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Encephalomyelopathy Following High- Dose 5 C N U Therapy

PETER C. BURGER, MD,* ELIZABETH KAMENAR, MD,t S. CLIFFORD SCHOLD, MD,$ JOSEPH W. FAY, MD,§ GORDON L. PHILLIPS, MD,” AND GEOFFREY P. HERZIG, MD”

Autopsies were performed on four patients who had been treated with high-dose BCNU therapy for visceral, cutaneous, or lymphoid malignancies. Three had developed an encephalopathy or encephalomyelopathy within five weeks before death. In all four patients distinctive lesions were found within the central nervous system that were either (1) discrete foci of swollen axis cylinders and myelin vacuolization or (2) larger, symmetric areas of edema with white and gray matter necrosis. Fibrinoid necrosis and fibrin microthrombi were much more prominent in the latter. The small discrete foci of axonal and myelin alterations are similar, if not identical, to lesions previously associated with cranial radiation or combined cranial radiotherapy and chemotherapy. The larger lesions share features with “methotrexate encephalopathy” and delayed radionecrosis. The presence of these lesions in these patients, who had not received cranial radiation, suggests that high-dose BCNU therapy alone is associated with, and may produce, certain distinctive structural changes in the central nervous system. The presence of fibrinoid necrosis and fibrin microthrombi suggests that this possible pathologic effect of BCNU could be mediated by the drug’s effect on the cerebrospinal vascula- ture.

Cancer 48:1318-1327, 1981.

H E C O M B I N A T I O N of high-dose antineoplastic T chemotherapy and autologous bone marrow transplantation delivers the maximum concentration of drug to a tumor while circumventing the principal toxic consequence of most agents-bone marrow suppres- sion. I ,3-Bis-(2-chloroethyl)-l-nitrosourea (BCNU) is a particularly attractive agent in this regard because of its alkylating properties, lipid solubility, wide tissue distribution, and the relatively low incidence of extra-

Presented in part at the 32nd Annual Meeting of the American Academy of Neurology, May 2, 1980, New Orleans, Louisiana.

From the Duke University Medical Center, Durham, North Carolina; the Cleveland Clinic Foundation, Cleveland, Ohio; and Washington University School of Medicine, St. Louis, Missouri.

* Department of Pathology. Duke University Medical Center. ‘i Department o f Neurology, Cleveland Clinic Foundation. 4: Division of Neurology, Duke University Medical Center. $ Division of Hematology-Oncology, Duke University Medical

Center. ‘ I Division of Hematology, Washington University School o f

Medicine. Dr. Fay is a recipient of a Young Investigator’s Award, National

Cancer Institute CA 26401. Doctor Herzig is a Scholar of the Leukemia Society of America.

Address for reprints: Dr. Peter C. Burger, Department of Pathol- ogy, Box 3712, Duke University Medical Center, Durham, NC 27710.

Accepted for publication July 20, 1980.

medullary toxicity produced at conventional doses. Therapeutic trials are presently assessing the efficacy of such high-dose BCNU therapy and seeking to de- termine the maximum tolerated dose.’

This report derives from an ongoing Phase 1-11 study of high-dose BCNU therapy with autologous bone marrow transplantation for metastatic neoplastic disease. We have encountered three patients with a clinically unexplained encephalopathy or encephalomyelopathy. An additional but asymptomatic indi- vidual had lesions of the brain morphologically similar to those of the symptomatic subjects. This report re- cords the clincial expressions and pathologic anatomy of the central nervous system lesions in these four patients, and considers the possible role of BCNU in their genesis.

Materials and Methods

Putient Selection

Each of the four patients had metastatic cancer refractory to conventional forms of chemotherapy. None had received other chemotherapeutic agents within 30 days of the high-dose BCNU and no cranial or spinal

0008-543X/81/0915/1318 $1.00 D American Cancer Society

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No. 6 ENCEPHALOMYELOPATHY A N D BCNU . Burger et al. 1319

TABLE I . Clinical Data

Intervals (days) between completion of high-dose BCNU therapy and

Total high- dose BCNU Other Neurologic First neurologic

Patient Neoplasm (mg/m2) chemotherapy* disturbance symptom Death

1 Hodgkin's disease, 1500 Vcr Altered mental cervical nodes CDP status, seizures

Vlb BCNU Pcb Bleo NHz Ctx Act D Vlb CDP Adria Bleo

3 Malignant melanoma, 2850 None Diplopia, ataxia,

4 Malignant melanoma, 1200 Vcr None skin confusion

skin 2250 Bleo - __ 3450 BCNU

2 Embyonal cell 2250 carcinoma, testis

Quadriparesis, diplopia, confusion

36 53

25 55

47 62 - 87

18 -

* BCNU = 1-3-Bis(2-chloroethyl)-I-nitrosourea; Vcr = vincristine; Vlb = vinblastine; Pcb = procarbazine; Bleo = bleomycin; NH, = nitrogen mustard; Adria = doxorubicin (Adriamycin); CDP

= cis-diaminoplatinum; Ctx = cyclophosphamide (Cytoxan); Act D = actinomycin D.

irradiation had been administered to any patient at any time prior to the high-dose BCNU therapy. As described below, spinal irradiation was subsequently given to Patient 2 , but this was the only irradiation that any patient received. The clinical data, type of neoplasm, and details of previous chemotherapy are pro- vided in Table 1 .

fectious complications occurred during the period of pancytopenia.

C/inical and Radiologic Evaluation

Patients were evaluated before receiving high-dose BCNU therapy by physical examination, electro-

Bone Marrow Storage

Morphologically normal bone marrow was obtained 12- 14 days prior to transplantation and preserved in the frozen state as previously described.'

Chemotherapy and Transplantation

BCNU was given intravenously in three equally di- vided daily doses on subsequent days. One week following the last dose the bone marrow was rapidly thawed at 37 C and reinfused intravenously without a filter. All patients received transfusions of erythro- cytes to maintain the hemoglobin between 9- 10 g/dl and of platelets to maintain a count above 20,000/mm3. All blood products were allogeneic and were treated with 3000 rads Drior to transfusion. Either oral or

the transplant interval. No serious hemorrhagic or in- cortex of the medial temporal lobes (H & EILFB).

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FIG. 2. Patient 1 . Interstitial edema fluid and poorly stained myelin are largely responsible for the white matter pallor seen in Figure 1 ( H & EILFB, x 100).

encephalogram, neurologic consultation (S.C.S.), and appropriate blood chemistries. Computerized tomo- graphic (CT) scans were performed in three patients after the onset of neurologic symptoms. Treatment re-

Flc;. 3. Patient 1. Within the pale white matter of the temporal lobe are rare hypocellular coagulative foci (bottom) (H & EILFB, x 100).

sponse was assessed by measurement of palpable or radiographically demonstrable lesions.

Case Reports

Case I

CANCER September 15 1981 Vol. 48

sions in the deeper layers of the cortex. These were accom-

Clinical history: The patient was a 50-year-old man in whom Hodgkin’s disease had been diagnosed by biopsy of enlarged cervical lymph nodes. After progression of the disease following conventional chemotherapy with vincristine, cis-platinum, vinblastine, BCNU, procarbazine, bleomycin, and nitrogen mustard, high-dose BCNU therapy (a total of 1500 mg/m2) was given. Before the BCNU treatment, the patient’s only neurologic abnormality was the absence of deep tendon reflexes, which was attributed to the vincristine therapy. An electroencephalogram (EEG) showed no abnormality.

Five weeks after the BCNU treatment the patient began to exhibit inappropriate behavior with paranoid thoughts and disorientation. A CT scan was within normal limits. The cerebrospinal fluid (CSF) contained one lymphocyte/mm3; the protein and glucose concentrations were 40 mg/dl and 199 mg/dl, respectively. Cytologic examinations, fungal and bacterial cultures, an india ink preparation, and determina- tions of cryptococcal antigen in the CSF showed no abnormalities. An electroencephalogram (EEG) showed bilateral theta and delta activity with no evidence of normal alpha rhythms. The irregular delta slowing was somewhat more prominent in the left midtemporal region. The patient gradu- ally became more obtunded without focal neurologic signs and developed generalized seizures. He never regained con- sciousness and died 17 days after the onset of his terminal neurologic illness and 53 days after completing the high-dose BCNU therapy. No craniospinal radiation therapy had been given at any time during the patient’s illness.

Necropsy findings: No residual lymphoma was found. There were a moderate bronchopneumonia and a markedly hypocellular bone marrow.

On the external surface of the 1600-g brain were multiple petechiae on the inferior surfaces of both temporal lobes. Internally, the white matter of the anterior temporal and the insular aspects of the frontal lobes were soft, greenish, stippled with petechiae, and merged indistinctly with the over- lying cortices, which also contained petechiae. The amygdalae were symmetrically soft. The basis pontis contained multiple, pinpoint, dull, translucent foci.

Histologically, with the hematoxylin and eosinlluxol fast blue method, there was marked symmetrical pallor of the temporal lobe white matter and the extreme capsules (Fig. 1). The deep white matter in these areas was eosinophilic, hypocellular, and focally suffused with eosinophilic interstitial and perivascular fluid (Fig. 2). Necrosis was not ap- parent except for focal areas in the temporal lobes, which were converted into well-defined areas of hypocellularity or granular coagulation necrosis (Fig. 3). Larger, more amorphous, and more densely eosinophilic areas of necrosis in the subcortical white matter were contiguous with similar le-

No. 6 ENCEPHALOMYELOPATHY A N D BCNU . Burger et al. 1321

panied by prominent fibrinoid necrosis (as discussed below). Only one focus of swollen and necrotic axons was noted in the white matter of the temporal lobes. A few perivascular polymorphonuclear leukocytes and lymphocytes constituted the only inflammatory response. There were scattered reactive astrocytes and a few gitter cells. The petechiae seen grossly were perivascular and ball hemorrhages.

A few small vessels in the cortex of the medial temporal lobes were altered to the amorphous eosinophilic state consistent with “fibrinoid necrosis.” Such vessels were positive with the phosphotungstic acid hematoxylin stain and were continuous with a corona of tinctorially similar material that radiated into the surrounding parenchyma (Fig. 4). Most vessels in the white matter were not frankly necrotic but many exuded fibrin. Vessels of either type were also observed at the periphery of the grossly affected regions where the only parenchymal changes were edema and astrocyte hypertrophy. Capillary proliferation, endothelial enlarge- ment and hyperchromatism, fibroproliferative vessel thick- ening, and recanalized or duplicated channels were also noted. The cerebral white matter distant to the gross abnormalities in the frontotemporal area was slightly pale and contained hypertrophic astrocytes and scattered prominent small blood vessels with enlarged and hyperchromatic endothelial cells. Some small vessels contained fibrin (Fig. 5) . A rare vessel exuded fibrin. In the white matter of one frontal lobe was a single globoid eosinophilic “microglia,” which has been seen in the brains of patients receiving radiotherapy and combined radiotherapy and chemotherapy.z

Throughout the brain stem (Fig. 6) and the white matter of the centrum semiovale (Fig. 5) , corpus callosum, cerebellum, and cervical and thoracic spinal cord were discrete foci of myelin vacuolization and swollen axis cylinders. The swollen axis cylinders were most prominent in the pontine lesions whereas vacuolization was more pronounced in the corpus callosum and spinal cord. In the pons these focal abnormalities often were confined to either bundles of crossing or descending fibers, but some lesions straddled the boundries and involved both (Fig. 7). In contrast to similar foci of swollen axons elsewhere in the nervous system, those in the pons were sometimes contiguous with gray matter (the pontine nuclei) where fibrinoid necrosis and/or exudations of fibrin were noted. As in the frontotemporal lesions, evidence of inflammation in the pontine lesions was minimal and confined to a few karyorrhectic polymorphonuclear leukocytes.

Special stains for bacteria and fungi applied to sections from the temporal lobe and brain stem did not disclose organisms. No viral particles were seen by electron micros- copy of temporal tissue and viruses were not identified in cultures of tissue from the frontal lobe. There was no metastatic carcinoma in the brain. Fibrin thrombi were not observed in other organs.

Case 2

Clinical history: The patient was a 19-year-old man in whom an embryonal cell carcinoma of the testis was discovered in July 1978. A left radical orchiectomy was performed,

FIG. 4. Patient 1. Fibrin incontinence, fibrin thrombi, and fibrinoid necrosis characterize many small blood vessels in the medial temporal cortex (PTAH, x 100).

at which time metastases to periaortic and renal hilar lymph nodes were noted. Cyclophosphamide, actinomycio D, vinblastine, cis-platinum, doxorubicin, and bleomycin were ad-

FIG. 5 . Patient 1. In the anterior frontal lobe remote from the changes illustrated in Figures 1-4, is a focus of swollen axons (below) and a vessel with a hyaline thrombus (top) (H & E/LFB, x 250).

1322 CANCER September 15 1981 Vol. 48

FIG. 6. Patient 1 . The pons is shot with multiple, discrete, pale lesions. An identical appearance was observed in the brain stems of Patients 2, 3, and 4 (H & E/LFB).

ministered, but the disease progressed. He then received high-dose BCNU therapy (a total of 2250 mg/m2). At this time he was neurologically intact and an EEG showed no abnor- mali t y .

Twenty-five days after completing BCNU therapy, the patient had a transient, unexplained episode of diplopia. Three days later he developed spastic paraparesis with bilateral Babinski responses. The cerebrospinal fluid was normal except for a protein concentration of 81 mg/dl. A CT scan of the brain and complete myelography showed no abnor-

Fic,. 7 . Patient I . The discrete pontine lesions as seen in Patient 1 are foci of swollen axis cylinders (H & EILFB, ~ 2 5 0 ) .

malities. The leg weakness progressed to complete para- plegia with a midthoracic sensory level to all modalities over the following week. Two 300-rad doses of irradiation were administered to the thoracic cord, but no cranial radiation was given. Weakness of the upper extremities evolved and within two weeks of the onset of his neurologic disease he was quadriparetic with loss of sensation below the neck. He became progressively more confused and obtunded. There were no overt abnormalities of the cranial nerves. He died 30 days after the onset of his neurologic disease and 55 days after completing high-dose BCNU therapy.

Necropsy findings: Metastatic embryonal cell carcinoma replaced multiple abdominal lymph nodes, surrounded a segment of the large bowel, obstructed the left proximal ureter, dotted the liver, and appeared as a solitary pulmo- nary nodule. The bone marrow was markedly hypocellular and there was bilateral bronchopneumonia. There was no neoplasm in the parenchyma of the central nervous system, the spinal meningeal, or extradural spaces.

Coronal sections of the 1650-g brain revealed petechiae and marked softening in the midline of the body of the corpus callosum at the level of the thalamus, as well as smaller necrotic foci extending anteriorly to the genu.

Microscopically, the corpus callosum contained both discrete foci of swollen axons and larger pale-staining amorphous areas of necrosis similar to that found in Patients 1 and 3 (Fig. 8). The smaller lesions were composed entirely of brightly eosinophilic swollen axons, but these structures were restricted to the periphery in the larger lesions. A few small ball hemorrhages were present. Additional rare foci of dilated axons were present in the frontal, temporal, and parietal, and cerebellar white matter, as well as the internal capsules and fimbriae and bodies of the fornices. Multiple similar lesions stippled the brain stem, especially in the basis pontis, and riddled the dorsal, ventral, and lateral columns of the cervical spinal cord. In the cord, the lesions were more vacuolated and contained fewer swollen axis cylinders than in similar foci in the brain stem (Figs. 9 and 10). Spinal nerve roots were intact. There were no vascular lesions such as fibrinoid necrosis, fibrin thrombi, or endothelial cell en- largement anywhere within the central nervous system.

Case 3

Clinical history: The patient was a 34-year-old woman with widely metastatic malignant melanoma. She was treated with a total of 2850 mg/mZ of BCNU. N o other chemotherapy was given. Before receiving BCNU therapy the patient was neurologically intact and an EEG showed no abnormality.

Forty-seven days after the BCNU treatment, she developed diplopia, ataxia, and confusion. On hospitalization, she was alert but moderately disoriented. Funduscopic examination was within normal limits and the pupils were reactive to light. Extraocular movements were full but there was coarse horizontal nystagmus on right lateral gaze with a slight clockwise rotatory component. In addition, there was low amplitude vertical nystagmus on upward gaze and fine horizontal nystagmus on left lateral gaze. No extraocular motor weakness could be detected and the corneal reflexes

No. 6 ENCEPHALOMYELOPATHY A N D BCNU . Burger er al. 1323

were intact. The face moved symmetrically and the functions of the lower cranial nerves were normal. There were a mild diffuse quadriparesis with hyperactive reflexes and bilateral Babinski responses and a moderate left hemiataxia with the leg and arm equally involved. Sensory examination showed no abnormalities. A CT scan and a lumbar puncture showed no abnormality, and an EEG revealed moderate diffuse slowing.

The patient’s condition continued to deteriorate with progressive obtundation and confusion, persistent asymmetrical nystagmus, and spastic quadriparesis. Liver function tests showed progressive disturbances and bilirubin was 3.0 mg/dl; these abnormalities were not thought sufficient to ex- plain her neurologic syndrome. She died 15 days after the onset of her neurologic disease and 62 days after the administration of the high-dose BCNU. No therapeutic irradiation was given to the brain or spinal cord at any time during the patient’s illness.

Necropsy findings: There was metastatic neoplasm in the skin and lungs, bronchopneumonia, and hepatic centrilobu- lar necrosis.

Coronal sections of the 1210-g brain disclosed lesions in the corpus callosum, hypothalamus, anygdalae, and brain stem. Straddling the midline of the body and genu of the corpus callosum was a 6 x 4 x 5 mm slightly retracted area of softening similar to that seen macroscopically in Patient 2. Isolated similar, but smaller, foci were noted laterally on both sides. The posterior hypothalamus was green, speckled with petechiae, and slightly expansile at the expense of the interposed posterior-inferior third ventricle (Fig. 11). Similar but less intense alterations were present in the amygdalae. In the right pontine base and right inferior cerebellar peduncle were translucent foci several millimeters in diameter.

Microscopically, the retracted lesion in the corpus callosum was a confluent area of recent necrosis similar to that in Patients 1 and 2. In some areas swollen axons were present; in others, the tissue was pale-staining, amorphous, and without evidence of prior axonal injury. Small discrete foci of swollen axis cylinders were present laterally in the corpus callosum, the bodies and fimbriae of the fornices, and occasionally in the centrum semiovale and the white matter of the cerebellum. They also abounded in the brain stem and cervical and thoracic spinal cord. The brain stem lesions were concentrated in the pontine base and inferior cerebellar peduncles; there were only a few in the midbrain. The spinal lesions were highly vacuolated, as in Patient 2, and were randomly scattered in the dorsal, lateral, and ventral columns. Step sections disclosed rare fibrin microthrombi in association with the lesions of the corpus callosum, pons, medulla, and spinal cord, but no fibrinoid necrosis was seen. In the corpus callosum and pons, mild endothelial and perithelial hyperplasia was noted.

There were many small vessels with fibrinoid necrosis and occlusive fibrin microthrombi bilaterally in the hypothalamus, amygdala, and medial thalamus (Figs. 12 and 13). These were noted both in the center of the lesion, in which edema fluid, coagulation necrosis, and gliosis were prominent, and also at the periphery where there were no parenchymal changes. These vascular alterations were sim-

FIG. 8. Patient 2. Several discrete foci of pallor straddle the midline of the corpus callosum (arrows). Similar lesions were noted in the corpus callosums in Patients I and 3 (H & EILFB).

ilar to those in the temporal lesions in Patient 1 , although fibrinoid necrosis, fibrin-incontinent nonnecrotic vessels, and karyorrhectic polymorphonuclear leukocytes were con-

FIG. 9. Patient 2. Multiple pale foci are randomly dispersed within the white matter of the spinal cord as they were in Patients 1 and 3 (H & EILFB).


FIG. 10. Patient 2. The spinal cord lesions of Patient 2 are regions of marked vacuolation of myelin and focal swollen axis cylinders (H & EILFB, X250).

siderably more evident. Foci of swollen axis cylinders were present in the adjacent mamillothalamic tracts. Neither the mammilary bodies nor the periaqueductal gray matter was

FIG. 11. Patient 3. The hypothalamus is symmetrically discol- ored, swollen, and stippled with petechiae.

involved with vascular changes or petechiae. In the posterior hypothalamus, subthalamus, and anterior mesencephalon was moderate ill-defined pallor. No microorganisms were seen with special stains in any of the lesions in the nervous system.

Neither vascular abnormalities nor gliosis was noted in the centrum semiovale or cerebellar white matter. A micro- scopic nodule of melanocarcinoma was found in the right occipital lobe and in the cerebellum. No fibrin thrombi were found in other organs.

Case 4

Clinical history: The patient was a 26-year-old white man with a malignant melanoma of the scalp. He underwent a wide excision of the primary lesion and a radical neck dis- section in which two positive lymph nodes were discovered. He was begun on immunotherapy with BCG and melanoma cell vaccine. Local recurrence at the primary site necessi- tated another excision, and metastasis to the ileum required segmental enterectomy. Vincristine, bleomycin, conventional doses of BCNU, and immunotherapy were then administered.

Thirty days later he received high-dose BCNU therapy (1200 mg/m2). Most of the palpable tumor regressed and he did well for six weeks, but recurrent neoplasm appeared. An additional 2250 mg/m* of BCNU was given. Subsequently, intermittent fevers, congestive heart failure, and hyperbili- rubinemia developed. He died 87 days after completing the first course of high-dose BCNU therapy and 18 days after the second. No abnormal neurologic signs or symptoms were present at any time during the patient’s illness. No craniospinal radiotherapy had been given.

Necropsy Jindings: There was residual metastatic melanoma in an axillary lymph node and the ileum. The bowel, heart, and lungs were hemorrhagic. The bone marrow was markedly hypocellular and the heart was focally necrotic.

The 1420-g brain was unremarkable grossly except for a minimal collection of subdural hemorrhage bilaterally. One block each of frontal lobe, hippocampus, and pons was available for review. Step sections of the pontine tissue revealed several foci of vacuolization of myelin with swollen axis cylinders identical to those seen in the same location in Patients 1, 2, and 3. There were no associated vascular lesions. The cerebral and hippocampal white matter was mildly gliotic, but no necrotic lesions were seen and the blood vessels were unremarkable.

Discussion

T h r e e o f t h e f o u r p a t i e n t s i n t h i s s t u d y had neurologic dysfunction that could not be explained, either during life or at postmortem examination, by alterations in their metabolic status or the presence in the nervous system of infectious or metastatic disease. They had progressive, subacute, multifocal central nervous system diseases occurring 25-47 days after the administration of high-dose BCNU and bone marrow autotransplantation. Both the C T scan and CSF

No. 6 ENCEPHALOMYELOPATHY AND BCNU . Burger et al. 1325

analysis showed no abnormalities, except for ele- vated CSF protein concentrations; the electroencephalogram showed mild to moderate diffuse slowing. The fourth patient was neurologically asymptomatic.

Two types of lesions were found in the brains studied at postmortem. The first, which was seen in all four individuals, consisted of foci of swollen axis cylinders that were noteworthy for their discrete quality, paucity of associated inflammation, affinity for white matter, and generally random distribution in affected regions. These lesions favored the brain stem (especially the pons), the corpus callosum, and the spinal cord. Larger and more symmetrical areas of softening in the corpus callosum appeared similar. Vascular abnormalities were not prominent in these lesions, although fibrinoid necrosis was sometimes noted in the pontine lesions, especially where gray matter was involved. The second type of lesion was found in two of the symptomatic patients (Patients 1 and 3) and consisted of larger, less well-defined regions that were noteworthy for their bilateral symmetry, content of perivascular and interstitial edema, paucity of swollen axis cylinders, prominence of fibrin thrombi, fibrin incontinence, and fibrinoid necrosis. These larger lesions were present in the temporal lobes and insular surfaces of the frontal lobes in Patient 1 and in the hypothalamus and amygdalae in Patient 3.

Discrete foci of necrosis with swollen axis cylinders, such as were present in Patients 1-4 of this study, have been noted previously in patients with lymphoid, hematopoietic, visceral, and cerebral neoplasms treated with combined chemotherapy and cranial radiation."' At issue has been the relative contribution of these two therapeutic modalities to the pathogenesis of these lesions.

It is clear from experience with the radiated brains of experimental animalsP1O that discrete foci of necrosis with swollen axons can be produced by ionizing radiation alone. Similar foci are also noted in the spinal cord of man as part of delayed radiation myelopathy." The experimental lesions have been widely disseminated in the cerebral white matter and share the con- spicuous affinity for the brain stem, especially the pons, with the similar lesions of the present patients. These experimental lesions are noteworthy for the absence of the hyalin thrombi and fibrinoid necrosis that was occasionally observed in Patient 1 of this study. Mineralization of the swollen axons has been noted previously, although not observed here.

Attention has also been focused on chemotherapeutic drugs in the genesis of these same small lesions, with intrathecal methothrexate attracting particular interest because it appears in but not all,2*3*6 of the therapeutic histories. To our knowledge, how-

FIG. 12. Patient 3. At low magnification, the hypothalamus con- tains petechiae and many small, ill-defined areas of increased den- sity (arrows) (H & E, x25) .

were described had also received cranial radiation. In one case, however, 2000 rad was given to the scalp rather than the brain6 and a role for radiation in the genesis of these small foci of necrosis in all patients seems unlikely. Identical lesions, furthermore, have been seen in a non-irradiated patient given parenteral and intrathecal gentamycin for meningitis, and,

FIG. 13 . Patient 3. The multiple densities seen in the hypothalamus of Patient 3 are small blood vessels with fibrinoid necrosis. Karvorrhectic Do~vmomhonuciear leukocytes permeate . -

ever, the reported patients in whom similar lesions the parenchyma (H & EILFB, x i00).


importantly, in experimental animals given a large dose of the same drug in a single intracisternal injection.”

These cases establish a relationship between chemotherapy and small discrete foci of necrosis, and exclude a pathogenic role for radiation as none was given, except to the spinal cord of Patient 2 after the lesions had expressed themselves clinically. Review of the treatment protocols of Patients 1, 2, and 4 discloses the same multiplicity of drugs as is recorded in patients reported with these lesions, but in this study it is high-dose BCNU therapy that stands out as suspect, especially because it was the only chemotherapeutic agent given to Patient 3.

Thus, on the basis of past experience and that in the present study, it appears that similar, if not identical, small foci of necrosis with swollen axis cylinders are associated with chemotherapy, radiotherapy, or combined radio- and chemotherapy. A critical but unre- solved issue is the potentiating or additive effects of these therapeutic modalities upon each other.

The second type of lesion found in two symptomatic patients was an ill-defined region in temporal and frontal lobes of Patient 1, and the hypothalamus, thalamus, and amygdalae in Patient 3. These lesions were distinguished from the aforementioned discrete foci of necrosis by their striking symmetry and large size, amount of edema fluid, paucity of swollen axons, and prominence of fibrinoid necrosis. These two types of lesions shared features and may reflect the same insult, but, because of the differences enumerated above, consideration as two separate processes seems reasonable in want of further experience. We are not aware of past encounters with the larger and symmetrical lesions, although they share a number of features with “methotrexate encephalopathy” and delayed radionecrosis.

Cerebral lesions associated with intrathecal methotrexate therapy span a spectrum from diffuse white matter pallor and gliosis to extensive regions of overt coagulation ne c ro s i s. 3-5*1 ’-I6 S ymmetric in- volvement of the centrum semiovale is typical and vascular changes including fibrinoid necrosis and fibrin incontinence have been noted in some instances. As is discussed above, foci of swollen axons can also be present and may occur in the brain stem. The symmetric lesions in the present report in Patients 1 and 3 share the delayed onset, presence of fibrinoid necrosis, and, in Patient 1, both necrosis and the diffuse pallor with coagulative foci. On the other hand, the “methotrexate” lesions usually are situated more su- periorly in the centrum semiovale and less prone to involve gray matter. It is worth noting that patients who have developed the large “methotrexate” lesions have also received cranial radiotherapy and the latter

has been considered by some as a possible contributing pathogenetic factor, much as it has been for the smaller discrete foci of necrosis as discussed above.’”I6 In some of these patients with the large lesions of methotrexate encephalopathy , however, the cranial radiation was given only to the posterior fossa remote from the necrotic foci in the cerebral hemi- spheres,I3 and others have been radiated only after the presumptive symptoms of this encephalopathy had al- ready appeared.I2 Thus, radiation therapy may not be essential to the development of these lesions in all patients. Radiotherapy, clearly, was not a contributing factor in the present cases.

The symmetric lesions encountered in Patients 1 and 3 of this report also bear a similarity to human late delayed radionecrosis in the late onset and presence of fibrinoid necrosis. They are, however, more symmetric than the typical delayed radionecrosis, somewhat more prone to involve gray matter, and, in the white matter of the temporal lobes of Patient 1, more acute and less coagulated and mummified than the typical radionecrosis in humans.17 The diffuse edema in the temporal lobes of Patient 1, however, appears similar to the delayed results of radiation in certain experimental animals.18”Y

The pathogeneses of the two types of lesions in this series is unknown, but past experience with the com- plex metabolic and immunologic states of such drasti- cally ill patients enjoins consideration of metabolic, immunologic, infectious, and vascular origins unre- lated to direct effects of BCNU. Although such mech- anisms cannot be excluded, the character and pattern of the lesions do not suggest such vitamin deficiency states as Wernicke’s encephalopathy or subacute combined degeneration, and no organisms were seen in any case. The prominent hyalin thrombi in Patients 1 and 3 raise the issue of disseminated intravascular coagulation (DIC). However, the symmetry of the lesions in Patients 1 and 3 and the predominant white matter localization of the small discrete foci of necrosis in Patients 1, 2, 3, and 4 are at odds with lesions found in some cases of DIC.20 Other reports of this latter condition stress the paucity of neurologic findings in this syndrome and the rarity of cerebral ischemic lesions.21 In addition, no fibrin thrombi were found in any other organs in the present patients.

The mechanism by which BCNU could produce these lesions is clearly speculative. We are impressed, nevertheless, by the close association between either of the two types of lesions reported in this study, but especially the larger and symmetrical foci, with vascular changes of fibrinoid necrosis, fibrin incontinence, and fibrin thrombi. At issue, as it is in delayed radionecrosis, is the possible cause and effect relation-

No. 6 ENCEPHALOMYELOPATHY AND BCNU * Burger er al. 1327

ship between vascular changes and the parenchymal alterations. In the established lesion, it is impossible to distinguish between a primary vascular change pro- ducing parenchymal infarction or an area of necrosis secondarily incorporating an innocent vessel. Nevertheless, the striking fibrinoid necrosis and the exudation of fibrin in Patients 1 and 3 where parenchymal necrosis was incomplete, and especially at the periphery of the lesions where there was no parenchymal changes, suggests that vascular changes are primary and that parenchymal necrosis is secondary and ischemic. The marked interstial edema in the temporal lobes of Patient 1 also suggests a vascular in- competence. In addition, the fibrin thrombi and‘endothelial atypia that occurred throughout the brain in Patient 1 are consistent with the effect of a primary microvascular insult. We suggest, therefore, that both types of lesions in Patients 1-4 are consequences of a vasculopathy, a pathogenetic mechanism that has many advocates for delayed radionecrosis and has also been proposed for methotrexate leukoencephalopathy.16 The identity of the primary insult on these vessels is unknown but, for reasons elaborated above, attention must focus on the high doses of BCNU.

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