13
insulin/kg body-weight after which blood and urine samples were examined for sugar at 30-min intervals for 2 h. Throughout the test the patient was encouraged to drink plenty of water to promote urine flow. If none of the urine samples collected after the insulin injection was sugar-free, the test had to be repeated with a slightly larger dose of insulin or with the patient fasting before the test. Urine specimens were tested for sugar by ’Clinitest’ tablets and blood-glucose was measured by the Nelson-Somogyi units of soluble
method.5 The patient was asked to report any unusual symptoms occurring during the test such as hunger, sweating, tremor, or faintness. Blood-glucose levels were measured when these
symptoms occurred in order to determine the level at which hypoglycaemic symptoms appeared; the patient was then given biscuits and sugar and the test was continued.
Results
The group studied consisted of five women and five whose average age was 54 years; eight patients were aged over fifty, and the other two were a woman of 24 and a man of 44. Seven required insulin for the control of their diabetes, three needed only oral hypoglycxmic drugs, and one needed both insulin and oral
men
drugs. Three patients, (patients B, C, and G in the table), had diabetic retinopathy. The changes were especially gross in patient B, a 60-year-old man who had been diabetic for more than 17 years. He had waxy exudates, microaneurysms, and haemorrhages in both fundi. The other patients with retinopathy were two women who had been diabetic for 4 months and 1½years respec-
tively. The mean renal threshold for glucose in all ten patients (see accompanying table) was 81 85 mg/dl (range 39.3-145.5mg/dl). In all but two patients the mean threshold for glucose was below 100 mg/dl. Hypoglycxmic symptoms were experienced by five of the ten patients, symptoms occurring at blood-sugar levels of 33-58 mg/dl. One man (patient B) had diabetic neuropathy with loss of vibration sense and impotence. One woman (patient G), who was admitted with diabetic gangrene of the right index finger, had a positive Romberg’s sign and impaired joint-position sense and vibration sense. None of the patients had evidence of serious renal impairment. The mean blood-urea was 42 mg/dl and mean serum-creatinine was 1.2 mg/dl (normal serum-creatinine for Nigerians6 0.5-2 mg/dl). Slight albuminuria was noted in two women for which no cause was found. The mean serum-albumin was 4.8 g/dl, the mean serum-cholesterol was 218 mg/dl, and the highest blood-glucose recorded at any time in the whole group was 344 mg/dl. =
Discussion We consider the low renal threshold for glucose in the 10 diabetic patients studied to be a highly significant finding since it suggests that this is a common feature among Nigerian diabetics. In a developing country where facilities for blood-glucose estimation are not readily available for routine use, a low renal threshold produces difficulties in the management of diabetics according to urine sugar alone. This seems to be the experience of most doctors looking after diabetics in
Nigeria.
The danger of precipitating hypoglycaemic attacks by excessive medication during attempts to achieve good control according to urine sugars alone is especially true in cases of mild diabetes requiring oral hypoglycaemic drugs and in whom the usual aim is to make the urine sugar-free. It seems therefore wise to modify this dictum with respect to Nigerian diabetics on oral hypoglycaemic drugs. We suggest that they be allowed traces of sugar in their urine provided the 2-hour post-prandial bloodsugar levels are 80 mg/dl or less. The I.M.I.R.T. as described in this paper has been found extremely useful in the management of these cases. Not only did it allow the determination of the renal threshold for glucose in a patient but it also provided a profile of the levels of blood-glucose relative to the levels of sugar in the urine which can be used as a guide at follow-up clinics when only urine-sugar measurements are available. The other question that these findings raise is whether the renal threshold for glucose is also low in non-diabetic Nigerians who have been shown to have relatively low fasting blood-glucose levels.7 Low fasting blood-glucose levels have also been reported in other black Africans. 8,9 It is possible that non-diabetic black Africans, like their diabetic counterparts, have lower renal thresholds for glucose than Caucasians. Unfortunately it is not possible to determine this by an oral glucose-tolerance test because Nigerians tend to have flat curves in which the blood-glucose levels do not reach very high values. This question can, perhaps, be better answered by an intravenous infusion of glucose. It would have been interesting to include Caucasian diabetics in this study but they are difficult to come by in Nigeria. REFERENCES 1. Butterfield, W. J. H. Proc. R. Soc. Med. 1964, 57, 196. 2. Kinnear, T. W. East Afr. med. J. 1963, 40, 288. 3. Dodu, S. R. A., Hathorn, M. H. Ghana med.J. 1966, 5, 2. 4. Osuntokum, B. O., Akinkugbe, F. M., Francis, T. I., Reddy, S., Osuntokun, O., Taylor, G. O. West Afr. med. J. 1971, 20, 295. 5. Nelson, N. J. biol. Chem. 1944, 153, 375. 6. Normal Laboratory Values of Clinical Importance, Chemical Pathology Laboratory, University College Hospital, Ibadan, Nigeria, 1973. 7. Isichei, U. P., Umez-Eronini, E. M., Egwuatu, V. E. Personal communication, 1977. 8. Tulloch, J. A., Patel, K. M. Trans. R Soc. trop. Med. Hyg. 1969, 63, 644. 9. Walker, A. R. P., Walker, B. F., Richardson, B P. Lancet, 1970, ii, 51
ACUTE ENCEPHALOPATHY AFTER INITIATION OF CRANIAL IRRADIATION FOR MENINGEAL LEUKÆMIA W. ARCHIE BLEYER ALLEN OLIFF DAVID G. POPLACK Pediatric
Oncology Branch of the National Cancer Institute,
Bethesda, Maryland, and Division
of Hematology/Oncology,
Orthopedic Hospital and Medical Center and the Department of Pediatrics, University of Washington, Seattle, Washington, U.S.A. Children’s
Summary
Five
patients experienced severe encephalopathy within hours of receiving
their initial dose of cranial irradiation for the treatment of central-nervous-system leukæmia. Neurological findings included cranial-nerve palsies, seizures, ataxia, depressed consciousness, increased intracranial pressure,
14
and signs of herniation. Symptoms developed within 3-30 hours of the first radiation treatment of 50-200 rad. Each patient had also received one or more injections of intrathecal chemotherapy before encephalopathy developed. The a’tiology of this syndrome is uncertain but may involve transient cerebral oedema and/or an altered blood-brain barrier produced by the combination of intrathecal chemotherapy and cranial irradiation.
Introduction ADVERSE complications of central-nervous-system (C.N.s.) radiotherapy have largely been limited to encephalopathic reactions beginning weeks or months after
treatment.’ We describe
an acute form of severe neurowhich logical toxicity developed within hours of the initiation of C.N. s. irradiation.
Case-reports Case 1.—A 14-year-old boy had three episodes of meningeal leukaemia during 18 months’ continuous bone-marrow remission from acute lymphoblastic leukaemia. The first two episodes occurred 5 and 9 months after diagnosis and were treated with intrathecal methotrexate alone. Five doses were administered over a 3-week period for the first episode and four doses were used for the second episode. No untoward reactions were noted. 10 months later the third episode of C.N.S. leukasmia was when cerebrospinal fluid (c.s.F.) examination showed 610 lymphoblasts/µl. Treatment was begun with both intrathecal methotrexate and cranial irradiation. 3 days after the initial intrathecal injection the patient received his first dose of irradiation (200 rad) and a second dose of intrathecal methotrexate. 4 hours later ocular pain, a right hemiparesis, dysconjugate gaze, dysarthria, and disorientation developed. Dexamethasone and mannitol were administered. Cardiopulmonary arrest occurred 6 h after admission. At necropsy extensive leuk2emic infiltration of the arachnoid, perivascular spaces, and the sub-ependymal parenchyma was noted. Most of the lymphoblasts in these areas appeared to be pyknotic and fragmented. Acute and chronic ependymitis, scattered disruption of the ventricular ependyma, possible mild hydrocephalus, and a 2 cm diameter haemorrhage over the right temporal lobe were also found. Case 2.-A 3-year-old boy with acute lymphoblastic teukasmia also had three episodes of meningeal leukaemia. The first occurred 2tyears after diagnosis and was treated with five intrathecal injections of methotrexate. Each lumbar puncture was followed by a headache which lasted several hours. 8 months later a c.s.F. examination showed 130 lymphoblasts/1. Daily intrathecal injections of cytarabine were started. On the day of the fourth injection the patient received 200 rad cranial irradiation. 3 h later intractable vomiting and an unusually severe headache developed. Dexamethasone was administered, and over the next 48 h the headache and vomiting improved. As these symptoms resolved we found that he was unable to walk. Neurological examination revealed truncal ataxia, dysmetria, dysarthria, and symmetrically decreased deep-tendon reflexes. A brain scan was normal and a repeat spinal tap revealed no abnormalities. The abnormal neurological findings resolved over a 3-day period. 4 days after the initial dose of irradiation, c.N.s. X-ray therapy was resumed and completed without complications. The third episode of C.N.S. leukaemia occurred 1 month later. Intrathecal methotrexate alone, without irradiation, was administered. The encephalopathy did not recur. Case 3.---c.N.s. leukxmia was detected 5 months after diagnosis in this 14-month-old boy with lymphosarcoma-cell leukeemia. There were 18 000 lymphoblasts/p.l in the c.s.F. The patient’s only symptom was slight lethargy. Intrathecal methotrexate and cranial radiation were started on the same day. Within 6 h status epilepticus, which was refractory to dia-
diagnosed
zepam and phenobarbitone, developed. The seizures eventually responded to dexamethasone and mannitol. The following morning he became apnceic and required endotracheal intubation. He remained comatose for 4 days. Subdural taps revealed bilateral subdural effusions. The patient recovered completely in about a month. During this interval he received two additional intrathecal methotrexate injections and two cytarabine injections. No complications were noted with these injections and the c.s.F. was ultimately cleared of lympho-
blasts. Case
4.-Hyperphagia and intermitterit left hemiparesis developed 3t years after diagnosis of acute lymphoblastic leukaemia in this 6-year-old boy. An electroencephalogram (E.E.G.)
and brain scan were normal, but a lumbar puncture revealed 5350 lymphoblasts/µl in the c.s.F., an opening pressure of 250 mm H20, and a protein concentration of 128 mg/dl. Two doses of intrathecal methotrexate, 4 days apart, were administered. 2 days after the second dose, the c.s.F. white-cell count fell to 157/µl, the protein concentration to 70 mg/dl, and the opening pressure to 230 mm H20. A single fraction of cranial irradiation (50 rad), administered from the left side, was given on the next day. 3 h later, the patient became semi-comatose with signs of an uncal herniation syndrome-i.e., deviation of the left eye towards the left side, dilation and paresis of the left pupil, bilateral papillcedema, generalised hyperreflexia, and decorticate posturing. Skull X-rays revealed suture separation and E.E.G. demonstrated diffuse slowing. An echoencephalogram was normal. The patient was treated with dexamethasone and mannitol and the radiation was continued-i.e., 25 rad from each side, daily. After an initial 1-day period of continued deterioration, the patient eventually recovered. Subsequently, intrathecal methotrexate therapy was administered without difficulty. Case 5.-This 16-year-old boy with acute lymphoblastic leukaemia received prophylactic c.N.s. therapy in the 2nd month after diagnosis. The therapy, consisting of cranial irradiation (2400 rad) and six doses of intrathecal methotrexate, were administered without complications. In October, 1977, headaches prompted a lumbar puncture which revealed 350 lymphoblasts/µl in the c.s.F. An Ommaya reservoir was inserted and a 3-day course of intraventricular methotrexate therapy was administed. The patient complained of headache, nausea, and vertigo for 2 days during the therapy. A second course of intraventricular methotrexate therapy was administered 2 weeks later. Nausea and headaches again developed, but he remained alert and oriented. 6 days later, cranial irradiation, 200 rad daily, was initiated. Within 6 h of the second radiation treatment, the patient’s level of consciousness rapidly deteriorated and by the next morning he was in a coma with generalised flaccidity. Dexamethasone was administered. Over the next 48 h, he recovered, becoming only slightly lethargic and confused. A computerised tomographic brain scan performed at this time revealed dilated ventricles with no other abnormalities. The patient continued to improve and was able to return home 9 days after admission with only slight headache and nausea.
Discussion In these five patients with c.N.s. leukaemia who were treated with cranial irradiation and intrathecal chemotherapy severe encephalopathy developed shortly after initial radiation treatment. Various neurological abnormalities were seen-i.e., depressed consciousness, cranial-nerve palsies, seizures, ataxia, dysmetria, increased intracranial pressure, and signs of impending herniation. The severity ranged from somnolence and areflexia to coma and death. Encephalopathy developed within 3 to 30 h of the first radiation treatment with 50-200 rad. In one patient there was rapid neurological deterioration 4 h after his second dose of daily radiation.
15
The reaction seemed to become more severe during the first 12-48 h, despite the use of intravenous steroids and mannitol. These cases have several features in common. All of the patients had overt C.N.S. leukxmia at the time of their cranial irradiation, with c.s.F. lymphoblast-counts ranging from 130 to 18 000/p before treatment. All received one or more doses of intrathecal therapy before radiotherapy was started. Four were treated with intrathecal methotrexate and one received cytarabine. All experienced rapid neurological deterioration within hours of the first or second fraction of irradiation (total dose 50-400 rad). One patient (case 4) had previously received prophylactic cranial X-ray therapy (2400 rad) without a neurotoxic reaction developing. This patient’s course supports the hypothesis that active c.N.s. leukaemia is required for this toxicity syndrome to develop. Although intrathecal methotrexate can produce severe neurotoxicity, it is unlikely that the encephalopathy in these patients was due primarily to methotrexate. Encephalopathy associated with intrathecal chemotherapy generally does not occur immediately after therapy, but requires weeks or months to develop.l.2 A syndrome of nuchal rigidity, low back pain, fever, and signs of increased intracranial pressure ("arachnoiditis") may begin within hours of a dose of intrathecal chemotherapy, but is usually associated with a c.s.F. granulocytosis.3.4 None of the patients in this report demonstrated this C.S.F. pattern. Furthermore, all patients received intrathecal methotrexate alone, before or after radiation, without encephalopathy developing. Hence, the patients reported seemed to have a form of hyperacute neurological toxicity triggered by the initiation of radiation therapy but dependent on the presence of leukaemic cells in the c.N.s. and possibly concomitant intrathecal chemotherapy. The acute events described above are not consistent with previously described adverse reactions of cranial irradiation. The somnolence syndrome of cranial irradiation generally occurs 5-8 weeks after treatment.5 Other reported forms of radiation-induced c.N.s. toxicity, such as necrosis and demyelination occur even later, usually months or years after irradiation. 6. The most likely explanation for this reaction pattern is that the initial radiation treatment produced oedema within or around areas of leuksemic infiltration. In a patient susceptible to increased intracranial pressure-a common feature of C.N.S. leukxmia-the additional oedema may be catastrophic. Another possibility is that the radiation may have augmented the toxicity of intrathecal chemotherapy. Some workers have postulated that radiation increases the permeability of the brain to chemotherapeutic agents.7Griffin et al. have shown that cranial irradiation in mice increases the amount of methotrexate entering the brain after intraperitoneal administration. Perhaps, presence of leukaemic cells in the c.N.s. further contributes to this phenomenon by disrupting the normal barriers to drug entry, or by inhibiting the removal of drugs from the C.N.s.9 This hypothesis is consistent with the necropsy findings in case 1 in which the ependyma was disrupted and the subependymal layers were oedematous and necrotic. These cases illustrate a serious complication of the treatment of overt c.N.s. leukaemia, which may be produced within hours of the initiation of cranial irradia-
tion. Further characterisation of this syndrome together with additional data establishing its mechanism of action are needed. Requests for reprints should be addressed to A. 0., Pediatric Oncology Branch, Building 10, Room 3B-12, National Cancer Institute, Bethesda, Maryland 20014, U.S.A. REFERENCES
Pochedly, C. Med. pediat. Oncol. 1977, 3, 101. Kay, H. E. M., Knapton, P. J., O’Sullivan, J. P., Wells, D. G., Harris, R. F., Innes, E. M., Stuart, J., Schwartz, F. C. M., Thompson, E. N. Archs Dis. Child. 1972, 47, 344. 3. Duttera, M. J., Bleyer, W. A., Pomeroy, T. C., Leventhal, C. M., Leventhal, B. G. Lancet, 1973, ii, 703. 4. Geiser, C. F., Bishop, Y., Jaffe, N., Furman, L., Traggis, D., Frei, E. Blood,
1. 2.
1975, 45, 189. 5. Freeman, J. E., Johnston, P. G. B., Voke, J. M. Br. med. J. 1973, iv, 523. 6. Hendin, B., DeVivo, D. C., Torack, R., Lell, M. E., Ragab, A., Vietti, 7. 8. 9.
T. J. Cancer, 1974, 33, 468. Price, R. A., Jamieson, P. A. ibid. 1975, 35, 306. Rubinstein, L. J., Herman, M. M., Lowy, T. F., Jordan, R. Griffin, T. W., Rasey, J. S., Bleyer, A. ibid. 1977, 40, 1109.
W. ibid.
p. 291.
THAW-SIPHON TECHNIQUE FOR PRODUCTION OF CRYOPRECIPITATE CONCENTRATE OF FACTOR VIII E. C. MASON Red Cross Blood
Transfusion Service, 409 Adelaide Street, Brisbane, Queensland 4000, Australia Plasma, which has been deep-frozen in
Summary
plastic packs as flat slabs, is thawed in a 3-5°C water-bath, and allowed to siphon continually into an attached satellite pack external to the bath. This thaw-siphon procedure is completed within 55-65 min and the cryoprecipitate, retained in the residual 25 ml of frozen plasma, contains 70-100% of the original plasma factor VIII. Clinical observations in hæmophilic patients treated with these cryoprecipitates, have confirmed that the higher in-vitro content of factor VIII is associated with enhanced in-vivo effectiveness. Introduction a concentrated preparation of factor vni (anti-hxmophilic factor human-blood-clotting [A.H.F.]), is routinely produced in blood-transfusion services throughout the world, and is the factor-viii concentrate most commonly used in haemostasis therapy in haemophiliacs. It is usually prepared from a blooddonation (430 ml) that has been collected into a suitable anticoagulant solution, with uninterrupted flow and within 7 min, in the primary pack of a triple plastic pack system. After the pack system has been centrifuged, the supernatant plasma is expressed into the secondary pack. The primary pack containing the red-cell concentrate is detached from the other two, and is available for clinical use. The plasma pack is then deep-frozen to below -30°C and placed in a room at 4°C to thaw overnight.l,2 The cryoprecipitate, visible as a white, gelatinous mass sus-
CRYOPRECIPITATE,1.2
pended in at
the
4°C. After
liquid plasma, is separated by centrifuging drawing off the supernatant into the ter-
insulin/kg body-weight after which blood and urine samples were examined for sugar at 30-min intervals for 2 h. Throughout the test the patient was encouraged to drink plenty of water to promote urine flow. If none of the urine samples collected after the insulin injection was sugar-free, the test had to be repeated with a slightly larger dose of insulin or with the patient fasting before the test. Urine specimens were tested for sugar by ’Clinitest’ tablets and blood-glucose was measured by the Nelson-Somogyi units of soluble
method.5 The patient was asked to report any unusual symptoms occurring during the test such as hunger, sweating, tremor, or faintness. Blood-glucose levels were measured when these
symptoms occurred in order to determine the level at which hypoglycaemic symptoms appeared; the patient was then given biscuits and sugar and the test was continued.
Results
The group studied consisted of five women and five whose average age was 54 years; eight patients were aged over fifty, and the other two were a woman of 24 and a man of 44. Seven required insulin for the control of their diabetes, three needed only oral hypoglycxmic drugs, and one needed both insulin and oral
men
drugs. Three patients, (patients B, C, and G in the table), had diabetic retinopathy. The changes were especially gross in patient B, a 60-year-old man who had been diabetic for more than 17 years. He had waxy exudates, microaneurysms, and haemorrhages in both fundi. The other patients with retinopathy were two women who had been diabetic for 4 months and 1½years respec-
tively. The mean renal threshold for glucose in all ten patients (see accompanying table) was 81 85 mg/dl (range 39.3-145.5mg/dl). In all but two patients the mean threshold for glucose was below 100 mg/dl. Hypoglycxmic symptoms were experienced by five of the ten patients, symptoms occurring at blood-sugar levels of 33-58 mg/dl. One man (patient B) had diabetic neuropathy with loss of vibration sense and impotence. One woman (patient G), who was admitted with diabetic gangrene of the right index finger, had a positive Romberg’s sign and impaired joint-position sense and vibration sense. None of the patients had evidence of serious renal impairment. The mean blood-urea was 42 mg/dl and mean serum-creatinine was 1.2 mg/dl (normal serum-creatinine for Nigerians6 0.5-2 mg/dl). Slight albuminuria was noted in two women for which no cause was found. The mean serum-albumin was 4.8 g/dl, the mean serum-cholesterol was 218 mg/dl, and the highest blood-glucose recorded at any time in the whole group was 344 mg/dl. =
Discussion We consider the low renal threshold for glucose in the 10 diabetic patients studied to be a highly significant finding since it suggests that this is a common feature among Nigerian diabetics. In a developing country where facilities for blood-glucose estimation are not readily available for routine use, a low renal threshold produces difficulties in the management of diabetics according to urine sugar alone. This seems to be the experience of most doctors looking after diabetics in
Nigeria.
The danger of precipitating hypoglycaemic attacks by excessive medication during attempts to achieve good control according to urine sugars alone is especially true in cases of mild diabetes requiring oral hypoglycaemic drugs and in whom the usual aim is to make the urine sugar-free. It seems therefore wise to modify this dictum with respect to Nigerian diabetics on oral hypoglycaemic drugs. We suggest that they be allowed traces of sugar in their urine provided the 2-hour post-prandial bloodsugar levels are 80 mg/dl or less. The I.M.I.R.T. as described in this paper has been found extremely useful in the management of these cases. Not only did it allow the determination of the renal threshold for glucose in a patient but it also provided a profile of the levels of blood-glucose relative to the levels of sugar in the urine which can be used as a guide at follow-up clinics when only urine-sugar measurements are available. The other question that these findings raise is whether the renal threshold for glucose is also low in non-diabetic Nigerians who have been shown to have relatively low fasting blood-glucose levels.7 Low fasting blood-glucose levels have also been reported in other black Africans. 8,9 It is possible that non-diabetic black Africans, like their diabetic counterparts, have lower renal thresholds for glucose than Caucasians. Unfortunately it is not possible to determine this by an oral glucose-tolerance test because Nigerians tend to have flat curves in which the blood-glucose levels do not reach very high values. This question can, perhaps, be better answered by an intravenous infusion of glucose. It would have been interesting to include Caucasian diabetics in this study but they are difficult to come by in Nigeria. REFERENCES 1. Butterfield, W. J. H. Proc. R. Soc. Med. 1964, 57, 196. 2. Kinnear, T. W. East Afr. med. J. 1963, 40, 288. 3. Dodu, S. R. A., Hathorn, M. H. Ghana med.J. 1966, 5, 2. 4. Osuntokum, B. O., Akinkugbe, F. M., Francis, T. I., Reddy, S., Osuntokun, O., Taylor, G. O. West Afr. med. J. 1971, 20, 295. 5. Nelson, N. J. biol. Chem. 1944, 153, 375. 6. Normal Laboratory Values of Clinical Importance, Chemical Pathology Laboratory, University College Hospital, Ibadan, Nigeria, 1973. 7. Isichei, U. P., Umez-Eronini, E. M., Egwuatu, V. E. Personal communication, 1977. 8. Tulloch, J. A., Patel, K. M. Trans. R Soc. trop. Med. Hyg. 1969, 63, 644. 9. Walker, A. R. P., Walker, B. F., Richardson, B P. Lancet, 1970, ii, 51
ACUTE ENCEPHALOPATHY AFTER INITIATION OF CRANIAL IRRADIATION FOR MENINGEAL LEUKÆMIA W. ARCHIE BLEYER ALLEN OLIFF DAVID G. POPLACK Pediatric
Oncology Branch of the National Cancer Institute,
Bethesda, Maryland, and Division
of Hematology/Oncology,
Orthopedic Hospital and Medical Center and the Department of Pediatrics, University of Washington, Seattle, Washington, U.S.A. Children’s
Summary
Five
patients experienced severe encephalopathy within hours of receiving
their initial dose of cranial irradiation for the treatment of central-nervous-system leukæmia. Neurological findings included cranial-nerve palsies, seizures, ataxia, depressed consciousness, increased intracranial pressure,
14
and signs of herniation. Symptoms developed within 3-30 hours of the first radiation treatment of 50-200 rad. Each patient had also received one or more injections of intrathecal chemotherapy before encephalopathy developed. The a’tiology of this syndrome is uncertain but may involve transient cerebral oedema and/or an altered blood-brain barrier produced by the combination of intrathecal chemotherapy and cranial irradiation.
Introduction ADVERSE complications of central-nervous-system (C.N.s.) radiotherapy have largely been limited to encephalopathic reactions beginning weeks or months after
treatment.’ We describe
an acute form of severe neurowhich logical toxicity developed within hours of the initiation of C.N. s. irradiation.
Case-reports Case 1.—A 14-year-old boy had three episodes of meningeal leukaemia during 18 months’ continuous bone-marrow remission from acute lymphoblastic leukaemia. The first two episodes occurred 5 and 9 months after diagnosis and were treated with intrathecal methotrexate alone. Five doses were administered over a 3-week period for the first episode and four doses were used for the second episode. No untoward reactions were noted. 10 months later the third episode of C.N.S. leukasmia was when cerebrospinal fluid (c.s.F.) examination showed 610 lymphoblasts/µl. Treatment was begun with both intrathecal methotrexate and cranial irradiation. 3 days after the initial intrathecal injection the patient received his first dose of irradiation (200 rad) and a second dose of intrathecal methotrexate. 4 hours later ocular pain, a right hemiparesis, dysconjugate gaze, dysarthria, and disorientation developed. Dexamethasone and mannitol were administered. Cardiopulmonary arrest occurred 6 h after admission. At necropsy extensive leuk2emic infiltration of the arachnoid, perivascular spaces, and the sub-ependymal parenchyma was noted. Most of the lymphoblasts in these areas appeared to be pyknotic and fragmented. Acute and chronic ependymitis, scattered disruption of the ventricular ependyma, possible mild hydrocephalus, and a 2 cm diameter haemorrhage over the right temporal lobe were also found. Case 2.-A 3-year-old boy with acute lymphoblastic teukasmia also had three episodes of meningeal leukaemia. The first occurred 2tyears after diagnosis and was treated with five intrathecal injections of methotrexate. Each lumbar puncture was followed by a headache which lasted several hours. 8 months later a c.s.F. examination showed 130 lymphoblasts/1. Daily intrathecal injections of cytarabine were started. On the day of the fourth injection the patient received 200 rad cranial irradiation. 3 h later intractable vomiting and an unusually severe headache developed. Dexamethasone was administered, and over the next 48 h the headache and vomiting improved. As these symptoms resolved we found that he was unable to walk. Neurological examination revealed truncal ataxia, dysmetria, dysarthria, and symmetrically decreased deep-tendon reflexes. A brain scan was normal and a repeat spinal tap revealed no abnormalities. The abnormal neurological findings resolved over a 3-day period. 4 days after the initial dose of irradiation, c.N.s. X-ray therapy was resumed and completed without complications. The third episode of C.N.S. leukaemia occurred 1 month later. Intrathecal methotrexate alone, without irradiation, was administered. The encephalopathy did not recur. Case 3.---c.N.s. leukxmia was detected 5 months after diagnosis in this 14-month-old boy with lymphosarcoma-cell leukeemia. There were 18 000 lymphoblasts/p.l in the c.s.F. The patient’s only symptom was slight lethargy. Intrathecal methotrexate and cranial radiation were started on the same day. Within 6 h status epilepticus, which was refractory to dia-
diagnosed
zepam and phenobarbitone, developed. The seizures eventually responded to dexamethasone and mannitol. The following morning he became apnceic and required endotracheal intubation. He remained comatose for 4 days. Subdural taps revealed bilateral subdural effusions. The patient recovered completely in about a month. During this interval he received two additional intrathecal methotrexate injections and two cytarabine injections. No complications were noted with these injections and the c.s.F. was ultimately cleared of lympho-
blasts. Case
4.-Hyperphagia and intermitterit left hemiparesis developed 3t years after diagnosis of acute lymphoblastic leukaemia in this 6-year-old boy. An electroencephalogram (E.E.G.)
and brain scan were normal, but a lumbar puncture revealed 5350 lymphoblasts/µl in the c.s.F., an opening pressure of 250 mm H20, and a protein concentration of 128 mg/dl. Two doses of intrathecal methotrexate, 4 days apart, were administered. 2 days after the second dose, the c.s.F. white-cell count fell to 157/µl, the protein concentration to 70 mg/dl, and the opening pressure to 230 mm H20. A single fraction of cranial irradiation (50 rad), administered from the left side, was given on the next day. 3 h later, the patient became semi-comatose with signs of an uncal herniation syndrome-i.e., deviation of the left eye towards the left side, dilation and paresis of the left pupil, bilateral papillcedema, generalised hyperreflexia, and decorticate posturing. Skull X-rays revealed suture separation and E.E.G. demonstrated diffuse slowing. An echoencephalogram was normal. The patient was treated with dexamethasone and mannitol and the radiation was continued-i.e., 25 rad from each side, daily. After an initial 1-day period of continued deterioration, the patient eventually recovered. Subsequently, intrathecal methotrexate therapy was administered without difficulty. Case 5.-This 16-year-old boy with acute lymphoblastic leukaemia received prophylactic c.N.s. therapy in the 2nd month after diagnosis. The therapy, consisting of cranial irradiation (2400 rad) and six doses of intrathecal methotrexate, were administered without complications. In October, 1977, headaches prompted a lumbar puncture which revealed 350 lymphoblasts/µl in the c.s.F. An Ommaya reservoir was inserted and a 3-day course of intraventricular methotrexate therapy was administed. The patient complained of headache, nausea, and vertigo for 2 days during the therapy. A second course of intraventricular methotrexate therapy was administered 2 weeks later. Nausea and headaches again developed, but he remained alert and oriented. 6 days later, cranial irradiation, 200 rad daily, was initiated. Within 6 h of the second radiation treatment, the patient’s level of consciousness rapidly deteriorated and by the next morning he was in a coma with generalised flaccidity. Dexamethasone was administered. Over the next 48 h, he recovered, becoming only slightly lethargic and confused. A computerised tomographic brain scan performed at this time revealed dilated ventricles with no other abnormalities. The patient continued to improve and was able to return home 9 days after admission with only slight headache and nausea.
Discussion In these five patients with c.N.s. leukaemia who were treated with cranial irradiation and intrathecal chemotherapy severe encephalopathy developed shortly after initial radiation treatment. Various neurological abnormalities were seen-i.e., depressed consciousness, cranial-nerve palsies, seizures, ataxia, dysmetria, increased intracranial pressure, and signs of impending herniation. The severity ranged from somnolence and areflexia to coma and death. Encephalopathy developed within 3 to 30 h of the first radiation treatment with 50-200 rad. In one patient there was rapid neurological deterioration 4 h after his second dose of daily radiation.
15
The reaction seemed to become more severe during the first 12-48 h, despite the use of intravenous steroids and mannitol. These cases have several features in common. All of the patients had overt C.N.S. leukxmia at the time of their cranial irradiation, with c.s.F. lymphoblast-counts ranging from 130 to 18 000/p before treatment. All received one or more doses of intrathecal therapy before radiotherapy was started. Four were treated with intrathecal methotrexate and one received cytarabine. All experienced rapid neurological deterioration within hours of the first or second fraction of irradiation (total dose 50-400 rad). One patient (case 4) had previously received prophylactic cranial X-ray therapy (2400 rad) without a neurotoxic reaction developing. This patient’s course supports the hypothesis that active c.N.s. leukaemia is required for this toxicity syndrome to develop. Although intrathecal methotrexate can produce severe neurotoxicity, it is unlikely that the encephalopathy in these patients was due primarily to methotrexate. Encephalopathy associated with intrathecal chemotherapy generally does not occur immediately after therapy, but requires weeks or months to develop.l.2 A syndrome of nuchal rigidity, low back pain, fever, and signs of increased intracranial pressure ("arachnoiditis") may begin within hours of a dose of intrathecal chemotherapy, but is usually associated with a c.s.F. granulocytosis.3.4 None of the patients in this report demonstrated this C.S.F. pattern. Furthermore, all patients received intrathecal methotrexate alone, before or after radiation, without encephalopathy developing. Hence, the patients reported seemed to have a form of hyperacute neurological toxicity triggered by the initiation of radiation therapy but dependent on the presence of leukaemic cells in the c.N.s. and possibly concomitant intrathecal chemotherapy. The acute events described above are not consistent with previously described adverse reactions of cranial irradiation. The somnolence syndrome of cranial irradiation generally occurs 5-8 weeks after treatment.5 Other reported forms of radiation-induced c.N.s. toxicity, such as necrosis and demyelination occur even later, usually months or years after irradiation. 6. The most likely explanation for this reaction pattern is that the initial radiation treatment produced oedema within or around areas of leuksemic infiltration. In a patient susceptible to increased intracranial pressure-a common feature of C.N.S. leukxmia-the additional oedema may be catastrophic. Another possibility is that the radiation may have augmented the toxicity of intrathecal chemotherapy. Some workers have postulated that radiation increases the permeability of the brain to chemotherapeutic agents.7Griffin et al. have shown that cranial irradiation in mice increases the amount of methotrexate entering the brain after intraperitoneal administration. Perhaps, presence of leukaemic cells in the c.N.s. further contributes to this phenomenon by disrupting the normal barriers to drug entry, or by inhibiting the removal of drugs from the C.N.s.9 This hypothesis is consistent with the necropsy findings in case 1 in which the ependyma was disrupted and the subependymal layers were oedematous and necrotic. These cases illustrate a serious complication of the treatment of overt c.N.s. leukaemia, which may be produced within hours of the initiation of cranial irradia-
tion. Further characterisation of this syndrome together with additional data establishing its mechanism of action are needed. Requests for reprints should be addressed to A. 0., Pediatric Oncology Branch, Building 10, Room 3B-12, National Cancer Institute, Bethesda, Maryland 20014, U.S.A. REFERENCES
Pochedly, C. Med. pediat. Oncol. 1977, 3, 101. Kay, H. E. M., Knapton, P. J., O’Sullivan, J. P., Wells, D. G., Harris, R. F., Innes, E. M., Stuart, J., Schwartz, F. C. M., Thompson, E. N. Archs Dis. Child. 1972, 47, 344. 3. Duttera, M. J., Bleyer, W. A., Pomeroy, T. C., Leventhal, C. M., Leventhal, B. G. Lancet, 1973, ii, 703. 4. Geiser, C. F., Bishop, Y., Jaffe, N., Furman, L., Traggis, D., Frei, E. Blood,
1. 2.
1975, 45, 189. 5. Freeman, J. E., Johnston, P. G. B., Voke, J. M. Br. med. J. 1973, iv, 523. 6. Hendin, B., DeVivo, D. C., Torack, R., Lell, M. E., Ragab, A., Vietti, 7. 8. 9.
T. J. Cancer, 1974, 33, 468. Price, R. A., Jamieson, P. A. ibid. 1975, 35, 306. Rubinstein, L. J., Herman, M. M., Lowy, T. F., Jordan, R. Griffin, T. W., Rasey, J. S., Bleyer, A. ibid. 1977, 40, 1109.
W. ibid.
p. 291.
THAW-SIPHON TECHNIQUE FOR PRODUCTION OF CRYOPRECIPITATE CONCENTRATE OF FACTOR VIII E. C. MASON Red Cross Blood
Transfusion Service, 409 Adelaide Street, Brisbane, Queensland 4000, Australia Plasma, which has been deep-frozen in
Summary
plastic packs as flat slabs, is thawed in a 3-5°C water-bath, and allowed to siphon continually into an attached satellite pack external to the bath. This thaw-siphon procedure is completed within 55-65 min and the cryoprecipitate, retained in the residual 25 ml of frozen plasma, contains 70-100% of the original plasma factor VIII. Clinical observations in hæmophilic patients treated with these cryoprecipitates, have confirmed that the higher in-vitro content of factor VIII is associated with enhanced in-vivo effectiveness. Introduction a concentrated preparation of factor vni (anti-hxmophilic factor human-blood-clotting [A.H.F.]), is routinely produced in blood-transfusion services throughout the world, and is the factor-viii concentrate most commonly used in haemostasis therapy in haemophiliacs. It is usually prepared from a blooddonation (430 ml) that has been collected into a suitable anticoagulant solution, with uninterrupted flow and within 7 min, in the primary pack of a triple plastic pack system. After the pack system has been centrifuged, the supernatant plasma is expressed into the secondary pack. The primary pack containing the red-cell concentrate is detached from the other two, and is available for clinical use. The plasma pack is then deep-frozen to below -30°C and placed in a room at 4°C to thaw overnight.l,2 The cryoprecipitate, visible as a white, gelatinous mass sus-
CRYOPRECIPITATE,1.2
pended in at
the
4°C. After
liquid plasma, is separated by centrifuging drawing off the supernatant into the ter-
