- Email: [email protected]
LONG-TERM TRANSFER-FACTOR TREATMENT FOR MULTIPLE SCLEROSIS
851
tendency to improve and no differential response to drug therapy. Thus the scope of the antipsychotic effect may be more limited than was suggested by an analysis of the 1964 National Institute of Mental Health trial,21 in which the benefits of neuroleptic drugs appeared to be as great on some negative features of the disease (e.g., social withdrawal, lack of self-care) as on the positive symptoms. Negative symptoms (identified in a clinical interview, rather than on behavioural ratings as in the earlier study) are uncommon in acute schizophrenia but are prominent in the "defect state", in which neuroleptics may be less effective. 22 Our attempts to subdivide the population by adopting different diagnostic criteria (fig. 3) demonstrate that the antipsychotic effect in patients with the most characteristically schizophrenic illnesses as defined by the presence of deterioration and by lack of affective symptoms is as great as, and possibly greater than, in other groups of patients (e.g., those with :schizoaffective psychoses). The highly significant improvement in patients on placebo (only 2 of whom had received additional chlorpromazine in regular dosage) must presumably be attributed to the effects of admission, the ward treatment regime, spontaneous remission, or a combination of these factorst Whereas these changes were greatest in the first 2 weeks of the study, the therapeutic effects attributable to medication began to emerge only between weeks 2 and 3. This time-course suggests that although the antipsychotic effect may depend on dopamine-receptor blockade, such blockade may be necessary only to allow other, longer-term, processes to take place. This trial was approved by the Northwick Park Hospital ethical committee and conducted within the guidelines laid down by this committee. We are grateful to Dr L. L. Iversen for drawing our attention to the possibility of this trial, and to Lundbeck Ltd for making available the isomers of flupenthixol and for their interest and encouragement. We also thank Sister I. Crichlow and the nursing staff of Eastlake Ward for their help in carrying out the trial and Mrs P. Wright and Mrs M.
Conant for secretarial assistance.
Requests for reprints should be addressed to T. J. C.
LONG-TERM TRANSFER-FACTOR TREATMENT FOR MULTIPLE SCLEROSIS LENE PEDERSEN TORBEN FOG SLAVENKA KAM-HANSEN NIELS E. RAUN EVA MELLERUP
Department of Neurology, Kommunehospitalet, Copenhagen PER PLATZ
LARS P. RYDER BODIL K. JAKOBSEN
Tissue-Typing Laboratory, State University Hospital,
Copenhagen, Denmark PETER GROB Section
of Clinical Immunology, Department of Medicine, University Hospital, Zürich, Switzerland
Introduction ALTHOUGH the aetiology and pathogenesis of multiple sclerosis (M.S.) is unknown there is mounting evidence that viruses and host immunological abnormalities are involved.1-4 Transfer factor (T.F.) enhances the immunological response of patients with M.S.5 and other diseases,6 and in 1977 we published a pilot study of T.F. treatment in M.S.: T.F. did not prevent clinical progression but a moderating effect on the disease could not be excluded; specific responses to both measles and parainfluenza virus antigens were temporarily changed towards normal8 and T.F. had a prolonged effect on lymphocyte membrane metabolism.9 In a double-blind study we have examined the effect Of T.F. treatment on the clinical progression of M.S.
REFERENCES S.
Patients
1. Goldberg, C., Klerman, L., Cole, J. O. Br. J. Psychiat. 1965, 111, 120. 2. Klein, D. F., Davis, J. M. Diagnosis and Drug Treatment of Psychiatric Disorder. Baltimore, 1969. 3. Miller, R. J., Horn, A. S., Iversen, L. L. Molec. Pharmac. 1974, 10, 759. 4. Clement-Cormier, Y. C., Kebabian, J. W., Petzold, G. L., Greengard, P. Proc. natn. Acad. Sci. U.S.A., 1974, 71, 1113. 5. Seeman, P., Lee, T., Chau-Wong, M., Wong, K. Nature, 1976, 261, 717. 6. Creese, I., Burt, D. R., Snyder, S. H. Science, 1976, 192, 481. 7. Enna, S. J., Bennett, J. P., Burt, D. R., Creese, I., U’Prichard, D. C., Greenberg, D. A., Snyder, S. H. Nature, 1977, 267, 183. 8. Wing, J. K., Cooper, J. E., Sartorius, N. Measurement and Classification of 9.
G.
Psychiatric Symptoms. London, 1974. Krawiecka, M., Goldberg, D., Vaughan, M. Acta psychiat.
scand.
1977, 55,
299.
10. Brockington,
In groups of 16
patients with multiple 13 months’ double-blind treatsclerosis, ment with transfer factor from random normal donors differed from placebo treatment only in producing a temporary restoration of lymphocyte reactivity to measles virus antigen, and did not arrest the degeneration of nerve tissue. Summary
I. F., Kendell, R. E. Personal communication.
The 32 patients (18 female, 14 male, aged 19-54 years) all had multiple symptoms of progressive M.S. in repeated neurological examinations but were not restricted to a wheelchair. They were randomly divided into two groups of 16 with similar disease duration, sex, age, and HLA-Dw2 frequency. Patients were admitted into the treatment groups in parallel over 8 weeks. During the trial, drug treatment was continued and only altered for the usual indications. Corticosteroids were only given for severe relapse (4 patients). Some of the patients had three months’ physical rehabilitation during the trial.
11. Feighner, J. P., Robins, E., Guze,
S. B., Woodruff, R. A., Winokur, G., Munoz, R. Archs gen. Psychiat. 1972, 26, 57. 12. Robinson, J. D., Risby, D., Johnstone, E. C., Crow, T. J. Unpublished. 13. Horn, A. S., Phillipson, O. T. Eur. J. Pharmac. 1976, 37, 1. 14. Miller, R. J. Biochem. Pharmac. 1976, 25, 537. 15. Peroutka, S. J., U’Prichard, P. C., Greenberg, D. A., Snyder, S. H. Neuropharmacology, 1977, 16, 549. 16. Møller-Nielsen, I., Pedersen, V., Nymark, M., Franck, K. F., Boeck, V., Fjalland, B., Christensen, A. V. Acta pharmac. tox. 1973, 33, 353. 17. Iversen, L. L., Rogawski, M. J., Miller, R. J. Molec. Pharmac. 1976, 12, 251. 18. Bennett, J. P., Snyder, S. H. Brain Res. 1975, 94, 523. 19. Holden, J. M. C., Itil, T., Keskiner, A., Gannon, P. J. clin. Pharmac. 1971, 11, 220. 20. Gallant, D. M., Bishop, M. P. Curr. Ther. Res. 1968, 10, 461.
21. National Institute of Mental Health Psychopharmacology Service Center Collaborative Study Group, Archs gen. Psychiat. 1964, 10, 246. 22. Letemendia, F. J. J., Harris, A. D.
Br. J. Psychiat. 1967, 113, 950.
Methods
Transfer Factor T.F. (1 unit equivalent to 1-2xl09 leucocytes) from prepared buffy coats of twenty 400 ml blood-samples by freezing and thawing (twelve times), ultrafiltration (Sartorius apparatus, SM 12136 membranes with cut-off at 10 000 mol.wt.) and freeze-drying. 10 The placebo was lyophilised saline which, after reconsititution in coded ampoules, was indistinguishable from T.F.
10 units of
were
Protocol
Subcutaneous
injections of
3 units
(9 ampoules)
of
T.F. or
852 in 20 ml distilled water were given monthly with an additional dose 1 week after the first. A neurologicalexamination was done, B lymphocytes and T lymphocytes were counted, and lymphocyte migration and transformation in response to various antigens were assessed before treatment and immediately before each injection. Agar gel electrophoresis of cerebrospinal fluid (C.S.F.) (Neurochemical Institute, Copenhagen) was assessed before and after treatment. Clinical Examination Each patient was usually examined by the same clinician using a neurological scoring system." To further reduce bias the examiner was not aware of the scores obtained at the previous examination. Each sign and symptom was graded clinically and converted by computer program into a total neurological deficit, expressed as a percentage of a hypothetical maximum, which quantified the state of the disease.12 The total neurological deficit was similar in both patient groups. For each patient the neurological deficit was plotted against time of study and the rate of change of neurological deficitthe slope of the regression line against time (regression coefficient)-was calculated. The trial was planned to last 3 years with an initial analysis at 12 months, at which point the trial could be stopped if there were no signs of a beneficial effect of T.F. or if the average rate of progression was decreased by at least 50% in the T.F. group. The regression coefficients for patients treated with placebo or T.F. were compared by the Mann-Whitney rank sum test and the mean rate of progression in the two groups was calculated.
placebo
Results
The trial was stopped after 13 months because as found in our pilot study7 there was no significant difference in the coefficients of progression of the placebotreated and T.F.-treated groups (see figure). None of the 32 patients improved during treatment and 16 deteriorated significantly. Of these 16, 9 had received T.F. and 7 placebo, further emphasising the ineffectiveness of T.F. treatment.
Lymphocyte reactivity to measles antigen (measured by lymphocyte-migration inhibition) appeared tempor-
in the T.F.-treated group but lymphocyte transformation and T-cell and B-cell numbers changed only slightly. These results will be published in detail elsewhere.t2 15 of the 32 patients were HLA-Dw2 positive, a proportion similar to that previously reported in M.S. patients" and higher than that in the normal Danish population (20%). M.S. tends to progress more quickly in Dw-2 positive patients than in Dw-2 negative patients" and T.F. treatment did not alter this association. 27 of the 32 patients had a lumbar puncture both before and after the trial (3 patients objected to second lumbar puncture, 2 were technically unsuccessful). 20 of these 27 patients had oligoclonal f3-T4 bands in c.s.F. before treatment; in 8 cases these bands had disappeared after the trial. In 4 of the remaining 7 patients oligoclonal Y3--Ya bands were found only after treatment. These changes were independent of treatment with T.F.
arily
placebo. Slight soreness and swelling around the injection site was the only side-effect. Of a total of approximately 470 injections, 10 small skin necroses were found in 6 patients (4 on placebo, 2 on T.F.). or
Discussion
Quantifying neurological signs and symptoms in M.s. is difficult15 but our scoring system8 takes into account the greatest possible variability in signs and symptoms. For assessing the clinical course of M.s. a scoring system of some sort is preferable to the neurologist’s subjective impressions or the incidence of attacks or exacerbations;16 in 25% of the cases in this trial there were differences between the examiners’ estimation and the computer calculation of the disease course, and the relapse rate in the trial (0-3-1-11 per patient per year depending upon definitions and investigators) was too small for use in studies below 50-100 patients for 1-2 years.17 New acute or subacute symptoms appeared in 3 patients and there were 13 relapses in 10 patients. These developments were unrelated to the use of T.F. or placebo, emphasising the conclusion from the scoring system that the clinical course of m. s. was unaffected by T.F. treatment.
previous studies ofT.F. treatment in M.S., Zabriskie al.18 and Fog et al.9 reported inconclusive results. Behan et all found that T.F. had no effect in a doubleblind study of 30 patients but their patients were treated with low doses of T.F. for a short time, and only a few clinical investigations were done. The absence in the trial reported here of the placebo effect observed in our pilot study9 might be due either to the selection of patients or to the examiners’ knowing that a placebo In
et
group was included. The appearance and disappearance of oligoclonal T3*"T4 bands in the c.s.F. could not be correlated with T.F. treatment. The appearance of oligoclonal IgG is irreversible in the individual M.s. patient2o-’2 and so it is possible that technical errors may explain the appearance or disappearance of oligoclonal bands in c.s.F. from 12 of 27 patients.
Progression of M.S. in patients treated with T.F. or placebo. Shaded areas are rates of change in neurological deficit per year. - =mean (±2s.E.). Course of disease is similar in the two treatment groups.
We thank the staff of the department of neurology, Kommunehospitalet for their cooperation and Dr Coleman Smith for critical comments. The study was supported by the Danish Multiple Sclerosis Society, the Warwara Larsen Foundation, the Swiss Multiple Sclerosis Society, and the Swiss National Science Foundation (grant no.
6.155-0.75).
853 Requests for reprints should be addressed to T.F., Department of Neurology, Kommunehospitalet, DK-1399 Copenhagen K, Denmark.
REFERENCES
1. Salmi, A., Gollmar, Y., Norrby, E., Panelius, M.
Acta
path. microbiol.
scand. Sect. B. 1973, 81, 627. 2. Ciongoli, A. K., Platz, P., Dupont, B.,
Svejgaard, A., Fog, T., Jersild, C. Lancet, 1973, ii, 1147. 3. Platz, P., Fog, T., Morling, N., Svejgaard, A., Sønderstrup, G., Ryder, L. P., Thomsen, M., Jersild, C. Acta path. microbiol. scand. Sect. C. 1976, 84, 501. 4. Offner, H., Konat, G., Clausen, J. Acta neurol. scand. 1974, 50, 791. 5. Jersild, C., Platz, P., Thomsen, M., Hansen, G. S., Svejgaard, A., Dupont, B., Fog, T., Ciongoli, A. K., Grob, P. Lancet, 1973, ii, 1381. 6. Spitler, L. E., Levin, A. S., Fudenberg, H. H. in Immunodeficiency in Man and Animals (edited by D. Bergsma). Birth defects vol. xi, 1, 449. Sunder-
land, Massachusetts, 1975. 7. Fog, T., Jersild, C., Platz, P., Svejgaard, A., Pedersen, L., Kam-Hansen, S., Raun, N. E., Mellerup, E., Jakobsen, B., Linnemann, F., West, P. Acta neurol. scand. suppl. 63, 1977, 55, 253. 8. Platz, P., Jersild, C., Thomsen, M., Svejgaard, A., Fog, T., Midholm, S., Raun, N. E., Kam-Hansen, S., Grob, P. in Transfer Factor, London, 1976. 9. Offner, H., Raun, N. E., Konat, G., Clausen, J. Acta neurol. scand. 1977,
56, 465. 10. Grob, P. J., Reymond, J. F., Häcki, M. A., Frey-Wettstein, M. in Transfer Factor, Basic Properties and Clinical Applications (edited by M. S. Ascher, A. A. Gottlieb, C. H. Kirkpatrick); p. 247. New York, 1976. 11. Fog. T., Raun, N. E. Computerised Forms in Multiple Sclerosis for Medical History and Full Neurological Examination. Kommunehospitalet, Copen-
hagen, 1976.
Case-reports Case1 This male baby was born at 40 weeks after an uncomplicated pregnancy. Delivery was normal and birth-weight was 2700 g. When he was 1 week old he was admitted to hospital with persistent vomiting, and was found to have gastro-oesophageal reflux. He was treated by total parenteral nutrition and was kept in a propped-up position. Repeated attempts to feed him were unsuccessful, and after 5 weeks’ conservative treatment he was referred to our hospital where the possibility of operative treatment was considered. On admission he weighed 3200 g and examination revealed no abnormal findings. The right internal jugular vein was cannulatedl so that intravenous (l.v.) hyperalimentation could be continued. The i.v. line was connected to an infusion pump. Several hours later progressive respiratory distress developed. Tachypnoea (80 breaths per min) with intercostal and subcostal2 retraction was noted. Diminished air-entry was heard over both lung fields. Chest X-ray showed pronounced widening of the mediastinum (fig 1). Blood gases while 40% oxygen was being given by mask were p a02’ 30 mm Hg, and P ac02’ 66 mm Hg. The cannula was immediately removed from the internal jugular vein and assisted ventilation via an endotracheal tube was started. Several hours later respiration had markedly improved and extravasation into the mediastinum was no longer visible on X-ray (fig 2).
12. Platz, P., and others. Unpublished. 13. Jersild, C., Fog, T., Hansen, G. S., Thomsen, M.,
Svejgaard, A., Dupont, B. Lancet, 1973, ii, 1221. 14. Jersild, C., Dupont, B., Fog, T., Platz, P., Svejgaard, A. Transplant. Rev. 1975, 22, 148. Symposium of Multiple Sclerosis in Acta neurol. scand. suppl. 58, 1974, 50, 27. 16. Fog, T. Unpublished. 17. Lhermitte, F., Masteau, R., Gazengel, J., Dordain, G., Deloche, G. Z. Neurol. 1973, 205, 47. 18. Zabriskie, J. B., Espinoza, L. R., Plank, C. R., Collino, R. C. Acta neurol. scand. suppl. 63, 1975, 55, 239. 19. Behan, P. D., Durward, W. F., Melville, I. D., McGeorge, A. P., Behan, W. M. H. Lancet, 1976, i, 988, 20. Link, H. Acta neurol. scand. suppl. 63, 1977, 55, 173. 21. Link, H. ibid. p. 215. 22. Olsson, J. E., Link, H. Archs Neurol. 1973, 28, 392. 15. International
A LIFE-THREATENING COMPLICATION OF THE INFUSION PUMP AMRAM AYALON YACOV BERLATZKY
HAIM ANNER MEDAD SCHILLER
Department of Pædiatric Surgery, Hadassah Hospital, Jerusalem, Israel
Summary
University
of case 1 showing pronounced widening of the mediastinum because of extravasation of an infusion being given into in the internal jugular vein.
Fig. 1--Chest X-ray
respiration and developed in 2 infants in vein was controlled by a
Serious disturbances in venous return
whom infusion into a central peristaltic pump. The effects were the result of extravasation which led to a build-up of pressure in the mediastinum. Introduction INFUSION pumps are widely used in infants and to whom fluids are often administered at low rates and in whom intravenous (i.v.) lines therefore tend to become occluded. To deliver a specified volume, without taking into account the pressure needed to overcome unpredictable resistance to flow through needles and catheters, the infusion pump develops a pressure greater than 850 mm Hg. We describe the development of life-threatening complications in 2 infants in whom infusion into a central vein was controlled by a peristaltic pump.
children,
Fig. 2-Chest X-ray of case 1, 24 hours later. Extravasated fluid has been resorbed, and the contour of the mediastinum has returned to normal.
tendency to improve and no differential response to drug therapy. Thus the scope of the antipsychotic effect may be more limited than was suggested by an analysis of the 1964 National Institute of Mental Health trial,21 in which the benefits of neuroleptic drugs appeared to be as great on some negative features of the disease (e.g., social withdrawal, lack of self-care) as on the positive symptoms. Negative symptoms (identified in a clinical interview, rather than on behavioural ratings as in the earlier study) are uncommon in acute schizophrenia but are prominent in the "defect state", in which neuroleptics may be less effective. 22 Our attempts to subdivide the population by adopting different diagnostic criteria (fig. 3) demonstrate that the antipsychotic effect in patients with the most characteristically schizophrenic illnesses as defined by the presence of deterioration and by lack of affective symptoms is as great as, and possibly greater than, in other groups of patients (e.g., those with :schizoaffective psychoses). The highly significant improvement in patients on placebo (only 2 of whom had received additional chlorpromazine in regular dosage) must presumably be attributed to the effects of admission, the ward treatment regime, spontaneous remission, or a combination of these factorst Whereas these changes were greatest in the first 2 weeks of the study, the therapeutic effects attributable to medication began to emerge only between weeks 2 and 3. This time-course suggests that although the antipsychotic effect may depend on dopamine-receptor blockade, such blockade may be necessary only to allow other, longer-term, processes to take place. This trial was approved by the Northwick Park Hospital ethical committee and conducted within the guidelines laid down by this committee. We are grateful to Dr L. L. Iversen for drawing our attention to the possibility of this trial, and to Lundbeck Ltd for making available the isomers of flupenthixol and for their interest and encouragement. We also thank Sister I. Crichlow and the nursing staff of Eastlake Ward for their help in carrying out the trial and Mrs P. Wright and Mrs M.
Conant for secretarial assistance.
Requests for reprints should be addressed to T. J. C.
LONG-TERM TRANSFER-FACTOR TREATMENT FOR MULTIPLE SCLEROSIS LENE PEDERSEN TORBEN FOG SLAVENKA KAM-HANSEN NIELS E. RAUN EVA MELLERUP
Department of Neurology, Kommunehospitalet, Copenhagen PER PLATZ
LARS P. RYDER BODIL K. JAKOBSEN
Tissue-Typing Laboratory, State University Hospital,
Copenhagen, Denmark PETER GROB Section
of Clinical Immunology, Department of Medicine, University Hospital, Zürich, Switzerland
Introduction ALTHOUGH the aetiology and pathogenesis of multiple sclerosis (M.S.) is unknown there is mounting evidence that viruses and host immunological abnormalities are involved.1-4 Transfer factor (T.F.) enhances the immunological response of patients with M.S.5 and other diseases,6 and in 1977 we published a pilot study of T.F. treatment in M.S.: T.F. did not prevent clinical progression but a moderating effect on the disease could not be excluded; specific responses to both measles and parainfluenza virus antigens were temporarily changed towards normal8 and T.F. had a prolonged effect on lymphocyte membrane metabolism.9 In a double-blind study we have examined the effect Of T.F. treatment on the clinical progression of M.S.
REFERENCES S.
Patients
1. Goldberg, C., Klerman, L., Cole, J. O. Br. J. Psychiat. 1965, 111, 120. 2. Klein, D. F., Davis, J. M. Diagnosis and Drug Treatment of Psychiatric Disorder. Baltimore, 1969. 3. Miller, R. J., Horn, A. S., Iversen, L. L. Molec. Pharmac. 1974, 10, 759. 4. Clement-Cormier, Y. C., Kebabian, J. W., Petzold, G. L., Greengard, P. Proc. natn. Acad. Sci. U.S.A., 1974, 71, 1113. 5. Seeman, P., Lee, T., Chau-Wong, M., Wong, K. Nature, 1976, 261, 717. 6. Creese, I., Burt, D. R., Snyder, S. H. Science, 1976, 192, 481. 7. Enna, S. J., Bennett, J. P., Burt, D. R., Creese, I., U’Prichard, D. C., Greenberg, D. A., Snyder, S. H. Nature, 1977, 267, 183. 8. Wing, J. K., Cooper, J. E., Sartorius, N. Measurement and Classification of 9.
G.
Psychiatric Symptoms. London, 1974. Krawiecka, M., Goldberg, D., Vaughan, M. Acta psychiat.
scand.
1977, 55,
299.
10. Brockington,
In groups of 16
patients with multiple 13 months’ double-blind treatsclerosis, ment with transfer factor from random normal donors differed from placebo treatment only in producing a temporary restoration of lymphocyte reactivity to measles virus antigen, and did not arrest the degeneration of nerve tissue. Summary
I. F., Kendell, R. E. Personal communication.
The 32 patients (18 female, 14 male, aged 19-54 years) all had multiple symptoms of progressive M.S. in repeated neurological examinations but were not restricted to a wheelchair. They were randomly divided into two groups of 16 with similar disease duration, sex, age, and HLA-Dw2 frequency. Patients were admitted into the treatment groups in parallel over 8 weeks. During the trial, drug treatment was continued and only altered for the usual indications. Corticosteroids were only given for severe relapse (4 patients). Some of the patients had three months’ physical rehabilitation during the trial.
11. Feighner, J. P., Robins, E., Guze,
S. B., Woodruff, R. A., Winokur, G., Munoz, R. Archs gen. Psychiat. 1972, 26, 57. 12. Robinson, J. D., Risby, D., Johnstone, E. C., Crow, T. J. Unpublished. 13. Horn, A. S., Phillipson, O. T. Eur. J. Pharmac. 1976, 37, 1. 14. Miller, R. J. Biochem. Pharmac. 1976, 25, 537. 15. Peroutka, S. J., U’Prichard, P. C., Greenberg, D. A., Snyder, S. H. Neuropharmacology, 1977, 16, 549. 16. Møller-Nielsen, I., Pedersen, V., Nymark, M., Franck, K. F., Boeck, V., Fjalland, B., Christensen, A. V. Acta pharmac. tox. 1973, 33, 353. 17. Iversen, L. L., Rogawski, M. J., Miller, R. J. Molec. Pharmac. 1976, 12, 251. 18. Bennett, J. P., Snyder, S. H. Brain Res. 1975, 94, 523. 19. Holden, J. M. C., Itil, T., Keskiner, A., Gannon, P. J. clin. Pharmac. 1971, 11, 220. 20. Gallant, D. M., Bishop, M. P. Curr. Ther. Res. 1968, 10, 461.
21. National Institute of Mental Health Psychopharmacology Service Center Collaborative Study Group, Archs gen. Psychiat. 1964, 10, 246. 22. Letemendia, F. J. J., Harris, A. D.
Br. J. Psychiat. 1967, 113, 950.
Methods
Transfer Factor T.F. (1 unit equivalent to 1-2xl09 leucocytes) from prepared buffy coats of twenty 400 ml blood-samples by freezing and thawing (twelve times), ultrafiltration (Sartorius apparatus, SM 12136 membranes with cut-off at 10 000 mol.wt.) and freeze-drying. 10 The placebo was lyophilised saline which, after reconsititution in coded ampoules, was indistinguishable from T.F.
10 units of
were
Protocol
Subcutaneous
injections of
3 units
(9 ampoules)
of
T.F. or
852 in 20 ml distilled water were given monthly with an additional dose 1 week after the first. A neurologicalexamination was done, B lymphocytes and T lymphocytes were counted, and lymphocyte migration and transformation in response to various antigens were assessed before treatment and immediately before each injection. Agar gel electrophoresis of cerebrospinal fluid (C.S.F.) (Neurochemical Institute, Copenhagen) was assessed before and after treatment. Clinical Examination Each patient was usually examined by the same clinician using a neurological scoring system." To further reduce bias the examiner was not aware of the scores obtained at the previous examination. Each sign and symptom was graded clinically and converted by computer program into a total neurological deficit, expressed as a percentage of a hypothetical maximum, which quantified the state of the disease.12 The total neurological deficit was similar in both patient groups. For each patient the neurological deficit was plotted against time of study and the rate of change of neurological deficitthe slope of the regression line against time (regression coefficient)-was calculated. The trial was planned to last 3 years with an initial analysis at 12 months, at which point the trial could be stopped if there were no signs of a beneficial effect of T.F. or if the average rate of progression was decreased by at least 50% in the T.F. group. The regression coefficients for patients treated with placebo or T.F. were compared by the Mann-Whitney rank sum test and the mean rate of progression in the two groups was calculated.
placebo
Results
The trial was stopped after 13 months because as found in our pilot study7 there was no significant difference in the coefficients of progression of the placebotreated and T.F.-treated groups (see figure). None of the 32 patients improved during treatment and 16 deteriorated significantly. Of these 16, 9 had received T.F. and 7 placebo, further emphasising the ineffectiveness of T.F. treatment.
Lymphocyte reactivity to measles antigen (measured by lymphocyte-migration inhibition) appeared tempor-
in the T.F.-treated group but lymphocyte transformation and T-cell and B-cell numbers changed only slightly. These results will be published in detail elsewhere.t2 15 of the 32 patients were HLA-Dw2 positive, a proportion similar to that previously reported in M.S. patients" and higher than that in the normal Danish population (20%). M.S. tends to progress more quickly in Dw-2 positive patients than in Dw-2 negative patients" and T.F. treatment did not alter this association. 27 of the 32 patients had a lumbar puncture both before and after the trial (3 patients objected to second lumbar puncture, 2 were technically unsuccessful). 20 of these 27 patients had oligoclonal f3-T4 bands in c.s.F. before treatment; in 8 cases these bands had disappeared after the trial. In 4 of the remaining 7 patients oligoclonal Y3--Ya bands were found only after treatment. These changes were independent of treatment with T.F.
arily
placebo. Slight soreness and swelling around the injection site was the only side-effect. Of a total of approximately 470 injections, 10 small skin necroses were found in 6 patients (4 on placebo, 2 on T.F.). or
Discussion
Quantifying neurological signs and symptoms in M.s. is difficult15 but our scoring system8 takes into account the greatest possible variability in signs and symptoms. For assessing the clinical course of M.s. a scoring system of some sort is preferable to the neurologist’s subjective impressions or the incidence of attacks or exacerbations;16 in 25% of the cases in this trial there were differences between the examiners’ estimation and the computer calculation of the disease course, and the relapse rate in the trial (0-3-1-11 per patient per year depending upon definitions and investigators) was too small for use in studies below 50-100 patients for 1-2 years.17 New acute or subacute symptoms appeared in 3 patients and there were 13 relapses in 10 patients. These developments were unrelated to the use of T.F. or placebo, emphasising the conclusion from the scoring system that the clinical course of m. s. was unaffected by T.F. treatment.
previous studies ofT.F. treatment in M.S., Zabriskie al.18 and Fog et al.9 reported inconclusive results. Behan et all found that T.F. had no effect in a doubleblind study of 30 patients but their patients were treated with low doses of T.F. for a short time, and only a few clinical investigations were done. The absence in the trial reported here of the placebo effect observed in our pilot study9 might be due either to the selection of patients or to the examiners’ knowing that a placebo In
et
group was included. The appearance and disappearance of oligoclonal T3*"T4 bands in the c.s.F. could not be correlated with T.F. treatment. The appearance of oligoclonal IgG is irreversible in the individual M.s. patient2o-’2 and so it is possible that technical errors may explain the appearance or disappearance of oligoclonal bands in c.s.F. from 12 of 27 patients.
Progression of M.S. in patients treated with T.F. or placebo. Shaded areas are rates of change in neurological deficit per year. - =mean (±2s.E.). Course of disease is similar in the two treatment groups.
We thank the staff of the department of neurology, Kommunehospitalet for their cooperation and Dr Coleman Smith for critical comments. The study was supported by the Danish Multiple Sclerosis Society, the Warwara Larsen Foundation, the Swiss Multiple Sclerosis Society, and the Swiss National Science Foundation (grant no.
6.155-0.75).
853 Requests for reprints should be addressed to T.F., Department of Neurology, Kommunehospitalet, DK-1399 Copenhagen K, Denmark.
REFERENCES
1. Salmi, A., Gollmar, Y., Norrby, E., Panelius, M.
Acta
path. microbiol.
scand. Sect. B. 1973, 81, 627. 2. Ciongoli, A. K., Platz, P., Dupont, B.,
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Case-reports Case1 This male baby was born at 40 weeks after an uncomplicated pregnancy. Delivery was normal and birth-weight was 2700 g. When he was 1 week old he was admitted to hospital with persistent vomiting, and was found to have gastro-oesophageal reflux. He was treated by total parenteral nutrition and was kept in a propped-up position. Repeated attempts to feed him were unsuccessful, and after 5 weeks’ conservative treatment he was referred to our hospital where the possibility of operative treatment was considered. On admission he weighed 3200 g and examination revealed no abnormal findings. The right internal jugular vein was cannulatedl so that intravenous (l.v.) hyperalimentation could be continued. The i.v. line was connected to an infusion pump. Several hours later progressive respiratory distress developed. Tachypnoea (80 breaths per min) with intercostal and subcostal2 retraction was noted. Diminished air-entry was heard over both lung fields. Chest X-ray showed pronounced widening of the mediastinum (fig 1). Blood gases while 40% oxygen was being given by mask were p a02’ 30 mm Hg, and P ac02’ 66 mm Hg. The cannula was immediately removed from the internal jugular vein and assisted ventilation via an endotracheal tube was started. Several hours later respiration had markedly improved and extravasation into the mediastinum was no longer visible on X-ray (fig 2).
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A LIFE-THREATENING COMPLICATION OF THE INFUSION PUMP AMRAM AYALON YACOV BERLATZKY
HAIM ANNER MEDAD SCHILLER
Department of Pædiatric Surgery, Hadassah Hospital, Jerusalem, Israel
Summary
University
of case 1 showing pronounced widening of the mediastinum because of extravasation of an infusion being given into in the internal jugular vein.
Fig. 1--Chest X-ray
respiration and developed in 2 infants in vein was controlled by a
Serious disturbances in venous return
whom infusion into a central peristaltic pump. The effects were the result of extravasation which led to a build-up of pressure in the mediastinum. Introduction INFUSION pumps are widely used in infants and to whom fluids are often administered at low rates and in whom intravenous (i.v.) lines therefore tend to become occluded. To deliver a specified volume, without taking into account the pressure needed to overcome unpredictable resistance to flow through needles and catheters, the infusion pump develops a pressure greater than 850 mm Hg. We describe the development of life-threatening complications in 2 infants in whom infusion into a central vein was controlled by a peristaltic pump.
children,
Fig. 2-Chest X-ray of case 1, 24 hours later. Extravasated fluid has been resorbed, and the contour of the mediastinum has returned to normal.