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TREATMENT OF CENTRAL RETINAL VEIN THROMBOSIS WITH ANCROD
173
100 ml. were commonly observed. It proved impossible attach any particular clinical significance to them, however, and these instances of "asymptomatic to
best regarded as just state of carbohydrate altered aspect metabolism. Perhaps there has been a previous tendency to concentrate on these low readings because they have potential clinical excitement, and to ignore the high ones. Profound hypoglycasmia seemed to be a quite separate phenomenon. It occurred in a very ill child and was usually associated with coma, hypothermia, and severe bacterial or parasitic infection. This clinical tetrad has since been seen in 2 other children with severe kwashiorkor. They also died. It was not a truly symptomatic hypoglycxmia since the symptoms were not permanently abolished by maintaining the blood-glucose level. Possibly some lethal factor was responsible for both the symptoms and the hypoglycxmia-as may occur, for example, in cerebral birth injury, encephalitis, or " fatty degeneration of the viscera" .14-16 Many drowsy and comatose children with kwashiorkor are not hypoglyceemic. They have been considered elsewhere.1? If the clinical distinction between these hypoglycxmic states is accepted it becomes possible to explain the conflicting mortality-rates previously reported from Uganda. Deanwas worried by the rare clinical problem, while Whitehead and Harland3 were describing the relatively common biochemical phenomenon. It might also account for the apparent international differences in incidence and significance. The distinction has clear importance in prognosis and therapy, and this investigation has formed the basis for modification of our treatment regimen. Feeds are now given throughout the day and night during the first five days; the night feed is not omitted. Blood-glucose is determined immediately in any child whose temperature is below 97°F, who has a severe infection, or whose conscious level is deteriorating.g
hypoglycxmia"
one
are
probably
of the
I am grateful to Dr. H. Knight, Sister S. Healy, Sister A. Court, Sister E. Strange, Sister C. Roberts, Sister G. Crewe, Sister M. Hood and Sister S. Mukasa, who helped in the care of the children; to Miss S. Ward, who gave valuable technical assistance; to Prof. R. A. McCance, F.R.S., Dr. V. Marks, and Prof. C. E. Stroud for advice during the preparation of this report; to Dr. SerckHansen for fig. 2; and to Miss A. Playfoot for secretarial help. Requests for reprints should be addressed to the M.R.C. Infantile Malnutrition Research Unit, P.O. Box 7051, Kampala,
Uganda. REFERENCES 1. 2.
Preliminary Communication
Holmes, E. G., Trowell, H. C. Lancet, 1948, i, 395. Dean, R. F. A. in Recent Advances in Pædiatrics (edited by D. Gairdner); p. 234. London, 1965. 3. Whitehead, R. G., Harland, P. S. E. G. Br. J. Nutr. 1966, 20, 825. 4. Hadden, D. R. Lancet, 1967, ii, 589. 5. Senecal, J. Ann. N.Y. Acad. Sci. 1958, 69, 916. 6. Kahn, E., Wayburne, S. Proc. Nutr. Soc. S. Afr. 1960, 1, 21. 7. Slone, D., Taitz, L. S., Gilchrist, E. S. Br. med. J. 1961, i, 32. 8. McLean, A. E. M. Lancet, 1968, i, 772. 9. Hansen, J. D. L. Personal communication. 10. Baig, H. A., Edozien, J. C. Lancet, 1965, ii, 662. 11. Rao, K. S. J. Am. J. Dis. Child. 1965, 110, 519. 12. Wharton, B. A. Archs Dis. Childh. 1969, 44, 543. (abstr.). 13. Marks, V. Clin. chim. Acta, 1959, 4, 395. 14. Meakins, J. C. Ann. intern. Med. 1940, 13, 1830. 15. Reye, R. D. K., Morgan, G., Baral, J. Lancet, 1963, ii, 749. 16. Etheridge, J. E., Millichap, J. C. Neurology, Minneap. 1964, 14, 397. 17. Balmer, S. E., Howells, G. R., Wharton, B. A. Dev. Med. Child Neurol. 1968, 10, 766. 18. Staff, T. H. E. E. Afr. med. J. 1968, 45, 400.
TREATMENT OF CENTRAL RETINAL VEIN THROMBOSIS WITH ANCROD
V. J. MARMION
R. E. BOWELL
C. F. McCARTHY * Bristol Eye
Hospital, Bristol
1
occlusion of the central retinal vein were given intravenous doses of ancrod (’ Arvin ’), 1 unit per kg. bodyweight, 12 hourly. Ancrod induced fibrinogenopenia (defibrination) in all eight patients. Those treated within 7-10 days of the onset improved clinically and photographically and these results suggest that a full clinical trial of ancrod on patients in this group is Summary
Eight patients with
justified. INTRODUCTION
IN central retinal vein thrombosis there is a natural history, not fully documented, which may lead to complete loss of vision or to thrombotic glaucoma. The incidence of the thrombotic glaucoma is as variable as the course of the disease. Therapeutic measures to produce recanalisation are difficult to assess because of the variability in the natural history. Trials have been done with heparin,1 dicoumarol,2 and other coumarin derivatives, and clofibrate,3 but have rarely been conclusive. The defibrinating action of the venom of the Malayan pit viper is of use in thrombotic conditions, and we report here its use in a few cases of central retinal vein thrombosis. The criteria for success were improvement within 10 days of treatment and the recovery of central vision. PATIENTS AND METHODS
Eight patients attending the outpatient department with central retinal vein occlusion of varying duration were treated with ancrod (’ Arvin ’), the active principle in the venom of the Malayan pit viper. Patients with uncontrolled hypertension, glaucoma, diabetes, known neoplastic disease, or hepatic or renal dysfunction were excluded. The patients had to agree to come into hospital for the period of a week. All were given a complete physical examination and tests for visual acuity, intraocular pressure, full blood-count, erythrocyte-sedimentation rate, fibrinogen level, prothrombin-time, plasma-proteins, blood-sugar, and serumcholesterol. Photographs were taken on the day before therapy was started, and at the end of 1 and 2 weeks. Fibrinogen levels were measured during therapy. Ancrod was given initially in a dose of 1 unit per kg. body-weight over a period of 4 hours in 500 ml. of5°o dextrose in water. Thereafter, the same dose was given, also intravenously, in 20 ml. saline solution every 12 hours for 7 days. RESULTS
The eight patients varied in age from 40 to 80 years, and there were four men and four women. Apart from one patient with an incipient occlusion, they all showed an impaired acuity, and improvement in this was regarded as evidence of improvement in the condition. The improvement in the clinical picture of the fundus, "Present address: Department of Gastroenterology, Regional Galway, Republic of Ireland.
Hospital,
174 IMPROVEMENT IN EIGHT CASES OF CENTRAL RETINAL VEIN OCCLUSION
C.R.V.T.
which
=Central retinal vein thrombosis.
confirmed photographically, was the second of improvement. The rate of disappearance of the oedema, the regression of the haemorrhages and any exudates which may have been present, and reduction in the venous calibre were also assessed. Seven of the eight patients improved in one or more of these criteria. In four the acuity improved-three from 6/36 to 6/9, 6/12, and 6/18, respectively, and one from 5/60 to 6/60. This last patient showed evidence of senile macular degeneration and the improvement in the other criteria was considerably greater than the improvement in visual acuity. Three patients who did not improve in acuity showed evidence of clinical resolution in serial was
measure
photographs. In one patient long-term follow-up was impossible. One patient who did not improve on ancrod therapy had had a previous central retinal vein occlusion in the same eye, and one patient who showed some improvement in the florid condition of the retina showed no improvement in acuity (this patient may have tobacco amblyopia). One controlled diabetic improved to some extent clinically but an underlying diabetic retinopathy with maculopathy was unchanged. These results
are
summarised in the table. DISCUSSION
The dramatic improvement in the condition of central-vein thrombosis within 1 week of the start of therapy was unexpected. This improvement was observed only in those patients who had had the disease for a short time. Although there are many problems in the assessment of central-vein occlusion there is little doubt that the primary circulatory defect lies in transient arterial occlusion followed by venous spasm and venous occlusion. Recanalisation of this occlusion can happen spontaneously, it has been aided by therapeutic measures, and in this trial, it would seem to have been actively expedited when the disease process was at an early stage. The occlusion of the central retinal vein is, in up to 50 °o of cases, associated with chronic simple glaucoma. No patients with chronic simple glaucoma were admitted to this trial. As the age at onset suggests, arteriosclerosis and hypertension are often associated with this condition, and the disease develops in patients with diabetes although this is rare. Abnormalities of
plasma-proteins such as macroglobulinaemia may be accentuating cause, as also may be polycythaemia
an
or
leukxmia; these were not present in our series. Most cases have a complex aetiology, and the development of occlusion early in the morning shortly after rising, coincident with a sudden increase in the circulation and at a time when the intraocular pressure is at its highest, is fairly common.
The unsatisfactory results, with previous forms of therapy such as the anticoagulants give room for further investigation, and the current concepts of treatment of thrombotic disease by defibrination and fibrinolysis require investigation in relation to the ocular thrombotic
incidents.
Central-vein occlusion has been to be amenable to this
shown, in this small series,
therapeutic approach. We thank Dr. A. P. Fletcher and Dr. L. J. Fish of Twyford Laboratories. Requests for reprints should be addressed to R. E. B. REFERENCES 1. 2. 3.
Vanna, S., Orma, H. Archs Ophthal., Chicago, 1957, 58, 812. Thorne, B. Proc. R. Soc. Med. 1961, 54, 856. Clements, D. B. Br. J. Ophthal. 1968, 52, 111. ADDENDUM
We have treated four other patients with ancrod. Two had chronic simple glaucoma controlled on miotics. One of these patients had an incipient central retinal vein thrombosis improved from 6/12 to 6/6. The second, with an upper temporal and nasal branch vein occlusion, improved from 5/60 to 6/9. A third patient with a central retinal vein occlusion improved from 6/9 to 6/6 and a fourth patient with a more fulminating occlusion improved from 2/60 to 6/18. The improvement in the other criteria was equally satisfactory.
Methods and Devices PORTABLE LAMINAR-AIR-FLOW ISOLATOR WILLIAM Z.
PENLAND, JR.
SEYMOUR PERRY
Clinical Trials, National Cancer Institute, National Institutes of Bethesda, Maryland 20014, U.S.A.
Health,
IN the management of patients at high risk of infection variety of physical protection measures have been used. High-efficiency air filtration, direct physical barriers, ultraviolet irradiation, and positive-pressure areas have been tried in clinical situations in Europe and the United States.l--4 Particle-free rooms have been used for assembling space capsules and instruments 5; and the principle in these rooms-laminar air flow combined with high-efficiency filtration-has been applied to operating-theatres.6 A horizontal laminar air-flow room for patient use has been evaluated,and two units have lately been installed at the M. D. Anderson Hospital, Houston, Texas. Patients with cancer who are on treatment with cytotoxic or immunosuppressive drugs are especially at risk of infection, and, despite the use of antibiotics, infection is responsible for 70% of all deaths in acute leukaemia. 8,9
a
100 ml. were commonly observed. It proved impossible attach any particular clinical significance to them, however, and these instances of "asymptomatic to
best regarded as just state of carbohydrate altered aspect metabolism. Perhaps there has been a previous tendency to concentrate on these low readings because they have potential clinical excitement, and to ignore the high ones. Profound hypoglycasmia seemed to be a quite separate phenomenon. It occurred in a very ill child and was usually associated with coma, hypothermia, and severe bacterial or parasitic infection. This clinical tetrad has since been seen in 2 other children with severe kwashiorkor. They also died. It was not a truly symptomatic hypoglycxmia since the symptoms were not permanently abolished by maintaining the blood-glucose level. Possibly some lethal factor was responsible for both the symptoms and the hypoglycxmia-as may occur, for example, in cerebral birth injury, encephalitis, or " fatty degeneration of the viscera" .14-16 Many drowsy and comatose children with kwashiorkor are not hypoglyceemic. They have been considered elsewhere.1? If the clinical distinction between these hypoglycxmic states is accepted it becomes possible to explain the conflicting mortality-rates previously reported from Uganda. Deanwas worried by the rare clinical problem, while Whitehead and Harland3 were describing the relatively common biochemical phenomenon. It might also account for the apparent international differences in incidence and significance. The distinction has clear importance in prognosis and therapy, and this investigation has formed the basis for modification of our treatment regimen. Feeds are now given throughout the day and night during the first five days; the night feed is not omitted. Blood-glucose is determined immediately in any child whose temperature is below 97°F, who has a severe infection, or whose conscious level is deteriorating.g
hypoglycxmia"
one
are
probably
of the
I am grateful to Dr. H. Knight, Sister S. Healy, Sister A. Court, Sister E. Strange, Sister C. Roberts, Sister G. Crewe, Sister M. Hood and Sister S. Mukasa, who helped in the care of the children; to Miss S. Ward, who gave valuable technical assistance; to Prof. R. A. McCance, F.R.S., Dr. V. Marks, and Prof. C. E. Stroud for advice during the preparation of this report; to Dr. SerckHansen for fig. 2; and to Miss A. Playfoot for secretarial help. Requests for reprints should be addressed to the M.R.C. Infantile Malnutrition Research Unit, P.O. Box 7051, Kampala,
Uganda. REFERENCES 1. 2.
Preliminary Communication
Holmes, E. G., Trowell, H. C. Lancet, 1948, i, 395. Dean, R. F. A. in Recent Advances in Pædiatrics (edited by D. Gairdner); p. 234. London, 1965. 3. Whitehead, R. G., Harland, P. S. E. G. Br. J. Nutr. 1966, 20, 825. 4. Hadden, D. R. Lancet, 1967, ii, 589. 5. Senecal, J. Ann. N.Y. Acad. Sci. 1958, 69, 916. 6. Kahn, E., Wayburne, S. Proc. Nutr. Soc. S. Afr. 1960, 1, 21. 7. Slone, D., Taitz, L. S., Gilchrist, E. S. Br. med. J. 1961, i, 32. 8. McLean, A. E. M. Lancet, 1968, i, 772. 9. Hansen, J. D. L. Personal communication. 10. Baig, H. A., Edozien, J. C. Lancet, 1965, ii, 662. 11. Rao, K. S. J. Am. J. Dis. Child. 1965, 110, 519. 12. Wharton, B. A. Archs Dis. Childh. 1969, 44, 543. (abstr.). 13. Marks, V. Clin. chim. Acta, 1959, 4, 395. 14. Meakins, J. C. Ann. intern. Med. 1940, 13, 1830. 15. Reye, R. D. K., Morgan, G., Baral, J. Lancet, 1963, ii, 749. 16. Etheridge, J. E., Millichap, J. C. Neurology, Minneap. 1964, 14, 397. 17. Balmer, S. E., Howells, G. R., Wharton, B. A. Dev. Med. Child Neurol. 1968, 10, 766. 18. Staff, T. H. E. E. Afr. med. J. 1968, 45, 400.
TREATMENT OF CENTRAL RETINAL VEIN THROMBOSIS WITH ANCROD
V. J. MARMION
R. E. BOWELL
C. F. McCARTHY * Bristol Eye
Hospital, Bristol
1
occlusion of the central retinal vein were given intravenous doses of ancrod (’ Arvin ’), 1 unit per kg. bodyweight, 12 hourly. Ancrod induced fibrinogenopenia (defibrination) in all eight patients. Those treated within 7-10 days of the onset improved clinically and photographically and these results suggest that a full clinical trial of ancrod on patients in this group is Summary
Eight patients with
justified. INTRODUCTION
IN central retinal vein thrombosis there is a natural history, not fully documented, which may lead to complete loss of vision or to thrombotic glaucoma. The incidence of the thrombotic glaucoma is as variable as the course of the disease. Therapeutic measures to produce recanalisation are difficult to assess because of the variability in the natural history. Trials have been done with heparin,1 dicoumarol,2 and other coumarin derivatives, and clofibrate,3 but have rarely been conclusive. The defibrinating action of the venom of the Malayan pit viper is of use in thrombotic conditions, and we report here its use in a few cases of central retinal vein thrombosis. The criteria for success were improvement within 10 days of treatment and the recovery of central vision. PATIENTS AND METHODS
Eight patients attending the outpatient department with central retinal vein occlusion of varying duration were treated with ancrod (’ Arvin ’), the active principle in the venom of the Malayan pit viper. Patients with uncontrolled hypertension, glaucoma, diabetes, known neoplastic disease, or hepatic or renal dysfunction were excluded. The patients had to agree to come into hospital for the period of a week. All were given a complete physical examination and tests for visual acuity, intraocular pressure, full blood-count, erythrocyte-sedimentation rate, fibrinogen level, prothrombin-time, plasma-proteins, blood-sugar, and serumcholesterol. Photographs were taken on the day before therapy was started, and at the end of 1 and 2 weeks. Fibrinogen levels were measured during therapy. Ancrod was given initially in a dose of 1 unit per kg. body-weight over a period of 4 hours in 500 ml. of5°o dextrose in water. Thereafter, the same dose was given, also intravenously, in 20 ml. saline solution every 12 hours for 7 days. RESULTS
The eight patients varied in age from 40 to 80 years, and there were four men and four women. Apart from one patient with an incipient occlusion, they all showed an impaired acuity, and improvement in this was regarded as evidence of improvement in the condition. The improvement in the clinical picture of the fundus, "Present address: Department of Gastroenterology, Regional Galway, Republic of Ireland.
Hospital,
174 IMPROVEMENT IN EIGHT CASES OF CENTRAL RETINAL VEIN OCCLUSION
C.R.V.T.
which
=Central retinal vein thrombosis.
confirmed photographically, was the second of improvement. The rate of disappearance of the oedema, the regression of the haemorrhages and any exudates which may have been present, and reduction in the venous calibre were also assessed. Seven of the eight patients improved in one or more of these criteria. In four the acuity improved-three from 6/36 to 6/9, 6/12, and 6/18, respectively, and one from 5/60 to 6/60. This last patient showed evidence of senile macular degeneration and the improvement in the other criteria was considerably greater than the improvement in visual acuity. Three patients who did not improve in acuity showed evidence of clinical resolution in serial was
measure
photographs. In one patient long-term follow-up was impossible. One patient who did not improve on ancrod therapy had had a previous central retinal vein occlusion in the same eye, and one patient who showed some improvement in the florid condition of the retina showed no improvement in acuity (this patient may have tobacco amblyopia). One controlled diabetic improved to some extent clinically but an underlying diabetic retinopathy with maculopathy was unchanged. These results
are
summarised in the table. DISCUSSION
The dramatic improvement in the condition of central-vein thrombosis within 1 week of the start of therapy was unexpected. This improvement was observed only in those patients who had had the disease for a short time. Although there are many problems in the assessment of central-vein occlusion there is little doubt that the primary circulatory defect lies in transient arterial occlusion followed by venous spasm and venous occlusion. Recanalisation of this occlusion can happen spontaneously, it has been aided by therapeutic measures, and in this trial, it would seem to have been actively expedited when the disease process was at an early stage. The occlusion of the central retinal vein is, in up to 50 °o of cases, associated with chronic simple glaucoma. No patients with chronic simple glaucoma were admitted to this trial. As the age at onset suggests, arteriosclerosis and hypertension are often associated with this condition, and the disease develops in patients with diabetes although this is rare. Abnormalities of
plasma-proteins such as macroglobulinaemia may be accentuating cause, as also may be polycythaemia
an
or
leukxmia; these were not present in our series. Most cases have a complex aetiology, and the development of occlusion early in the morning shortly after rising, coincident with a sudden increase in the circulation and at a time when the intraocular pressure is at its highest, is fairly common.
The unsatisfactory results, with previous forms of therapy such as the anticoagulants give room for further investigation, and the current concepts of treatment of thrombotic disease by defibrination and fibrinolysis require investigation in relation to the ocular thrombotic
incidents.
Central-vein occlusion has been to be amenable to this
shown, in this small series,
therapeutic approach. We thank Dr. A. P. Fletcher and Dr. L. J. Fish of Twyford Laboratories. Requests for reprints should be addressed to R. E. B. REFERENCES 1. 2. 3.
Vanna, S., Orma, H. Archs Ophthal., Chicago, 1957, 58, 812. Thorne, B. Proc. R. Soc. Med. 1961, 54, 856. Clements, D. B. Br. J. Ophthal. 1968, 52, 111. ADDENDUM
We have treated four other patients with ancrod. Two had chronic simple glaucoma controlled on miotics. One of these patients had an incipient central retinal vein thrombosis improved from 6/12 to 6/6. The second, with an upper temporal and nasal branch vein occlusion, improved from 5/60 to 6/9. A third patient with a central retinal vein occlusion improved from 6/9 to 6/6 and a fourth patient with a more fulminating occlusion improved from 2/60 to 6/18. The improvement in the other criteria was equally satisfactory.
Methods and Devices PORTABLE LAMINAR-AIR-FLOW ISOLATOR WILLIAM Z.
PENLAND, JR.
SEYMOUR PERRY
Clinical Trials, National Cancer Institute, National Institutes of Bethesda, Maryland 20014, U.S.A.
Health,
IN the management of patients at high risk of infection variety of physical protection measures have been used. High-efficiency air filtration, direct physical barriers, ultraviolet irradiation, and positive-pressure areas have been tried in clinical situations in Europe and the United States.l--4 Particle-free rooms have been used for assembling space capsules and instruments 5; and the principle in these rooms-laminar air flow combined with high-efficiency filtration-has been applied to operating-theatres.6 A horizontal laminar air-flow room for patient use has been evaluated,and two units have lately been installed at the M. D. Anderson Hospital, Houston, Texas. Patients with cancer who are on treatment with cytotoxic or immunosuppressive drugs are especially at risk of infection, and, despite the use of antibiotics, infection is responsible for 70% of all deaths in acute leukaemia. 8,9
a