The complication rate of edrophonium testing for suspected myasthenia gravis Edsel B. Ing, *MD, FRCSC; Sabrina Y. Ing, BSc; Tom Ing, * MD, FRCSC; John A. Ramocki, t MD ABSTRACT • RESUME Background: The incidence of life-threatening complications from edrophonium chloride (Tensilon) testing for suspected myasthenia gravis is thought to be extremely low. We carried out a survey to determine the rate of serious complications from such testing. Methods: In April 1998, 357 physicians listed in the 1998 roster of the North American Neuro-ophthalmology Society were mailed a questionnaire for anonymous completion. Questions asked included the number of years the clinician had practised neuro-ophthalmology, the estimated number of edrophonium tests performed since completion of training, the number and nature of major complications from edrophonium, and whether the clinician preferred the sleep test or ice test to edrophonium testing. Results: The response rate was 56% ( 199/357). Of the 199 respondents, I05 (53%) had practised neuro-ophthalmology for at least I0 years. The group estimated that they had performed at least 23 I I I edrophonium tests, of which 37 (0.16%) were associated with a serious complication, mostly attributed to bradyarrythmias and syncope. Respiratory failure, seizure, severe vomiting and transient ischemic attack were also reported. Thirty-one respondents ( 16%) preferred the sleep test or ice test to the edrophonium test; one-third of this group reported a serious complication with edrophonium. Interpretation: The rate of significant complications of edrophonium testing is low, but the complications can be potentially life threatening. Clinicians should know the nature and incidence of these complications when obtaining informed consent for edrophonium testing.
Contexte : On croit qu'il est extremement rare que des complications mena~ant Ia vie du malade surviennent a Ia suite de !'administration du test au chlorure d'edrophonium (Tensilon) effectue lorsqu'une myasthenie grave est soup~onnee. Nous avons mene une enquete pour determiner le taux de complications serieuses de ce test. Methodes : En avril 1998, 357 medecins dont le nom figurait sur le tableau de 1998 de Ia North American Neuro-ophthalmology Society ont re~u par Ia paste un questionnaire qu'ils ont ete pries de remplir en gardant l'anonymat. On leur a
From *the MD Eye Clinic, Windsor, Ont., and tthe Kresge Eye Institute, Detroit, Mich. Ms. Ing is a medical student at the University of Toronto, Toronto, Ont.
Reprint requests to: Dr. Edsel B. Ing, 1617 Ouellette A':e., Windsor ON N8X 1K9; fax (519) 252-1167,
[email protected]
Accepted for publication Dec. 2, 1999
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Edrophonium complications-Ing et al demande d'indiquer le nombre d'annees d'exercice de Ia neuro-ophtalmologie qu'ils comptaient, le nombre approximatif de tests a l'edrophonium qu'ils avaient administres apres avoir termine leur formation, le nombre et Ia nature des complications majeures qu'ils avaient enregistrees apres avoir administre le produit et s'ils preferaient le test du sommeil ou celui de Ia glace au test a l'edrophonium. Resultats : Le taux de reponse a ete de 56 % ( 199/357). Des 199 repondants, IOS (53 %) exerc;aient Ia neuro-ophtalmologie depuis au mains dix ans. Pour !'ensemble des repondants, le nombre approximatif de tests a l'edrophonium s'elevait a 23 I II, dont 37 (0, 16 %) etaient associes a des complications serieuses, principalement attribuees a une bradyarythmie et a une syncope. Des defaillances respiratoires, des crises d'epilepsie, des vomissements graves et des accidents ischemiques transitoires ont aussi ete signales. Trente-et-un repondants ( 16 %) preferaient le test du sommeil ou celui de Ia glace au test a l'edrophonium; un tiers de ce groupe a signale une complication serieuse avec l'edrophonium. Interpretation : Le taux de complications serieuses du test a l'edrophonium est faible, mais les complications peuvent menacer Ia vie du malade. Les cliniciens devraient connaitre Ia nature et Ia frequence de ces complications lorsqu'ils obtiennent du malade un consentement donne en connaissance de cause au test a l'edrophonium.
E
drophonium chloride (Tensilon, ICN Canada Ltd., Montreal) is a short-acting anticholinesterase commonly used in the diagnosis of ocular myasthenia gravis. Edrophonium produces minor cholinergic side effects, such as diaphoresis, lacrimation, salivation, fasciculations and abdominal cramps, as well as major cholinergic side effects, such as bronchiolar constriction, hypotension, apnea, bradycardia and ventricular asystole. I The incidence of life-threatening complications from edrophonium testing for myasthenia gravis is thought to be very low, but case reports are few.t We carried out a study to determine the incidence and nature of complications with edrophonium testing. METHODS
Physicians listed in the 1998 roster of the North American Neuro-ophthalmology Society who resided in the continental United States or Canada were sent a questionnaire for anonymous completion in April 1998. A stamped return envelope was included, and respondents who did not want to complete the questionnaire were asked to return the form blank. Respondents were asked to estimate the number of edrophonium tests they had performed and to indicate major complications of edrophonium testing, if any. To avoid duplication of reported events, respondents were asked to limit their answers to the tests they had performed since completion of their training. Criteria for a "major complication" of edrophonium testing were
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not specified in the survey. Respondents were given the latitude to specify any incidents they thought were particularly problematic or life threatening to the patient. Additional questions on the survey included number of years the clinician had practised neuroophthalmology and whether he or she preferred the sleep test2 or ice test3 to edrophonium testing. RESULTS
After a 6-month period, 203 questionnaires were returned. Four surveys were returned blank: in one case the physician had retired, another physician was ill, and two physicians indicated that neuro-ophthalmology was not their primary practice focus. The response rate for the survey was therefore 56% (199/357). At least 23 111 edrophonium tests were tallied in the group of 176 respondents who indicated the number of tests they had performed since completing training (group A). They documented 37 complications from the tests, suggesting a complication rate of 0.16%. The number of edrophonium tests performed by this group may be an underestimate since many prefaced their estimate with a "greater than" sign. Twenty-three respondents did not provide an estimate of the number of edrophonium tests they had performed (group B). Ofthe 23, 19 did not give any indication of how many tests they had performed; three complications of testing were documented in this
Edrophonium complications-Ing et al group. The four remaining respondents did not provide an estimate of the number of edrophonium tests they had performed but used modifiers such as "lots" or "too numerous to count;" no complications were reported in this group. Of the 40 major complications reported, 29 were cardiac complications, such as syncope, bradycardia, heart block or asystole (Table 1). One of the patients with syncope had a history of ventricular tachycardia that was not known to the physician before testing. The patient lived. Another patient had 15 seconds of asystole documented on a rhythm strip despite pretreatment with atropine. Four patients were thought to have severe respiratory compromise during testing. These episodes were described as "apnea" in two patients, "asthma" in one and "severe hypoxia" in one. Three patients were reported to have had a seizure. Vomiting was considered a major complication in two patients. The vomiting was problematic in one patient, who had insulin-dependent diabetes mellitus, because of its long duration. Another patient vomited while wearing a fixation collar needed to support vertebrae that had been eroded by metastatic cancer. One patient had a transient ischemic attack with loss of consciousness after testing. In the remaining case the respondent did not give the details of the major complication. One clinician in group A reported a case of syncopal bradycardia but did not feel it was a major complication. None of the respondents reported the death of a patient after edrophonium testing. The respondents had various levels of experience: 91 (46%) had less than 10 years of experience in neuro-ophthalmology, 105 (53%) had practised neuroophthalmology for 10 years or more, and 40 (21%) had practised neuro-ophthalmology for 20 years or more. Three respondents did not indicate how long they had been in clinical practice. Of the 30 respondents who reported a complication, 22 (73%) had practised neuro-ophthalmology for at least 10 years. Of the 199 respondents 138 (69%) indicated that they used the edrophonium test primarily in the diagnosis of ocular myasthenia gravis and rarely used the sleep test or the ice test. Thirty-one respondents ( 16%) preferred the sleep test, with or without ice, to edrophonium testing; of the 31, 11 (35%) had experienced a major complication with the latter test. Several clinicians indicated that they used a 5-minute sleep test rather than a half-hour sleep test. One respondent preferred the neostigmine test, and six indicated that they used both the edrophonium and the sleep test fre-
Table 1-Major complications of edrophonium testing for myasthenia gravis reported in a 1998 survey of 199 members of the North American Neuro-ophthalmology Society Complication Cardiovascular compromise (syncope, bradycardia, asystole) Respiratory compromise (apnea, asthma, severe hypoxia) Seizure Vomiting Transient ischemic attack (following loss of consciousness) No details given
No. of respondents
29 4 3 2
40
Total
quently. Twenty-four respondents did not indicate a preference. INTERPRETATION
A weakness of our study is the potential bias of the 56% of neuro-ophthalmologists who chose to respond to the survey. However, over half of the respondents had practised neuro-ophthalmology for 10 years or more. Although there is missing information, the 40 major complications reported and the nature of the complications are informative. In comparison, Van Dyk and Florence's telephone survey of 25 neuroophthalmologistsi yielded three cases of major complications from edrophonium testing: cardiac arrest, hypotension with bradycardia, and apnea with unconsciousness. Some of the more notable complications in our study highlight several points. First, a thorough history to exclude cardiorespiratory disease must be taken before edrophonium testing. Second, pretreatment with atropine may not prevent complications such as asystole. Third, vomiting is usually considered a minor complication of edrophonium testing. However, vomiting is a potentially life threatening complication when the patient's airway cannot be accessed easily. The rate of complications of edrophonium testing for myasthenia gravis among the respondents who indicated the number of tests they had performed was 0.16%. Sources of error in this estimate include unreported edrophonium tests and unreported complications. Many of these clinicians prefaced their estimate
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Edrophonium complications-Ing et al with a "greater than" sign. However, unreported tests would have minimally affected the estimated complication rate, given the large denominator in this group (23 111). Even if these clinicians grossly underreported their edrophonium tests, say, by 5000, the complication rate would be relatively unchanged (0.13% [37/28 111]). One of the respondents in the group who indicated the number of their tests did not feel that his or her case of syncopal bradycardia was a major complication. If this case were included among the complications, the complication rate would remain 0.16% (38/23 111). Three complications were reported in the group of 23 respondents who did not indicate the number of edrophonium tests they had performed. If each of these clinicians performed the average number of tests carried out by the first group, 131.3, the overall number of tests would be 26 131, for a complication rate of 0.15% (40/26 131). In the unlikely event that each of the 23 clinicians performed only one edrophonium test since completing training, the complication rate would be 0.17% (40/23 134). No deaths from edrophonium testing were reported by the respondents in our survey. However, clinicians who experienced complications with edrophonium may have been less motivated to return the questionnaire. The survey was designed for anonymous completion in hopes of minimizing this possibility. The incidence of complications likely varies with the dosing regimen of edrophonium. Our survey did not elicit information about this factor. However, one respondent specifically indicated that he or she did not give more than 3 mg of edrophonium during the test. It has been suggested that edrophonium dosages larger than 5 mg often do not produce a positive result if lower dosages are not effective. 4 However, a dosage of 10 mg administered intravenously is commonly used in adults. Most texts suggest an initial dosage of 2 mg. If after approximately 1 minute the patient has no complications, the remainder of the drug can be administered as an 8-mg dose or two 4-mg doses.s-7 Pretreatment with atropine is controversial,5 but there is no dispute that this agent should be available at the time of edrophonium testing. Edrophonium testing can be performed safely in adequately screened patients in both the office and the outpatient clinic setting. Resuscitation equipment should be available, the vital signs should be monitored, and venous access should be maintained throughout the test for possible atropine administra-
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tion. Although pulse oximetry and heart monitoring are ideal and, in our opinion, are preferable in the hospital clinic setting, they are not mandatory in appropriately screened patients. The sleep test, the ice test, a trial of pyridostigmine bromide (Mestinon, Hoffmann-La Roche Limited, Mississauga, Ont.), testing for acetylcholine receptor antibodies and electromyography are possible alternatives to edrophonium testing. Before the sleep test the degree of ptosis or ophthalmoparesis is documented. It may be helpful to photograph the ptosis. In the original sleep test the patient is asked to sleep or rest with the eyes closed for 30 minutes. 2 If there is significant resolution of the ptosis or improved motility immediately after the rest period, the result is positive and is suggestive of myasthenia gravis. Local cooling is thought to improve muscle function in myasthenia gravis. In the ice test crushed ice can be placed over the more ptotic eyelid for 2 minutes. 3 The opposite lid may be used as a control. If the degree of ptosis in the covered eye decreases on removal of the ice-pack, the result is considered positive and is suggestive of myasthenia gravis. In summary, edrophonium testing for myasthenia gravis is generally safe for appropriately screened patients. In our survey serious complications occurred in 0.16% of tests and included cardiorespiratory collapse, seizures and severe vomiting. The sleep test with or without the ice test was preferred over the edrophonium test by 16% of the clinicians surveyed. REFERENCES
1. VanDyk H, Florence L. The Tensilon test: a safe office procedure. Ophthalmology 1980;87:210-2. 2. Ode! J, Winterkom J, Behrens M. The sleep test for myasthenia gravis- a safe alternative to Tensilon. J Clin Neuro Ophthalmoll99l;ll:288-92. 3. Sethi K, Rivner M, Swift T. Ice pack test for myasthenia gravis. Neurology 1987;37:1383-5. 4. Weinberg DA, Lesser R, Vollmer TL. Ocular myasthenia: a protean disorder. Surv Ophthalmoll994;39:l69-210. 5. Kuncl RW, Hoffman PN. Myopathies and disorders of neuromuscular transmission. In: Miller NR, Newman NJ, editors. Walsh & Hoyt's clinical neuro-ophthalmology. 5th ed. voll. Baltimore: Williams & Wilkins; 1998. p. 1351-460. 6. O'Connor PS. Ancillary clinical procedures. In: Kline LB, Bajandas FJ, editors. Neuro-ophthalmology review manual. 4th ed. Thorofare (NJ): Slack Incorporated; 1996. p. 211-8. 7. Compendium of pharmaceuticals and specialties. 31st ed. Ottawa: Canadian Pharmaceutical Association; 1996. p. 1449.
Key words: edrophonium, complications, myasthenia gravis, sleep test
Edrophonium complications-Ing et al
Discussion ·After 16 years practising neuro-ophthalmology (and doing edrophonium tests without complication) at McGill University, Montreal, I moved to the University of British Columbia, Vancouver, and within the first 4 months of practice I had one case of respiratory arrest and one of cardiac asystole from edrophonium testing in the neuro-ophthalmology clinic. These patients had been referred for assessment of unexplained ptosis and diplopia, and both ended up intubated in the intensive care unit with numerous vascular access lines and monitors, and I suspect they (and all the other patients in my now-empty waiting room) wished they had never been referred to me. Following this, I reviewed my own experience and the literature on the risks of edrophonium testing, and I presented the findings to the North American Neuroophthalmology Society meeting. After my presentation it was agreed that the published reports suggested that complications of edrophonium testing were extremely rare, although 9 or 10 neuro-ophthalmologists at the meeting attested to their own isolated serious complications. As a result of this experience, I now feel it is unsafe to perform an edrophonium test if one is alone in one's office without some nursing or resident assistance as well as some minimal monitoring ability. I was hopeful about the sleep test and the ice test, but in my clinic no one could possibly sleep, and it is difficult to monitor that the patient is keeping his or her eyes closed. The ice test often causes some erythema and slight swelling of the affected eyelid, and I have not found it reliable. A well-performed pyridostigmine
trial appears to be much safer and just as informative (albeit somewhat slower) than the edrophonium test. We start with 60 mg/d ofpyridostigmine and increase the dosage by 60 mg every 2 days until the symptoms resolve or diarrhea develops. We then see the patient at the maximum dosage to document the presence or absence of a pyridostigmine effect. There is no rush to make the diagnosis of myasthenia gravis, as the disease will eventually declare itself. Pyridostigmine testing is diagnostic in the vast majority of cases. Having a neurologic colleague expert in diagnosis and management of myasthenia is a huge help, as are testing for acetylcholine receptor antibodies and electromyography. Dr. Edsel Ing and his colleagues are to be congratulated for the efforts they have made to get at the true risk of edrophonium testing. Although there are some potential shortfalls and biases with a questionnaire response rate of 56%, their survey covers a great number of person-years of practice and, as such, is extremely useful. Since it is human nature to overestimate the number of things one has done in life and to underestimate the problems one has had with them, I suspect the true complication rate may be slightly higher than the 0.16% suggested by the authors. Although this may seem like an extremely low complication rate, the complications are serious, as pointed out by the authors. It is gratifying to see that no deaths were reported.
Duncan P. Anderson, MD, FRCSC Department of Ophthalmology St. Paul's Hospital Vancouver, BC
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