needle hub was predictive of intravascular injection in less than half of the documented vascular injections (44.7% to 45.9% sensitivity).138,147 The reduced sensitivity is most likely not related to patient position (supine vs prone) or needle gauge (22 vs 25 G). The low sensitivity may be the result of inadequate pressure in the venous system to result in spontaneous flow of blood through the needle into the needle hub. Attempted aspiration may result in sufficient negative pressure to collapse the vessel, thus preventing uptake of blood through the needle in the hub, regardless of whether a 22- or 25-G needle is used. However, during injection of contrast or medications, there is enough positive pressure to keep smaller vessels distended, which can result in intravascular injection. Therefore, the absence of blood at the needle hub, either spontaneously or after aspiration, should not be considered a reliable means of preventing subsequent intravascular injection. To avoid intravascular injections, there is a need for contrast injection with live fluoroscopic imaging before injection.147,149 Furman and coworkers138 examined the lack of reliability of negative aspiration of blood in a prospective observational study that included 504 transforaminal injections performed in 337 patients. They concluded that the absence of flashback after needle placement was not indicative of whether the needle had been placed within a vessel, inasmuch as the vessel itself may collapse under the negative pressure created by pulling back on the syringe. This is most likely due to the small vessel caliber and lack of rigidity of adventitial structural elements. Currently, methylprednisolone, dexamethasone, and triamcinolone contain benzyl alcohol as a preservative, whereas betamethasone derivatives do not. Debate exists as to the potential role of benzyl alcohol neurotoxicity. Paraplegia, neural degeneration, and demyelination have been reported to occur with its use.36,150 However, all case reports found had immediate onset of symptoms, which is more consistent with an embolic event than with demyelinating sequelae following injection of a neurotoxic chemical agent. Arterial dissection Death is considered an extremely rare complication. One case report involved a 44-year-old white female with a C7 radiculopathy. She underwent a transforaminal ESI via the left C6-C7 neural foramen with a 25-G, 3.5-inch spinal

needle. After needle positioning under fluoroscopic guidance, aspiration of blood was positive and the needle was repositioned. Negative aspiration for blood was then obtained followed by appropriate dye spread using Omnipaque, 300 mEq. Two milliliters ([80 mg) of methylprednisolone, ⫹ 1 mL of 0.75% bupivacaine was injected, followed immediately by unconsciousness in the patient and subsequent death. Autopsy demonstrated dissection and thrombosis of the left vertebral artery with subsequent massive cerebral edema and cerebellar herniation. To avoid such devastating complications, the authors recommended the use of CT guidance (possible CT fluoroscopy) for cervical transforaminal injections as well as aborting the procedure if blood is encountered on aspiration. A case could be made to abandon cervical transforaminal injections in light of the severe neurological complications that can result. There may be still be a role for cervical selective nerve root blocks with local anesthetic alone to localize the source of pain and assist with surgical planning when imaging and clinical symptoms are discrepant. Perhaps, argue some practitioners, the cervical interlaminar approach is a more appropriate treatment, but this technique too has had severe reported complications. Prevention. The following recommendations have been suggested to minimize the risk of ischemic/embolic complications.17,26 1. Using real-time fluoroscopy with nonionic contrast and digital subtraction to maximize detection of vascular uptake. According to the data obtained from the literature reviewed, occurrence of ischemic complications does not depend on the imaging modality used to guide the injection, ie, fluoroscopy17,139-142,151 or CT.142 Previous injection of a contrast medium through the needle resulting in no vascular opacification is not a warranty against ischemic complication, since both the operator and the technician may easily miss a fleeting fluoroscopic image, or secondary subtle displacement of the needle between the injection of the contrast medium and that of the corticosteroid may occur.138 2. Using a test dose of local anesthetic before injection with corticosteroid to prevent irreversible neurologic sequelae. 3. Using microbore extension tubing to minimize needle manipulation while changing syringes. 4. Using minimal if any sedation to allow for neurologic monitoring. 5. Using a short-acting local anesthetic, such as lidocaine, to minimize the duration of high spinal anesthesia. 6. Use a blunt or short-bevel needle to minimize vessel trauma. Using larger gauge needles may prevent falsenegative aspirations. 7. Screening for arterial dissection risk factors, such as migraine headaches, recent infection, smoking, hypertension, oral contraceptive use, family history of spontaneous dissection, arteriopathy, cystic medial necrosis,

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Ehlers–Danlos syndrome, Marfan syndrome, alpha-1antitrypsin deficiency, osteogenesis imperfecta, and polycystic kidney disease.26 8. Using nonparticulate steroid, such as dexamethasone. Dexamethasone is the only steroid that has not yet been implicated in brain/spinal cord infarctions following cervical transforaminal ESIs. In a recent study,152 30 patients with cervical radiculopathy were randomized to receive a cervical transforaminal ESI with 12.5 mg dexamethasone or 60 mg triamcinolone. Although the effectiveness of dexamethasone was slightly less than triamcinolone, both groups had a significant reduction in pain scores at 4 weeks and were not statistically different from each other. The authors concluded that it is reasonable to consider using nonparticulate steroids due to the reduced risk of embolization when compared with particulate steroids. 9. Slow injection of corticosteroid with frequent negative aspiration. Please note, the absence of blood in the needle hub spontaneously or after aspiration is not sufficient precaution.138 Reasons for falsely negative aspiration include a needle tip lodged against the vessel’s inner wall or aspiration causing the vessel to collapse.12 10. Ability to provide emergency airway, ventilation, and cardiovascular support if the need arises. Management. There is no current consensus on the management of spinal cord infarctions, but data have been extrapolated from the cerebral infarction and spinal cord injury literatures. The following options have been recommended.141 1. Early recognition combined with expedited exclusion of a compressive lesion, such as an epidural hematoma, which is an emergency surgical lesion. In the largest series analyzing patients presenting with a spinal cord infarction, Cheshire and coworkers149 reported that 8 of 14 MRIs performed “acutely” were normal; on follow-up imaging, there was interval development of focal swelling and increased T2 signal within the spinal cord. 2. Avoidance of secondary injury due to hypoxemia and hypotension. 3. The use of high-dose steroids may facilitate neurologic recovery; however, there are no data on the use of steroids in the setting of spinal cord infarction, due to its low incidence and the lack of controlled trials. In the spinal cord injury literature, there is evidence that administration of intravenous methylprednisolone within 8 hours of injury results in improved outcome at 6 weeks, 6 months, and 1 year. However, the inclusion criteria for his trial did not include patients with spinal cord infarction.

Conclusions Although generally considered a safe and efficacious procedure for the short-term management of spinal and radicular pain, epidural steroid administration has been associ-

247 ated with minor as well as major complications that include permanent neurologic sequelae and death. Proper patient selection, risk factor identification (eg, immunocompromise, anticoagulation, anatomic abnormality), detection of potential periprocedural hazards (eg, intravascular injection), and prompt recognition and aggressive adequate management of complications will potentially minimize risk and reduce the severity of sequelae from complications related to ESIs.

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