208 agents used were transhexanamic acid and F.E.i.B.A. We do not believe that this striking demonstration of normal healing in our patient could be ascribed to transhexanamic acid alone. Pollock and Lewis in their patient were unable to demonstrate either in-vitro correction of abnormal clotting tests or clinical haemostasis after using F.E.I.B.A. In contrast, we obtained near complete correction of in-vitro clotting tests associated with an eventual satisfactory outcome, in an injury known to carry a high mortality in patients with normal haemostasis. We have since used F.E.I.B.A. in another patient where we have been able to demonstrate near complete correction of abnormal clotting tests in association with a useful clinical effect. From our two patients it might appear that correction of abnormal clotting tests is prerequisite for the successful clinical use of F.E.i.B.A. Department of
Clinical
Hæmatology,
Royal Infirmary, Manchester M13 9WL
P. J. ENGLISH E. M. SHEPPARD R. T. WENSLEY
CHILDHOOD SEIZURES
SIR,-In Harrison and Taylor’s follow-up of the social and medical outcome of childhood seizures, the children were originally identified only on the basis of having had "at least one seizure in early childhood". Although one gets the impression that the material covers most of the children with seizures in the Oxford area between 1948 and 1953, it is not clearly stated whether the series is strictly unselected. We have just finished an epidemiological study in Gothenburg on children, born in 1956 and 1957, with seizure disorders. The series was collected through the electroencephalogram (E.E.G.) reports from the only neurophysiological laboratory in Gothenburg, and in the follow-up none was lost. Seizures appearing in the neonatal period only and febrile convulsions before the age of 5 years only were not included because we knew that E.E.G. was not always done in such cases; otherwise the series was complete and unselected. We took one or more seizures at age 1 month to 15 years as the basis for the material. 175 children (40 with one seizure only, 135 with epilepsy) were found, giving a frequency of 14.7per 1000 (3-77 for those with one seizure only, and 11 for those with epilepsy) in the population less than 16 years of age. There are some interesting similarities and differences between Harrison and Taylor’s study and ours. The mortality in their material was 10-1% (29-5% of all deaths were caused by convulsions) while the corresponding figure in our material was only 5-1%, and none died in convulsions. Harrison and Taylor found that 17-5% were "completely or semi-illiterate", a figure identical to our material. Those with continuing epilepsy represented 24.2% of their sample, 24.77% in ours. There are remarkable similarities between Oxford and Gothenburg with regard childhood seizures. We also agree with the Oxford workers’ impression that epilepsy is commonly "regarded as a frightening illness". We did miss, however, a further analysis in Harrison and Taylor’s material. Probably the result would have been the same as in our study and Brorson’s2—namely, that poor prognosis of epilepsy is correlated to the presence of abnormal neurological signs and/or mental retardation. In children with normal intelligence and normal physical examination there is in contrast no reason to be frightened for the prognosis. Furthermore, drug treatment is now more effective. Perhaps Cohen’s statement3 that 80% of people with epilepsy can live normally will soon no longer be in Harrison and Taylor’s words, "an artefact of the viewer’s location". Department of Pædiatrics, Östra Sjukhuset, Gothenburg, Sweden
LEVAMISOLE AND CELL-MEDIATED IMMUNITY AND SERUM-IMMUNOGLOBULINS IN RHEUMATOID ARTHRITIS
far with levamisole in rheumatoid arthritis (R.A.) confusing. Encouraging benefit has been reported;’ -4 but Dinai and Prasin a double-blind controlled trial, observed no improvement and even suggested deleterious effect with levamisole. We treated a selected group of 20 patients (ages 25-76) with severe active R.A. and skin anergy to tuberculin and D.N.C.B. Levamisole (’Decaris,’ Gedeon Richter Ltd, Hungary) was given in a single daily dose of 150 mg over four weeks. Skin tests and serum levels of IgG, IgA, and IgM were compared before and after treatment. After treatment, a definitely positive skin response to tuberculin was restored in 60% of cases. The reversion of skin anergy to D.N.C.B. was less frequent (30%). Initially high mean serum levels of IgG, IgA, and IgM fell during treatment (see accompanying table). The mean decrease in IgG was significant. The accompanying figure shows that most pronounced fall in immunoglobulin was in cases with extremely high pretreatment values. Clinical improvement, evaluated by duration of morning stiffness, degree of joint swelling, and quantity of analgesic drugs needed, was observed in 11 patients and was considerable in 8. No improvement was seen or even some deterioration occurred in 9 patients. Levamisole induced neither side-effects nor changes in blood-cell counts during the period of observation. We conclude that the effects of of levamisole in man are not limited to enhancement of cell-mediated immunity. In R.A.,
SIR,-Results
so
are
Schuermans, Y Lancet, 1975, i, 11 Basch, C. M., Spiter, L. E., Engelman, E. P. Arthr. Rheum 1975, 18, 385 Huskisson, E. C., Scott, J., Balme, H W., Dieppe, P. A , Trapnell, J., Willoughby, D. A Lancet, Feb 21, 1976, p.393 4. Veys, E N., Mielants, H., de Bussere, A., Decrans, L., Gabriel, P. ibid. Apnl 10, 1976. p. 808. 5. Dinai, Y., Pras, D. M. ibid. 1975, n, 556.
1
2. 3.
G. HAGBERG O. HANSSON
1. Harrison, R. M., Taylor, D C Lancet, 1976, i, 948. 2 Brorson, I.. O in T he Care of Epileptics in Swedish). The National Board of Health and Welfare, Stockholm 1970. 3 Cohen. Br med J 1958, ii, 672
Serum-immunoglobulins (Úó levaniisole
treatment.
of
mean
control
value) before and after
209 MEAN SERU,A-IIAMUNGGLOBULINS (mg/dl) IN 19 PATIENTS WITH RHEUMATOID ARTHRITIS BEFORE AND AFTER LEVAMISOLE TREATMENT
stimulation of skin delayed-hypersensitivity tests was associated with depression of serum-immunoglobulins. This observation is consistent with the findings of Huskisson et al.3 A late de-
in antibody titres was observed by Renoux et al. in elderly levamisole-treated patients immunised with influenza crease
vaccine. Levamisole should therefore be considered rather as an immunomodulating agent than as a general immunostimulant. Yaron et al. gave an indication that levamisole can have an anti-inflammatory action independent of its effect on the immune system. We are tempted to suggest that further comparisons between the clinical effects of levamisole and immunoreactivity and intensity of inflammatory process in R.A. would make it possible to select patients who could benefit from this drug. H. SZPILMAN Institute of
Rheumatology,
Spartańska 1, 02-637
Warsaw, Poland
THE HEPARIN-THROMBIN CLOTTING-TIME
SIR,-The heparin-thrombin clotting-time (H.T.C.T.) is referred to in your exemplary editorial’ about antithrombin and the diagnosis of prethrombotic states. In case there’could be any confusion, I write to emphasise that this H.T.c.T. test is not influenced by antithrombin levels. Since we use the patient’s plasma as substrate, theoretically such an influence is possible; however, we accept an H.T.c.T. result only if a dilutethrombin clotting-time is strictly normal. You refer to this test as possibly useful in distinguishing between a diagnosis of acute myocardial infarction and "nonspecific chest pain". We continue to find the H.T.c.T. valuable in this situation, but the most striking abnormality in true infarction may not develop for two to four days. (The original studies were "between the first and the seventh day".) I think the H.T.c.T. may have greater value in detecting a prethrombotic state; the test has twice shown significantly shorter clotting-times in groups of patients studied long after various kinds of thrombosis who presumably are at greater risk than normal of further trouble_23 You do not mention that we think this test measures platelet factor 4 released from platelets and so reflects the degree of platelet activation. Portsmouth and South East Hampshire District Pathology Service, St.
Mary’s Hospital,
J. R. O’BRIEN
Portmouth PO3 6AG
S. LUFT D. GLIŃSKA-URBAN W. FISCHER M. PLACHECKA
LEVAMISOLE AS ADJUNCT TO DAPSONE IN LEPROSY
ALPHA-FETOPROTEIN ASSAY IN ALL AMNIOCENTESIS SAMPLES
SIR,-We envy Broch and Scrimgeour’s false-positive rate zero,8 and suspect we understand the reason. They regard an amniotic-fluid sample containing fetal blood as unusable, while our results9 simply reflect a total experience without prior sample selection. We do not feel that a sample contamiof
nated with fetal blood should be discarded since some 47% of fluids derived from pregnancies where the fetus had anencephaly contained fetal hoemoglobin.10 Since fetal blood seems to be present so often in these particular cases, repeat amniocenteses may be of no avail. We have lately been able to modify our assay, which is now more sensitive. Over 800 samples have been re-assayed, including the 15 (0-4) reported as "definite" false positives out of the 3536 cases studied.2 With the modified assay, only 5 of these now remain with A.F.P. values >3 S.D. above the mean. This suggests a very similar false-positive rate z 1%) to that reported in the European Medical Research Council report." Since we have not re-assayed all 3536 cases, our exact rate cannot now be stated, but it is clearly in the range where routine A.F.P. assays of all amniotic fluids would be justified. Even by declaring samples with fetal haemoglobin unusable, we predict that a zero false-positive rate will not be maintained. We offer ultrasound and amniographic studies as additional approaches when faced with borderline elevations of A.F.P., and do not rely solely on the A.F.P. value. Eunice
Kennedy
Shriver
Center,
altham, and Massachusetts General Hospital,
W
Boston, Massachusetts, U S A
6 Renoux, G .
AUBREY MILUNSKY MARGARET E. KIMBALL
Renoux, M., Morand, P., Dartigues, P. Rev. med. Tours, 1973,
7, 797. Yaron, I., Herzberg, M Lancer, Feb. 14, 1976, p. 369 H., Scrimgeour, J. B Lancet, 1976, i, 1404. 9 Milunsky, A . Alpert, E. ibid. 1976, i, 1015. 10 Milunsky, A.. Alpert, E Obstet Gynec. in the press . 11 Lindsten, J, Zetterstrom, R., Ferguson-Smith, M. in Prenatal Diagnosis of Genetic Disorders of the Fœtus. I N.S.E R.M., Paris, 1976. 7 Yaron, M. Brock, D J
8
SIR,-Levamisole has a stimulatory effect on some aspects of the cellular immunity mechanism of the host. The mechanism of action is unclear. It has been suggested that levamisole has a immunostimulatory effect in leprosy patients with depressed cell-mediated immunity.56 We have tried to find out if levamisole would affect the course of the disease in patients with lepromatous and dimorphic leprosy treated with dapsone. Patients with nodular lepromatous or nodular dimorphic leprosy took part in the study. These patients were receivingdapsone, by mouth or by injection. Patients were evaluated monthly for clinical lesions and reactions. Clinical lesions were graded zero or 1-4, 4 being a nodular lesion and zero being a totally flat lesion (macule). The same observer graded these lesions every time but the treatment was unknown to the observer. Smears were read and graded by the same laboratory personnel who did not know the patient’s name or treatment. Sixteen patients were treated with dapsone 25mg by mouth every day and four received 450mg acedapsone intramuscularly once every two months. These patients were advised to take an additional pill, which was either levamisole (150 mg) or placebo, one pill every two weeks. At the end of six months of therapy, 12 patients finished the trial from the 20 who had started. All 12 had been clinical grade 4at the start. The 6 who had been on levamisole in addition to their dapsone (or acedapsone) had lesions of 1+ or zero at the end of the trial. Of the 6 patients taking placebo 4 ended see with
as
-3 and 2
as
0. This is what
one
would expect
to
dapsone alone.
1 Lancet, 1976, i. 1333 2. O’Brien, J. R, Etherington, M. D., Jamieson, S, Klaber, M. R . Lincoln, S. V Thromb Diath. Hœmorrh 1974, 31, 279 3 O’Brien, J R., Etherington, M. D., Jamieson, S., Lawford, P., Lincoln, S V. Alkjaersig, N 4 Symoens, J. in Proceedings of the 2nd International Conference on Modulation of Host Resistance in the Prevention or Treatment of Induced Neoplasias Bethesda, 1975edited by M A Chirigos U S Government Printing Office in the press 5 Cardama, J E., Gatti, J. C., Balina, I. H . Cabrera, H N, Fliess, L L Int. J Leprosy, 1973, 41, 567. 6 Saint-Andre, P., Louvet, M. Med Arm. 1976, 4, 223.
J ibid 1975, 34, 483.
Clinical
Hæmatology,
Royal Infirmary, Manchester M13 9WL
P. J. ENGLISH E. M. SHEPPARD R. T. WENSLEY
CHILDHOOD SEIZURES
SIR,-In Harrison and Taylor’s follow-up of the social and medical outcome of childhood seizures, the children were originally identified only on the basis of having had "at least one seizure in early childhood". Although one gets the impression that the material covers most of the children with seizures in the Oxford area between 1948 and 1953, it is not clearly stated whether the series is strictly unselected. We have just finished an epidemiological study in Gothenburg on children, born in 1956 and 1957, with seizure disorders. The series was collected through the electroencephalogram (E.E.G.) reports from the only neurophysiological laboratory in Gothenburg, and in the follow-up none was lost. Seizures appearing in the neonatal period only and febrile convulsions before the age of 5 years only were not included because we knew that E.E.G. was not always done in such cases; otherwise the series was complete and unselected. We took one or more seizures at age 1 month to 15 years as the basis for the material. 175 children (40 with one seizure only, 135 with epilepsy) were found, giving a frequency of 14.7per 1000 (3-77 for those with one seizure only, and 11 for those with epilepsy) in the population less than 16 years of age. There are some interesting similarities and differences between Harrison and Taylor’s study and ours. The mortality in their material was 10-1% (29-5% of all deaths were caused by convulsions) while the corresponding figure in our material was only 5-1%, and none died in convulsions. Harrison and Taylor found that 17-5% were "completely or semi-illiterate", a figure identical to our material. Those with continuing epilepsy represented 24.2% of their sample, 24.77% in ours. There are remarkable similarities between Oxford and Gothenburg with regard childhood seizures. We also agree with the Oxford workers’ impression that epilepsy is commonly "regarded as a frightening illness". We did miss, however, a further analysis in Harrison and Taylor’s material. Probably the result would have been the same as in our study and Brorson’s2—namely, that poor prognosis of epilepsy is correlated to the presence of abnormal neurological signs and/or mental retardation. In children with normal intelligence and normal physical examination there is in contrast no reason to be frightened for the prognosis. Furthermore, drug treatment is now more effective. Perhaps Cohen’s statement3 that 80% of people with epilepsy can live normally will soon no longer be in Harrison and Taylor’s words, "an artefact of the viewer’s location". Department of Pædiatrics, Östra Sjukhuset, Gothenburg, Sweden
LEVAMISOLE AND CELL-MEDIATED IMMUNITY AND SERUM-IMMUNOGLOBULINS IN RHEUMATOID ARTHRITIS
far with levamisole in rheumatoid arthritis (R.A.) confusing. Encouraging benefit has been reported;’ -4 but Dinai and Prasin a double-blind controlled trial, observed no improvement and even suggested deleterious effect with levamisole. We treated a selected group of 20 patients (ages 25-76) with severe active R.A. and skin anergy to tuberculin and D.N.C.B. Levamisole (’Decaris,’ Gedeon Richter Ltd, Hungary) was given in a single daily dose of 150 mg over four weeks. Skin tests and serum levels of IgG, IgA, and IgM were compared before and after treatment. After treatment, a definitely positive skin response to tuberculin was restored in 60% of cases. The reversion of skin anergy to D.N.C.B. was less frequent (30%). Initially high mean serum levels of IgG, IgA, and IgM fell during treatment (see accompanying table). The mean decrease in IgG was significant. The accompanying figure shows that most pronounced fall in immunoglobulin was in cases with extremely high pretreatment values. Clinical improvement, evaluated by duration of morning stiffness, degree of joint swelling, and quantity of analgesic drugs needed, was observed in 11 patients and was considerable in 8. No improvement was seen or even some deterioration occurred in 9 patients. Levamisole induced neither side-effects nor changes in blood-cell counts during the period of observation. We conclude that the effects of of levamisole in man are not limited to enhancement of cell-mediated immunity. In R.A.,
SIR,-Results
so
are
Schuermans, Y Lancet, 1975, i, 11 Basch, C. M., Spiter, L. E., Engelman, E. P. Arthr. Rheum 1975, 18, 385 Huskisson, E. C., Scott, J., Balme, H W., Dieppe, P. A , Trapnell, J., Willoughby, D. A Lancet, Feb 21, 1976, p.393 4. Veys, E N., Mielants, H., de Bussere, A., Decrans, L., Gabriel, P. ibid. Apnl 10, 1976. p. 808. 5. Dinai, Y., Pras, D. M. ibid. 1975, n, 556.
1
2. 3.
G. HAGBERG O. HANSSON
1. Harrison, R. M., Taylor, D C Lancet, 1976, i, 948. 2 Brorson, I.. O in T he Care of Epileptics in Swedish). The National Board of Health and Welfare, Stockholm 1970. 3 Cohen. Br med J 1958, ii, 672
Serum-immunoglobulins (Úó levaniisole
treatment.
of
mean
control
value) before and after
209 MEAN SERU,A-IIAMUNGGLOBULINS (mg/dl) IN 19 PATIENTS WITH RHEUMATOID ARTHRITIS BEFORE AND AFTER LEVAMISOLE TREATMENT
stimulation of skin delayed-hypersensitivity tests was associated with depression of serum-immunoglobulins. This observation is consistent with the findings of Huskisson et al.3 A late de-
in antibody titres was observed by Renoux et al. in elderly levamisole-treated patients immunised with influenza crease
vaccine. Levamisole should therefore be considered rather as an immunomodulating agent than as a general immunostimulant. Yaron et al. gave an indication that levamisole can have an anti-inflammatory action independent of its effect on the immune system. We are tempted to suggest that further comparisons between the clinical effects of levamisole and immunoreactivity and intensity of inflammatory process in R.A. would make it possible to select patients who could benefit from this drug. H. SZPILMAN Institute of
Rheumatology,
Spartańska 1, 02-637
Warsaw, Poland
THE HEPARIN-THROMBIN CLOTTING-TIME
SIR,-The heparin-thrombin clotting-time (H.T.C.T.) is referred to in your exemplary editorial’ about antithrombin and the diagnosis of prethrombotic states. In case there’could be any confusion, I write to emphasise that this H.T.c.T. test is not influenced by antithrombin levels. Since we use the patient’s plasma as substrate, theoretically such an influence is possible; however, we accept an H.T.c.T. result only if a dilutethrombin clotting-time is strictly normal. You refer to this test as possibly useful in distinguishing between a diagnosis of acute myocardial infarction and "nonspecific chest pain". We continue to find the H.T.c.T. valuable in this situation, but the most striking abnormality in true infarction may not develop for two to four days. (The original studies were "between the first and the seventh day".) I think the H.T.c.T. may have greater value in detecting a prethrombotic state; the test has twice shown significantly shorter clotting-times in groups of patients studied long after various kinds of thrombosis who presumably are at greater risk than normal of further trouble_23 You do not mention that we think this test measures platelet factor 4 released from platelets and so reflects the degree of platelet activation. Portsmouth and South East Hampshire District Pathology Service, St.
Mary’s Hospital,
J. R. O’BRIEN
Portmouth PO3 6AG
S. LUFT D. GLIŃSKA-URBAN W. FISCHER M. PLACHECKA
LEVAMISOLE AS ADJUNCT TO DAPSONE IN LEPROSY
ALPHA-FETOPROTEIN ASSAY IN ALL AMNIOCENTESIS SAMPLES
SIR,-We envy Broch and Scrimgeour’s false-positive rate zero,8 and suspect we understand the reason. They regard an amniotic-fluid sample containing fetal blood as unusable, while our results9 simply reflect a total experience without prior sample selection. We do not feel that a sample contamiof
nated with fetal blood should be discarded since some 47% of fluids derived from pregnancies where the fetus had anencephaly contained fetal hoemoglobin.10 Since fetal blood seems to be present so often in these particular cases, repeat amniocenteses may be of no avail. We have lately been able to modify our assay, which is now more sensitive. Over 800 samples have been re-assayed, including the 15 (0-4) reported as "definite" false positives out of the 3536 cases studied.2 With the modified assay, only 5 of these now remain with A.F.P. values >3 S.D. above the mean. This suggests a very similar false-positive rate z 1%) to that reported in the European Medical Research Council report." Since we have not re-assayed all 3536 cases, our exact rate cannot now be stated, but it is clearly in the range where routine A.F.P. assays of all amniotic fluids would be justified. Even by declaring samples with fetal haemoglobin unusable, we predict that a zero false-positive rate will not be maintained. We offer ultrasound and amniographic studies as additional approaches when faced with borderline elevations of A.F.P., and do not rely solely on the A.F.P. value. Eunice
Kennedy
Shriver
Center,
altham, and Massachusetts General Hospital,
W
Boston, Massachusetts, U S A
6 Renoux, G .
AUBREY MILUNSKY MARGARET E. KIMBALL
Renoux, M., Morand, P., Dartigues, P. Rev. med. Tours, 1973,
7, 797. Yaron, I., Herzberg, M Lancer, Feb. 14, 1976, p. 369 H., Scrimgeour, J. B Lancet, 1976, i, 1404. 9 Milunsky, A . Alpert, E. ibid. 1976, i, 1015. 10 Milunsky, A.. Alpert, E Obstet Gynec. in the press . 11 Lindsten, J, Zetterstrom, R., Ferguson-Smith, M. in Prenatal Diagnosis of Genetic Disorders of the Fœtus. I N.S.E R.M., Paris, 1976. 7 Yaron, M. Brock, D J
8
SIR,-Levamisole has a stimulatory effect on some aspects of the cellular immunity mechanism of the host. The mechanism of action is unclear. It has been suggested that levamisole has a immunostimulatory effect in leprosy patients with depressed cell-mediated immunity.56 We have tried to find out if levamisole would affect the course of the disease in patients with lepromatous and dimorphic leprosy treated with dapsone. Patients with nodular lepromatous or nodular dimorphic leprosy took part in the study. These patients were receivingdapsone, by mouth or by injection. Patients were evaluated monthly for clinical lesions and reactions. Clinical lesions were graded zero or 1-4, 4 being a nodular lesion and zero being a totally flat lesion (macule). The same observer graded these lesions every time but the treatment was unknown to the observer. Smears were read and graded by the same laboratory personnel who did not know the patient’s name or treatment. Sixteen patients were treated with dapsone 25mg by mouth every day and four received 450mg acedapsone intramuscularly once every two months. These patients were advised to take an additional pill, which was either levamisole (150 mg) or placebo, one pill every two weeks. At the end of six months of therapy, 12 patients finished the trial from the 20 who had started. All 12 had been clinical grade 4at the start. The 6 who had been on levamisole in addition to their dapsone (or acedapsone) had lesions of 1+ or zero at the end of the trial. Of the 6 patients taking placebo 4 ended see with
as
-3 and 2
as
0. This is what
one
would expect
to
dapsone alone.
1 Lancet, 1976, i. 1333 2. O’Brien, J. R, Etherington, M. D., Jamieson, S, Klaber, M. R . Lincoln, S. V Thromb Diath. Hœmorrh 1974, 31, 279 3 O’Brien, J R., Etherington, M. D., Jamieson, S., Lawford, P., Lincoln, S V. Alkjaersig, N 4 Symoens, J. in Proceedings of the 2nd International Conference on Modulation of Host Resistance in the Prevention or Treatment of Induced Neoplasias Bethesda, 1975edited by M A Chirigos U S Government Printing Office in the press 5 Cardama, J E., Gatti, J. C., Balina, I. H . Cabrera, H N, Fliess, L L Int. J Leprosy, 1973, 41, 567. 6 Saint-Andre, P., Louvet, M. Med Arm. 1976, 4, 223.
J ibid 1975, 34, 483.
