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Quantitative observations of the subacute effects of X irradiation on brain capillary permeability: Part II
036@301679/091633-03$02.00/0
Onrology Biol. Phys., Vol. 5, p. 1633-1635 c, Pergamon Press Ltd., 1979. Printed In the U. I .A.
Int. J. Radiation
??Other Drugs
QUANTITATIVE OBSERVATIONS OF THE SUBACUTE EFFECTS OF X IRRADIATION ON BRAIN CAPILLARY PERMEABILITY: PART 11-t MICHAEL S. EDWARDS, The Brain Tumor Research
M.D.,
VICTOR A. LEVIN, M.D.,
and ANNE BYRD, B.A.
Department of Neurological Surgery, School of Medicine, University of California, San Francisco, CA 94143, U.S.A.
Center,
Male Fischer 344 rats received cerebral irradiation at 300 t-ad/day, four days/wk for three wk, to a total dose of 3600 tad. The capillary permeability coefficients for gafactitol, urea, and sodium determined at 6, 10 and 12 wk postirradiation were not statistically different when they were compared to control rats. We found no evidence for the “early” delayed effects of X irradiation based on alteration of brain capillary permeability. We feel this syndrome is the result of alteration in the processes that control the maintenance of myelfn. Further investigation of cellular and biochemical effects of irradiation would be more informative than additional capillary membrane studies. X-irradiation, Capillary permeability, Early delayed subacute effects.
24NaC1 were determined at 6, 10, and 12 weeks after a total of 3600 rad of cranial irradiation were given in graded doses.
INTRODUCTION The clinically observed toxic effects of radiation on the central nervous system (CNS) may be manifested as an early transitory encephalopathy that occurs two weeks to three months after the completion of therapy.*,4,6,‘3 The symptoms and signs may mimic tumor recurrence or, more commonly, a diffuse encephalopathy (headache, confusion, lethargy). The symptoms may last several days or as long as six weeks. Symptoms and signs may be minor, or they may be severe enough to require hospitalization and supportive therapy. In a syndrome with transient manifestations, the relationship between a specific treatment and clinical improvement is often unclear. However, improvement in neurologic status often appears attributable to initiation or escalation of corticosteroids. The etiology of this syndrome remains unclear. Deterioration has been ascribed to the alteration in cerebral capillary permeability leading to either edema or the leakage of toxic products across capillaries into the CNS,4 or to the direct demyelinative effects of photon irradiation.2~7~8J3 The purpose of this study was to quantitate the subacute effects of X-irradiation on normal rat brain capillary permeability. The capillary permeability coefficients (P) for 3H-galactitol, 14C-urea, and
METHODS AND MATERIALS Male Fischer 344 rats weighing between 160-220 g were irradiated with an X-ray unit? (230 KV at 15 MA, added filtration of 0.5 mm Cu + 1 mm Al, a dose rate of 108.5 rad/min, and a half value layer (HVL) of 1.8 mm of Cu). A total dose of 3600 rad was given at 300 rad/day, four days/wk, for three weeks. During irradiation, anesthetized rats were restrained in plexiglass holders and shielded with lead, except for the brain. The radiopurities of 14Curea, 3H-galactitol and 24NaCl were determined to be >99%, >98%, and >97%, respectively. The technique for measuring capillary permeability in the rat brain has been reported.2~sJ0J1 Following the measurement of 24Na radioactivity, the isotope was allowed to decay to background levels before 14C-urea and 3H-galactitol radioactivities were counted. Quench correction was made using the method of external standardization. RESULTS Table 1 summarizes the results urea, and sodium chloride:
*This research was supported in part by American Cancer Society Grant CH-75, National Institutes of Health Center Grant CA-13525, a gift of the Joe Gheen Foundation, American Cancer Society Faculty Research Award FRA-155 (V.A.L.), and American Cancer Society Junior Faculty Clinical Fellowship JFCF-389 (M.S.E.).
for galactitol,
Reprint requests to: Michael S. Edwards, M.D. AcltnowlPdgements-Neil Buckley provided editorial assistance. Dr. Adrian Be88 assisted with the irradiation aspect of these studies. tWestinghouse 1633
Quadrocondex.
1634
Radiation Oncology 0 Biology 0 Physics
September
1979, Volume 5, Number 9
Table 1. Effect of irradiation on the brain capillary permeability of galactitol, urea, and sodium chloride 94NaC 1
Y-Urea Control,cm/sec 6 Weeks
8.2E-07( 1.9) (N=24) +1.% (N=6)
3.9E-07( 1.7) (N=9) - 17.9% (N =6)$
4.2E-07(0.7) (N=9) - 14.3% (N=7)
(:=6) +7.3% (N=6)
- 10.3% (N=6) - 12.8% (N=6)$
-7.1% (N=6) -4.8% (N=6)
10 Weeks
12 Weeks
t300 rad, 4 fractionslwk for 3 wks. SPc.05 by T-test comparison to control group.
Galactitoi: The nine nonirradiated control rats had a permeability coefficient of 3.7 x 10e7 cm/set, a result consistent with drugs that do not cross the blood-brain barrier (BBB).” The P values determined at 6, 10, and 12 weeks after an irradiation dose of 300 rad x 12 were not statistically different from nonirradiated control animals. Urea: In 24 nonirradiated control rats, the permeability coefficient was 8.1 x lo-’ cm/set. The P values determined at 6, 10, and 12 weeks postirradiation after a dose of 300 rad x 12 were not statistically different from nonirradiated control animals. Sodium chloride: The P in nine nonirradiated control animals was 4.2 x IO-’ cm/set. Again, no statistical difference in capillary permeability was measured at 6, 10, and 12 weeks after administration of 300 rad x 12 radiation doses.
DISCUSSION In this study we found no evidence for early delayed effects of X irradiation on brain capillary permeability. Compared to control rats, we found no statistical differences in the capillary permeability for galactitol, a drug that normally has restricted BBB transport, or for urea, a compound that slowly crosses the intact BBB, 612 weeks after a total dose of 3600 rad was administered in 12 fractions. The fact that sodium capillary permeability was not altered by the radiation doses suggests further that there was no alteration in the extracellular sodium-coupled water transport, which may be important in the development of cerebral edema.
Although it is possible that permeability changes in capillaries in tumor or brain adjacent to tumor could account for this syndrome, the fact that the syndrome occurs in the absence of tumor makes this unlikely. The etiology of this syndrome remains unclear, but it has been attributed to vascular permeability changes4*” or to demyelination.2*7*8*13 Since earlier studies of irradiation on capillary permeability utilized extremely high dose fractions (7500 rad) and large molecules or dyes, they give little experimental information on the subacute clinical effects of more conventional radiation doses on the CNS.3,12*14Griffen et al.” have shown that a single dose of irradiation (2000 rad) produces an acute alteration of the BBB in mice and produces detectable levels of methotrexate in the brain. However, lower single irradiation doses (500-1500 t-ad) did not produce these effects. Our studies of the acute effects of radiation on brain capillary permeability also did not show much of an increase in permeability following doses of 200-2500 rad.g We feel that the syndrome is the result of an alteration in the processes that control the maintenance of myelin. Lampert, et a1.7*8 and RiderI have reported pathologic changes consistent with desiminated demylination with vascular change confined to the irradiated regions in patients with early delayed neurologic deterioration who died three-four months after irradiation. In our judgment, further investigation of cellular and biochemical effects of irradiation would be more informative than additional capillary membrane studies.
X-rays and capillary permeability 0
M. S. EDWARDS et al.
1635
REFERENCES 1. Boldrey, E., Sheline, G.: Delayed transitory clinical manifestations after radiation treatment of intracranial tumors. Acta Radiol. Ther. Phys. Biol. 55-10, 1%7. 2. Brownson, R.H., Suter, D.B., Diller, D.A.: Acute brain damage induced by low dosage of x-irradiation. Neurology 13: 181-191, 1%3. 3. Clemente, C.D., Hoist, E.A.: Pathological changes in neurons, neuroglia and blood-brain barrier induced by x-irradiation of the heads of monkeys. Arch. Neurol. Psycho/. 71: 679, 1954. 4. Freeman, J.E., Johnston, P.G.B., Voke, J.M.: Somnolence after prophylactic cranial irradiation in children with acute lymphoblastic leukemia. Br. Med. J. 4: 523-525, 5. Griffen,
1973.
T.W., Rasey, J.S., Bleyer, W.A.: The effect of photon irradiation on blood-brain barrier permeability to methotrexate in mice. Cancer 40: lloP_1111, 1977. 6. Hoffman, W.F., Levin, V.A., Heilbron, D.C., Wilson, C.B.: Prognostic significance of the pretreatment computed tomographic scan on time to progression for patients. J. Neurosurg. (Submitted) 7. Lampert, P.W., Davis, R.L.: Delayed effects of radiation on the human central nervous system. Neurology
14: 912-917, 1964. 8. Lampert, P.W., Tom, M.I., Rider, W.D.: Disseminated demyelination of the brain following CoBo (gamma) radiation. Arch. Path. 68: 322, 1959. 9. Levin, V.A., Edwards, M.S., Byrd, A.: Quantitative observations of the acute effects of X irradiation on brain capillary permeability: I. Int. J. Radiat. Oncol. Biol. Phys. 5: 1627-1631, 1979. 10. Levin, V.A., Landahl, H.D., Freeman-Dove, M.A.: The application of brain capillary permeability coeficient measurements to pathological conditions and the selection of agents which cross the blood-brain barrier. J. Pharmacokin.
Biopharm.
11. Levin, V.A., Patlak, of 24Na kinetics in cerebrospinal fluid. J. 12. Nair, V., Roth, L.J.: other treatments on
4: 499-519,
1976.
C.S.: A compartmental analyses rat cerebrum, sciatic nerve and Physiol. 224: 55S581,
1972.
Effect of x-irradiation and certain blood-brain barrier permeability. Rad. Res. 23: 249-264, 1964. 13. Rider, W.D.: Radiation damage to the brain-A new syndrome. J. Can. Assoc. Radiol. 14: 67-69, 1%3. 14. Schettler, T., Shealy, C.N.: Experimental selective alteration of blood-brain barrier by x-irradiation. J. Neurosurg.
32: 89-94,
1970.
Onrology Biol. Phys., Vol. 5, p. 1633-1635 c, Pergamon Press Ltd., 1979. Printed In the U. I .A.
Int. J. Radiation
??Other Drugs
QUANTITATIVE OBSERVATIONS OF THE SUBACUTE EFFECTS OF X IRRADIATION ON BRAIN CAPILLARY PERMEABILITY: PART 11-t MICHAEL S. EDWARDS, The Brain Tumor Research
M.D.,
VICTOR A. LEVIN, M.D.,
and ANNE BYRD, B.A.
Department of Neurological Surgery, School of Medicine, University of California, San Francisco, CA 94143, U.S.A.
Center,
Male Fischer 344 rats received cerebral irradiation at 300 t-ad/day, four days/wk for three wk, to a total dose of 3600 tad. The capillary permeability coefficients for gafactitol, urea, and sodium determined at 6, 10 and 12 wk postirradiation were not statistically different when they were compared to control rats. We found no evidence for the “early” delayed effects of X irradiation based on alteration of brain capillary permeability. We feel this syndrome is the result of alteration in the processes that control the maintenance of myelfn. Further investigation of cellular and biochemical effects of irradiation would be more informative than additional capillary membrane studies. X-irradiation, Capillary permeability, Early delayed subacute effects.
24NaC1 were determined at 6, 10, and 12 weeks after a total of 3600 rad of cranial irradiation were given in graded doses.
INTRODUCTION The clinically observed toxic effects of radiation on the central nervous system (CNS) may be manifested as an early transitory encephalopathy that occurs two weeks to three months after the completion of therapy.*,4,6,‘3 The symptoms and signs may mimic tumor recurrence or, more commonly, a diffuse encephalopathy (headache, confusion, lethargy). The symptoms may last several days or as long as six weeks. Symptoms and signs may be minor, or they may be severe enough to require hospitalization and supportive therapy. In a syndrome with transient manifestations, the relationship between a specific treatment and clinical improvement is often unclear. However, improvement in neurologic status often appears attributable to initiation or escalation of corticosteroids. The etiology of this syndrome remains unclear. Deterioration has been ascribed to the alteration in cerebral capillary permeability leading to either edema or the leakage of toxic products across capillaries into the CNS,4 or to the direct demyelinative effects of photon irradiation.2~7~8J3 The purpose of this study was to quantitate the subacute effects of X-irradiation on normal rat brain capillary permeability. The capillary permeability coefficients (P) for 3H-galactitol, 14C-urea, and
METHODS AND MATERIALS Male Fischer 344 rats weighing between 160-220 g were irradiated with an X-ray unit? (230 KV at 15 MA, added filtration of 0.5 mm Cu + 1 mm Al, a dose rate of 108.5 rad/min, and a half value layer (HVL) of 1.8 mm of Cu). A total dose of 3600 rad was given at 300 rad/day, four days/wk, for three weeks. During irradiation, anesthetized rats were restrained in plexiglass holders and shielded with lead, except for the brain. The radiopurities of 14Curea, 3H-galactitol and 24NaCl were determined to be >99%, >98%, and >97%, respectively. The technique for measuring capillary permeability in the rat brain has been reported.2~sJ0J1 Following the measurement of 24Na radioactivity, the isotope was allowed to decay to background levels before 14C-urea and 3H-galactitol radioactivities were counted. Quench correction was made using the method of external standardization. RESULTS Table 1 summarizes the results urea, and sodium chloride:
*This research was supported in part by American Cancer Society Grant CH-75, National Institutes of Health Center Grant CA-13525, a gift of the Joe Gheen Foundation, American Cancer Society Faculty Research Award FRA-155 (V.A.L.), and American Cancer Society Junior Faculty Clinical Fellowship JFCF-389 (M.S.E.).
for galactitol,
Reprint requests to: Michael S. Edwards, M.D. AcltnowlPdgements-Neil Buckley provided editorial assistance. Dr. Adrian Be88 assisted with the irradiation aspect of these studies. tWestinghouse 1633
Quadrocondex.
1634
Radiation Oncology 0 Biology 0 Physics
September
1979, Volume 5, Number 9
Table 1. Effect of irradiation on the brain capillary permeability of galactitol, urea, and sodium chloride 94NaC 1
Y-Urea Control,cm/sec 6 Weeks
8.2E-07( 1.9) (N=24) +1.% (N=6)
3.9E-07( 1.7) (N=9) - 17.9% (N =6)$
4.2E-07(0.7) (N=9) - 14.3% (N=7)
(:=6) +7.3% (N=6)
- 10.3% (N=6) - 12.8% (N=6)$
-7.1% (N=6) -4.8% (N=6)
10 Weeks
12 Weeks
t300 rad, 4 fractionslwk for 3 wks. SPc.05 by T-test comparison to control group.
Galactitoi: The nine nonirradiated control rats had a permeability coefficient of 3.7 x 10e7 cm/set, a result consistent with drugs that do not cross the blood-brain barrier (BBB).” The P values determined at 6, 10, and 12 weeks after an irradiation dose of 300 rad x 12 were not statistically different from nonirradiated control animals. Urea: In 24 nonirradiated control rats, the permeability coefficient was 8.1 x lo-’ cm/set. The P values determined at 6, 10, and 12 weeks postirradiation after a dose of 300 rad x 12 were not statistically different from nonirradiated control animals. Sodium chloride: The P in nine nonirradiated control animals was 4.2 x IO-’ cm/set. Again, no statistical difference in capillary permeability was measured at 6, 10, and 12 weeks after administration of 300 rad x 12 radiation doses.
DISCUSSION In this study we found no evidence for early delayed effects of X irradiation on brain capillary permeability. Compared to control rats, we found no statistical differences in the capillary permeability for galactitol, a drug that normally has restricted BBB transport, or for urea, a compound that slowly crosses the intact BBB, 612 weeks after a total dose of 3600 rad was administered in 12 fractions. The fact that sodium capillary permeability was not altered by the radiation doses suggests further that there was no alteration in the extracellular sodium-coupled water transport, which may be important in the development of cerebral edema.
Although it is possible that permeability changes in capillaries in tumor or brain adjacent to tumor could account for this syndrome, the fact that the syndrome occurs in the absence of tumor makes this unlikely. The etiology of this syndrome remains unclear, but it has been attributed to vascular permeability changes4*” or to demyelination.2*7*8*13 Since earlier studies of irradiation on capillary permeability utilized extremely high dose fractions (7500 rad) and large molecules or dyes, they give little experimental information on the subacute clinical effects of more conventional radiation doses on the CNS.3,12*14Griffen et al.” have shown that a single dose of irradiation (2000 rad) produces an acute alteration of the BBB in mice and produces detectable levels of methotrexate in the brain. However, lower single irradiation doses (500-1500 t-ad) did not produce these effects. Our studies of the acute effects of radiation on brain capillary permeability also did not show much of an increase in permeability following doses of 200-2500 rad.g We feel that the syndrome is the result of an alteration in the processes that control the maintenance of myelin. Lampert, et a1.7*8 and RiderI have reported pathologic changes consistent with desiminated demylination with vascular change confined to the irradiated regions in patients with early delayed neurologic deterioration who died three-four months after irradiation. In our judgment, further investigation of cellular and biochemical effects of irradiation would be more informative than additional capillary membrane studies.
X-rays and capillary permeability 0
M. S. EDWARDS et al.
1635
REFERENCES 1. Boldrey, E., Sheline, G.: Delayed transitory clinical manifestations after radiation treatment of intracranial tumors. Acta Radiol. Ther. Phys. Biol. 55-10, 1%7. 2. Brownson, R.H., Suter, D.B., Diller, D.A.: Acute brain damage induced by low dosage of x-irradiation. Neurology 13: 181-191, 1%3. 3. Clemente, C.D., Hoist, E.A.: Pathological changes in neurons, neuroglia and blood-brain barrier induced by x-irradiation of the heads of monkeys. Arch. Neurol. Psycho/. 71: 679, 1954. 4. Freeman, J.E., Johnston, P.G.B., Voke, J.M.: Somnolence after prophylactic cranial irradiation in children with acute lymphoblastic leukemia. Br. Med. J. 4: 523-525, 5. Griffen,
1973.
T.W., Rasey, J.S., Bleyer, W.A.: The effect of photon irradiation on blood-brain barrier permeability to methotrexate in mice. Cancer 40: lloP_1111, 1977. 6. Hoffman, W.F., Levin, V.A., Heilbron, D.C., Wilson, C.B.: Prognostic significance of the pretreatment computed tomographic scan on time to progression for patients. J. Neurosurg. (Submitted) 7. Lampert, P.W., Davis, R.L.: Delayed effects of radiation on the human central nervous system. Neurology
14: 912-917, 1964. 8. Lampert, P.W., Tom, M.I., Rider, W.D.: Disseminated demyelination of the brain following CoBo (gamma) radiation. Arch. Path. 68: 322, 1959. 9. Levin, V.A., Edwards, M.S., Byrd, A.: Quantitative observations of the acute effects of X irradiation on brain capillary permeability: I. Int. J. Radiat. Oncol. Biol. Phys. 5: 1627-1631, 1979. 10. Levin, V.A., Landahl, H.D., Freeman-Dove, M.A.: The application of brain capillary permeability coeficient measurements to pathological conditions and the selection of agents which cross the blood-brain barrier. J. Pharmacokin.
Biopharm.
11. Levin, V.A., Patlak, of 24Na kinetics in cerebrospinal fluid. J. 12. Nair, V., Roth, L.J.: other treatments on
4: 499-519,
1976.
C.S.: A compartmental analyses rat cerebrum, sciatic nerve and Physiol. 224: 55S581,
1972.
Effect of x-irradiation and certain blood-brain barrier permeability. Rad. Res. 23: 249-264, 1964. 13. Rider, W.D.: Radiation damage to the brain-A new syndrome. J. Can. Assoc. Radiol. 14: 67-69, 1%3. 14. Schettler, T., Shealy, C.N.: Experimental selective alteration of blood-brain barrier by x-irradiation. J. Neurosurg.
32: 89-94,
1970.