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Canadian Journal of Anesthesia 54:49-53 (2007)
© Canadian Anesthesiologists' Society, 2007
Case Reports/Case Series

Encephalopathy and rhabdomyolysis induced by iotrolan during epiduroscopy

[Encéphalopathie et rhabdomyolyse provoquées par l’iotrolan durant l’épiduroscopie]

Ju Mizuno, MD*,{dagger}, Tobias Gauss, MD{dagger}, Masahiro Suzuki, MD*, Masakazu Hayashida, MD*, Hideko Arita, MD* and Kazuo Hanaoka, MD*

* From the Department of Anesthesiology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan; and the
{dagger} Service d’Anesthésie- Réanimation, SMUR, Hôpital Beaujon, Clichy, France.

Address correspondence to: Dr. Ju Mizuno, Assistant Professor, Department of Anesthesiology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. Phone: +81-3-5800-8668; Fax: +81-3-5800-8938; E-mail: mizuno_ju4{at}yahoo.co.jp


   Abstract
TOP
 Abstract
Introduction
 Case report
 Discussion
 References
 
Purpose: We describe a complication of epiduroscopy with encephalopathy and rhabdomyolysis associated with the contrast medium iotrolan.

Clinical features: A 76-yr-old man with failed back surgery syndrome underwent epiduroscopy. Sufficient lysis could not be achieved in the epidural space above the level of L4 due to dense adhesions and scar tissue. After epidural injections of iotrolan and mepivacaine, he developed motor weakness and hypoesthesia in both legs, which lasted for three hours. He also became confused, agitated, disoriented, and developed neck stiffness and tremors involving the head and legs. Computed tomography revealed diffuse contrast enhancement within the intracranial cerebrospinal fluid (CSF) spaces, indicating an intraoperative dural tear. Marked increases in serum creatinine phosphokinase and myoglobin indicated subsequent acute rhabdomyolysis. Crystalloid infusion and semi-recumbent positioning facilitated iotrolan absorption from the CSF, and the patient recovered uneventfully.

Conclusions: Dural tear during epiduroscopy may allow access of contrast media into the CSF. Neurotoxicity secondary to iotrolan within the CSF was a likely contributing factor to the encephalopathy and subsequent rhabdomyolysis. This is an instructive example of the importance of diagnosing inadvertent dural tear during epiduroscopy under iotrolan, for avoidance of adverse events such as encephalopathy and rhabdomyolysis.


   Introduction
TOP
 Abstract
 Introduction
Case report
 Discussion
 References
 
LUMBAR epidural adhesions involving nerve roots can be responsible for persistent low back and leg pain. Epiduroscopy enables direct visualization of structures within the epidural space, appropriate adhesiolysis, and administration of local anesthetic agents and steroids to target specifically affected nerve roots.1,2 Epiduroscopy can provide substantial and prolonged pain relief to patients with chronic low back and leg pain due to lumbar disc herniation, spinal canal stenosis, and failed back surgery syndrome (FBSS).1,2 Although epiduroscopy has been considered to be a safe procedure in experienced hands, severe complications such as retinal bleeding with visual impairment3 and epidural abscess4 have been occasionally reported. Iotrolan, a non-ionic water-soluble radiographic contrast medium, has often been used for epidurography.5 We report a case of encephalopathy and rhabdomyolysis, probably induced by iotrolan following an accidental dural tear during epiduroscopy. Consent for publication was obtained according to guidelines of the University of Tokyo Hospital.


   Case report
TOP
 Abstract
 Introduction
 Case report
Discussion
 References
 
A 76-yr-old man with chronic low back pain and sciatica due to FBSS presented for epiduroscopy. His medical history included hypertension and diabetic mellitus, but no alcoholism, psychosis, or epilepsy. He underwent laminoplasty at L4 and L5 ten years previously, posterior lumbar fusion with instrumentation at L4 and L5, as well as subsequent removal of infected implants six years previously, and autogenous bone grafting at L5 five years prior to the current presentation. On examination, straight leg raising test was positive for nerve root tension, without evidence of sensory, motor, or reflex abnormality. Magnetic resonance imaging revealed epidural adhesions with postoperative changes, spinal canal stenosis with bulging discs at L2–3, L3–4, L4–5, and L5-S1, and anterior spondylolisthesis of L5. A variety of pain therapies, including non-steroidal anti-inflammatory drugs (NSAIDs) and opioids, and nerve blocks were ineffective. Preoperative laboratory tests were normal except for mild renal insufficiency (TableGo).


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  		TABLE Hematology and blood chemistry
 
In the operation room and following application of routine monitors, he was placed in the prone position and lightly sedated with midazolam 2.5 mg iv and fentanyl 100 µg iv. Cefazolin 1 g was infused prophylactically at the time of incision. Under aseptic conditions, and with local anesthesia, an 18.5-G Tuohy needle was introduced by an epiduroscopist into the epidural space through the sacral hiatus. Correct needle placement was confirmed by injection of iotrolan 10 mL (Isovist 240®, 240 mg I·mL–1, Schering, Berlin, Germany) under fluoroscopy. The epidurography showed complete block of contrast flow at the level of L4–5. An introducer sheath was advanced into the sacral epidural space using the Seldinger technique. A 0.9-mm flexible endoscope (3000E, Myelotec, Roswell, GA, USA), covered with a 2.9-mm steering catheter (2000, Myelotec, Rosswell, GA, USA), was introduced through the sheath and advanced cephalad into the epidural space, under frequent fluoroscopic monitoring. Adhesions in the epidural space were mobilized with the tip of the instrument under careful direct vision. However, sufficient lysis could not be achieved in the epidural space above the level of L4 due to dense adhesions and scar tissue. A further attempt of adhesiolysis was abandoned and the operation was terminated after 38 min, due to his frequent complaints of low back pain and movement during the procedure, despite one additional dose of midazolam 1 mg iv and fentanyl 100 µg iv. The epidurography with iotrolan 10 mL demonstrated complete contrast filling of the epidural space at L5-S1, but incomplete, narrow filling at L2–L4 (Figure 1Go). At the end of epiduroscopy, 0.25% mepivacaine 30 mL were injected into the epidural space for analgesia. The total volume of saline used for epidural irrigation was 300 mL.


Figure 1
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  		FIGURE 1 Epidurography with iotrolan following epiduroscopy
There is complete contrast filling of the epidural space at L5-S1, but incomplete filling at the L2–L4 spinal levels.

 
No sooner had the epiduroscopy been completed than he developed muscle weakness and hypoesthesia of both legs, which persisted for three hours. Ninety minutes postoperatively, he became confused, disoriented, and agitated, moving vigorously, calling out while remaining unresponsive to command. He developed urinary incontinence and occasional tremors involving the head and legs, which deteriorated to a state of extreme agitation, requiring bed restraint. To manage the delirium chlorpromazine 50 mg iv and haloperidol 5 mg iv were administered. A computed tomography (CT) scan of the head obtained 4.5 hr postoperatively revealed diffuse contrast enhancement throughout the intracranial cerebrospinal fluid (CSF) spaces (Figure 2Go). After being returned to the ward, he was febrile, with his temperature peaking at 39.1°C eight hours postoperatively, despite treatment with cooling and administration of NSAIDs and cefazolin 1 g iv every eight hours. He was maintained in a 30° head-up position to minimize cephalad migration of iotrolan. Crystalloid was administered in an attempt to facilitate iotrolan absorption from the CSF and excretion into urine. The psychomotor agitation slowly resolved over several hours and he regained nearly full consciousness and orientation by the 13th hour postoperatively. All symptoms and signs but the tremors and neck stiffness resolved.


Figure 2
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  		FIGURE 2 Non-contrast head computed tomography 4.5 hr postoperatively
There is diffuse contrast enhancement throughout the intracranial cerebrospinal fluid spaces, including cortical sulci, basal cisterns, and cerebral ventricles.

 
Blood counts and serum chemistries at 18 hr and 24 hr postoperatively showed marked elevations in serum creatinine phosphokinase (CK) and myoglobin (Mb), indicating occurrence of rhabdomyolyis (TableGo). He had mild renal insufficiency, moderate leukocytosis, and elevated serum C-reactive protein. Serum CK and Mb levels peaked at 24 hr, and decreased thereafter. Vigorous hydration and antibiotics were continued, and analgesics, including NSAIDs and pentazocine, were administrated repeatedly to relieve generalized myalgia-like pain. The remaining tremors and neck stiffness disappeared completely by the 20th hour postoperatively, and he was able to resume walking 24 hr postoperatively. A repeat CT scan of the head on the fourth postoperative day revealed no residual contrast. His recovery proceeded uneventfully and he was discharged home seven days postoperatively.


   Discussion
TOP
 Abstract
 Introduction
 Case report
 Discussion
References
 
This case presents a rather dramatic constellation of signs of acute psychomotor disturbance occurring with-in a few hours following epiduroscopy. The clinical signs resolved over the next several hours while supportive therapy was administered, to be followed by biochemical evidence of acute rhabdomyolysis. A dural tear, not detected during epiduroscopy, was suspected from the appearance of regional motor and sensory blocks. Evidence for the dural tear was confirmed subsequently with a CT scan revealing diffuse contrast enhancement within the intracerebral CSF. We assume migration of iotrolan into the CSF via a dural tear, resulted in the encephalopathy and secondary rhabdomyolysis.

As a contrast medium, iotrolan is considered to be associated with a lower risk of seizures and adverse events for intrathecal use, because it does not interfere with glucose metabolism and normal metabolic pathways. 6,7 However, mild side effects such as headache, neck pain, neck stiffness, tinnitus, nausea, vomiting, dizziness, and allergic reactions may occur up to two to four days following iotrolan following myelography in as many as 24–36% of procedures.6–9 The frequency of side effects for cervical myelography may approach 56%.8 Subarachnoid injection of iotrolan actually induced agitation and seizures in a rabbit model.10 Myelography with iotrolan has also been shown to result in symptomatic aseptic chemical meningitis.11,12 Further, hydrocephalus after myelography with iotrolan has been reported, possibly due to arachnoiditis, hypersensitivity reaction, or dural sinus thrombosis.13 Rhabdomyolysis secondary to anticonvulsant-resistant seizures following myelography with iohexol, a non-ionic contrast medium, has also been reported.14 Such adverse responses may be dose-dependent.15 As iotrolan is a dimer, and thus a larger molecule compared to iohexol, it has a longer half-life in the CSF, and a decreased rate of resorption.16 The plasma concentration following subarachnoid injection of iotrolan peaks after two to six hours.17 As there are no reported side effects of epidurally-administered iotrolan, it seems very plausible that the encephalopathic signs and rhabdomyolysis observed in this patient resulted from direct neurotoxicity of iotrolan penetrating into the central nervous system via the CSF following a dural tear during epiduroscopy. This case warns of inadvertent dural tear, resulting in known neurotoxicity of iotrolan or other contrast agents.

In this patient, we opted for conservative management with iv hydration and elevation of the head and trunk18 in an effort to minimize the cephalad migration of iotolan. While use of a lumbar intrathecal catheter has been described for the purpose of performing drainage and lavage of the intrathecal space,11,13,18 we would warrant caution for the introduction of another invasive procedure without clear indications.

There are three different ways to detect a dural tear, which include direct visualization with an epiduroscope, aspiration of CSF from the epidural space, and contrast injection under fluoroscopy. In this patient, as adhesions and scar tissue were dense and an accidental dural tear might have been difficult to observe, we failed to demonstrate4,19 a dural tear initially by any of the above methods. Further, as a moderate saline infusion was used during the procedure, it was difficult to aspirate any CSF.

Marked elevations in serum CK and Mb concentrations indicated development of rhabdomyolysis. Tremors persisted for hours in this patient, and such vigorous involuntary movement might have contributed to the development of rhabdomyolysis. Further, unusual skeletal muscle hyperactivity due to vigorous struggling against physical restraint most likely contributed to exertional rhabdomyolysis20 in this patient. A malignant neuroleptic syndrome secondary to neuroleptics21 was considered unlikely, as symptoms developed before administration of chlorpromazine and haloperidol. It has been recommended that neuroleptics e.g., phenothiazine derivatives, should be discontinued 48 hr before myelography and avoided 24–48 hr after myelography with iotrolan, because they reduce the seizure threshold.22 In the case of our patient, it is difficult to ascertain how the use of these neuroleptics affected the course of the psychomotor disturbance and subsequent rhabdomyolysis.

Electroencephalographic (EEG) studies have shown that radiocontrast materials can alter seizure thresholds, in the form of non-convulsive status epilepticus, including absence status epilepticus and complex partial status epilepticus.22 The symptoms are often indistinguishable from delirium.23 The psychological disorders accompanying EEG alterations are not rare in humans after cervical myelography with iotrolan.24

In conclusion, we describe a patient who experienced an acute encephalopathy and subsequent rhabdomyolysis following an accidental dural tear associated with epiduroscopy, most probably secondary to neurotoxicity of iotrolan migrating into the CSF. This case highlights a potential and serious complication of epiduroscopy where a dural tear may be difficult to diagnose. Clearly, all precautions should be taken to avoid an intrathecal injection of iotrolan, if the dura is inadvertently injured.


   Acknowledgments
 
We sincerely thank Drs. Hiroko Tsujihara, Hiroshi Sekiyama, Makoto Ogawa, and Mieko Chinzei for their excellent advice and help with the preparation of this manuscript.


   Footnotes
 
Competing interests: None declared.

Accepted for publication October 2, 2006. Revision accepted October 20, 2006.


   References
TOP
 Abstract
 Introduction
 Case report
 Discussion
 References
 
1 Geurts JW, Kallewaard JW, Richardson J, Groen GJ. Targeted methylprednisolone acetate/hyaluronidase/clonidine injection after diagnostic epiduroscopy for chronic sciatica: a prospective, 1-year follow-up study. Reg Anesth Pain Med 2002; 27: 343–52.[Medline]

2 Igarashi T, Hirabayashi Y, Seo N, Saitoh K, Fukuda H, Suzuki H. Lysis of adhesions and epidural injection of steroid/local anaesthetic during epiduroscopy potentially alleviate low back and leg pain in elderly patients with lumbar spinal stenosis. Br J Anaesth 2004; 93: 181–7.[Abstract/Free Full Text]

3 Gill JB, Heavner JE. Visual impairment following epidural fluid injections and epiduroscopy: a review. Pain Med 2005; 6: 367–74.[Medline]

4 Anderson SR. Epiduroscopy. In: Raj PP (Ed.). Textbook of Regional Anesthesia. PA: Churchill Livingstone; 2002: 787–93.

5 Yokoyama M, Hanazaki M, Fujii H, et al. Correlation between the distribution of contrast medium and the extent of blockade during epidural anesthesia. Anesthesiology 2004; 100: 1504–10.[Medline]

6 Wagner A, Jensen C, Saebye A, Rasmussen TB. A prospective comparison of iotrolan and iohexol in lumbar myelography. Acta Radiol 1994; 35: 182–5.[Medline]

7 Hoffmann B, Becker H, Wenzel-Hora BI. Influence of the spread and period of retention of iotrolan in the subarachnoid space on the side effects rate in myelography. Neuroradiology 1987; 29: 380–4.[Medline]

8 Ringel K, Klotz E, Wenzel-Hora BI. Iotrolan versus iopamidol: a controlled, multicenter, double-blind study of lumbar and direct cervical myelography. Fortschr Geb Rontgenstrahlen Nuklearmed Erganzungsbd 1989; 128: 153–7.[Medline]

9 Bien S, Schumacher M, Berger W, Wenzel-Hora BI. Iotrolan, a non-ionic dimeric contrast medium in myelography. Fortschr Geb Rontgenstrahlen Nuklearmed Erganzungsbd 1989; 128: 158–60.[Medline]

10 Sundgren P, Baath L, Maly P. CNS-effects from subarachnoid injections of iohexol and the non-ionic dimers iodixanol and iotrolan in the rabbit. Acta Radiol 1995; 36: 307–11.[Medline]

11 Bender A, Elstner M, Paul R, Straube A. Severe symptomatic aseptic chemical meningitis following myelography: the role of procalcitonin. Neurology 2004; 63: 1311–3.[Abstract/Free Full Text]

12 Nakakoshi T, Moriwaka F, Tashiro K, Nakane K, Miyasaka K. Aseptic meningitis complicating iotrolan myelography. AJNR Am J Neuroradiol 1991; 12: 173.[Medline]

13 Tseng SH, Tseng WS. Acute hydrocephalus after iotrolan lumbar myelography. Neuroradiology 1997; 39: 863–4.[Medline]

14 Canbay O, Bal N, Akinci S, Kanbak M, Aypar U. Rhabdomyolysis after intraoperative myelography. Paediatr Anaesth 2004; 14: 509–13.[Medline]

15 Simon JH, Ekholm SE, Kido DK, Utz R, Erickson J. High-dose iohexol myelography. Radiology 1987; 163: 455–8.[Abstract]

16 Castel JC, Dorcier F, Caille JM. Penetration of the brain by non-ionic water soluble tri- and hexaiodinated contrast media. Experimental autoradiographic study of two contrast media: iotrol and iopamidol labelled with iodine 125. Neuroradiology 1987; 29: 206–10.[Medline]

17 Skutta T, Vogelsang H, Galanski M, Hammer B, Weinmann HJ. Clinical trial of iotrol for lumbar myelography. AJNR Am J Neuroradiol 1983; 4: 302–3.[Abstract]

18 van der Leede H, Jorens PG, Parizel P, Cras P. Inadvertent intrathecal use of ionic contrast agent. Eur Radiol 2002; 12(Suppl 3): S86–93.

19 Gillespie G, MacKenzie P. Epiduroscopy - a review. Scott Med J 2004; 49: 79–81.[Medline]

20 Russell TA. Acute renal failure related to rhabdomyolysis: pathophysiology, diagnosis, and collaborative management. Nephrol Nurs J 2005; 32: 409–19.[Medline]

21 Susman VL. Clinical management of neuroleptic malignant syndrome. Psychiatr Q 2001; 72: 325–36.[Medline]

22 Fedutes BA, Ansani NT. Seizure potential of concomitant medications and radiographic contrast media agents. Ann Pharmacother 2003; 37: 1506–10.[Abstract/Free Full Text]

23 Drislane FW. Nonconvulsive status epilepticus in patients with cancer. Clin Neurol Neurosurg 1994; 96: 314–8.[Medline]

24 Fiirgaard B, Madsen HH, Svare U, Eriksen FB, Skjodt T, Zeeberg I. Intracranial iotrolan distribution following cervical myelography. Postmyelographic registration of adverse effects, psychometric assessment and electroencephalographic recording. Acta Radiol 1995; 36: 77–81.[Medline]





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