- Email: [email protected]
PENTAMIDINE OR CO-TRIMOXAZOLE FOR PNEUMOCYSTIS CARINII PNEUMONIA
1300 conditions present as bloody diarrhoea, abdominal pain, and but without significant fever; and in both barium enema vomiting,10,12 features are compatible with acute ischaemic colitis and characterised by the descriptions "thumbprinting", "pseudotumour", and "transverse ridging". This suggests that HUS and haemorrhagic colitis belong in a spectrum of clinical manifestations of the same underlying disease process. The radiological thumbprinting pattern has been reproduced experimentally by reversible vascular occlusion of the colon and represents submucosal haemorrhage and oedema. Evidence that Shiga toxin acts on the bowel in this manner again comes from the work of Cavanagh et al6 who, in 1956, showed that rats injected with this toxin acquire a haemorrhagic enterocaecitis characterised by submucosal haemorrhage and oedema. We propose that verotoxin is of direct aetiological importance in the pathogenesis of both HUS and haemorrhagic colitis. For this hypothesis to be valid, it would need to be shown that the pathological picture in HUS and haemorrhagic colitis is the direct result of circulating cytotoxin. Although circulating verotoxin has not yet been demonstrated in human cases, indirect evidence from animal work suggests that "toxaemia" may be important in the pathogenesis. "Oedema disease" is a naturally occurring illness of pigs that resembles HUS and haemorrhagic colitis. 14,15 The natural disease follows enteric infection by cytotoxin-producing E coli whose serotypes are different from those of strains associated with human disease. The cytotoxin of the porcine strains has the same biological activity as verotoxin, but the relation between these toxins remains to be established.16 Natural oedema disease of pigs can be reproduced by the parenteral administration of the toxin:15 this is strong evidence for involvement of "cytotoxaemia" in this disease and suggests that the human disease may have a similar basis. Additional evidence that verotoxin has a direct role in HUS is the fact that patients mounted significant serological responses to the
toxin.2
If verotoxin is of direct pathogenic significance in HUS and haemorrhagic colitis, these diseases might be by immunisation. Almost thirty years ago Howard showed that injection of Shiga toxoid into laboratory animals gives rise to neutralising antibodies and protects them from the lethal effects of Shiga toxin. The role of pre-existing immunity in the development of verotoxin-associated HUS and haemorrhagic colitis remains to be established. However, the age distribution of the endemic variety of HUS suggests that susceptibility to this disease, as to other specific infections of childhood, is probably related to the absence of specific antibodies.
preventable
Departments of Bacteriology and Virology, Hospital for Sick Children, Toronto, Ontario, Canada M5G IXG; and Department of Microbiology, University of Toronto
M. A. KARMALI M. PETRIC C. LIM P. C. FLEMING
Department of Paediatrics, McMaster University, Hamilton, Ontario
B. T. STEELE
EARLY DIAGNOSIS OF MUCOPOLYSACCHARIDOSIS marrow transplantation is to be offered as a for mucopolysaccharidosis, as we believe it should, early referral before mental deterioration has gone too far, is important. No child with Hurler’s disease who has had a successful bone marrow transplant has subsequently shown any further mental deterioration. Our first patient, treated in June, 1980, aged 11I
SIR,-If bone
treatment
12. Peterson RB, Meseroll WP, Shrago GG, Gooding CA. Radiographic features of colitis associated with the hemolytic-uremic syndrome. Radiol 1976; 118: 667-71. 13. Schwartz S, Boley S, Lash J, Sternhill V. Roentgenologic aspects of reversible vascular occlusion of the colon, and its relationship to ulcerative colitis. Radiol 1963; 80: 625-35. 14. Timoney JF. Oedema disease of swine. Irish Vet J 1950; 62: 748-55. 15. Clugston RE, Nielsen NO, Smith DLT. Experimental edema disease of swine (E coli enterotoxemia) III: Pathology and pathogenesis. Can J Comp Med 1974; 38: 34-43. 16. Dobrescu L. New biological effect of edema disease principle (Escherichia colineurotoxin) and its use as an in-vitro assay for this toxin. Am J Vet Res 1983; 44: 31-34. 17. Howard JG. Observations on the intoxication produced in mice and rabbits by the neurotoxm of Shigella shigae. Br J Exp Pathol 1955; 36: 439-46.
months,
nearly 41/z years old. He has, if anything, progressed according to Griffith’s developmental assessments. The same applies to the next two cases who have now been followed-up is
now
for 21f2 and 21/4 years. In four cases the mother noticed the lumbar gibbus within the first few months of life but the significance of this was not appreciated by the doctors to whom she pointed it out. Most of these children had been operated on for inguinal or umbilical hernias by the age of 6 months. Surely the need for surgery is unusual in cases of simple umbilical hernia. The other important alternative diagnosis (hypothroidism) will in many centres now be excluded by neonatal
screening. INCIDENCE OF HERNIAS BY AGE SIX MONTHS IN CHILDREN WITH MUCOPOLYSACCHARIDOSIS
*I=Hurler, ll=Hunter; III=Sanfilippo; IV=Morquio.
The accompanying table shows the very high incidence of hernias before the age of 6 months in cases of mucopolysaccharidosis associated with mental deterioration, except for Sanfilippo’s disease. May I ask paediatricians and community doctors screening young babies, and surgeons who repair hernias in children, to exclude the rare but now treatable disease of mucopolysaccharidosis. A lateral X-ray of the lumbar spine will almost certainly be diagnostic in Hurler’s and Hunter’s disease (but not in Sanfilippo’s). Testing a random urine for glycosaminoglycan: creatinine ratio will always exclude these diagnoses. This test, which is not expensive and can be done in regional centres, is essential because the hepatosplenomegaly of mucopolysaccharidosis is not necessarily obvious at the time that the baby has its hernia. Bone Marrow Transplant Unit, Westminster Children’s Hospital, London SW1P 2NS
KENNETH HUGH-JONES
PENTAMIDINE OR CO-TRIMOXAZOLE FOR PNEUMOCYSTIS CARINII PNEUMONIA
1109) describe diffuse erythematous maculopapular eruptions eight of eighteen homosexual men with acquired immunodeficiency syndrome (AIDS) treated with co-trimoxazole (trimethoprim/sulfamethoxazole, TMP/SMZ). They suggest that this type of adverse reaction is immunologically mediated and that pentamidine rather than TMP/SMZ be considered for the initial therapy of Pneumocystis carinii pneumonia (PCP) in this grouup of patients. Until their randomised trial of pentamidine against TMP/SMZ is complete we would caution against this suggested replacement. A 26-year-old homosexual man with a 3-month history of fever, cough, and weight loss was admitted to hospital. His haemoglobin was 11-2 2 g/dl, the white blood cell count 6000/1 and the platelet count 114 OOOIIAI. Chest X-ray was normal. Bronchoscopy revealed PCP, and oral co-trimoxazole was started (TMP 20 and SMZ 100 mg/kg daily). After 9 days of therapy, during which the patient was afebrile and almost free of symptoms, a diffuse, itchy, maculopapular eruption developed. His haemoglobin was 10-66 g/dl, the white cell count 2600/1, and the platelet count 135 000/(1. TMP/SMZ was discontinued for 2 days after which the rash had almost disappeared. Since we were reluctant to start pentamidine therapy the patient was rechallenged with one double-strength SiR.—Dr Jaffe and colleagues (Nov 12,
p
in
no reaction occurred. The white blood cell returned to normal and the haemoglobin and platelet count remained as before. 4 months after this rechallenge the patient is
tablet of TMP/SMZ; count
JR, et al Reversal of clinical features of Hurler’s disease and biochemical improvement after treatment by bone-marrow transplantation. Lancet 1981; ii:
1. Hobbs
709-12.
1301 still on regular TMP/SMZ (one double-strength tablet twice a day) without any skin complaint. Jaffe et al rechallenged only four of their patients. Perhaps the other four would have reacted as our patient did. We cannot explain the mechanism involved. However, it might well be advisable, in similar cases, to try a rechallenge before switching to a drug that is I probably less effective and safe than TMP/SMZ. Medical Polyclinic,
University of Munich, 8000 Munich 2, West Germany
MICHAEL M. KOCHEN CLAUDIA HERRMANN FRANK D. GOEBEL
association with the vaccine to be claimed. No long-term reaction has been reported and we know of no case of transmission of hepatitis B or non-A, non-B hepatitis by the vaccine. No case of acquired immunodeficiency syndrome has been reported in vaccine recipients. Thus long-term experience confirms the safety of HBV vaccine of French manufacture.
Pharmaceutical Division, Institut Pasteur Production, 92430 Marnes-la-Coquette, France
HEPATITIS B VACCINE: CLINICAL EXPERIENCE AND SAFETY
SIR,-The French manufactured hepatitis B virus (HBV) vaccine prepared from human plasma containing surface antigen (HBsAg) that has been purified and inactivated by biophysical and biochemical processes.2Pilot studies began eight years ago3 and is
randomised controlled trials have demonstrated the vaccine’s 4 efficacy in preventing hepatitis B among susceptible individuals. The vaccine was licensed in May, 1981, and a large body of clinical experience has subsequently been collated. In France, over 100 000 people have been vaccinated. Besides the pilot and controlled trials (1495 people), there have been twelve studies on 2479 health care workers and dialysis patients. Follow-up of vaccine recipients has ranged from a few months to eight years. Worldwide up to one million doses have been administered and twenty-five follow-up studies (6830 people) have been mounted. Because of the plasma origin of the HBsAg, the major hypothetical side-effects of this vaccine are reactions to blood substances and the transmission of HBV or other blood borne agents. Information on illnesses developing after receipt of the HBV vaccine has been collected by spontaneous notifications, by inquiries by a surveillance unit at Institut Pasteur Production, and by telephone interviews with French monitoring centres. As of Sept 1, 1983, 295 illnesses had been reported in the French vaccinated population. More than half began after the first dose. Local side-effects (induration, erythema) were recorded in 99 people. Moderate general illnesses were reported in 192 vaccinees: 33 febrile episodes, 7 skin lesions (herpes zoster, erythema nodosum, rash), 1 Quinck oedema, 74 gastrointestinal reactions (nausea, vomiting, diarrhoea), and 76 miscellaneous complaints
(chills, asthenia, insomnia). 2 HBV infections were observed. A 60-year-old male dialysis 2 months after the third vaccine injection, had HBs antigenaemia without increased transaminases. Since only 19% of dialysis patients aged 60 or more responded to HBV vaccinethis
patient,
HBV infection may well have been in a non-responder. The second HBV infection was in a 27-year-old nurse who reported an HBsAgpositive needlestick exposure 12 weeks before vaccination. Clinical hepatitis developed 4 weeks after the third injection. This case of hepatitis B may be explained by immunisation in the incubation period of HBV infection. Active immunisation to abort the clinical course of HBV infection is suggested only when it can be started shortly after exposure. There have been 2 cases of serious illness. 1 patient had nephrotic syndrome 10 days after the first injection. Biopsy revealed a membranous glomerulonephritis. No anti-HBs was detected. The other had a painful bilateral peripheral neuropathy at C5/C6 . The symptoms began 22 days after immunisation. Short-term illnesses probably attributable to the vaccine have been local or mild while serious illness has been too rare for an Young LS. Trimethoprim-sulfamethoxazole in the treatment of adults with pneumonia due to Pneumocystis carinii. Rev Infect Dis 1982; 4: 608-13. 2. Adamowicz P, et al. Large scale production of an hepatitis B vaccine. In: Maupas P, Guesry P, eds. Proceedings of International Symposium on Hepatitis B Vaccine. Amsterdam: Excerpta Medica, 1980: 37-49. 3. Maupas P, et al. Potency and efficacy ofHB vaccine applied to a high risk population: a five year study. In: Proceedings of International Symposium on Hepatitis B Vaccine. Amsterdam: Excerpta Medica, 1980: 117-31. 1.
4.
Crosnier J,
5.
Goudeau A,
et al. Randomised placebo controlled trial of hepatitis B surface antigen vaccine in French haemodialysis units. Lancet 1981; i: 455-59, 797-800 et al. Hepatitis B vaccine: Clinical trials in high risk-settings in France. Devel Biol Standard (in press).
M. T. NUTINI F. N. MARIE C LOUCQ F. TRON
PREMENSTRUAL UNCERTAINTIES
SiR,-We agree with much of your editorial on the premenstrual syndrome (PMS) (Oct 22, p 950) but feel that valuable positive and negative premenstrual "certainties" were ignored, which could provide an insight into this complex condition. First, cyclical symptoms, be they mild or severe, are almost universal in women during their fertile years, and are accepted as normal by most women.Secondly, and conversely, these symptoms do not occur at times when cyclical ovarian activity is absent, such as before puberty, during pregnancy, and after the menopause.2Thirdly, menstruation itself is not essential, since cyclical symptoms continue after hysterectomy, provided ovarian function is conserved.3 Fourthly, a history of postnatal dysphoria is common in PMS sufferers, at a time not only of emotional vulnerabili7 but also
of great hormone and metabolic fluxes after delivery. Fifthly, psychological factors must play an important role in aetiology to explain the large placebo response of up to 89% reported in controlled therapeutic trials.5 These positive observations-taken in conjunction with the mass of negative findings relating to aetiology suggesting that metabolically complainers and non-complainers are similarand the lack of any convincingly superior therapy to placebo 7-lead us to suggest that it is the fluctuation of hormones and other metabolites with the ovarian cycle rather than their absolute concentrations that is of primary importance in the pathogenesis of cyclical symptoms, which include not only the PMS but also other cyclical conditions such as menstrual migraine.8 Women who complain of PMS seem to differ from non-complainers not by the metabolic events of the ovarian cycle but by their psychological maladjustment to these changes, giving rise to exaggerated symptoms. Such sensitivity to the metabolic signals associated with ovulation may be the result of everyday stresses, life problems, or personality weaknesses. Logical therapy should therefore, we feel, be aimed at either stabilising the hormonal milieu or at readjusting the interpretation of these cyclically related symptoms by psychological or social means. The former approach seems to us more practicable. Although this is the effect of the combined contraceptive pill, at least when taken continuously, the benefits of anovulation may be overshadowed by the adverse mental and physical effects of the progestagen componentsWe are now looking at the use of anovulatory doses of subcutaneous oestradiol implants, combined with cyclical progestagen to prevent endometrial hyperplasia, as a rational form of therapy. PMS Clinic, Dulwich Hospital, London SE22 8PT
ADAM L. MAGOS
JOHN STUDD
Taylor JW. The timing of menstruation-related symptoms assessed by a daily symptom rating scale. Acta Psychiatr Scand 1979; 60: 87-105. 2. Studd JWW The premenstrual tension syndrome Br Med J 1979; i: 410. 3. Backstrom T, Boyle H, Baird DT. Persistence of symptoms of premenstrual tension in hysterectomized women Br J Obstet Gynaecol 1981; 88: 530-36. 4. Magos AL, Collins WP, Studd JWW. Management of the premenstrual syndrome by subcutaneous implants of oestradiol In: Proceedings of the 3rd International Congress on the Menopause (Antwerp, 1983) (In press.) 5. Mattson B, non Schoultz B. A comparison between lithium, placebo and a diuretic in premenstrual tension. Acta Psychiatr Scand 1974; suppl 244: 75-84. 6. Reid RL, Yen SSC. Premenstrual syndrome Am J Obstet Gynecol 1981; 139: 85-104. 7. Magos AL, Studd JWW. The premenstrual syndrome. In: Studd JWW, ed. Progress in obstetrics and gynaecology: Vol IV Edinburgh- Churchill Livingstone (in press). 8. Magos AL. Zilkha KJ, Studd JWW. Treatment of menstrual migraine by oestradiol implants. J Neurol Neurosurg Psychiatry (in press). 1.
toxin.2
If verotoxin is of direct pathogenic significance in HUS and haemorrhagic colitis, these diseases might be by immunisation. Almost thirty years ago Howard showed that injection of Shiga toxoid into laboratory animals gives rise to neutralising antibodies and protects them from the lethal effects of Shiga toxin. The role of pre-existing immunity in the development of verotoxin-associated HUS and haemorrhagic colitis remains to be established. However, the age distribution of the endemic variety of HUS suggests that susceptibility to this disease, as to other specific infections of childhood, is probably related to the absence of specific antibodies.
preventable
Departments of Bacteriology and Virology, Hospital for Sick Children, Toronto, Ontario, Canada M5G IXG; and Department of Microbiology, University of Toronto
M. A. KARMALI M. PETRIC C. LIM P. C. FLEMING
Department of Paediatrics, McMaster University, Hamilton, Ontario
B. T. STEELE
EARLY DIAGNOSIS OF MUCOPOLYSACCHARIDOSIS marrow transplantation is to be offered as a for mucopolysaccharidosis, as we believe it should, early referral before mental deterioration has gone too far, is important. No child with Hurler’s disease who has had a successful bone marrow transplant has subsequently shown any further mental deterioration. Our first patient, treated in June, 1980, aged 11I
SIR,-If bone
treatment
12. Peterson RB, Meseroll WP, Shrago GG, Gooding CA. Radiographic features of colitis associated with the hemolytic-uremic syndrome. Radiol 1976; 118: 667-71. 13. Schwartz S, Boley S, Lash J, Sternhill V. Roentgenologic aspects of reversible vascular occlusion of the colon, and its relationship to ulcerative colitis. Radiol 1963; 80: 625-35. 14. Timoney JF. Oedema disease of swine. Irish Vet J 1950; 62: 748-55. 15. Clugston RE, Nielsen NO, Smith DLT. Experimental edema disease of swine (E coli enterotoxemia) III: Pathology and pathogenesis. Can J Comp Med 1974; 38: 34-43. 16. Dobrescu L. New biological effect of edema disease principle (Escherichia colineurotoxin) and its use as an in-vitro assay for this toxin. Am J Vet Res 1983; 44: 31-34. 17. Howard JG. Observations on the intoxication produced in mice and rabbits by the neurotoxm of Shigella shigae. Br J Exp Pathol 1955; 36: 439-46.
months,
nearly 41/z years old. He has, if anything, progressed according to Griffith’s developmental assessments. The same applies to the next two cases who have now been followed-up is
now
for 21f2 and 21/4 years. In four cases the mother noticed the lumbar gibbus within the first few months of life but the significance of this was not appreciated by the doctors to whom she pointed it out. Most of these children had been operated on for inguinal or umbilical hernias by the age of 6 months. Surely the need for surgery is unusual in cases of simple umbilical hernia. The other important alternative diagnosis (hypothroidism) will in many centres now be excluded by neonatal
screening. INCIDENCE OF HERNIAS BY AGE SIX MONTHS IN CHILDREN WITH MUCOPOLYSACCHARIDOSIS
*I=Hurler, ll=Hunter; III=Sanfilippo; IV=Morquio.
The accompanying table shows the very high incidence of hernias before the age of 6 months in cases of mucopolysaccharidosis associated with mental deterioration, except for Sanfilippo’s disease. May I ask paediatricians and community doctors screening young babies, and surgeons who repair hernias in children, to exclude the rare but now treatable disease of mucopolysaccharidosis. A lateral X-ray of the lumbar spine will almost certainly be diagnostic in Hurler’s and Hunter’s disease (but not in Sanfilippo’s). Testing a random urine for glycosaminoglycan: creatinine ratio will always exclude these diagnoses. This test, which is not expensive and can be done in regional centres, is essential because the hepatosplenomegaly of mucopolysaccharidosis is not necessarily obvious at the time that the baby has its hernia. Bone Marrow Transplant Unit, Westminster Children’s Hospital, London SW1P 2NS
KENNETH HUGH-JONES
PENTAMIDINE OR CO-TRIMOXAZOLE FOR PNEUMOCYSTIS CARINII PNEUMONIA
1109) describe diffuse erythematous maculopapular eruptions eight of eighteen homosexual men with acquired immunodeficiency syndrome (AIDS) treated with co-trimoxazole (trimethoprim/sulfamethoxazole, TMP/SMZ). They suggest that this type of adverse reaction is immunologically mediated and that pentamidine rather than TMP/SMZ be considered for the initial therapy of Pneumocystis carinii pneumonia (PCP) in this grouup of patients. Until their randomised trial of pentamidine against TMP/SMZ is complete we would caution against this suggested replacement. A 26-year-old homosexual man with a 3-month history of fever, cough, and weight loss was admitted to hospital. His haemoglobin was 11-2 2 g/dl, the white blood cell count 6000/1 and the platelet count 114 OOOIIAI. Chest X-ray was normal. Bronchoscopy revealed PCP, and oral co-trimoxazole was started (TMP 20 and SMZ 100 mg/kg daily). After 9 days of therapy, during which the patient was afebrile and almost free of symptoms, a diffuse, itchy, maculopapular eruption developed. His haemoglobin was 10-66 g/dl, the white cell count 2600/1, and the platelet count 135 000/(1. TMP/SMZ was discontinued for 2 days after which the rash had almost disappeared. Since we were reluctant to start pentamidine therapy the patient was rechallenged with one double-strength SiR.—Dr Jaffe and colleagues (Nov 12,
p
in
no reaction occurred. The white blood cell returned to normal and the haemoglobin and platelet count remained as before. 4 months after this rechallenge the patient is
tablet of TMP/SMZ; count
JR, et al Reversal of clinical features of Hurler’s disease and biochemical improvement after treatment by bone-marrow transplantation. Lancet 1981; ii:
1. Hobbs
709-12.
1301 still on regular TMP/SMZ (one double-strength tablet twice a day) without any skin complaint. Jaffe et al rechallenged only four of their patients. Perhaps the other four would have reacted as our patient did. We cannot explain the mechanism involved. However, it might well be advisable, in similar cases, to try a rechallenge before switching to a drug that is I probably less effective and safe than TMP/SMZ. Medical Polyclinic,
University of Munich, 8000 Munich 2, West Germany
MICHAEL M. KOCHEN CLAUDIA HERRMANN FRANK D. GOEBEL
association with the vaccine to be claimed. No long-term reaction has been reported and we know of no case of transmission of hepatitis B or non-A, non-B hepatitis by the vaccine. No case of acquired immunodeficiency syndrome has been reported in vaccine recipients. Thus long-term experience confirms the safety of HBV vaccine of French manufacture.
Pharmaceutical Division, Institut Pasteur Production, 92430 Marnes-la-Coquette, France
HEPATITIS B VACCINE: CLINICAL EXPERIENCE AND SAFETY
SIR,-The French manufactured hepatitis B virus (HBV) vaccine prepared from human plasma containing surface antigen (HBsAg) that has been purified and inactivated by biophysical and biochemical processes.2Pilot studies began eight years ago3 and is
randomised controlled trials have demonstrated the vaccine’s 4 efficacy in preventing hepatitis B among susceptible individuals. The vaccine was licensed in May, 1981, and a large body of clinical experience has subsequently been collated. In France, over 100 000 people have been vaccinated. Besides the pilot and controlled trials (1495 people), there have been twelve studies on 2479 health care workers and dialysis patients. Follow-up of vaccine recipients has ranged from a few months to eight years. Worldwide up to one million doses have been administered and twenty-five follow-up studies (6830 people) have been mounted. Because of the plasma origin of the HBsAg, the major hypothetical side-effects of this vaccine are reactions to blood substances and the transmission of HBV or other blood borne agents. Information on illnesses developing after receipt of the HBV vaccine has been collected by spontaneous notifications, by inquiries by a surveillance unit at Institut Pasteur Production, and by telephone interviews with French monitoring centres. As of Sept 1, 1983, 295 illnesses had been reported in the French vaccinated population. More than half began after the first dose. Local side-effects (induration, erythema) were recorded in 99 people. Moderate general illnesses were reported in 192 vaccinees: 33 febrile episodes, 7 skin lesions (herpes zoster, erythema nodosum, rash), 1 Quinck oedema, 74 gastrointestinal reactions (nausea, vomiting, diarrhoea), and 76 miscellaneous complaints
(chills, asthenia, insomnia). 2 HBV infections were observed. A 60-year-old male dialysis 2 months after the third vaccine injection, had HBs antigenaemia without increased transaminases. Since only 19% of dialysis patients aged 60 or more responded to HBV vaccinethis
patient,
HBV infection may well have been in a non-responder. The second HBV infection was in a 27-year-old nurse who reported an HBsAgpositive needlestick exposure 12 weeks before vaccination. Clinical hepatitis developed 4 weeks after the third injection. This case of hepatitis B may be explained by immunisation in the incubation period of HBV infection. Active immunisation to abort the clinical course of HBV infection is suggested only when it can be started shortly after exposure. There have been 2 cases of serious illness. 1 patient had nephrotic syndrome 10 days after the first injection. Biopsy revealed a membranous glomerulonephritis. No anti-HBs was detected. The other had a painful bilateral peripheral neuropathy at C5/C6 . The symptoms began 22 days after immunisation. Short-term illnesses probably attributable to the vaccine have been local or mild while serious illness has been too rare for an Young LS. Trimethoprim-sulfamethoxazole in the treatment of adults with pneumonia due to Pneumocystis carinii. Rev Infect Dis 1982; 4: 608-13. 2. Adamowicz P, et al. Large scale production of an hepatitis B vaccine. In: Maupas P, Guesry P, eds. Proceedings of International Symposium on Hepatitis B Vaccine. Amsterdam: Excerpta Medica, 1980: 37-49. 3. Maupas P, et al. Potency and efficacy ofHB vaccine applied to a high risk population: a five year study. In: Proceedings of International Symposium on Hepatitis B Vaccine. Amsterdam: Excerpta Medica, 1980: 117-31. 1.
4.
Crosnier J,
5.
Goudeau A,
et al. Randomised placebo controlled trial of hepatitis B surface antigen vaccine in French haemodialysis units. Lancet 1981; i: 455-59, 797-800 et al. Hepatitis B vaccine: Clinical trials in high risk-settings in France. Devel Biol Standard (in press).
M. T. NUTINI F. N. MARIE C LOUCQ F. TRON
PREMENSTRUAL UNCERTAINTIES
SiR,-We agree with much of your editorial on the premenstrual syndrome (PMS) (Oct 22, p 950) but feel that valuable positive and negative premenstrual "certainties" were ignored, which could provide an insight into this complex condition. First, cyclical symptoms, be they mild or severe, are almost universal in women during their fertile years, and are accepted as normal by most women.Secondly, and conversely, these symptoms do not occur at times when cyclical ovarian activity is absent, such as before puberty, during pregnancy, and after the menopause.2Thirdly, menstruation itself is not essential, since cyclical symptoms continue after hysterectomy, provided ovarian function is conserved.3 Fourthly, a history of postnatal dysphoria is common in PMS sufferers, at a time not only of emotional vulnerabili7 but also
of great hormone and metabolic fluxes after delivery. Fifthly, psychological factors must play an important role in aetiology to explain the large placebo response of up to 89% reported in controlled therapeutic trials.5 These positive observations-taken in conjunction with the mass of negative findings relating to aetiology suggesting that metabolically complainers and non-complainers are similarand the lack of any convincingly superior therapy to placebo 7-lead us to suggest that it is the fluctuation of hormones and other metabolites with the ovarian cycle rather than their absolute concentrations that is of primary importance in the pathogenesis of cyclical symptoms, which include not only the PMS but also other cyclical conditions such as menstrual migraine.8 Women who complain of PMS seem to differ from non-complainers not by the metabolic events of the ovarian cycle but by their psychological maladjustment to these changes, giving rise to exaggerated symptoms. Such sensitivity to the metabolic signals associated with ovulation may be the result of everyday stresses, life problems, or personality weaknesses. Logical therapy should therefore, we feel, be aimed at either stabilising the hormonal milieu or at readjusting the interpretation of these cyclically related symptoms by psychological or social means. The former approach seems to us more practicable. Although this is the effect of the combined contraceptive pill, at least when taken continuously, the benefits of anovulation may be overshadowed by the adverse mental and physical effects of the progestagen componentsWe are now looking at the use of anovulatory doses of subcutaneous oestradiol implants, combined with cyclical progestagen to prevent endometrial hyperplasia, as a rational form of therapy. PMS Clinic, Dulwich Hospital, London SE22 8PT
ADAM L. MAGOS
JOHN STUDD
Taylor JW. The timing of menstruation-related symptoms assessed by a daily symptom rating scale. Acta Psychiatr Scand 1979; 60: 87-105. 2. Studd JWW The premenstrual tension syndrome Br Med J 1979; i: 410. 3. Backstrom T, Boyle H, Baird DT. Persistence of symptoms of premenstrual tension in hysterectomized women Br J Obstet Gynaecol 1981; 88: 530-36. 4. Magos AL, Collins WP, Studd JWW. Management of the premenstrual syndrome by subcutaneous implants of oestradiol In: Proceedings of the 3rd International Congress on the Menopause (Antwerp, 1983) (In press.) 5. Mattson B, non Schoultz B. A comparison between lithium, placebo and a diuretic in premenstrual tension. Acta Psychiatr Scand 1974; suppl 244: 75-84. 6. Reid RL, Yen SSC. Premenstrual syndrome Am J Obstet Gynecol 1981; 139: 85-104. 7. Magos AL, Studd JWW. The premenstrual syndrome. In: Studd JWW, ed. Progress in obstetrics and gynaecology: Vol IV Edinburgh- Churchill Livingstone (in press). 8. Magos AL. Zilkha KJ, Studd JWW. Treatment of menstrual migraine by oestradiol implants. J Neurol Neurosurg Psychiatry (in press). 1.