Myelin basic protein and magnetic resonance imaging for diagnosing radiation myelopathy

The identification of radiation myelopathy using biochemical assays and imaging techniques has not previously been accomplished but has clear clinical application. Measurement of myelin basic protein (MBP) in the cerebrospinal fluid (CSF) and visualization of the spinal cord using magnetic resonance imaging (MRI) gives a potentially accurate diagnosis of radiation myelopathy. Female New Zealand white rabbits were irradiated to the thoracic spinal cord with single doses of 15-45 Gy. Animals receiving higher doses (greater than or equal to 22 Gy) generally demonstrated an early paresis (4-8 weeks) that temporarily improved, and then progressed to complete paralysis by 14-18 weeks. MBP levels in the CSF became strikingly elevated to 100-1000 times the normal value. Subsequent, experiments in which rabbits were serially assessed for MBP levels demonstrated a transient elevation, which corresponded to the transient paresis, followed by dramatic elevations concurrent with the onset of paralysis. Magnetic resonance imaging (MRI) of the irradiated spinal cord showed a geographically distinct region of abnormality that corresponded to the radiation field. Histopathology demonstrated demyelination, focal astrocytosis, erythrodiapedesis, and perineuronal edema in the irradiated sections. It appears that MBP levels in the CSF reflect not only radiation-induced myelopathy but also transient demyelination, and that MRI may have the potential to indicate the region of damage.     

Lhermitte's sign following head and neck radiotherapy

Lhermitte's sign is an uncommon sequel of radiotherapy to the cervical spinal cord. Although the exact mechanism underlying its occurrence remains unclear; it is felt to be the result of a temporary interference with the turnover and synthesis of myelin, leading to focal demyelination. We have undertaken a detailed analysis of the radiation delivered to four patients who developed the sign after irradiation for malignancies of the head and neck. Our data support the view that radiation dose is crucial to its development, but calculations using the linear-quadratic radiobiological model raise interesting questions regarding the dose-response relationship. In particular, we find that calculations of biologically effective doses are predictive of a late rather than an early normal tissue response. The onset of symptoms after irradiation was apparent in all four patients within 4 months, with resolution in all being complete within a further 6 months. The recognition of this benign transient form of radiation-induced paraesthesia and its differentiation from the later onset, progressive and unremitting symptoms associated with radiation myelopathy is essential in reassuring patients undergoing head and neck irradiation.     

Changes in oligodendrocytes and myelin gene expression after radiation in the rodent spinal cord

PURPOSE: The aim of this study was to assess changes in oligodendrocytes (OL), myelin gene expression, and their relationships with late demyelination after irradiation. METHODS AND MATERIALS: Adult rats were given single doses of 8 or 22 Gy to the cervical spinal cord. Immunohistochemistry for APC or GST-pi was used to identify OL. Changes in myelin gene expression were assessed using RT-PCR for proteolipid protein (PLP). Luxol fast blue staining was used to assess demyelination. CNP-(beta)geo transgenic mice were used to confirm some of the results of the rat model. Cells of the oligodendroglial lineage in these animals express beta-galactosidase (beta-gal). RESULTS: Early apoptosis of APC, GST-pi, and beta-galactosidase positive cells was observed in the spinal cord of rats and CNP-(beta)geo mice. At 24 h after 22 Gy, there was a significant decrease in OL density. Cell density continued to decline thereafter after both 8 and 22 Gy, and a reduction in PLP expression was observed at 4-5 weeks. A further decrease in PLP expression was seen beginning at 18 weeks after 22 Gy only. Demyelination was observed at 19 weeks after 22 Gy. CONCLUSIONS: Apoptosis of OL and changes in OL density and PLP gene expression were observed early after both 8 and 22 Gy. This suggests that these early changes are unlikely to be directly related to the late demyelination observed.     

Paralysis following stereotactic spinal irradiation in pigs suggests a tolerance constraint for single-session irradiation of the spinal nerve

Background and purpose

Paralysis observed during a study of vertebral bone tolerance to single-session irradiation led to further study of the dose-related incidence of motor peripheral neuropathy.

Materials and methods

During a bone tolerance study, cervical spinal nerves of 15 minipigs received bilateral irradiation to levels C5–C8 distributed into three dose groups with mean maximum spinal nerve doses of 16.9 ± 0.3 Gy (n = 5), 18.7 ± 0.5 Gy (n = 5), and 24.3 ± 0.8 Gy (n = 5). Changes developing in the gait of the group of pigs receiving a mean maximum dose of 24.3 Gy after 10–15 weeks led to the irradiation of two additional animals. They received mean maximum dose of 24.9 ± 0.2 Gy (n = 2), targeted to the left spinal nerves of C5–C8. The followup period was one year. Histologic sections from spinal cords and available spinal nerves were evaluated. MR imaging was performed on pigs in the 24.9 Gy group.

Results

No pig that received a maximum spinal nerve point dose ?19.0 Gy experienced a change in gait while all pigs that received ?24.1 Gy experienced paralysis. Extensive degeneration and fibrosis were observed in irradiated spinal nerves of the 24.9 Gy animals. All spinal cord sections were normal. Irradiated spinal nerve regions showed increased thickness and hypointensity on MR imaging.

Conclusion

The single-session tolerance dose of the cervical spinal nerves lies between 19.0 and 24.1 Gy for this model.     

The role of tumor necrosis factor signaling pathways in the response of murine brain to irradiation.

Late effects after radiotherapy for brain tumors can be severe and tend to limit the efficacy of this treatment modality. The mechanisms governing the development of late radiation-induced lesions in the brain are not clear, but they are preceded by cycles of molecular and cellular events including production of cytokines, one of which is tumor necrosis factor (TNF)-alpha. There is literature to support possible roles for TNF-alpha as a contributor to edema, gliosis, and demyelination in the brain, all of which are histopathologically associated with radiation-induced brain damage. We have examined the role of TNF-alpha signaling in the response to brain irradiation using TNFRp55- or TNFRp75-deficient and control mice. Mice lacking TNFRp75 exhibited increased early radiation-induced apoptosis in putative stem cell regions of the brain. At 1 month, they had decreased proliferative responses in the same regions, and by 3 months they were demonstrating dose-dependent seizures and other severe neurological abnormalities that were not seen in control or TNFRp55-/- mice. Seizure activity correlated with the onset of extensive demyelination, and by 6 months, levels of myelin basic protein in irradiated TNFRp75-/- mice were approximately 40% of those seen in the other two strains; the animals were moribund and had to be euthanized. These observations indicate that radiation-induced TNF-alpha, acting through TNFRp75, protects against the development of late complications of brain irradiation.     

Radiation dose response of normal brain

Dose response relationships were determined after hemibrain x-irradiation of normal beagle dogs. Radiation doses of 11.5, 13.5, 14.3, and 17 Gy were delivered in a single dose and results were compared to previous studies using doses of 15 and 30 Gy. Brain injury was quantified using computed tomography (CT), with serial studies obtained monthly up to 1 year following irradiation. Quantitative endpoints included low density volume and contrast enhancement. Doses above 14.3 Gy resulted in high lethality 5-8 months following irradiation, and an LD50 of 14.9 Gy was calculated. At these lethal doses, low density volume representing edema, demyelination, and necrosis had a similar response with an ED50 of 14.6 Gy. Radiation-induced decreases in white matter density appeared 5-6 months after sublethal doses (less than or equal to 14.3 Gy) and the volume of tissue characterized by this low density increased with time and dose. This sublethal low density change had an ED50 of 12.8 Gy, and may reflect a loss or generalized atrophy of glial cells and/or myelin. These results show that: (a) the dose response curves obtained after hemibrain x-irradiation are extremely steep; and (b) at least two processes may be involved in the development of late radiation damage, one that is rapid upon onset (a "delayed acute" reaction) and the other which is a slower and more degenerative process.     

Peripheral neuropathies following experimental intraoperative radiation therapy (IORT)

Injury to peripheral nerves in the lumbar para-aortic region was evaluated in beagle dogs 2 years following fractionated irradiation (EBRT), intraoperative irradiation (IORT), or a combination of IORT and EBRT. Time to onset of peripheral neuropathy was determined by means of serially completed neurological and electrophysiological examinations. Peripheral neuropathies were seen beginning as early as 6 months following 35 Gy (or greater) IORT only and 35 Gy plus 50 Gy EBRT. The incidence of peripheral neuropathies increased with increasing IORT doses beginning at 15 Gy. Onsets of peripheral neuropathies following IORT alone were clustered between 6 and 18 months, with onset in some dogs occurring as late as 24 months. The combination of IORT and EBRT resulted in an incidence and latency to onset of neuropathies similar to that seen with IORT alone. Neuropathies were not seen with EBRT alone at doses from 50 Gy to 80 Gy. Recovery of nerve function did not occur in affected dogs. Histological studies of nerves 2 years following irradiation demonstrated loss of axons and myelin, with a corresponding increase in endoneurial, perineurial, and epineurial connective tissue. Percentage of axon and myelin decreased to about 60% of normal at 15 Gy IORT, and additionally at higher doses. An insignificant decrease in percentage of axon and myelin was seen following EBRT alone. A significant lesion occurring in and around nerves at most IORT doses was necrosis and hyalinization of the media of small arteries and arterioles. The dose for a 50% probability for causing severe vessel lesions in the 2-year study was 19.5 Gy IORT only and 18.7 Gy when IORT was combined with EBRT. These lesions were not seen with any EBRT only dose. These studies suggest that peripheral nerve is a dose limiting normal tissue in IORT. Neuropathies appear to result from direct effects of irradiation on nerve and secondary effects to nerve resulting from damage to regional vasculature.     

Paraplegia following intrathecal chemotherapy: neuropathologic findings and elevation of myelin basic protein

An 11-year-old boy developed a severe myelopathy after an eight-year history of acute lymphoblastic leukemia and numerous courses of intrathecal chemotherapy. Myelin basic protein in the cerebrospinal fluid (CSF) was elevated. Neuropathologic examination disclosed extensive microvacuolar changes in the white matter of the spinal cord. The pathogenesis of myelopathy following intrathecal chemotherapy administered by lumbar puncture includes an early effect on the myelin sheath. Serial assessment of CSF myelin basic protein levels in patients receiving intrathecal chemotherapy may be useful in the early diagnosis of this disorder.     

Regional differences in radiosensitivity across the rat cervical spinal cord

PURPOSE: To study regional differences in radiosensitivity within the rat cervical spinal cord. METHODS AND MATERIALS: Three types of inhomogeneous dose distributions were applied to compare the radiosensitivity of the lateral and central parts of the rat cervical spinal cord. The left lateral half of the spinal cord was irradiated with two grazing proton beams, each with a different penumbra (20-80% isodoses): lateral wide (penumbra = 1.1 mm) and lateral tight (penumbra = 0.8 mm). In the third experiment, the midline of the cord was irradiated with a narrow proton beam with a penumbra of 0.8 mm. The irradiated spinal cord length (C1-T2) was 20 mm in all experiments. The animals were irradiated with variable single doses of unmodulated protons (150 MeV) with the shoot-through method, whereby the plateau of the depth-dose profile is used rather than the Bragg peak. The endpoint for estimating isoeffective dose (ED(50)) values was paralysis of fore and/or hind limbs within 210 days after irradiation. Histology of the spinal cords was performed to assess the radiation-induced tissue damage. RESULTS: High-precision proton irradiation of the lateral or the central part of the spinal cord resulted in a shift of dose-response curves to higher dose values compared with the homogeneously irradiated cervical cord to the same 20-mm length. The ED(50) values were 28.9 Gy and 33.4 Gy for the lateral wide and lateral tight irradiations, respectively, and as high as 71.9 Gy for the central beam experiment, compared with 20.4 Gy for the homogeneously irradiated 20-mm length of cervical cord. Histologic analysis of the spinal cords showed that the paralysis was due to white matter necrosis. The radiosensitivity was inhomogeneously distributed across the spinal cord, with a much more radioresistant central white matter (ED(50) = 71.9 Gy) compared with lateral white matter (ED(50) values = 28.9 Gy and 33.4 Gy). The gray matter did not show any noticeable lesions, such as necrosis or hemorrhage, up to 80 Gy. All lesions induced were restricted to white matter structures. CONCLUSIONS: The observed large regional differences in radiosensitivity within the rat cervical spinal cord indicate that the lateral white matter is more radiosensitive than the central part of the white matter. The gray matter is highly resistant to radiation: no lesions observable by light microscopy were induced, even after a single dose as high as 80 Gy.     

Effects of single doses of X-rays on renal function in the pig after the irradiation of both kidneys

Irradiation of a single kidney in the pig with relatively low doses of X-rays, in the order of 8 Gy, produces a pronounced reduction in both glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). This apparent high radiosensitivity may be due, in part, to the compensatory hypertrophy displayed by the contralateral unirradiated kidney. This could suppress any potential for recovery by the irradiated kidney. To test this hypothesis, both kidneys of 14-week-old Large White pigs were sequentially irradiated with single doses of 250 kV X-rays, in the range 8.8 to 12.6 Gy. Sequential measurements of individual kidney GFR and ERPF were made for periods up to 24 weeks after irradiation. Time-related changes in haematocrit (Hct) were also studied. Two weeks after irradiation, GFR and ERPF increased markedly in all irradiated kidneys; levels then declined in a dose-dependent manner. Following a dose of 8.8 Gy renal haemodynamics returned to control values within 4 weeks of irradiation and remained essentially constant throughout the study. After higher doses, GFR and ERPF decreased markedly and remained below control values up to 24 weeks after irradiation. Associated with these changes in renal haemodynamics was a fall in Hct within 3 weeks of irradiation, with minimal levels being found approximately 8 weeks after irradiation. Although there was some recovery between weeks 12 and 24, Hct values remained below those of age-matched controls. At all doses the mean functional status of irradiated kidneys in animals in which both kidneys were irradiated (BI) was significantly greater than that previously observed in the irradiated kidney of pigs in which only one kidney was irradiated (UI). Moreover, in BI pigs there appeared to be a marked imbalance between the contribution each kidney makes to the total renal function. In terms of ERPF, the functional status of the right kidney, relative to that of the left kidney, showed a dose-related decline. These findings support the hypothesis that the compensatory response exhibited by the contralateral unirradiated kidney in UI pigs suppresses the potential for functional recovery by the irradiated kidney. The findings also indicate that individual kidneys in the same animal may differ in their response to a similar nephrotoxic insult.     

The influence of neonatal thymectomy on the development of radiation myelopathy in rats.

To investigate the possible contribution of cellular immunity in the development of radiation injury of the central nervous system, Wag/Rij rats were thymectomized at birth and irradiated to the cervical spinal cord at the age of 3 months. At the time of paralysis or at the end of the follow-up period (when rats were 1-year-old) the animals were sacrificed and the mediastinum was examined histologically. In 95% of the neonatally thymectomized animals no thymus was left. These rats showed a firm impairment of the cellular immunity, as they had a 40% reduction of the T-lymphocytes in the spleen, and a 70% reduction of the mixed lymphocyte reaction, compared to age-matched controls. Both single dose and two-fraction irradiation experiments were performed. No modification of the latency time to develop paralysis was observed comparing thymectomized and age-matched controls. The incidence of foreleg paralysis after cervical spine irradiation (single dose or two-fraction) was identically distributed in the follow-up period for both neonatally thymectomized and control Wag/Rij rats. The ED50 value derived in the single dose experiments was 20.3 Gy for the control animals, and 20.9 Gy for thymectomized rats, and in the two fraction experiments 29 Gy for controls and 29.6 Gy for thymectomized rats. None of these differences are significant. It appears that neonatal thymectomy, in spite of its firm suppression of the cellular immunity, has no major influence on the development of radiation myelopathy in rats.     

The effect of hyperfractionation on spinal cord response to radiation.

The T10-L2 level of the spinal cord of C3Hf mice was irradiated using a conventionally fractionated regimen of 2.0 Gy once daily or a hyperfractionated regimen of 1.2 Gy twice daily separated by 8 hr. After a fractionated dose of 24-60 Gy given by either regimen, a top-up dose of 15 Gy was given. Hind limb strength was then measured weekly for 15 months. The time to onset of paralysis was inversely associated with the total dose. Overall, the spinal cord was not spared by hyperfractionation to the extent predicted by the modified Ellis power law or the linear-quadratic model. The threshold dose for the development of paralysis was higher in the hyperfractionated than in the conventionally fractionated group. However, the latent period for paralysis and the dose producing hind limb paralysis in 50% of the mice (ED50) were not significantly different between the two regimens. The continuation of the process of sublethal damage (SLD) repair in the spinal cord beyond 8 hr after irradiation may have influenced these results. The slow component of SLD repair should be considered in the design of hyperfractionated or accelerated radiation therapy schedules for clinical use.     

Radiation response of the central nervous system

This report reviews the anatomical, pathophysiological, and clinical aspects of radiation injury to the central nervous system (CNS). Despite the lack of pathognomonic characteristics for CNS radiation lesions, demyelination and malacia are consistently the dominant morphological features of radiation myelopathy. In addition, cerebral atrophy is commonly observed in patients with neurological deficits related to chemotherapy and radiation, and neurocognitive deficits are associated with diffuse white matter changes. Clinical and experimental dose-response information have been evaluated and summarized into specific recommendations for the spinal cord and brain. The common spinal cord dose limit of 45 Gy in 22 to 25 fractions is conservative and can be relaxed if respecting this limit materially reduces the probability of tumor control. It is suggested that the 5% incidence of radiation myelopathy probably lies between 57 and 61 Gy to the spinal cord in the absence of dose modifying chemotherapy. A clinically detectable length effect for the spinal cord has not been observed. The effects of chemotherapy and altered fractionation are also discussed. Brain necrosis in adults is rarely noted below 60 Gy in conventional fractionation, with imaging and clinical changes being observed generally only above 50 Gy. However, neurocognitive effects are observed at lower doses, especially in children. A more pronounced volume effect is believed to exist in the brain than in the spinal cord. Tumor progression may be hard to distinguish from radiation and chemotherapy effects. Diffuse white matter injury can be attributed to radiation and associated with neurological deficits, but leukoencephalopathy is rarely observed in the absence of chemotherapy. Subjective, management, and analytic (SOMA) parameters related to radiation spinal cord and brain injury have been developed and presented on ordinal scales.     

Modulation of rodent spinal cord radiation tolerance by administration of platelet-derived growth factor

PURPOSE: To examine the role of platelet-derived growth factor (PDGF) for ameliorating radiation myelopathy of the cervical spinal cord in a rodent model. METHODS AND MATERIALS: After developing the technique for cannulation of the basal cistern, initial animal experiments were conducted to test the feasibility of intrathecal continuous infusion of PDGF in a model of cervical spinal cord irradiation in adult Fisher F-344 rats and to determine the most effective dose level of PDGF. Subsequently, the dose-modification factor was determined in a larger group of rats. Irradiation was given in 2 fractions (16 Gy followed by 14-24 Gy) and animals were examined for the development of paresis. RESULTS: The initial dose-finding experiment revealed significant differences in the incidence of radiation myelopathy (100% in saline-treated control rats, 25% with the most effective dose of PDGF, up to 100% with less effective doses). The most effective dose of PDGF was 0.014 mug per day. Subsequent experiments revealed a median effective dose (ED(50)) of 35.6 Gy (95% confidence interval, 34.7-36.5 Gy) for animals receiving this dose of PDGF in contrast to 33.8 Gy (33.4-34.3 Gy) for the control group (p = 0.003). The dose-modification factor obtained with this dose of PDGF was 1.05. CONCLUSIONS: Intrathecal administration of PDGF concomitant to irradiation of the cervical spinal cord in rats was feasible. Treatment with PDGF significantly increased the tolerance of the spinal cord. The PDGF experiments should be viewed as a proof of principle that brief therapeutic intervention in the earliest phase of damage induction can reduce late effects in the spinal cord. They form the basis for further studies of growth factor administration in this particular model.     

Radiation tolerance of the spinal cord previously-damaged by tumor and operation: Long term neurological improvement and time-dose-volume relationships after irradiation of intraspinal gliomas

Of 26 patients with intramedullary spinal cord gliomas (9 astrocytomas, 5 glioblastomas, 12 ependymomas) seen at the Massachusetts General Hospital from 1962–1980, 24 were irradiated (21 initially and 3 after post-surgical recurrence). Those 19 patients who survived at least 1 year after completion of irradiation were evaluated for post-irradiation neurological changes. No patient developed radiation myelopathy. Return to a permanently and completely normal neurological status occurred for $\text{33}\text{51}$ (65%) of pre-irradiation neurological deficits. The major cause of post-irradiation neurological deterioration was tumor recurrence.Although 18/19 patients had their thoracic or lumbar spinal cords irradiated, each with field sizes greater than 10 cm, spinal cord doses approaching, equalling, or occasionally exceeding various definitions of spinal cord tolerance were tolerated well without evidence of radiation myelopathy. Spinal cords of patients with intramedullary gliomas, often with major neurological deficits prior to irradiation, may be treated safely to doses approaching or equalling spinal cord tolerance levels. These doses are expected to locally control most ependymomas and astrocytomas without an increased risk of radiation myelopathy. Caution should be observed if doses higher than this are contemplated in an attempt to cure a glioblastoma, because the 5 % tolerance level of the damaged spinal cord remains to be defined.     

Tolerance of the human spinal cord to high energy p(66)Be(49) neutrons

The risk of post irradiation myelopathy was evaluated in 76 patients followed for 1-5 years after neutron irradiation of the cervical and thoracic regions. No overt myelopathy was observed. Forty-six patients received doses (central cord dose) in excess of 10 Gy, 9 received doses in excess of 12 Gy, and 5 received doses between 13 and 17 Gy, all without any evidence of spinal cord injury. On careful questioning, a subjective transient neuropathy (a tingling sensation in one extremity) was reported by 6 patients, but this was apparently unrelated to dose. A review of available literature revealed a total of 14 patients with myelopathy, 13 of whom received doses in excess of 13 Gy delivered with relatively low energy neutrons generated by the deuteron + beryllium reaction. It is concluded from these studies that the tolerance limit for the human spinal cord irradiated with high energy [p(66)Be(49)] neutrons is close to 15 Gy, above which the risk of cord injury becomes significant. Central cord doses of 13 Gy or less appear to be well tolerated with little, if any, risk of myelopathy. These conclusions are valid for a treatment time of 4 weeks or more with two or more fractions per week (9 or more fractions). The RBE for the human spinal cord irradiated under the above conditions compared with conventionally fractionated photon therapy does not exceed 4.0.     

Nephropathy in the mature pig after the irradiation of a single kidney: a comparison with the immature pig

The right kidney of 11 mature 10-month-old Large White female pigs was irradiated with single doses of 9.8-14.0 Gy of 60Co gamma rays. Individual kidney glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured using 99mTc-DTPA and 131I-hippuran renography for periods up to 24 weeks after irradiation. Renal function was assessed either as a functional index, FI (FI = irradiated/unirradiated kidney function), or as the individual kidney GFR and ERPF. The radiation-induced changes after the irradiation of a single kidney (unilaterally irradiated--UI) of mature pigs were compared with those previously observed in 14-week-old immature pigs. Irradiation resulted in a dose-dependent reduction in the FI for both GFR and ERPF. However, these reductions were significantly less than those previously seen in immature pigs. Within 2 weeks of irradiation GFR increased in both the irradiated and the unirradiated kidneys in each animal, compared with unirradiated age-matched control kidneys. No marked changes in renal hemodynamics were seen in mature animals after a single dose of 9.8 Gy. This was in marked contrast to the pronounced reduction in the GFR and ERPF in the irradiated kidney previously observed in immature animals irradiated with an equivalent single dose of X rays. After higher doses, the irradiated kidney in mature pigs showed a dose-dependent reduction in GFR and ERPF. However, the extent of this reduction was significantly less than that seen in immature animals. There was no apparent difference in the response of the unirradiated kidneys in mature or immature pigs. The ED50 values, based on a probit fit to the data for the proportion of functional tests in which the irradiated kidney showed a greater than or equal to 50% reduction in GFR or ERPF, were higher in the mature animals; for example for ERPF the ED50 values were 11.76 +/- 0.28 Gy and 7.67 +/- 0.34 Gy for mature and immature animals, respectively. Thus, the UI kidney in mature pigs appears to be less radiosensitive than the UI kidney in immature animals.     

Radiation myelopathy in primates treated with conventional fractionation

A rhesus monkey model was used to assay the radiation tolerance of the spinal cord to 60Co radiation given in 2.2 Gy fractions. The D50 was found to be 76.1 Gy (SEM = 1.9 Gy); the estimated doses for 1% and 0.1% myelopathy were 59.1 +/- 5.5 Gy and 52.1 +/- 7.1 Gy, respectively. The latent period ranged from 5 to 20 months and decreased with increasing dose. All symptomatic animals had white-matter parenchymal lesions involving major motor tracts, and most also had vascular lesions in the white matter. Spinal cords of asymptomatic animals had either no histopathologic changes or small white-matter lesions that did not involve motor tracts.     

Radiation-induced heart disease in rats

After local irradiation of the rat heart with X ray doses of over 10 Gy (single dose), animals developed symptoms of radiation-induced heart disease, which at higher doses would lead to fatal cardiac failure. The LD 50 at 1 year was between 15 Gy and 20 Gy. The pericardium and epicardium responded to irradiation with exudative pericarditis after 4 months. Focal myocardial damage was secondary to progressive capillary damage.