MULTIPLE SCLEROSIS AND SINUSITIS

1158

neurologist to differentiate between bouts and exacerbations provoked by either physical or psychological factors. It is well known that infections-particularly in connection with feverprovoke deteriorations which are indistinguishable from bouts but should not be counted as such. On the other hand, multiple sclerosis (MS) patients do not consult their doctors with each bout, and this might be more likely when sinusitis and a bout occur together. It is remarkable that the well-known higher frequency of bouts after childbirth has not been found in this study, although Gay and co-workers state that they looked at "medical procedures, or other medical disorders ... and their coincidence with episodes of the

demyelination". There is no information on treatment. MS patients are frequently receiving corticosteroids and/or immunosuppressive drugs and this medication might have favoured sinus infections. But even if we assume that Gay et al were aware of these pitfalls and considered them, the results bear other interpretations. Patients with a particular immunological make-up could be prone to coin

Amount of

CMV-specific IgM (arbitrary units)

found in

sera

from

heart, kidney, and liver transplant recipients experiencing

primary zit) and reactivated (0) CMV infection.

readings. The amount of CMV-specific IgM in serum was determined by reference to a standard curve plotted from the results obtained with the reference positive control series. The figure shows that primary CMV infections (as defined above) were associated with 1 to over 33 units of CMV IgM, while reactivation/reinfection produced 0-10 units of CMV IgM. While there is some overlap, sera from kidney and heart transplant recipients containing 3 - 3 units or more of CMV IgM and sera from liver transplant recipients containing 10 or more units of CMV IgM are much more likely to be associated with primary CMV infection than with reactivation/reinfection. Such a finding may thus be an important prognostic indicator of primary CMV infection, for which treatment regimens are becoming available. We have found similar results with the Northumbria Biologicals CMV IgM assay, although positive control sera with a range of arbitrary units are not provided in the kits. Our experience in closely monitoring the CMV IgM response in heart transplant recipients, however, indicates that if CMV IgM is found early in the course of infection, it is often present at high levels (10 units or more) in the absence of detectable CF antibody. Microbiology and Public Health Laboratory, Addenbrooke’s Hospital, Cambridge CB2 2QW Division of Microbiological Reagents and Quality Control, Central Public Health Laboratory, London NW9

MS bouts and sinusitis. To eliminate this possibility, matching for HLA-groups is warranted. Compston et al2 compared the frequency of infections in DR2 positive MS patients and DR2 positive controls; no difference could be found between the two. Although viruses seem to be better candidates in the aetiology and/or of MS, bacteria are far from being ruled out. Morris speculates, in a letter on Sibley’s report on frequent correlations between upper respiratory infections and bouts of MS,4 that viral infections might disturb the normal bacterial flora and lead to overgrowth of staphylococci, streptococci, or gramnegative bacilli. A cross-reaction between bacterial antigens and human brain proteins might precipitate MS bouts. That spirochaetes, however, are involved in nasopharyngeal infections and could act as such triggers is unlikely, although Gay et al mention immunological and pathological similarities between Lyme disease and MS. The clinical spectrum of Lyme disease is, as a rule, different from that ofMS and the authors cited by Gay et al report the typical

pathogenesis

5

picture of meningoradiculitis. There seems to exist a progressive encephalomyelitis caused by Ixodes ricinus-Borrelia,6but the frequency and significance of this event remains to be established. Epidemiology of I ricinus distribution and risk for MS show a different pattern, and we have thus far found no patient diagnosed as MS with local formation of antibodies against I ricinus-Borrelia in the cerebrospinal fluid (unpublished data), which would be a proof of borrelia as a causal agent of central nervous involvement. Neurological Department of Göttingen University, D3400 Göttingen, West Germany

SIGRID POSER

T. G WREGHITT

J. J. GRAY

C. CHANDLER

Cytomegalovirus infection in transplant patients Progr Med Virol 1982; 28: 44-64 2 Betts RF, Freeman RB, Douglas RG, Talley TE, Rundell B Transmission of cytomegalovirus infection with renal allograft. Kidney Int 1975; 8: 387-94 3. Klintmalm G, Lönnqvist B, Oberg B, et al. Intravenous foscarnet for the treatment of severe cytomegalovirus infection in allograft recipients ScandJ Infect Dis 1985; 17: 157-63. 4. Ringden O, Wilczek H, Lönnqvist B, Gahrton G, Wahren B, Lernestedt J-O. Foscarnet for cytomegalovirus infections. Lancet 1985; i: 1503-04. 5. Wreghitt TG, Hicks J, Gray JJ, O’Connor C. Development ofa competitive enzymelinked immunosorbent assay for detecting cytomegalovirus antibody. J Med Virol 1986, 18: 119-29 1. Betts RF.

MULTIPLE SCLEROSIS AND SINUSITIS

SIR,-Although Dr Gay and his colleagues (April 12, p 815) state that "general practice records, contrary to popular belief, are often well organised and comprehensive", it is doubtful whether the occurrence and exact timing of bouts can be accurately ascertained by this retrospective procedure. In most cases it is difficult even for

1. Poser S, Poser W. Multiple sclerosis and gestation. Neurology 1983; 33: 1422-27. 2. Compston DAS, Vakarelis BN, Paul E, McDonald WI, Batchelor JR, Mims CA. Viral

infection in patients with multiple sclerosis and HLA-DR matched controls Brain 1986; 109: 325-44. 3. Morris JA. Clinical viral infections and multiple sclerosis. Lancet 1985; ii: 273 4. Sibley WA, Bamford CR, Clark K. Clinical viral infections and multiple sclerosis Lancet 1985; i: 1313-15. 5 Steere AC, Malawista StE, Bartenhagen NH, Spieler PN, Newman JH, Rahn DW, et al. The clinical spectrum and treatment of Lyme disease Yale J Biol Med 1984, 57: 453-61. 6. Ackermann

R, Gollmer E, Rehse-Küpper Enzephalomyelitis Deutsch Med Wschr 1985; 110:

B.

Progressive

Borrelien-

1039-42.

SIR,-Permit me to suggest that the association between chronic sinusitis and multiple sclerosis exists because both result from a third factor. Both MS and Hodgkin’s disease are associated with chronic respiratory disease, as exemplified by a frequent history of childhood tonsillectomy. 1,2 Hodgkin’s disease has a bimodal ageincidence curve and the first peak coincides, around age 30, with the single peak in the curve for MS. Both conditions in young adults are concentrated in the temperate zones of North America, Europe, and Australasia. In each case the earliest manifestations tend to appear during the winter months. These facts, and the existence of timespace clusters of both conditions, have led to strong suspicions of slow virus infections acquired during late childhood or adolescence

1159 Other

parallel epidemiological

features

are

the

of familial

susceptibility

Whites, farmers, and upper socioeconomic groups and

a

tendency in both conditions.2,3 The geography of dairying closely coincides with the geography of MS and Hodgkin’s disease.4,5 Bovine leukaemia virus (BLV) is one plausible biological link between dairy products and both MS6,7 and lymphoproliferative disorders.s,9 The immunological effect of cow’s milk protein is another.5 Moreover, milk proteins cause chronic respiratory disease.10,11 The following scheme is probably too simple, but it draws together many of the facts. MS and Hodgkin’s disease occur in separate groups of people (sex-predominance and HLA markers differ for the two diseases) but both groups share a susceptibility to chronic upper respiratory disease (sinusitis, adenotonsillitis) and to infection by retroviruses such as BLV. During childhood or adolescence in the temperate zone a retrovirus genome is established in the lymphocytes of susceptible individuals. Additional viral infections (measles, Epstein-Barr virus)2,3 or the steady assault

by2 non-replicating antigens (food proteins, woodworking, phenytoin) are co-factors that activate the latent retrovirus. Of course, it maybe

the other way around: a latent retrovirus may alter the host’s immune response to viruses, &c. (It does appear, by the way, that mucosal surfaces are frequently abnormal in patients with MS12 or and are likely to permit antigen entry.) In any case, cell proliferation in lymphoid tissues becomes uncontrolled (Hodgkin’s) or there is recurrent activation of the lymphocyte network in the central nervous system, causing immune damage to myelin sheaths. The shared epidemiological features of these conditions be The clues to environmental causes. that a possibility potent single environmental factor may contribute in a major way to these very different diseases should not be too forbidding-particularly if we recall tobacco, or the fibre hypothesis.13 Perhaps we should not be so unfair to the cow. Sheep may be suspects as wel1.14

lymphomas5

may

Mary Imogene Bassett Hospital, Cooperstown, NY 13326, USA.

ALLAN S. CUNNINGHAM

1. Poskanzer DC. Tonsillectomy and multiple sclerosis. Lancet 1965; ii: 1264-66. 2. Kaplan HS. Hodgkin’s disease, 2nd ed. Cambridge: Harvard University Press, 1980: 16-51. 3. Acheson ED. Epidemiology of multiple sclerosis. Br Med Bull 1977; 33: 9-14. 4 Agranoff BW, Goldberg D. Diet and geographical distribution of multiple sclerosis. Lancet 1974; ii: 1061-66. 5. Cunningham AS. Lymphomas and animal-protein consumption. Lancet 1976; ii: 1184-86. 6. Koprowski H, DeFreitas EC, Harper ME, et al. Multiple sclerosis and human T-cell lymphotropic viruses. Nature 1985; 318: 154-60. 7. Cunningham AS. Bovine leukaemia virus and multiple sclerosis. Nature 1986; 320: 219. 8 Donham KJ, Berg JW, Sawin RS. Epidemiologic relations of the bovine population and human leukemia in Iowa. Am J Epidemiol 1980; 112: 80-92. 9 Giles GG, Lickiss JN, Baikie MJ, Lowenthal RM, Pantor J. Myeloproliferative and lymphoproliferative disorders in Tasmania, 1972-80: Occupational and familial aspects. J Natl Cancer Inst 1984; 72: 1233-40. 10 Holland NH, Hong R, Davis NC, West CP. Significance of precipitating antibodies to milk proteins in the serum of infants and children. J Pediatr 1962; 61: 181-95. 11. Boat TF, Polmar SH, Whitman V, Kleinerman JI, Stern RC, Doershuk CF. Hyperreactivity to cow milk in young children with pulmonary hemosiderosis and cor pulmonale secondary to nasopharyngeal obstruction. J Pediatr 1975; 87: 23-29. 12. Lange LS, Shiner M. Small-bowel abnormalities in multiple sclerosis. Lancet 1976; ii: 1319-22. 13. Burkitt DP. Are our commonest diseases preventable? Prev Med 1977; 6: 556-59. 14. Symonds CP. Multiple sclerosis and the swayback story. Lancet 1975; i: 155-56.

SIR,-We are currently analysing data collected in an epidemiological, virological, and immunogenetic study of MS conducted in 1983 in the Hautes-Pyrenees (South-west France). All practitioners were contacted to identify patients with MS. Each patient was examined at home and the diagnosis was classified according to the criteria of Poser et al. 91 MS cases were found (prevalence 40 per 100 000), 71 patients agreed to answer a detailed questionnaire and were interviewed at home. Several questions related to medical history, including chronic sinusitis and other upper airways infections. A control group (n=70) was constituted with unrelated individuals,

living in the same area, matched for age

and

sex.

An additional control group

(n=40)

was

drawn from

patients’ siblings. We did not observe any significant difference between MS and controls. Indeed, attacks of sinusitis were found in 14 - 5% of MS patients as compared with 11-4% in unrelated controls and 20% in siblings. These proportions are smaller than those observed by Dr Gay and colleagues, who observed 69’5% in MS patients and 17 - 4% in matched controls. Clearly, attacks of sinusitis have not been inquired about in the same way in the two studies but it is unlikely that this difference could explain so large a disparity in MS patients when rates of chronic sinusitis in controls were similar.

patients

INSERM Unit 169, 94807 Villejuif, France

Hôpital Purpan, Hôpital

La

Toulouse

Salpêtrière, Pans

A. ALPEROVITCH M. CLANET

J. L. MAS

Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13: 227-31.

1. Poser CM,

SIR,-To be entered into the study of Dr Gay and co-workers, the MS

patients had to have been seen by a consultant neurologist and

criteria. There is no record of a similar evaluation of the sinusitis patients; indeed none appears to have been seen by an otolaryngologist. The diagnosis, particularly of chronic sinusitis, is difficult to make clinically and radiological examination is generally used.2 The proportion of single attacks of sinusitis that were confirmed by X-ray is not stated, but from table I only 18 of the 50 patients with recurrent sinusitis had radiological examinations to confirm the diagnosis. This raises the strong possibility that these patients really had other non-infective conditions such as allergic or vasomotor rhinitis, septal deviation, or nasal polyps. Furthermore, the criteria for the diagnosis of sinusitis in those who underwent radiological evaluation are not mentioned. This is important since different criteria correlate to a different degree with antral puncture

satisfy McAlpine’s

findings.2

Experimentally, rhinitis can be induced by stress,3and therefore it is possible that the stress of having MS can induce symptoms that can easily be confused with sinusitis in the absence of strict diagnostic criteria. Gay et al have expounded what amounts to an extension of an oldfashioned theory that sinusitis can cause mental disorders4-a hypothesis that was discredited over 30 years ago.With evidence of sinusitis taken purely from GP records it is similarly not possible to infer an association between sinusitis and multiple sclerosis. Department of Otolaryngology, Radcliffe Infirmary, Oxford OX2 6HE

1. Pfleiderer 2. 3.

H. T. JOSEPH G. M. O’DONOGHUE

AG, Drake-Lee AB, Lowe D Ultrasound of the sinuses:

a

worthwhile

procedure? Clin Otolaryngol 1984; 9: 335. Axelsson A, Grebelius N, Jensen C. The correlation between radiological examination and the irrigation findings in maxillary sinusitis. Acta Otolaryngol 1970, 69: 302. Saruya F. Influence of psychic stress on the mucous membrane of the nose and accessory sinuses in experimental animals. Otolaryngologia Tokyo 1967; 10: 1.

4. Pickworth FA. Chronic nasal sinusitis and its relation to mental disorder. London: Lewis, 1935. 5. Scott-Brown WG. Some general considerations in sinusitis. In: Scott-Brown WG, Ballantyne J, Groves J, eds Diseases of the ear nose and throat, 2nd ed. London: Butterworths, 1965.

SIR,-How did Dr Gay and his colleagues define "sinusitis"? In parts of their article they describe it as chronic sinus infection; in other parts as chronic relapsing nasopharyngeal infection; elsewhere as chronic catarrh, chronic sinusitis, seasonal rhinitis, and chronic tonsillitis (the existence of which ENT surgeons

including myself deny). I would also be grateful to know how they confirmed sinus infection by radiology. Chronic purulent sinusitis is now fairly uncommon whereas radiological abnormalities of the sinuses due to allergy, vasomotor rhinitis, retained mucus, and previous surgery are very common, and can probably be found in at

1160 least half the normal population. Finally, I could not find any report of the results of the bacteriology of their patients with sinusitis, and I am left wondering how they came to the conclusion that it would be worthwhile investigating the place of a spirochaete. I" University Department of Oto-rhino-laryngology, Royal Liverpool Hospital, Liverpool L69 3BX

P. M. STELL

SEASONAL VARIATION IN ANTIBODIES AGAINST EBOLA VIRUS IN KENYAN FEVER PATIENTS

SIR,-Having found evidence of both Marburg and Ebola virus activity in Kenya,I-3 the Virus Research Centre in Nairobi set up a laboratory incorporating clothing changing rooms, ultraviolet airlock, filtered air extraction units maintaining negative air pressure to the atmosphere, and Vickers absolute biological containment isolators, so permitting more intensive study of these potentially epidemic viruses. Acute and convalescent phase blood samples were drawn from patients admitted to four hospitals in a high rainfall area of western Kenya, one in a semi-arid area to the northwest, and one in an intermediate rainfall area on the eastern side of the Rift Valley. A brief questionnaire to obtain epidemiological and clinical details was filled out for each patient who, in the opinion of the participating doctors, might have a viral haemorrhagic fever. Sera, stored in liquid nitrogen at the hospitals, were transported to the Virus Research Centre where acute samples were inoculated into Vero cells, observed daily for cytopathic changes, and tested at 10 and 20 days for Marburg and Ebola antigens by indirect immunofluorescence (IFA).4This was repeated after blind passage of the cell culture fluids. Convalescent sera were tested for antibodies by IFA on infected Vero cells inactivated by gamma -

irradiation 5 471 patients

with suspected viral haemorrhagic fever were identified between May, 1984, and October, 1985. Symptoms of

high fever, headache, throat, chest, abdominal, muscle, joint, or back pain, and diarrhoea and/or vomiting with or without blood were characteristic and ranged from mild to severe. 53-8% of the patients were male. There was no difference in the age distribution between the sexes. 9’8% (46/471) of the patients had antibodies against the Zaire and/or Sudan Ebola virus serotypes. 16 had inverse titres of 16, 17 of 32, 6 of 64, 5 of 128, and 2 of 256. Antibodies were detected at all of the hospitals although the hospital east of the Rift Valley had a lower rate (3’7%) than the total western Kenya sample ( 10 . 3%). It is uncertain whether this represents a true difference or results from subjectivity in case definition. Paired sera were obtained on 350 patients of which 24 (6-8%) either seroconverted or exhibited rising Ebola antibody titres during the illness (2-fold or more). Limited follow-up investigations suggest that antibody levels tend to fall within 2-3 months, which is

in contrast to known Ebola cases where titres remain high for at least a year after infection. The case fatality rate among those with antibodies was no higher than in those without (about 5%). Ebola virus antibody rates were higher during two periods of the year (June to August and December/January) coinciding with the ends of the long spring rainy season and the short autumn rains (figure). Three times more males than females between the ages of 20 and 30 (11/50 vs 3/34) were found to be antibody positive. No difference was noted in other age groups. No virus was recovered from any sample, either in Vero cells or in cyclophosphamide immunosuppressed guineapigs inoculated at the US Army Medical Research Institute of Infectious Diseases. The difficulty in virus isolation, the generally low titres, and the transience of the antibodies all suggest that this virus is neither of the known Ebola serotypes, .but a related filovirus which crossreacts with Ebola virus antigen. The findings indicate that an Ebolarelated virus is a significant cause of morbidity in Kenya. The case fatality rate, which seems low, would be higher if some patients die before antibodies develop. The seasonal variation in antibody positivity and the preponderance of seropositivity in 20-30-year-old males suggest that certain environmental conditions, possibly related to reservoir, vector, or specific human activities, increase the risk of infection among certain groups. This work was

supported in part by grant DAMD-83-G-9535 frorrf the US

Army. Virus Research Centre, Kenya Medical Research Institute, PO Box 20752,

Nairobi, Kenya Disease Assessment Division, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland USA

B. K. JOHNSON D. OCHENG S. OOGO L. G. GITAU

E.

C. WAMBUI A. GICHOGO D. LIBOMDO P. M. TUKEI

D. JOHNSON

DH, Johnson BK, Isaacson M, et al. Marburg virus disease in Kenya. Lancet 1982; i: 816-20. 2. Johnson BK, Ocheng D, Gichogo A, et al. Antibodies against haemorrhagic fever viruses in Kenya populations. Trans Roy Soc Trop Med Hyg 1982; 77: 731-33. 3. Teepe RGC, Johnson BK, Ocheng D, et al. A probable case of Ebola virus haemorrhagic fever in Kenya. E Afr Med J 1983; 60: 718-22. 4. Wulffe H, Lange JV. Indirect immunofluorescence for the diagnosis of Lassa fever infection. Bull World Health Org 1975; 52: 429-36. 5. Lupton HW. Inactivation of Ebola virus with 60Co irradiation. J Infect Dis 1981, 143: 1. Smith

291.

TIMING OF MAINTENANCE CHEMOTHERAPY FOR CHILDHOOD ACUTE LYMPHOBLASTIC LEUKAEMIA

SiR,-Dr Rivard and colleagues (Dec 7, p 1264) report improved survival when maintenance chemotherapy with 6-mercaptopurine and methotrexate was given in the evening (after 1700 hours) rather than the morning (before 1000 hours) to 118 children with acute lymphoblastic leukaemia (ALL). The timing of treatment was left to the parents. 36 children were treated in the evening and 82 in the

morning. Despite the similarity of the baseline characteristics of the two groups unsuspected bias. could have affected the results. Seasonality is seldom considered a prognostic factor for malignant diseases. Nonetheless, in

a series of 522 women with breast cancer treated with adjuvant chemotherapy, the initial diagnosis of breast cancer had been reached about three times more frequently in spring or autumn than in summer or winter in those 162 who subsequently relapsed (p 0 -005). No difference was found with respect to month of diagnosis for the other women.Indeed spring seems to represent a high-risk season for this disease.2 In 196 children with ALL, Cohen et al3 noted a more favourable survival in those patients whose ALL was diagnosed in summer or autumn than in those with a diagnosis made in winter or early spring.3 Was the monthtv distribution of diagnoses similar in the groups treated by Rivard et al? Another question relates to dosages. Circadian rhythms in tolerance for twenty anti-cancer drugs, including methotrexate.4 =

Distribution of cases with rising Ebola virus antibody titres in Kenya between May, 1984 and June, 1985.