Are  Anaesthetists  at  Particular Risk  of  Developing  MS?
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Alone asking this question suggests a bias, and I must therefore recommend the reader to exert caution to a possibly imbalanced search.

Only one Swedish study [1] is so far available, suggesting a connection – and while being available only as an abstract, it shall be considered to a greater detail here:
    The authors requested in the occupational magazine of Swedish anaesthesia nurses plus a magazine issued by an organization for neurological handicaped. 90 anaesthesia nurses responded, among whom 10 with definite MS had had at least one year of exposure to anaesthetic gases before diagnosis of MS in 1980-99. This is compared with an expected level (adjusted for age and sex) of 2.8 (1.3-5.2) from MS registers in Denmark and Sweden among the little more than 2000 (2046-83) jobs as anaesthesia nurses.
    The study has methodological weaknesses, as pointed out by its authors: The incidence might be higher with a more systematical analysis. On the other hand, the positions of anaesthesia nurse shows a certain fluctuancy. However, this study is the first indication of a possible connection.
    But then, if there is a link between inhalation of vaporous and gaseous anaesthetics, any other country than Sweden would be better to show the connection – save that the authors are Swedish – since this is the country in which the sharpest initiatives have been taken to reduce the occupational exposure. Other countries may have the same borderline levels but only in Scandinavia are they also controlled and respected, leading to the invention of Swedish scavenging measures still hardly understood outside the Nordic countries [2-6]. Still, even in other countries, one must remember that both the exposing agents and the magnitude of exposure has changed in the course of time. There is hardly any reason to consider drugs for i.v. injection, to which the anaesthetist or anaesthesia nurse never had any direct contact. If there is a connection, it must be caused by nitrous oxide or various volatile agents, possibly both.
    In a large epidemiological study, involving 49,585 exposed operating room personal and 23,911 unexposed controls, interrogared by the American Society of Anaesthetists [7], a significant in crease of leukaemia and lymphomas (along with liver diseases, among others) was found in the exposed group. Among anaesthetists themselves, increased exposure to general anaesthetics resulted in a 2-3 fold increase in various cerebral symptoms [8]. It deserves mention, though not quotation, that quite a number of studies exist, with controversial conclusions, concerning cognitive parameters among anaesthetists in dependence of exposure.
Apart from such, unfortunately non-existing epidemiological studies, only two study sources would seem appropriate for appoaching the problem: 1) Effect of anaesthetics on patients with an already established MS and 2) experimental study concerning cellular effects of anaesthetic gaseous or volatile agents.

Effect of anaesthetics on patients with MS

For patients with MS, anaesthesia presents only a brief exposure and the cause of anaesthesia (accident or larger operation) may deteriorate defense mechanisms, prompting a relapse.
    Most reviews have dealt with the forensic aspects of performing a regional anaesthesia in MS patients. Obviously, the presence of peripheral neural defects and the expectancy of more to come has led to fear among anaesthesists that the foreseen development might be contributed to regional anaesthesia. Typical for contemporary medicine, the fear of forensic prosecution often overweighs the desire to perform the best possible measurement but the mutual conclusion, that regional anaesthesia can be performed as well in MS patients as in other subjects, has been confirmed in several reviews.
    On the contrary, the actual effect of a general anaesthesia cannot be estimated according to the study of patients. Although massive, the exposition is of a brief duration and MS yields no sensitive parameter which could indicate a temporary deterioration, as if it was possible to segregate anaesthesia from what has made it necessary. Only experimental studies may therefore offer some insight into this problem.

Cellular effects of anaesthetic gaseous or volatile agents

The literature is dominated by the interest for the effect of halothane upon the liver, but the free-radical intermediates may both be active in other tissues or generated there. In a review of the matter, Morio et al. [9] emphasized that anaerobic metabolism of halothane is increased by hypoxia and its intermediate production produces a free radical. Even in the absence of hypoxia, halothane biotransformation by cytochrome P-450 produces reactive intermediates along both oxidative (acyl chloride) and reductive (free radical) pathways [10]. These free radical intermediates may initiate lipid peroxidation [11.
    In guinea pigs, Tsuchiya et al. [12] found that halothane causes an increase of superoxide production, which is correlated with (and possibly caused by) an activation of phospholipid-dependent protein kinase C. In these animals, American authors [10] found that inhibition of oxidative metabolism with deuterated halothane reduces resultant injury in our guinea pig model of acute halothane hepatoxicity. Similarly, Durak et al. [13] found in guinea pigs that halothane causes impairment in the hepatic antioxidant defense system and accelerates peroxidation reactions. Although vitamin E prevents peroxidative damage, it does not ameliorate ultrastructural changes caused by halothane treatment. Also in rats [12], dogs [14] and rabbits [15], halothane-induced lipid peroxidation was demonstrated.
    Following inhalation of halothane 8-12 ppm for 8 hours a day, 5 days a week (a dose relating to the anaesthetists working condition without scavenging measures), central nervous damages were demonstrated in two experimental studies on rats [16,17].

Additional exposures

To a certain degree, operating room staff are exposed to increased levels of ionizing radiation. The scarce protection of the trunk rather increases exposure to the rest of the body, in particular head and arms. In two case-control studies, Axelson et al. [18] reported an odds ratio of 4.4 for radiological work. In one of the studies, 5 cases but none of the controls had been treated with ionizing radiation.
     Another exposure is the anaesthetist’s close contact to the patients salivation, until recently only rarely protected by gloves. This undoubtedly predisposes anaesthetists to microbes, but if these are of importance in the pathogenesis of MS is again another matter.

Nitrous oxide and Vit B12

The intensive care unit has, unfortunately, developed a human toxicological test station for adverse effects of anaesthetics. These drugs have been designed for a brief use in the operating but are then transferred to the ICU in order to create tolerance to intolerable ventilatory measures. Once this use has been discovered to be associated with adverse effects, the drug tested (or shall we say, just used) is apt to loose favour as an anaesthetic as well. The list of anaesthesics, falling into disrepute in the ICU, is rather long, but the first drug losing favour among ventilated patients was nitrous oxide [19].
    Prolonged exposure to nitrous oxide (but unknown in which minimal concentration) will disturb the metabolism of vitamin B12 [VitB12]. Neurological defects have been shown following prolonged exposure [20,21], but with a preexistant deficiency of VitB12, it is possible that neurological defects may result following a single anaesthesia [22]. The role of this vitamin in the generation of MS will be emphasized shortly here.

In Summary,

the subject has not received the attention it deserves. This seems indeed to be a neglected area of medical studies, in spite of the 3-fold increase in prevalence of MS in the cited study. From the experimental studies, all of halothane effects in the liver, there seems to be some indication that free oxygen radicals may act causative, but without direct study of the matter, even this conclusion seems to be weak.


Thanks to Dr. Olav Axelson, Linköping (Sweden) for important suggestings and supportive literature.


  1. Flodin U, Landtblom AM, Axelson O. Multipel skleros och narkossköterskor. Abstract of lecture presented at NAM 2001 (ISBN 82-90688-10-5).
  2. Berner O. Concentration and elimination of anaesthetic gases in operating theatres. Acta Anaesthesiol Scand 1978;22:46-54.
  3. Nilsson K, Sonander H, Stenquist O. Close scavenging of anaesthetic gases during mask anaesthesia. Acta Anaesthesiol Scand 1981;25:4216.
  4. Carlsson P, Ljungquist B, Hallén B. The effect of local scavenging on occupational exposure to nitrous oxide. Acta Anaesthesiol Scand 1983;27:470-5.
  5. Reiz S, Gustavson A-S, Häggmark S, Lindkvist K, Lindkvist R, Normal M, Strömberg B. The double-mask – a new scavenging system for anaesthetic gases and volatile agents. Acta Anaesthesiol Scand 1986;30:260-5.
  6. Schou J, Kübler J, Cartellieri M. Die "Doppelmaske". Anaesthesist 1990;39: 122-4.
  7. American Society of Anesthesiologists. Occupational disease among operating roomr personal. Anesthesiology 1974;41:321-40.
  8. Buchberger J, Greuter W, Kündig S. Berufliche Narkosegasexposition des Spitalpersonals in der Schweiz. Arbeitsärztlicher Dienst des Bundesamtes für Industrie, Gewerbe und Arbeit, Bern 1985.
  9. Morio M, Yuge O, Fujii K. Biotransformation and toxicity of inhalational anaesthetics. Can J Anaesth 1990;37:Scxvi-Scxxiii
  10. Lind RC, Gandolfi AJ. Covalent binding of oxidative biotransformation reactive intermediates to protein influences halothane-associated hepatotoxicity in guinea pigs. Adv Exp Med Biol 1991;283:763-6.
  11. Awad JA, Horn JL, Roberts LJ, Franks JJ. Demonstration of halothane-induced hepatic lipid peroxidation in rats by quantification of F2-isoprostanes. Anesthesiology 1996;84:910-6.
  12. Tsuchiya M, Okimasu E, Ueda W, Hirakawa M, Utsumi K. Halothane, an inhalation anesthetic, activates protein kinase C and superoxide generation by neutrophils. FEBS Lett 1988;242:101-5.
  13. Durak I, Guven T, Birey M, Ozturk HS, Kurtipek O, Yel M, Dikmen B, Canbolat O, Kavutcu M, Kacmaz M. Halothane hepatotoxicity and hepatic free radical metabolism in guinea pigs; the effects of vitamin E. Can J Anaesth 1996;43:741-8.
  14. Yamazoe K, Inaba T, Bonkobara M, Matsuki N, Ono K, Kudo T. Changes of hepatic tissue phospholipid peroxidation, malondialdehydes, and antioxidative enzyme activities in dogs with halothane inhalation. J Vet Med Sci 1998;60:15-21.
  15. Yesilkaya A, Ertug Z, Yegin A, Melikoglu M, Baskurt OK. Deformability and oxidant stress in red blood cells under the influence of halothane and isoflurane anesthesia. Gen Pharmacol 1998;31:33-6.
  16. Chang LW, Dudley AW, Lee YK, Katz J. Ultrastructural changes in the nervous system after chronic exposure to halothane. Exp Neurol 1974;45:209-19.
  17. Quimby KL, Aschenase LJ, Bowman RE, Katz J, Chang LW. Enduring learning defects and cerebral synaptic malformation from exposure to 10 parts of halothane per million. Science 1974;185:625-7.
  18. Axelson O, Landtblom A-M, Flodin U. Multiple sclerosis and ionizing radiation. Neuroepimediology 2001;20:175-8.
  19. Lassen HCA, Henriksen E, Neukirch A, Kristensen HS. Treatment of tetanus: severe bone marrow depression after prolonged use of nitrous oxide.
  20. Layzer RB. Myeloneurpathy after prolonged exposure to nitrous oxide. Lancet 1978;ii:1227-30.
  21. Lazyer RB, Fishman RA, Schafer JA, Neuropathy following abuse of nitrous oxide. Neurology 1978;28:504-6.
  22. Schilling RF. Is nitrous oxide a dangerous anaesthetic for vitamin B12-deficient subjects. JAMA 1986;255:1605-6.

Inserted February 16, 2002

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