Journal of Neurology, Neurosurgery, and Psychiatry 1991;54:584-589 A prospective study of physical trauma and multiple sclerosis William A Sibley, Colin R Bamford, Katherine Clark, Michael S Smith, Jose F Laguna Abstract During an eight year period 170 multiple sclerosis (MS) patients and 134 controls without physical impairment were fol- lowed closely to record all episodes of physical trauma and to measure their effect on exacerbation rate and progres- sion of MS. There was a total of 1407 instances of trauma, which were sorted into various categories. Overall there was no significant correlation between all-traumas and disease activity. There was, however, a statistically significant negative correlation between traumatic episodes and exacerbations in 95 patients who had exacerbations during the pro- gramme, due primarily to less activity of the disease during a three month period following surgical procedures and frac- tures. Electrical injury had a significant positive association with exacerbation using a three month at-risk period, but there were no other significant positive correlations in any other category of trauma, including minor head injuries; there were no cases of head injury with prolonged unconsciousness. There was no linkage between the frequency of trauma and progression of disability. MS patients had two to three times more trauma than controls. Department of Neurology, University of Arizona College of Medicine and the University Hospital, Tucson, Arizona, USA W A Sibley C R Bamford K Clark M S Smith J F Laguna Correspondence to: Dr Sibley, University Hospital, Tucson, Arizona 85724, USA Received 16 August 1990 and in final revised form 26 November 1990. Accepted 5 December 1990 In spite of their potential significance, environmental factors which might influence the course of multiple sclerosis (MS) have seldom been studied in a systematic prospec- tive way. The older medical literature, much of it anecdotal, suggests that many factors may be responsible for new attacks of MS, but most of these studies were retrospective and relied on chart reviews or the memories of patients and their families. Memories can be quite selective: events such as emotional stress or trauma that are followed by an exacerbation are more likely to be recorded than events not followed by worsening of the disease. This problem, and the need for statistical validation of a proposed relationship between trauma and MS, was recognised by McAlpine et al.1 For eight years our clinic conducted a pros- pective study of MS patients in an effort to uncover external factors which might be risk factors. Several years ago we published a report based on the first three years of data on the effects of physical trauma; there was a trend for electrical injuries to be a risk factor, although this did not reach statistical sig- nificance. We could not, however, find a positive relationship with other forms of trauma.2 Since then, five more years of data have been accumulated, all of it has been re- analysed in greater detail and we now present a report on the completed study. Methods During an eight year period 170 MS patients were followed at monthly intervals. One hun- dred and four were female (F:M ratio 1-6:1). Their mean age was 43 years. All patients with clinically definite MS3 in the community were eligible to participate if they were able to attend the clinic for periodic examination and willing to cooperate with the rules of the programme. They received no immuno- suppressive or other prophylactic treatment during the study, although the more severe clinical exacerbations were commonly treated with 10-14 days of intramuscular cortico- tropin or oral prednisone. Some patients did not complete the full eight years of the programme due to relocation or late recruit- ment. Four discontinued to enter a trial of prophylactic immunotherapy and five because of advanced disability (DSS 8 or 9). The mean time in the programme per patient was 5 2 years. There were 134 controls of similar age and sex without neurological disease followed in a similar manner to permit comparison of the frequency of various events in the two groups. There were 85 females (F:M ratio 1-7:1) and the mean age was 40 years. Most of the controls were healthy at entry into the study, although two had rheumatoid arthritis. Many were intermittently disabled for short periods by intercurrent illnesses. One purpose of the study was to have both patients and controls complete a questionnaire every 30 days, concerned with recording the occurrence of a wide variety of events during the previous month. Included were questions about the occurrence of physical trauma, stressful life events, infections and a variety of other factors. If the questionnaires were not returned, subjects were contacted by telephone and the data recorded by the clinic nurse (KC). Changes in the patients' symptoms were promptly reported to the same person. Multiple sclerosis patients had a complete neurological examination routinely every three months, including the recording of Kurtzke Functional Scores and Disability 584 on November 22, 2021 by guest. Protected by copyright. http://jnnp.bmj.com/ J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.54.7.584 on 1 July 1991. Downloaded from
Transcript
Journal of Neurology, Neurosurgery, and Psychiatry 1991;54:584-589
A prospective study of physical trauma andmultiple sclerosis
William A Sibley, Colin R Bamford, Katherine Clark, Michael S Smith, Jose F Laguna
AbstractDuring an eight year period 170 multiplesclerosis (MS) patients and 134 controlswithout physical impairment were fol-lowed closely to record all episodes ofphysical trauma and to measure theireffect on exacerbation rate and progres-sion of MS. There was a total of 1407instances of trauma, which were sortedinto various categories. Overall therewas no significant correlation betweenall-traumas and disease activity. Therewas, however, a statistically significantnegative correlation between traumaticepisodes and exacerbations in 95 patientswho had exacerbations during the pro-gramme, due primarily to less activity ofthe disease during a three month periodfollowing surgical procedures and frac-tures. Electrical injury had a significantpositive association with exacerbationusing a three month at-risk period, butthere were no other significant positivecorrelations in any other category oftrauma, including minor head injuries;there were no cases of head injury withprolonged unconsciousness. There wasno linkage between the frequency oftrauma and progression of disability.MS patients had two to three times moretrauma than controls.
Department ofNeurology, UniversityofArizonaCollege ofMedicineand the UniversityHospital, Tucson,Arizona, USAW A SibleyC R BamfordK ClarkM S SmithJ F LagunaCorrespondence to:Dr Sibley, UniversityHospital, Tucson, Arizona85724, USAReceived 16 August 1990and in final revised form26 November 1990.Accepted 5 December 1990
In spite of their potential significance,environmental factors which might influencethe course of multiple sclerosis (MS) haveseldom been studied in a systematic prospec-tive way. The older medical literature, muchof it anecdotal, suggests that many factors maybe responsible for new attacks of MS, butmost of these studies were retrospective andrelied on chart reviews or the memories ofpatients and their families. Memories can bequite selective: events such as emotional stressor trauma that are followed by an exacerbationare more likely to be recorded than events notfollowed by worsening of the disease. Thisproblem, and the need for statistical validationof a proposed relationship between traumaand MS, was recognised by McAlpine et al.1For eight years our clinic conducted a pros-
pective study of MS patients in an effort touncover external factors which might be riskfactors. Several years ago we published a
report based on the first three years of data onthe effects of physical trauma; there was a
trend for electrical injuries to be a risk factor,
although this did not reach statistical sig-nificance. We could not, however, find apositive relationship with other forms oftrauma.2 Since then, five more years of datahave been accumulated, all of it has been re-analysed in greater detail and we now presenta report on the completed study.
MethodsDuring an eight year period 170 MS patientswere followed at monthly intervals. One hun-dred and four were female (F:M ratio 1-6:1).Their mean age was 43 years. All patientswith clinically definite MS3 in the communitywere eligible to participate if they were able toattend the clinic for periodic examination andwilling to cooperate with the rules of theprogramme. They received no immuno-suppressive or other prophylactic treatmentduring the study, although the more severeclinical exacerbations were commonly treatedwith 10-14 days of intramuscular cortico-tropin or oral prednisone. Some patients didnot complete the full eight years of theprogramme due to relocation or late recruit-ment. Four discontinued to enter a trial ofprophylactic immunotherapy and five becauseof advanced disability (DSS 8 or 9). Themean time in the programme per patient was5 2 years.There were 134 controls of similar age and
sex without neurological disease followed in asimilar manner to permit comparison of thefrequency of various events in the two groups.There were 85 females (F:M ratio 1-7:1) andthe mean age was 40 years. Most of thecontrols were healthy at entry into the study,although two had rheumatoid arthritis. Manywere intermittently disabled for short periodsby intercurrent illnesses.One purpose of the study was to have both
patients and controls complete a questionnaireevery 30 days, concerned with recording theoccurrence of a wide variety of events duringthe previous month. Included were questionsabout the occurrence of physical trauma,stressful life events, infections and a variety ofother factors. If the questionnaires werenot returned, subjects were contacted bytelephone and the data recorded by theclinic nurse (KC). Changes in the patients'symptoms were promptly reported to thesame person.
Multiple sclerosis patients had a completeneurological examination routinely everythree months, including the recording ofKurtzke Functional Scores and Disability
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A prospective study ofphysical trauma and multiple sclerosis
0-7-
0-6In Patient ann. rate (mean)
0.4 D Control ann. rate (mean)
0-3O
0.2-
0 I-?
A
z 40
Figure Frequency of various types of trauma inmultiple sclerosis patients and controls.
Ab/LacICon = abrasions, lacerations and contusions.
Status Scores (DSS).4 In addition, patientswere examined as soon as possible after theoccurrence of any change in symptoms thatsuggested a possible exacerbation.We defined an exacerbation as a worsening
of old symptoms, or the occurrence of newneurological symptoms, lasting at least 48hours (in the absence of fever) and associatedwith an appropriate change in the neurologicalexamination. New symptoms alone were notrecorded as an exacerbation. MRI scans werenot available during the major portion of thestudy.
All physical trauma was divided into thefollowing categories: 1) dental procedures(not including cleaning), 2) minor surgery(including suturing of lacerations, removal ofskin lesions, uterine dilatation and curettage,endoscopic procedures), 3) major surgery,4) fractures, 5) sprains (defined as painaround a joint after trauma lasting more thanthree days, with negative radiographs), 6)burns (with a subcategory of electricalshocks), 7) head injuries (with and withoutloss of consciousness), and 8) abrasions/lacerations/contusions (ab/lac/con).The three month (or six month) period
following any individual trauma wasarbitrarily designated as a period "at risk".Annual exacerbation rates were then cal-culated during cumulative at risk (AR)periods for each type of trauma, and com-pared with the annual exacerbation rates for
the same group of patients when not at risk(NAR) for any trauma. In the case of simul-taneous traumas, the period AR was assignedto the more serious injury. In the event offrequent successive traumas, the period ARterminated at the time of the next trauma:thus AR periods were not allowed to overlap.Because of these factors the cumulativeperiods AR are not simply a product of thenumber of incidents times three months (orsix months).
ResultsThe frequency ofmost types oftrauma was twoto three times higher in patients than in con-trols, as shown in the figure. The discrepancybetween the two groups was much higher thanthis for minor burns. The slightly higher rate ofmajor surgical procedures in the patients wasfully accounted for by operations requiredbecause of complications of the multiplesclerosis, for example, urological procedures.The 170 MS patients had a total of 246 acute
exacerbations during the course of five years;the distribution of these according to DSSentry score is shown in table 1. This table alsoshows the mean progression of these patientsduring the period of follow up. The data showthat exacerbation rates, and progression rateswere highest in those with the least disability atentry (DSS scores of five or less).The 170 MS patients sustained a total of
1407 episodes of physical trauma during theperiod of the study, which averaged 5 2 yearsper patient. The number ofpatients affected byeach category of trauma is outlined in table 2which also lists the time that affected patientswere AR for each type of trauma. Included alsois the total timeNAR for any type oftrauma forpatients in each row, and the annual exacer-bation rates during cumulative AR and NARperiods.There is no statistically significant difference
between the proportion of patients havingexacerbations AR and those having exacer-bations NAR in any of the rows. The criticalvalue for Chi square in each row is 3-84(p = 0 05); the Chi square calculation wasalways done on the actual occurrences, neveron the rates. Table 2 is an analysis of the datausing a three month AR period. A similar tablewas constructed using a six month AR periodwhich indicated essentially the same results:nothing approaching a significant difference for
Table 1 Progression of 170 untreated* MS patients during 5-2years in a prospective study
Mean age Mean observation Mean Exit DSS Mean increaseEntry DSS Pts years time (years) Exac exaclyr (mean) DSS/ Year
Table 2 Annual exacerbation rates when at-risk (AR) for various types of trauma, compared with rates in the samepatients when not at-risk (NAR) for any trauma (period AR = 3MOS)
Time AR Time NAR Exac/year Exac/yearType trauma Pts EPIS Exac/AR (years) Exac/NAR (years) AR NAR Chi square
any category of trauma. In the six month ARanalysis there were 115 exacerbations in 440years AR, and 131 exacerbations in 448 yearsNAR. Chi square for the three month ARanalysis was 0-9, and for the six month ARanalysis 0-8-neither significant.
Since patients with relatively advanced MSare not good indicators of disease activity (table1), we separately analysed ninety five patientswho had one or more exacerbations during thecourse of the programme. Table 3 is an analysisof exacerbation rates in this group (alltraumas), and shows a significantly higherproportion of the exacerbations occurringwhen NAR for any kind of trauma. (Note thattable 3 uses a six month AR period, and thatthere were 115 exacerbations AR in thisanalysis: the results are essentially the same
using a three month AR period). A detailedanalysis of this group of 95 patients is shown intable 4, using the three month AR period: thelargest negative correlations between traumaand exacerbation rates are in the categories ofsurgical trauma and fractures. When the lattertwo categories were grouped there were 56patients with 160 episodes of surgery or frac-ture: among these patients there were seven
exacerbations in 33 9 years AR, and 97 exacer-
bations in 217 years NAR, giving annualexacerbation rates of 0-21 and 0A45 AR andNAR, respectively. This difference was sig-nificant (p < 0 05; Chi square 4 04). The dif-ference in rates AR andNAR for all other typesof trauma grouped was not significant (Chisquare = 0 91).
Fifty three patients who had infrequenttrauma (mean 0 5 episodes/year) had ap-proximately the same rate of progression ofdisability as 44 patients experiencing six timesmore traumatic experiences (mean 3-1/year).The mean increase in DSS/year was 0 17 in theformer group and 0-21 in the latter; the dif-ference was not significant and better explainedby a higher entry DSS level in the formergroup. Additional evidence that disabilityprogression and trauma are not linked derivesfrom the fact that the annual frequency of
trauma was approximately the same in 11
patients having improvement in disability dur-ing the programme (2 2 traumas/year) as in 69patients having no change in disability (mean14 traumas/year), while 90 patients whoseDSS increased by one or more points had an
average of 1-7 traumas/year. In addition, in-spection of the data did not reveal that any
particular form of trauma was associated withsignificantly more rapid progression; long termquantitative analysis of this point is difficultbecause most patients were subjected to mul-tiple types of trauma during the programme.
Since there is a chance of overlooking pos-
sible important special relationships when bulkdata are presented, we have examined thequestion of whether more severe traumas, or
perhaps certain types of trauma within thevarious categories, might be those thatproduced exacerbation AR.The period AR following major surgical
procedures was a relatively safe time. Forty twopatients had 73 such procedures whichincluded the usual assortment in a non-MSpopulation. Thus there were operations on thehip (3), foot (3), knee (2), breast (3), eye (5),ear (2), thyroid (2), gall blader (3), prostate(2), caesarian section (2), laminectomy or
rhizotomy (3), hernia repair (4), hysterectomy(10) and miscellaneous other procedures. Someof the operations were related to multiplesclerosis or its complications: there were seven
operations involving kidney, bladder, or ureterfor stone, one patient had two vertebral arteryoperations elsewhere, and one had implanta-tion of a dorsal column stimulator, one a penileprosthesis, and two had thalamotomies. One ofthe three exacerbations AR is patient 5 in table5. The other two postoperative exacerbationsoccurred in one patient, two weeks and seven
weeks after separate eye surgeries.All the 140 head injuries were closed head
trauma; there were no instances of prolongedunconsciousness, but nine patients had 11episodes ofhead trauma associated with definiteor probable loss of consciousness for periodsvarying from seconds to a few minutes. The
Table 3 Effect ofphysical trauma on exacerbation rates in 95 patients having one or more exacerbations (total exac =246) (AR period = 6 months)
Time AR Time NAR Exac rate Exac rateExac Pts Exac/AR* (years) Exac/NAR (years) AR NAR Chi square
time AR for these 11 episodes was 2-15 yearsand two exacerbations occurred AR giving an
annual exacerbation rate AR of 0-92 for thissmall group. The same nine patients had 10exacerbations during 319 years NAR duringthe study (rate = 0-32). The difference is notsignificant (Chi square = 2 07). (One oftheARexacerbations was questionable: it occurred in amoderately disabled patient on the same day as
the head trauma, from a fall. Since the exacer-bation included increased weakness of the legsand ataxia, the new neurological symptomsmay have preceded, and caused, the headtrauma.)
Electrical injuries are included as instancesofburns in tables 2 and 4, but in fact none oftheinjuries were of sufficient current strength toproduce significant burns. Electric shock was
reported in 19 instances in 17 patients. Therewas an exacerbation four times during a threemonth AR period (five exacerbations during a
six month AR period). Two ofthe four patientswere handling a 110 volt alternating currentelectrical appliance (three of five for the sixmonthAR period). One other patient having anexacerbation AR reported an electric shockfrom a low voltage transcutaneous stimulator,and another reported an electric shock whileattempting to repair a television set. In the caseof the alternating current shocks, the currentpathway was arm-to-arm or arm-to-leg. Thecurrent pathway in the case of the television
repairman could not be determined-he ex-perienced ataxia and facial pain five days afterthe shock; it is not known if his head wasgrounded at the time of the shock, though thisseems unlikely. The history of the patienthaving arm-to-arm current flow was presentedin a previous report.'
Statistical analysis suggests that electricalshock is a risk factor (table 5); the distributionsof exacerbations AR and NAR reaches sig-nificance for the three month AR analysis. Theinterval between the shock and exacerbationwas one, five, 60, 60, 65 days, and five months inthe various cases cited.
Exacerbation occurred during a three monthAR period in 10 of 89 instances of sprain. Twoof 24 cases of lumbar back strain were followedby exacerbation after 30 and 44 days. Three of1 1 instances ofwrist/hand sprain were followedby exacerbation AR, two of 33 ankle sprains,one of two elbow sprains, and two of five necksprains. Exacerbation after neck sprainoccurred 20 days after trauma (unilateralretrobulbar neuritis) and 52 days later (rightarm weakness and numbness).Table 6 describes the 15 exacerbations
occurring within 14 days after a traumaticepisode. The exacerbation may be responsiblefor the trauma in cases 1, 2, and 6. Cases 4, 7, 8,11 and 13 in this table were associations withthe minor lacerations and contusions whichcommonly occurred in our patients.
Table 6 Exacerbations occurring two weeks or less after trauma
IntervalForm of trauma (days) Description of exacerbation
1) Head injury from fall 0 Paraparesis, Horner's syndrome2) Laceration hand, fall 0 Vertigo, numb face, dysarthria3) Electric shock, hands 1 Numbness left neck and breast4) Contusion right finger 2 Left hemiparesis5) Left knee surgery 2 Left leg weakness6) Sprain left ankle 2 Paresthesias, weakness both legs7) Laceration finger, razor 3 Paraparesis8) Laceration palm 4 Ataxia, pain right eye9) Electric shock, TV repair 5 Ataxia, facial pain
10) Thom in foot 9 Anarthria, later dysarthria, numbness hands11) Minor bums, hands 11 Diplopia12) Root canal, right 12 Right facial numbness, bilateral extemal rectus muscle
palsies13) Laceration leg, car door 12 Acute urinary retention14) Incision and drainage right peritonsillar abscess 12 Right facial weakness, dysarthria15) Surgery, retina 14 Acute paraparesis
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DiscussionThe possibility that trauma might influence thecourse of MS has been proposed by a numberof authors, including McAlpine et al,' Miller,'and Millar.6 The literature dealing with thisissue has been reviewed in detail by others.27McAlpine and Miller suggested that peripheraltrauma can result in exacerbation, postulating achange in vascular responses in the CNS aftersuch trauma. A deficiency in all reports of apositive association has been failure to includeall cases of trauma, a procedure necessary toestablish trauma as a risk factor in a disease sonotoriously variable as MS; also most reportshave been retrospective, which introduces apotential problem of selective memory forpositive associations.The current study is the only long-term
prospective study of the problem. It is also theonly study which has examined the issue oftrauma as a possible cause of exacerbation orincreased rate of progression in patients withestablished MS and recorded all instances oftrauma, and compared exacerbation rates inpost-traumatic periods to those occurring inthe same patients when not at risk. Certainlythe major conclusion from the study is thatperipheral trauma is not a significant risk factor,overall, or for any of the major subcategories oftrauma. An exception is the subcategory ofelectrical injury.McAlpine et al 8 and Miller and Schapira9
each reported single patients with worseningafter electrical injury: these patients developednumbness ofthe injured limb three and six daysfollowing a shock, very similar to the history ofone of our patients (case 3, table 6). Even ourfinding ofa statistically significant relationship,however, should be viewed cautiously, sincethe numbers are small and few other cases havebeen reported. Also the significance of theassociation in our series was increased byincluding one instance of exacerbation whenAR for an electric shock from a transcutaneousstimulator; these battery operated devices emitcurrents of very low strength, less than 100milliamps,'° II and such low voltage devices arenot usually associated with any biologicalinjury.'2 Thus the appropriatenesss of includ-ing this patient could be questioned.
In this report we have arbitrarily used both athree and a six month period AR. The sixmonth period was used in a previous report; werepeated the analysis using a three month riskperiod. The results ofthe two analyses were notsignificantly different, except in the case ofelectrical injury. We have not analysed the datausing shorter AR periods, although our findingthat 15 of86 exacerbations AR occurred duringthe first two weeks of the three month ARperiod is very close to what would be expectedby chance.Von Hoesslin was the first to propose a
relationship between the site of injury and thelevel of the new MS lesion in the nervoussystem;" subsequently McAlpine et al andMiller have cited selected cases in which thisrelationship has been striking, and mentionedthis as confirmatory evidence of the realityof traumatic precipitation of new attacks.
McAlpine found, for example, in a retrospec-tive study, that in 22 of 36 patients with dentalextraction there was a correlation betweeninjury site and the level of the initial MSlesion.' In the cases described in this report, wetoo saw examples of striking injury-site/lesioncorrelation. This was true in cases 3, 5, 12, and14 (table 6). One was a patient with arm-to-armelectric shock, and one a patient who developedweakness of the same leg two days after kneesurgery. The other two cases involved oralsurgery. Dental procedures were not, however,a risk factor (tables 2 and 4). In the cases of 10other patients having exacerbations 15-90 daysafter dental procedures the exacerbations wereprobably due to spinal cord or cerebral lesionsin seven, and in only three of these was brainstem localisation likely. Thus it would seem tous that injury site/lesion level correlation, aswell as the occurrence of new attacks shortlyafter traumatic events is most likely to befortuitous. Certainly the frequency of new MSlesions and the frequency of traumatic eventsallows ample opportunity for such chanceassociations.
Poser7 and Gonsette et al 3 suggest thatincreased vascular permeability is a necessaryevent in the development of a new MS lesion;as evidence they cite the demyelination seen insome brains of MS patients about the path oftrocars inserted during the course of thalamo-tomies, and Kelly's mention of frequentexacerbation after these procedures.'4 Posercites selected case reports showing a closetemporal relationship between trauma andexacerbation, but does not present data aboutunassociated traumas. He proposes that evenminor head and neck injuries may cause exacer-bation based on these anecdotal reports. All thehead injuries in our study were mild closedinjuries; while there was brief loss of conscious-ness in a number of patients, none had pro-longed loss of consciousness. Our data, how-ever, include an adequate sample of such minorhead injuries and fail to implicate these as a riskfactor.Without precise knowledge about the
pathogenesis of the MS lesions, it is difficult tobe sure if the increased vascular permeabilityseen in many MS lesions by enhanced scans issecondary to the inflammation associated withthese lesions, or if it is essential to theirdevelopment. Two of our patients had thala-motomies; both had rapidly progressive severedisease before, as well as after, making itimpossible to draw conclusions about the effectof the trauma of the procedures. Thus our datado not contribute any new information aboutthe effect of severe or penetrating head injuries;in such cases it would be very difficult todistinguish the effects of direct trauma from theeffects of MS.The greater frequency of trauma in our MS
patients than in controls is notable. UnlikeMcAlpine et al, we elected to record all in-stances of trauma, not just those judged to beunrelated to impairment; in many instancessuch judgements would have been difficult orimpossible. Also if the hypothesis that traumais capable of worsening the MS process is
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A prospective study ofphysical trauma and multiple sclerosis
correct, the distinction should be irrelevant.The statistically significant negative correla-
tion between trauma and exacerbation rate wasdue mostly to a low frequency of worseningafter surgical procedures and fractures. Therewas no logical reason to group these categoriestogether, although arguably these may havebeen the most severe traumas sustained by ourpatients. We grouped them primarily to showthe principal source of the negative association.Ridley and Schapira in a retrospective analysisof major surgical procedures also found thepost operative period to be relatively safe: in 57operations there were no acute exacerbations inthe first postoperative month.'5
If trauma is not a major risk factor in MS,what external circumstances did correlate withworsening in our patients during this prospec-tive study? We have previously reported thatclinical viral infections were the most impres-sive environmental influence; the exacerbationrate during cumulative periods AR for suchinfections was 0 64 per annum, compared witha rate of 0 23 during periods NAR (Chisquare = 56 3; p < 0_0001).16 Another reportfrom our clinic emphasised that stressful lifeevents were a much weaker risk factor with theexacerbation rates AR and NAR being 0 36 and0 26 respectively (Chi square = 4-8;p < 0 05); it seemed likely, however, that theapparent significance of stressful life eventsmight be spurious due to patient bias duringperiods when concurrent reporting of stressand exacerbation was possible.'7
This work was supported by grant 1048-C- 13 from the NationalMultiple Sclerosis Society, New York.
1 McAlpine D, Compston N. Some aspects of the naturalhistory of disseminated sclerosis. QJ Med 1952;21:135-67.
2 Bamford CR, Sibley WA, Thies C, Laguna JF, Smith MS,Clark K. Trauma as an etiologic and aggravating factor inmultiple sclerosis. Neurology 1981;31:1229-34.
3 Schumacher GA, Beebe G, Kibler RF, et al. Problems ofexperimental trials of therapy in multiple sclerosis: reportby the panel on evaluation ofexperimental trials of therapyin multiple sclerosis. Ann NY Acad Sci 1965;122:552-68.
4 Kurtzke JF. On the evaluation of disability in multiplesclerosis. Neurology 1961;11:686-94.
5 Miller H. Trauma and multiple sclerosis. Lancet1964;1 :848-50.
6 Millar J. Multiple sclerosis: a disease acquired in childhood.Springfield, Illinois: Charles C Thomas, 1971:65.
7 Poser C. Trauma and multiple sclerosis. An hypothesis. JNeurol 1987;234:155-9.
9 Miller H, Schapira K. Aetiological aspects of multiplesclerosis. BMJ 1959;1:707.
10 Shealy CN. Transcutaneous electrical stimulation for con-trol of pain. Clin Neurosurg 1974;21:269-77.
11 Panse F. Electrical trauma. In Vinken PJ, Bruyn GW, eds.Handbook of clinical neurology Vol 23. Amsterdam: NorthHolland, 1975:686.
12 Hoesslin R von. Uber multiple sklerose: exogene aetiologiepathogenese, und verlauf. Munich: Lehmans, 1934.
13 Gonsette R, Andre-Balisaux G, Delmotte P. La permeabilitedes vaisseaux cerebraux. Demyelinisation experimentaleprovoquee par des substances agissant sur la barrierehemato-encephalique. Acta Neurol Belg 1966;66:247-62.
14 Kelly R. Clinical aspects of multiple sclerosis. In: KoetsierJC, ed. Handbook of clinical neurology. Amsterdam:Elsevier, 1985:64.
15 Ridley A, Schapira K. Influence ofsurgical procedures on thecourse of multiple sclerosis. Neurology 1961 *1 1:81-92.
16 Sibley WA, Bamford CR, Clark K. Clinical viral infectionsand multiple sclerosis. Lancet 1985;1:1313-5.
17 Sibley WA. Risk factors in multiple sclerosis-implicationsfor pathogenesis. In: Serlupi Crescenzi G, ed. A multi-disciplinary approach to myelin diseases. New York:Plenum Press, 1988:227-32.
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