“Disappearing” Spinal Cord Compression: Oncolytic Effect of Glucocorticoids (and Other Chemotherapeutic Agents) on Epidural Metastases Jerome B. Posner, MD, John Howieson, MD, and Esteban Cvitkovic, MD
Four patients suffering spinal cord compression resulting from epidural metastases were treated with adrenocorticosteroid hormones. For 2 patients,pronqx relief of symptoms followed giurocorticoid therapy alone and was associated with marked shrinkage or disappearance of t h e metastasis, a direct oncolytic effect of t h e steroids. For the other 2 patients, glucocorticoids combined with other chemotherapeutic agents caused disappearance of t h e extradural tumor. For 1 patient, failure to recognize the oncolytic effects of the chemotherapy led to an unnecessary surgical procedure, and for a second patient an unnecessary operation was narrowly averted. Thus, for certain patients, glucocorticoids may occasionally have a marked oncolytic effect on epidural metastatic tumors. Posner JB, Howieson J, Cvitkovic E: “Disappearing” spinal cord compression: oncolytic effect of glucocorticoids (and other chemotherapeutic agents) on epidural metastases. Ann Neurol 2:409-413, 1977 Adrenocorticosteroids ameliorate clinical symptoms caused by a variety of primary and metastatic tumors of the central nervous system. Most investigators attribute thesc salutary effects to the relief of tumor-related cerebral or spinal cord edema [ 7 , 171. I n fact, neurologists and neurosurgeons are so accustomed t o attributing the beneficial effects ofglucocorticoids o n CNS tumors to the relief of edema that they may overlook instances in which clinical improvement results from the oncolytic action of glucocorticoids. Failure t o appreciate the oncolytic potenial of glucocorticoid therapy may lead to inappropriate treatment. This report concerns 4patients suffering spinal cord compression resulting from epidural metastases. For 2 patients, p r o m p t relief of symptoms followed glucocorticoid therapy alone and was associated with marked shrinkage or disappearance of the metastasis, a direct oncolytic effect of the steroids. For the other 2 patients, glucocorticoids combined with other chemotherapeutic agents caused disappearance of the extradural tumor. For 1 patient, failure to recognize the oncolytic effects of the chemotherapy led to an unnecessary surgical procedure, and for a second patient an unnecessary operation was narrowly averted.
From the Departments of Neurology, Diagnostic Radiology, and Medicine (Solid Tumor Service), Memorial Sloan-KetteringCancer Center, and the Department of Neurology, Cornell University
Medical College, New York, NY.
Case R e p o r t s Patient 1: Thynoma A 32-year-old dentist was first acirnitted to Memorial Sloan-Kettering Cancer Center because a 6.5 cm mass was found i n the anterior mediastinurn following a routine chest roentgeriograrn. O n J u l y 10, 1975, the tumor was removed and discovered ro be a mixed lymphoid and epithelial thymorna. The patient received 6,000 rads of megavoltage radiation to the mcdiastinum and supraclavicular areas. In January, 1976, he was hospitalized for radiation-induced pericarditis. In February he developed miclback pain that bj7 June had radiated down his legs and into his toes. In early July his legs became weak, and he developed constipation. H e was admitted to the hospital on July 7 with signs of spinal cord compression, including bilateral lower extremirp hyperreflexia, extensor plantar responses, and a pinprick response level ar the costal margin. A mpelograni revealed complete obsrruction to the column o f contrast agent by an epidural mass extending from TX to T12; the mass was circumferenrial, and 110 alteration of bone was found in rhar area. Dexamethasone, 4 mg four times daily, and radiation therapy (RT) were begun the same day. The patient received 3,000 rads to the area of the block and made a rapid recovery. The steroids were tapered, and he was discharged from the hospital fully ambulatory o n August 14. A myelogram done on December 12, five months after treatment for spinal cord compression, using the contrast
Accepted for publication June 2, 1977. Address requests Dr Posner,
York Avr, New
York, N Y 10021.
409
remaining from the first examination, revealed no evidence ofablock. Barely one month later, on January 15, 1977,the patient was readmitted complaining of back pain identical tco that associated with his prior episode of spinal cord compression. H e was ambulatory but had a mild parapaesis. Lumbar anct cisternal niyelography done on January 17 revealed extradural disease from T? to 7'1 2 and a complete block from T9 to T11 similar to that present one year before (Fig 1A). Dexamethasone, 4 nig every 6 hours, was begun, and since the patient had already received maximal Rl, neurosurgical consultation was requested. Because the patient's symptoms seemed to have stabilized on dexamethasone, the proposed laminectomp was scheduled as an elective procedure. The patient's pain resolved completely within 24 hours, and his neurological signs improved. Nine days after dexamethasone therapy was started, a repeat myelogram failed to reveal a block. However, the amount of contrast agent was insufficient to rule out a small extradural lesion; s o a large volume of contrast agent was injected on January 27 (Fig 1 8 ) . A second myelogram was entirely normal. We concluded that the steroids had been oncolytic and scheduled intermittent steroid therapy: prednisone, 60 mg daily, for one week out of every three. The patient was discharged from the hospital after one course of Aciriamycin and Cis-platinum (11) diamminedichloride (CPDII)as a d d tional chemotherapy. O n February 2 he returned complaining that three days following the abrupt discontinuation of the first one-week course of prednisone he developed pain extending from his knees to his ankles and experienced a feeling ofweakness in the thighs. The pain was sufficiently severe that he was unablc to stand. There was no change in his neurological examination and no tenderness in his muscles o r joints, and a diagnosis of sterod withdrawal syndrome was made [ I ] . 'The paticnt was given no further therapy, and the pain cleared i n three clays. However, back pain similar t o that which he had experienced during his previous episodes of cord compression recurred o n March 7, nine days after cornpletinn of his second course of prednisone. A myelograni performecl 011 March 10 revealed a complete block at 7 1 I (Fig IC). The patient was given dexamethasone, 96 nig daiiy for three days, 48 nig ilaily for two days, and then clecrrasing by half every two days to 16 mg daily. His syniptoms again resolved
A
Patient 2: Seminoviu A 27-pear-old man with seminoma of the testis developed low back pain radiating into the superior iliac crest early in Ileceniber, 1975. The pain was associated with difficulty urinating a n d progressive bilateral extremity weakness. Over a p e r i d of five days he became unable to walk. Two days later he was admitted to the hospital. At that time he had bilateral lower extremity weakness with hyperreflexia and extensor plantar responses, urine retention, and decreased pinprick sensation from the hips down. Lumbar and cisternal myelography revealed a complete block at T1 1 resulting from an epidural mass. He was treated with dexamethasone, 4 mg every 6 hours, and RT (300 rads daily for three days and 200 rads daily thereafter to a total dose of 2,300 rads). Steroids were discontinued in early January, 1976. He gradually regained strength and by mid-January was walking with a cane a d had reasonably good bladder and bowel function. On February 15 he was readmitted for CPDD chemotherapy. At that time he was free of pain. His motor power was normal, and bladder function was almost normal. H e was mildly ataxic, with loss of position
C
B
410 Annals of Neurology Vol 2
rapidly, and when the myelogram was repeated o n March 15, the extradural block on the right side of the cord had largely resolved (Fig 1D). When discharged, the patient was prescribed 16 mg of dexamethasone daily along with vinhlastine as chemotherapy. An outpatient myelogram on March 18 using the contrast already presenr i n the subarachnoid space was still mildly abnormal (Fig IE).
No 5
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E
and vibration sense to the ankles, and pin sensarion was mildly decreased up to the thighs. His deep tendon reflexes were hyperactive, and plantar responses were extensor. On April 29 a myelogram showed a slight left lateral epiCiuYd1 mass at T1 1. T h e patient was admitted for chemotherapy on August 26. At that time he complained of back pain anJ right paravertebral muscle cramps for one month. There was persistent numbness of the left leg below the thigh and of the right leg below the knee, but n o weakness, bowel o r bladder dysfhction, o r impotence. Examination revealed normal strength, hyperreflexia with extensor plantar responses, intact superficial sensation, and decreased proprioception in the lower extremities. O n August 27 he was given his fifth course of C P D D chemotherapy. A rnyelogram performed three days later because of recurrence of the back pain revealed an almost complete block at the level of TI0 by a right-sided anterior and posterior epidural mass (Fig 2A). Because the total dose of RT to the area had been 5,250 rads, n o further RT was possible. The patient was prescribed dexamethasone, 4 mg every 6 hours, and on September 3, after five days of steroid therapy, a decompressive laminectomy was performed. Surgical exploration revealed no evidence of tumor. Postoperative roentgenograms established that the surgeon had in fact explored the site of the myelographic block. A repeat myelogram o n the fourth postoperative day \FIBS normal (Fig 2B), the only changes being those of the laminectomy. Because we failed to recognize that the steroids might have been responsible for disappearance of the tumor and relief of the patient's symptoms, dexamethasone was discontinued in mid-September. T h e patient was discharged ainbulatory on September 9. O n October 5 he was readmitted complaining of about ten days of lower thoracic pain, with weakness of both lower extremities but no changes in sensation or bladderibowcl function. He was unable to walk. Lumbar and cisternal myelography revealed complete block from T9 t o T11. Surgical exploration the same day yielded necrotic, poorly differentiated epidural tumor in both lateral gutters at T10.
Unfortunately, the patient did not recciver. When last evaluated onJanuary 12, 1977, he had lost complete control of his bladder and bowels, had a sensory deficit below the umbilicus, a i d was paraplegic.
Patient 3: E u i n g ' s Sarcoma A I4-year-oId boy developed a right shoulder mass in 1970, which was diagnose11 as Ewing's sarcoma and treated with right shoulder disarticulation. A retrocardiac mass, apparent on chest roentgenogram, regressed after treatment with several chemotherapeutic agents. In February, 1974, nodules were apparent on chest roentgenogram, and these also improved after chemotherapy. In July, 1975, the boy developed Ion back pain that radiated down both legs. He also noted night sweats anti a 4.5 kg weight loss. Evaluation revealed evidence of widespread metastatic disease. Neurological examination on August I showed weakness of dorsifexion of the left foot, decreased pinprick sensation in an L4-5 distribution on the left, a mass in the left gluteal area, and edema of the left leg. Cliemorherapy was begun that same day with cyclophosphamicle, 300 mg/m2, actinomycin, 4 5 0 pg/m2,and bleomycin, 6 mg/m2. T h e patient was treated o n August 4 with 2.3 nig of vincristine and high-dose methotrexate, and it was observed that three tumor riodules (one o n the right eyelid, two on the scalp) had shown marked shrinkage. A myelogram done the same day revealed an epidural deposit lying mainly posterior and to the left of the spinal cord. The mass produced almost complete obstruction to the column of contrast material, and the small amount of contrast that could be passed anterior to the obstruction was insufficient to delineate the upper border of the lesion. An unsuccessful attempt at cisternal m);elography resulted in epidural and subdural injection of contrast medium. Immediately following the Inye~ogramthe patient received dexdmethasone, 10 mg intraveiiously at once and 4 m g every 6 hours thereafter. He also received 300 ratis of R T t o T6- 11. T h e following day he suddenl,, became unresponsive, and four days later he died without recovering consciousness. A t autopsy, Jeath appeared t o be the result of extensive hemorrhagic necrosis of a metastatic tumor in the left frontal and occipital cortex, with secondary uncal and cingulate herniation. The tumor was histologically identical to the original surgical specimen of 1970. Metastatic tumor was also found i n both lungs, liver, heart, and small and large inrestines. Despite a search, no definite tumor nodules were
Posner, Howieson, and Cvitkovic Steroids and Cord Compression
41 1
seen over the scalp or eye, where they had been clinically apparent prior to death. There were no vertebral metastases. The spinal cord was removed intact with the vertebral column, and no evidence of tumor involvement or compression at any level was discovered.
Patient 4: Malignant Lymphoma A 66-year-old man was admitted to another hospital o n April 18, 1976, complaining of intermittent fever for two months with recent onset of weakness and pain in his legs and with numbness of the soles of his feet. Neurological examination revealed weakness of‘hip flexion and unsteadiness of gait. Several epidural defects were found at myelography, t h e largest ofwhich was at C5-6. Cerebrospinal fluid protein was 395 mgidl. The patient was placed on dexamethasone, 12 mg daily, and the symptoms cleared within a few days. Several days later the myelogram was repeated, and n o epidural defecrs were found. The patient was prescribed dexamethasone and discharged from the hospital on Map 15. He was well until July, when night sweats recurred and he noted a swelling in his left groin. Biopsy of the groin revealed a mixed lymphoma, histiocytic type. He was treated with MOPP therapy [51, which required a change from dexamethasone to prednisone. He subsequently had RT to the left groin. He was first seen by the neurology service at Memorial Hospiial o n September 21 with problems of steroid diabetes, postherpetic neuralgia (at Ll), and paresthesias of all four extremities. Late in December, while t h e prednisone was being tapered and had reached a level of 5 nig daily, h e developed left shoulder pain. A myelogram revealed a large epidural mass at C5, where it had been o n the original myclogram. Because of severe diabetes the prednisone was not resumed, but RT was delivered to the area with relief. The patient was not on other chemotherapeutic agents at the time of the recurrence.
Discussion Ever since Galicich and French [ 7 ] popularized adrenocorticosteroids as a treatment for brain tumor, these drugs have been widely usedin avariety of C N S diseases associated with swelling of the brain [141. Their efficacy in the treatment of primary and metastatic brain tumors is indisputable. But it is less clear whether glucocorticoids are effective in the management of metastatic epidural spinal cord compression, because most physicians begin definitive treatment (either decompressive laminectomy or R T [8]) of spinal cord compression immediately, and thus few have observed the effects of glucocorticoids alone. Anecdotal reports of salutary effects of steroids, attributed to relief of spinal cord edema, have appeared in the literature [ 4 ] ,but even the presence of edema in the compressed spinal cord has not been established in man. Experimental evidence in a rat model of extradural spinal cord compression by tumor indicates that vasogenic edema is present in the area of spinal cord compressed by tumor, that the edema can be diminished by glucocorticoids, and that glucocor-
412
Annals of Neurology Vol 2 No 5
ticoids temporarily stabilize or improve the signs of spinal cord compression [171. There is still dispute about the mechanism by which glucocorticoids exert their salutary effects on signs and symptoms in patients with brain tumors and other edema-producing neurological diseases. Clinical and experimental evidence indicates that cerebral edema resolves on glucocorticoid treatment [ 121, but Pappius and McCann [133 have reported that in animals with freeze lesions, clinical improvement does not correlate well with the relief of edema. Other investigators using animal models of brain tumor have demonstrated that in addition to controlling edema, glucocorticoids actually shrink the tumors themselves [ 10, 11, 151. Oncolptic effects of glucocorticoids have been reported in rat glioma [ I 01, melanoma implanted in mouse brain [I 11, and ependymoblastoma implanted in mouse brain [ 151. Glucocorticoids are known to have oncolytic effects in a variety of human tumors as well, particularly lymphomas. Thus, the relief of symptoms and the resolution of epidural tumor seen on myelography in Patient 4 , who had a non-Hodgkin’s lymphoma, was not unexpected. Clarke and Saunders [GI reported 2 patients in whom paraparesis from epidural spinal cord compression caused by reticulum cell sarcoma disappeared o n corticosteroid therapy. Myelography, however, was not performed until they developed recurrence while off steroids. However, in Patient 1, the resolution of symptoms and complete disappeatance of the tumor were indeed unexpected. A single case report [ 9 ]documents the disappearance of a mediastinal thymoma after prednisone therapy given for another reason and then recurrence of the tumor months after the ptednisone was discontinued. Adrenocorticotropic hormone (ACTH) has also been reported effective in decreasing the size of a thpmoma [16]. In several other cases, reviewed by Boston [31, A C T H and glucocorticoids were ineffective. Patient 1’s response is particularly surprising since a mixed epithelial and lymphoid rather than a purely lymphoid tumor was present. It appears that in this case the first course of R T was probably unnecessary. Had the clinical situation been correctly assessed and had a repeat myelogram been done a few days following the onset of steroids, the patient would have continued to receive glucocorticoid therapy, which instead was discontinued when R T was completed. Only the patient’s rapid response to steroids on the second admission prevented what would undoubtedly have been a negative surgical exploration had it been carried out more than a few days after steroids were started. Patients 2 and 3 are more complicated cases since they received chemotherapeutic agents in addition to glucocorticoids. Patient 2 received CPDD, an agent effective in treating testicular tumors, three days be-
November 1977
fore myelographic block was discovered, on August 30, 1976. Dexamethasone was started on the day of myelography, and the negative surgical exploration was carried out four days later. It is not clear whether cis-platinum o r glucocorticoids or both were responsible for the tumor’s disappearance. The prompt reappearance of the tumor after glucocorticoid therapy was discontinued leads us to believe that that drug may have participated in the initial chemotherapeutic response. Had we recognized the possible role of steroids in the “mysterious” disappearance of Patient 2’s epidural tumor, we would have continued these drugs as oncolytic agents. Instead, the drugs were discontinued, and the tumor recurred within a month. We are unable t o find any previous reports of seminomas responsive to glucocorticoids, although testicular tumors responsive to other steroid hormones, especially rnedroxyprogesterone acetate, have been reported [21. Patient 3 received high-dose methotrexate and vinblastine along with acirenocorticosteroids the day the block was discovered on rnyelogram. Subcutatieous nodules on his face resolved, as did extradural tumor, but which of the chemotherapeutic agents was responsible is unclear. From the present observations as well as from studies on the use of glucocorticoids for treatment of spinal cord compression, we conclude that glucocorticoids should be given to all patients suffering from epidural spinal cord compression by malignant neoplasm. For many patients, relief of spinal cord edema will lead to some clinical improvement, and for a few, the oncolytic effects of steroids may be of substantial benefit. Because not all patients will be helped by steroids, definitive treatment (usually RT [Sj) should be undertaken as soon as possible after the diagnosis is established. If, however, resolution of clinical symptoms occurs rapidly after glucocorticoids have been given, myelography should be repeated. If the epidural tumor has regressed, definitive therapy should be continued, but the patient should be considered a glucocorticoid responder and this informa-
tion should he used in the continuing chemotherapy of his primary disorder.
References I . Amatruda T T Jr, Hurst Mhl, D’Esopo ND: Certain endocrine and metabolic facets ofthe sreroid withdrawal syndrome. J Clin Endocrinol Metab 25:1207-1217, 1965 2. Bloom HJG, Hendry WF: Possible role of hormones in trearment of metastatic testicular teratomas: turnour regression with medroxyprogesterone acetate. Br Med J 3:563-567, 1973 3. Boston B: Chemotherapy of invasive rhymoma. Cancer 38:40-52, 1976 1. Cancu RC: Corricosteroids for spinal metastases. Lancet 2:912, t 968 5 . Carter SK, Goldsmith MA: Combination chemotherapy and combined modality approaches to Hodgkin’s discase, i n Lacher hlJ (ed), Hodgkin‘s Disease. New York, John Wiley ilr Sons, 1976, pp 193-217 6. Clarke PRR, Saunders M: Steroid-induced remission in spinal canal reticulum cell sarcoma. reporr of r w o cases. J Neurosurg 42:346-348,1975 7. Galicich JH, French LA: Use of tkxamcrhasone in the treatment of cerebral cdema resulting from brain rumors and brain surgery. ,4m Pract Dig’l’rrat 12:lh0-174, 1‘161 8. Gilbcrr RW, Kim J-H, Posner JB: Epidural spinal cord compression from metastatic tumor. Ann Neurol (in press) 9. Green JD, Forman W H : Response of thymoma to steroids. Chest 65:114-116, 1074 10. Gurcay 0, Wilson C, Barker M, e t al: Corricosteroid effect on transplantable rat glioma. Arch Neurol 24:266-269, 197 1 11. Kotsilirnbas D G , Meyer L, Berson M, ct al: Corticosteroid effect on inrracerebral melanomata and a5sociated cerebral edema: some unexpected findings. Neurology (Minneap) 17:223-274, 1967 12. Lonli DM, Ilartmann JF. French LA: The response of expcrimental cerebral edema to glucosteroid administration. J Ncurosurg 24:843-854, 1966 13. Pappius H M , McCann WP: Effecrs of steroids on cerebral edema in cats. Arch Neurol 20:207-216, 1969 14. Reulen HJ: Vasogenic brain edema: new aspects In its formation, resolution and therapy. Br J Ansesth 48:711-752, 1976 15. Shapiro WK, Posner JR: Corticosteroid hormones: effects inan cxpcrimental brain rumor. Arch Neurol 3 0 : 2 17-22 1, 1974 16. Soffcr LJ, Gabrilove JL, Wolff BS: Effect of ACTH o n thymic masses. J Clin Endocrinol -Metab 12:690-696, 1952 17. Ushio Y , Posner R, Posner JB, e t al: Experimenral spinal cord compression by epidural neoplasms. Neurology (Minneap) 27:422-429, 1977
Posner, H o w i r s o n , and Cvirkovic: S t e r o i d s a n d Cord C o m p r e s s i o n
4 13
Four patients suffering spinal cord compression resulting from epidural metastases were treated with adrenocorticosteroid hormones. For 2 patients,pronqx relief of symptoms followed giurocorticoid therapy alone and was associated with marked shrinkage or disappearance of t h e metastasis, a direct oncolytic effect of t h e steroids. For the other 2 patients, glucocorticoids combined with other chemotherapeutic agents caused disappearance of t h e extradural tumor. For 1 patient, failure to recognize the oncolytic effects of the chemotherapy led to an unnecessary surgical procedure, and for a second patient an unnecessary operation was narrowly averted. Thus, for certain patients, glucocorticoids may occasionally have a marked oncolytic effect on epidural metastatic tumors. Posner JB, Howieson J, Cvitkovic E: “Disappearing” spinal cord compression: oncolytic effect of glucocorticoids (and other chemotherapeutic agents) on epidural metastases. Ann Neurol 2:409-413, 1977 Adrenocorticosteroids ameliorate clinical symptoms caused by a variety of primary and metastatic tumors of the central nervous system. Most investigators attribute thesc salutary effects to the relief of tumor-related cerebral or spinal cord edema [ 7 , 171. I n fact, neurologists and neurosurgeons are so accustomed t o attributing the beneficial effects ofglucocorticoids o n CNS tumors to the relief of edema that they may overlook instances in which clinical improvement results from the oncolytic action of glucocorticoids. Failure t o appreciate the oncolytic potenial of glucocorticoid therapy may lead to inappropriate treatment. This report concerns 4patients suffering spinal cord compression resulting from epidural metastases. For 2 patients, p r o m p t relief of symptoms followed glucocorticoid therapy alone and was associated with marked shrinkage or disappearance of the metastasis, a direct oncolytic effect of the steroids. For the other 2 patients, glucocorticoids combined with other chemotherapeutic agents caused disappearance of the extradural tumor. For 1 patient, failure to recognize the oncolytic effects of the chemotherapy led to an unnecessary surgical procedure, and for a second patient an unnecessary operation was narrowly averted.
From the Departments of Neurology, Diagnostic Radiology, and Medicine (Solid Tumor Service), Memorial Sloan-KetteringCancer Center, and the Department of Neurology, Cornell University
Medical College, New York, NY.
Case R e p o r t s Patient 1: Thynoma A 32-year-old dentist was first acirnitted to Memorial Sloan-Kettering Cancer Center because a 6.5 cm mass was found i n the anterior mediastinurn following a routine chest roentgeriograrn. O n J u l y 10, 1975, the tumor was removed and discovered ro be a mixed lymphoid and epithelial thymorna. The patient received 6,000 rads of megavoltage radiation to the mcdiastinum and supraclavicular areas. In January, 1976, he was hospitalized for radiation-induced pericarditis. In February he developed miclback pain that bj7 June had radiated down his legs and into his toes. In early July his legs became weak, and he developed constipation. H e was admitted to the hospital on July 7 with signs of spinal cord compression, including bilateral lower extremirp hyperreflexia, extensor plantar responses, and a pinprick response level ar the costal margin. A mpelograni revealed complete obsrruction to the column o f contrast agent by an epidural mass extending from TX to T12; the mass was circumferenrial, and 110 alteration of bone was found in rhar area. Dexamethasone, 4 mg four times daily, and radiation therapy (RT) were begun the same day. The patient received 3,000 rads to the area of the block and made a rapid recovery. The steroids were tapered, and he was discharged from the hospital fully ambulatory o n August 14. A myelogram done on December 12, five months after treatment for spinal cord compression, using the contrast
Accepted for publication June 2, 1977. Address requests Dr Posner,
York Avr, New
York, N Y 10021.
409
remaining from the first examination, revealed no evidence ofablock. Barely one month later, on January 15, 1977,the patient was readmitted complaining of back pain identical tco that associated with his prior episode of spinal cord compression. H e was ambulatory but had a mild parapaesis. Lumbar anct cisternal niyelography done on January 17 revealed extradural disease from T? to 7'1 2 and a complete block from T9 to T11 similar to that present one year before (Fig 1A). Dexamethasone, 4 nig every 6 hours, was begun, and since the patient had already received maximal Rl, neurosurgical consultation was requested. Because the patient's symptoms seemed to have stabilized on dexamethasone, the proposed laminectomp was scheduled as an elective procedure. The patient's pain resolved completely within 24 hours, and his neurological signs improved. Nine days after dexamethasone therapy was started, a repeat myelogram failed to reveal a block. However, the amount of contrast agent was insufficient to rule out a small extradural lesion; s o a large volume of contrast agent was injected on January 27 (Fig 1 8 ) . A second myelogram was entirely normal. We concluded that the steroids had been oncolytic and scheduled intermittent steroid therapy: prednisone, 60 mg daily, for one week out of every three. The patient was discharged from the hospital after one course of Aciriamycin and Cis-platinum (11) diamminedichloride (CPDII)as a d d tional chemotherapy. O n February 2 he returned complaining that three days following the abrupt discontinuation of the first one-week course of prednisone he developed pain extending from his knees to his ankles and experienced a feeling ofweakness in the thighs. The pain was sufficiently severe that he was unablc to stand. There was no change in his neurological examination and no tenderness in his muscles o r joints, and a diagnosis of sterod withdrawal syndrome was made [ I ] . 'The paticnt was given no further therapy, and the pain cleared i n three clays. However, back pain similar t o that which he had experienced during his previous episodes of cord compression recurred o n March 7, nine days after cornpletinn of his second course of prednisone. A myelograni performecl 011 March 10 revealed a complete block at 7 1 I (Fig IC). The patient was given dexamethasone, 96 nig daiiy for three days, 48 nig ilaily for two days, and then clecrrasing by half every two days to 16 mg daily. His syniptoms again resolved
A
Patient 2: Seminoviu A 27-pear-old man with seminoma of the testis developed low back pain radiating into the superior iliac crest early in Ileceniber, 1975. The pain was associated with difficulty urinating a n d progressive bilateral extremity weakness. Over a p e r i d of five days he became unable to walk. Two days later he was admitted to the hospital. At that time he had bilateral lower extremity weakness with hyperreflexia and extensor plantar responses, urine retention, and decreased pinprick sensation from the hips down. Lumbar and cisternal myelography revealed a complete block at T1 1 resulting from an epidural mass. He was treated with dexamethasone, 4 mg every 6 hours, and RT (300 rads daily for three days and 200 rads daily thereafter to a total dose of 2,300 rads). Steroids were discontinued in early January, 1976. He gradually regained strength and by mid-January was walking with a cane a d had reasonably good bladder and bowel function. On February 15 he was readmitted for CPDD chemotherapy. At that time he was free of pain. His motor power was normal, and bladder function was almost normal. H e was mildly ataxic, with loss of position
C
B
410 Annals of Neurology Vol 2
rapidly, and when the myelogram was repeated o n March 15, the extradural block on the right side of the cord had largely resolved (Fig 1D). When discharged, the patient was prescribed 16 mg of dexamethasone daily along with vinhlastine as chemotherapy. An outpatient myelogram on March 18 using the contrast already presenr i n the subarachnoid space was still mildly abnormal (Fig IE).
No 5
November 1077
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E
and vibration sense to the ankles, and pin sensarion was mildly decreased up to the thighs. His deep tendon reflexes were hyperactive, and plantar responses were extensor. On April 29 a myelogram showed a slight left lateral epiCiuYd1 mass at T1 1. T h e patient was admitted for chemotherapy on August 26. At that time he complained of back pain anJ right paravertebral muscle cramps for one month. There was persistent numbness of the left leg below the thigh and of the right leg below the knee, but n o weakness, bowel o r bladder dysfhction, o r impotence. Examination revealed normal strength, hyperreflexia with extensor plantar responses, intact superficial sensation, and decreased proprioception in the lower extremities. O n August 27 he was given his fifth course of C P D D chemotherapy. A rnyelogram performed three days later because of recurrence of the back pain revealed an almost complete block at the level of TI0 by a right-sided anterior and posterior epidural mass (Fig 2A). Because the total dose of RT to the area had been 5,250 rads, n o further RT was possible. The patient was prescribed dexamethasone, 4 mg every 6 hours, and on September 3, after five days of steroid therapy, a decompressive laminectomy was performed. Surgical exploration revealed no evidence of tumor. Postoperative roentgenograms established that the surgeon had in fact explored the site of the myelographic block. A repeat myelogram o n the fourth postoperative day \FIBS normal (Fig 2B), the only changes being those of the laminectomy. Because we failed to recognize that the steroids might have been responsible for disappearance of the tumor and relief of the patient's symptoms, dexamethasone was discontinued in mid-September. T h e patient was discharged ainbulatory on September 9. O n October 5 he was readmitted complaining of about ten days of lower thoracic pain, with weakness of both lower extremities but no changes in sensation or bladderibowcl function. He was unable to walk. Lumbar and cisternal myelography revealed complete block from T9 t o T11. Surgical exploration the same day yielded necrotic, poorly differentiated epidural tumor in both lateral gutters at T10.
Unfortunately, the patient did not recciver. When last evaluated onJanuary 12, 1977, he had lost complete control of his bladder and bowels, had a sensory deficit below the umbilicus, a i d was paraplegic.
Patient 3: E u i n g ' s Sarcoma A I4-year-oId boy developed a right shoulder mass in 1970, which was diagnose11 as Ewing's sarcoma and treated with right shoulder disarticulation. A retrocardiac mass, apparent on chest roentgenogram, regressed after treatment with several chemotherapeutic agents. In February, 1974, nodules were apparent on chest roentgenogram, and these also improved after chemotherapy. In July, 1975, the boy developed Ion back pain that radiated down both legs. He also noted night sweats anti a 4.5 kg weight loss. Evaluation revealed evidence of widespread metastatic disease. Neurological examination on August I showed weakness of dorsifexion of the left foot, decreased pinprick sensation in an L4-5 distribution on the left, a mass in the left gluteal area, and edema of the left leg. Cliemorherapy was begun that same day with cyclophosphamicle, 300 mg/m2, actinomycin, 4 5 0 pg/m2,and bleomycin, 6 mg/m2. T h e patient was treated o n August 4 with 2.3 nig of vincristine and high-dose methotrexate, and it was observed that three tumor riodules (one o n the right eyelid, two on the scalp) had shown marked shrinkage. A myelogram done the same day revealed an epidural deposit lying mainly posterior and to the left of the spinal cord. The mass produced almost complete obstruction to the column of contrast material, and the small amount of contrast that could be passed anterior to the obstruction was insufficient to delineate the upper border of the lesion. An unsuccessful attempt at cisternal m);elography resulted in epidural and subdural injection of contrast medium. Immediately following the Inye~ogramthe patient received dexdmethasone, 10 mg intraveiiously at once and 4 m g every 6 hours thereafter. He also received 300 ratis of R T t o T6- 11. T h e following day he suddenl,, became unresponsive, and four days later he died without recovering consciousness. A t autopsy, Jeath appeared t o be the result of extensive hemorrhagic necrosis of a metastatic tumor in the left frontal and occipital cortex, with secondary uncal and cingulate herniation. The tumor was histologically identical to the original surgical specimen of 1970. Metastatic tumor was also found i n both lungs, liver, heart, and small and large inrestines. Despite a search, no definite tumor nodules were
Posner, Howieson, and Cvitkovic Steroids and Cord Compression
41 1
seen over the scalp or eye, where they had been clinically apparent prior to death. There were no vertebral metastases. The spinal cord was removed intact with the vertebral column, and no evidence of tumor involvement or compression at any level was discovered.
Patient 4: Malignant Lymphoma A 66-year-old man was admitted to another hospital o n April 18, 1976, complaining of intermittent fever for two months with recent onset of weakness and pain in his legs and with numbness of the soles of his feet. Neurological examination revealed weakness of‘hip flexion and unsteadiness of gait. Several epidural defects were found at myelography, t h e largest ofwhich was at C5-6. Cerebrospinal fluid protein was 395 mgidl. The patient was placed on dexamethasone, 12 mg daily, and the symptoms cleared within a few days. Several days later the myelogram was repeated, and n o epidural defecrs were found. The patient was prescribed dexamethasone and discharged from the hospital on Map 15. He was well until July, when night sweats recurred and he noted a swelling in his left groin. Biopsy of the groin revealed a mixed lymphoma, histiocytic type. He was treated with MOPP therapy [51, which required a change from dexamethasone to prednisone. He subsequently had RT to the left groin. He was first seen by the neurology service at Memorial Hospiial o n September 21 with problems of steroid diabetes, postherpetic neuralgia (at Ll), and paresthesias of all four extremities. Late in December, while t h e prednisone was being tapered and had reached a level of 5 nig daily, h e developed left shoulder pain. A myelogram revealed a large epidural mass at C5, where it had been o n the original myclogram. Because of severe diabetes the prednisone was not resumed, but RT was delivered to the area with relief. The patient was not on other chemotherapeutic agents at the time of the recurrence.
Discussion Ever since Galicich and French [ 7 ] popularized adrenocorticosteroids as a treatment for brain tumor, these drugs have been widely usedin avariety of C N S diseases associated with swelling of the brain [141. Their efficacy in the treatment of primary and metastatic brain tumors is indisputable. But it is less clear whether glucocorticoids are effective in the management of metastatic epidural spinal cord compression, because most physicians begin definitive treatment (either decompressive laminectomy or R T [8]) of spinal cord compression immediately, and thus few have observed the effects of glucocorticoids alone. Anecdotal reports of salutary effects of steroids, attributed to relief of spinal cord edema, have appeared in the literature [ 4 ] ,but even the presence of edema in the compressed spinal cord has not been established in man. Experimental evidence in a rat model of extradural spinal cord compression by tumor indicates that vasogenic edema is present in the area of spinal cord compressed by tumor, that the edema can be diminished by glucocorticoids, and that glucocor-
412
Annals of Neurology Vol 2 No 5
ticoids temporarily stabilize or improve the signs of spinal cord compression [171. There is still dispute about the mechanism by which glucocorticoids exert their salutary effects on signs and symptoms in patients with brain tumors and other edema-producing neurological diseases. Clinical and experimental evidence indicates that cerebral edema resolves on glucocorticoid treatment [ 121, but Pappius and McCann [133 have reported that in animals with freeze lesions, clinical improvement does not correlate well with the relief of edema. Other investigators using animal models of brain tumor have demonstrated that in addition to controlling edema, glucocorticoids actually shrink the tumors themselves [ 10, 11, 151. Oncolptic effects of glucocorticoids have been reported in rat glioma [ I 01, melanoma implanted in mouse brain [I 11, and ependymoblastoma implanted in mouse brain [ 151. Glucocorticoids are known to have oncolytic effects in a variety of human tumors as well, particularly lymphomas. Thus, the relief of symptoms and the resolution of epidural tumor seen on myelography in Patient 4 , who had a non-Hodgkin’s lymphoma, was not unexpected. Clarke and Saunders [GI reported 2 patients in whom paraparesis from epidural spinal cord compression caused by reticulum cell sarcoma disappeared o n corticosteroid therapy. Myelography, however, was not performed until they developed recurrence while off steroids. However, in Patient 1, the resolution of symptoms and complete disappeatance of the tumor were indeed unexpected. A single case report [ 9 ]documents the disappearance of a mediastinal thymoma after prednisone therapy given for another reason and then recurrence of the tumor months after the ptednisone was discontinued. Adrenocorticotropic hormone (ACTH) has also been reported effective in decreasing the size of a thpmoma [16]. In several other cases, reviewed by Boston [31, A C T H and glucocorticoids were ineffective. Patient 1’s response is particularly surprising since a mixed epithelial and lymphoid rather than a purely lymphoid tumor was present. It appears that in this case the first course of R T was probably unnecessary. Had the clinical situation been correctly assessed and had a repeat myelogram been done a few days following the onset of steroids, the patient would have continued to receive glucocorticoid therapy, which instead was discontinued when R T was completed. Only the patient’s rapid response to steroids on the second admission prevented what would undoubtedly have been a negative surgical exploration had it been carried out more than a few days after steroids were started. Patients 2 and 3 are more complicated cases since they received chemotherapeutic agents in addition to glucocorticoids. Patient 2 received CPDD, an agent effective in treating testicular tumors, three days be-
November 1977
fore myelographic block was discovered, on August 30, 1976. Dexamethasone was started on the day of myelography, and the negative surgical exploration was carried out four days later. It is not clear whether cis-platinum o r glucocorticoids or both were responsible for the tumor’s disappearance. The prompt reappearance of the tumor after glucocorticoid therapy was discontinued leads us to believe that that drug may have participated in the initial chemotherapeutic response. Had we recognized the possible role of steroids in the “mysterious” disappearance of Patient 2’s epidural tumor, we would have continued these drugs as oncolytic agents. Instead, the drugs were discontinued, and the tumor recurred within a month. We are unable t o find any previous reports of seminomas responsive to glucocorticoids, although testicular tumors responsive to other steroid hormones, especially rnedroxyprogesterone acetate, have been reported [21. Patient 3 received high-dose methotrexate and vinblastine along with acirenocorticosteroids the day the block was discovered on rnyelogram. Subcutatieous nodules on his face resolved, as did extradural tumor, but which of the chemotherapeutic agents was responsible is unclear. From the present observations as well as from studies on the use of glucocorticoids for treatment of spinal cord compression, we conclude that glucocorticoids should be given to all patients suffering from epidural spinal cord compression by malignant neoplasm. For many patients, relief of spinal cord edema will lead to some clinical improvement, and for a few, the oncolytic effects of steroids may be of substantial benefit. Because not all patients will be helped by steroids, definitive treatment (usually RT [Sj) should be undertaken as soon as possible after the diagnosis is established. If, however, resolution of clinical symptoms occurs rapidly after glucocorticoids have been given, myelography should be repeated. If the epidural tumor has regressed, definitive therapy should be continued, but the patient should be considered a glucocorticoid responder and this informa-
tion should he used in the continuing chemotherapy of his primary disorder.
References I . Amatruda T T Jr, Hurst Mhl, D’Esopo ND: Certain endocrine and metabolic facets ofthe sreroid withdrawal syndrome. J Clin Endocrinol Metab 25:1207-1217, 1965 2. Bloom HJG, Hendry WF: Possible role of hormones in trearment of metastatic testicular teratomas: turnour regression with medroxyprogesterone acetate. Br Med J 3:563-567, 1973 3. Boston B: Chemotherapy of invasive rhymoma. Cancer 38:40-52, 1976 1. Cancu RC: Corricosteroids for spinal metastases. Lancet 2:912, t 968 5 . Carter SK, Goldsmith MA: Combination chemotherapy and combined modality approaches to Hodgkin’s discase, i n Lacher hlJ (ed), Hodgkin‘s Disease. New York, John Wiley ilr Sons, 1976, pp 193-217 6. Clarke PRR, Saunders M: Steroid-induced remission in spinal canal reticulum cell sarcoma. reporr of r w o cases. J Neurosurg 42:346-348,1975 7. Galicich JH, French LA: Use of tkxamcrhasone in the treatment of cerebral cdema resulting from brain rumors and brain surgery. ,4m Pract Dig’l’rrat 12:lh0-174, 1‘161 8. Gilbcrr RW, Kim J-H, Posner JB: Epidural spinal cord compression from metastatic tumor. Ann Neurol (in press) 9. Green JD, Forman W H : Response of thymoma to steroids. Chest 65:114-116, 1074 10. Gurcay 0, Wilson C, Barker M, e t al: Corricosteroid effect on transplantable rat glioma. Arch Neurol 24:266-269, 197 1 11. Kotsilirnbas D G , Meyer L, Berson M, ct al: Corticosteroid effect on inrracerebral melanomata and a5sociated cerebral edema: some unexpected findings. Neurology (Minneap) 17:223-274, 1967 12. Lonli DM, Ilartmann JF. French LA: The response of expcrimental cerebral edema to glucosteroid administration. J Ncurosurg 24:843-854, 1966 13. Pappius H M , McCann WP: Effecrs of steroids on cerebral edema in cats. Arch Neurol 20:207-216, 1969 14. Reulen HJ: Vasogenic brain edema: new aspects In its formation, resolution and therapy. Br J Ansesth 48:711-752, 1976 15. Shapiro WK, Posner JR: Corticosteroid hormones: effects inan cxpcrimental brain rumor. Arch Neurol 3 0 : 2 17-22 1, 1974 16. Soffcr LJ, Gabrilove JL, Wolff BS: Effect of ACTH o n thymic masses. J Clin Endocrinol -Metab 12:690-696, 1952 17. Ushio Y , Posner R, Posner JB, e t al: Experimenral spinal cord compression by epidural neoplasms. Neurology (Minneap) 27:422-429, 1977
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