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Fatal Ascending Tonic-Clonic Seizure Syndrome

James Dunford, MD A fatal case of ascending tonic-clonic seizure (ATCS) syndromeresulted from the inadvertent, unrecognized use of a hyperosmolarionic contrast agent during myelography. The patient presentedwith lower-extremity myoclonic jerking, agitation, hyperthermia,rhabdomyolysis, and disseminated intravascular coagulation.Emergency physicians must be cognizant of this unique toxidrometo initiate early, aggressive care.

[Dunford J: Fatal ascending tonic-clonic seizure syndrome. AnnEmerg Med November 1998;32:624-626.]

I N T R O D U C T I O N

Nonionic radiographic contrast agents have replaced ionicagents for intrathecal use because of their lesser neuro-toxicity.1 Although nonionic agents are generally safe forintrathecal use, hyperosmolar ionic contrast agents alterthe blood-brain barrier and result in direct neurotoxiceffects.2,3 The inadvertent intrathecal use of an ionic con-trast agent produces a characteristic and often fatal tox-idrome called the ascending tonic-clonic seizure (ATCS)syndrome.4 Both ionic and nonionic contrast agents areclear liquids, and stringent protocols and warnings havebeen created to prevent their inappropriate use. Afterreports of serious complications, in 1993 the US Food andDrug Administration (FDA) called on manufacturers toplace warning labels on the vials, cartons, and drug pack-age inserts of all water-soluble contrast agents not intendedfor intrathecal use. The American College of Radiologydeveloped an educational program to reinforce this FDA-mandated warning and to promote sound handling anddispensing of all intravascular contrast media.5 Despitethese precautions, accidents continue to occur. Rapidrecognition and aggressive supportive care, includingspinal fluid drainage, appear to offer the best opportunityfor salvage from this rare but frequently fatal condition.4,6-8

From the Department of EmergencyMedicine, University of California,San Diego Medical Center, San Diego, CA.

Received for publication April 17, 1998. Revision received July 28, 1998. Accepted for publication August 4, 1998.

Reprints not available from theauthor.

Address for correspondence: James Dunford, MD, UCSD MedicalCenter, 200 West Arbor Drive,#8676, San Diego, CA 92103-8676,619-533-4359, fax 619-533-3835,E-mail jdunford@ucsd.edu.

Copyright © 1998 by the AmericanCollege of Emergency Physicians.

0196-0644/98/$5.00 +047/1/93828

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ered a diagnosis of malignant hyperthermia secondary tosuccinylcholine. On the second hospital day, the radiol-ogy service determined that the patient had accidentallyreceived an intrathecal dose of 8 mL of the hyperosmolarionic contrast agent, meglumine diatrizoate (Hypaque 50%).A magnetic resonance imaging study demonstrated cyto-toxic edema. Despite continued supportive care, the patientfailed to regain consciousness and died 6 weeks later.

D I S C U S S I O N

Meglumine diatrizoate is a hyperosmolar, ionic, triiodi-nated derivative of benzoic acid. It is used for imagingprocedures including arteriography, venography, urogra-phy, and contrast-enhanced CT scanning. An intact blood-brain barrier limits entry of ionic contrast agents into thecentral nervous system.1 Ionic contrast agents are con-traindicated for intrathecal use because of their neurotoxic-ity. Direct application of ionic agents to the brain cortexinduces seizures. Topical application of these agents tospinal roots produces increased spontaneous ventral rootfiring caused by reversal of normal spinal inhibitory tone.2

Neurotoxicity is thought to result from both destabiliza-tion of membrane potentials and direct chemotoxic effects.3

There is minimal histologic evidence of cellular inflam-mation and only mild edema.9,10

Isolated case reports and small series indicate that theATCS syndrome is a rare event.4,6-8,10-14 The clinical fea-tures typically begin after a latent interval of 30 to 90minutes. Patients develop progressive lower-extremityparesthesias and brief episodes of intense, involuntary,myoclonic leg jerking. Such violent, opisthotonic spasmscan produce femoral12 and spinal15 fractures. Althoughextensor spasms are typical, hip flexor contraction maydominate.11 The spasms ascend and generalize over sev-eral hours, presumably as a result of cephalad circulationof the agent, which is heavier than spinal fluid. There is anaccompanying marked hypersympathetic state manifestedby restlessness, agitation, tachycardia, hypertension,hyperpyrexia, metabolic acidosis, rhabdomyolysis, anddisseminated intravascular coagulation. Fever higher than41.1°C (106°F) is common, probably because of bothstrenuous muscle contraction and a central thermoregu-latory defect.3 Patients are initially fully conscious, butprogressive obtundation and seizures characteristicallydevelop.

The morbidity and mortality rates of the ATCS syndromeare substantial.4,10,14 However, complete recovery hasoccurred after rapid recognition and aggressive manage-ment. Benzodiazepines alone have occasionally been

C A S E R E P O R T

A 60-year-old woman with a history of a lumbar laminec-tomy was brought by hospital gurney to the emergencydepartment from the radiology department complainingof inability to control her legs. Seventy-five minutes earlier,the patient had undergone fluoroscopically guided lumbarmyelography for suspected spinal stenosis. After beinggiven 8 mL of intrathecal contrast material, the patientcomplained of immediate lower-extremity pain and tin-gling and the procedure was terminated. A lumbar com-puted tomogram (CT) was attempted, but violent lower-extremity leg spasms prevented an adequate study. Tenmg of diazepam and 5 mg of intravenous midazolam pro-vided minimal relief. As a result of progressive spasms,anxiety, and paresthesias of the hands, the arms, and thevaginal and perioral regions, the patient was transferredto the ED accompanied by the treating radiologist.

Physical examination on arrival in the ED revealed analert, panicked woman who was terrified by her inabilityto control her legs. Every 5 to 30 seconds, she momentar-ily screamed in response to painful, involuntary, opistho-tonic (extensor) spasms lasting approximately 2 secondsoccurring at the hips. The patient’s vital signs were bloodpressure 150/90 mm Hg; pulse, 170 (sinus tachycardia);respirations, 32; and tympanic temperature, 36.6°C(97.9°F). The skin was diaphoretic and cool, but therewas no rash. The general physical examination was unre-markable. There was no focal neurologic abnormality, butthe patient could not elevate her legs more than 2.5 cm (1inch) between spasms. Sensation, deep tendon reflexes,and upper body strength were intact.

Oxygen, morphine, and lorazepam provided minimalrelief. Over the next 30 minutes, as the jerking leg move-ments slowed, the patient complained of difficulty swal-lowing and became progressively combative. After rapid-sequence intubation with succinylcholine, periodic thighmuscle twitching recurred and vecuronium was adminis-tered. Rectal temperature was recorded as 42°C (107.6°F),and icing, a cooling blanket, fanning, and dantrolene(10 mg/kg) were initiated. Laboratory values includedhemoglobin, 12.9 g/dL; leukocytes, 10,200 cells/mm3;platelets, 99,000/mm3; prothrombin time, longer than100 seconds; activated partial thromboplastin time, longerthan 300 seconds; fibrinogen, 141 mg/dL; D-dimer, higherthan 1000 mg/mL, and creatine phosphokinase, 1632 U/L.A head CT showed mild cerebral edema, and status epilep-ticus was confirmed on electroencephalography (EEG).The patient received dexamethasone, mannitol, pento-barbital, dopamine, norepinephrine, fresh-frozen plasma,platelets, and vitamin K. The admitting intensivist consid-

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its classic lower-extremity spasms in the context of recentmyelography) would have allowed better anticipation ofthis patient’s course and immediate needs.

Based on the available evidence, optimal managementof the ATCS syndrome should include early neuromuscu-lar paralysis, aggressive temperature and blood pressurecontrol, head elevation (to prevent cephalad migration ofcontrast agent), and spinal fluid drainage. Antiepilepticsare frequently required, and EEG monitoring is essential.Although dantrolene is valuable in succinylcholine-inducedmalignant hyperthermia, its utility in the ATCS syndromeis unknown.

Ionic and nonionic contrast agents have similar appear-ance but vastly different intrathecal neurotoxicities.Despite warning labels and protocols designed to preventthe inadvertent use of ionic agents for intrathecal proce-dures, human errors continue to occur. Emergencyphysicians must be capable of recognizing and rapidly ini-tiating appropriate resuscitative responses for the ATCSsyndrome.

R E F E R E N C E S1. Junck L, Marshall WH: Neurotoxicity of radiologic contrast agents. Ann Neurol1983;13:469-484.

2. Bryan RN, Dauth GW, Gilman S, et al: Effects of radiographic contrast agents on spinalcord physiology. Invest Radiol 1981;16:234-239.

3. Lalli AF: Contrast media reactions: Data analysis and hypothesis. Radiology 1980;134:1-12.

4. Bohn HP, Reich L, Suljaga-Petchel K: Inadvertent intrathecal use of ionic contrast mediafor myelography. AJNR Am J Neuroradiol 1992;13:1515-1519.

5. McClennan BL: Contrast media alert. Radiology 1993;189:35.

6. Killeffer JA, Kaufman HH: Inadvertent intraoperative myelography with Hypaque: Casereport and discussion. Surg Neurol 1997;48:70-73.

7. Nakazawa K, Yoshinari M, Kinefuchi S, et al: Inadvertent intrathecal administration ofamidetrizoate. Intensive Care Med 1988;15:55-57.

8. Rivera E, Hardjasudarma M, Willis BK, et al: Inadvertent use of ionic contrast material inmyelography: Case report and management guidelines. Neurosurgery 1995;36:413-415.

9. Campbell RL, Campbell JA, Heimburger RF, et al: Ventriculography and myelography withabsorbable radiopaque medium. Radiology 1964;82:286-289.

10. Hilz MJ, Huk W, Schellmann B, et al: Fatal complications after myelography with meglu-mine diatrizoate. Neuroradiology 1990;32:70-73.

11. Barbaccia JJ: Myoclonus in the postanesthesia care unit after an intraoperative myelo-gram. Anesth Analg 1995;80:413-414.

12. Morrey BF, O’Brien ET: Femoral neck fractures following water-soluble myelographyinduced spinal seizures. J Bone Joint Surg 1977;59A:1099-1100.

13. Wollin DG, Lamon CB, Cawley AJ, et al: The neurotoxic effect of water soluble contrastmedia in the spinal canal with emphasis on appropriate management. J Can Assoc Radiol1967;19:296-303.

14. Rosati G, Leto di Priolo S, Tirone P: Serious or fatal complications after inadvertent admin-istration of ionic water-soluble contrast media in myelography. Eur J Radiol 1992;15:95-100.

15. Haase J, Jepsen BV, Bech H, et al: Spinal fracture following radiculography using meglu-mine iothalamate (Conray). Neuroradiology 1973;6:65-70.

effective in the management of myoclonic jerking, butneuromuscular paralysis for several days is typicallyrequired to prevent violent spasms and the consequenthyperpyrexia, acidosis, rhabdomyolysis, and fractures.Early drainage and/or lavage of spinal fluid has been sug-gested to be beneficial, but no treatment guidelines existto determine when this approach should be used.4,6-8

One case report described a 65-year-old man who recov-ered completely from an episode of the ATCS syndrome.6

The patient had progressive painful ascending spasms,fever, obtundation, and rhabdomyolysis 3 hours after inad-vertently being given 10 mL of meglumine diatrizoate(Hypaque) during a myelogram. On recognition of theoperative error, the patient was paralyzed and intubated,the head of the bed was elevated, and 20 mL of spinal fluidwas removed by means of lumbar puncture. Aggressivecare, including sterile saline solution lavage via cervicaland lumbar spinal needles, resulted in a complete recovery6 hours after inadvertent instillation of 5 mL of amidetri-zoate.7 Conversely, some patients appear to recover with-out spinal fluid drainage. In a case series involving 10patients, 5 patients died and 4 survived without spinalfluid drainage, and 1 patient recovered after drainage of180 mL in 20-mL increments.4

There have been no reports of adverse effects from spinalfluid drainage. Given the progressive ascending toxicityof these agents as they circulate upward toward the brain,emergency removal of at least 20 mL of lumbar spinal fluidmakes clinical sense.

In summary, the patient described earlier was accidentallygiven 8 mL of the hyperosmolar ionic contrast agent meg-lumine diatrizoate. The patient was brought to the ED 75minutes later with classic manifestations of the ATCSsyndrome. Although some irritant effect of the myelogramwas suspected, the progressive and fulminant course causedby the intrathecal use of an ionic contrast agent was notconsidered initially. The ATCS syndrome went unrecog-nized to the radiology, emergency medicine, anaesthesiology,and critical care physicians involved in this case. Earlymanagement with analgesics and benzodiazepines wasunsuccessful. Progressive agitation developed, probablyas a result of both a central nervous system toxic effectand unrecognized worsening hyperthermia. Both theinitial tympanic temperature and the cool skin provedinsensitive indicators of the patient’s true core temper-ature. Neuromuscular paralysis, cooling measures, anddantrolene controlled the patient’s temperature, but pro-found vasomotor instability, disseminated intravascularcoagulation, rhabdomyolysis, and ultimately deathensued. Rapid recognition of the ATCS toxidrome (with