InI J Radralwn Onrolog~ Bwl Phs.5 Vol. 18. pp. 635-640 Pnnled in the US A. All nghts reserved
0360-30 I6190 $3.00 + .Xl Copyright (c‘ 1990 Pergamon Press plc
l Brief Communication
CAROTID
THROMBOSIS
FOLLOWING
NECK IRRADIATION
GREGORY K. CALL, M.D.,* PATRICK F. BRAY, M.D.,* WENDY R. K. SMOKER, M.D.,’ SAUNDRA S. BUYS, M.D.$ AND JOHN K. HAYES, M.D.$ University
of Utah School of Medicine,
Salt Lake City, Utah 84 132
Therapeutic irradiation may accelerate atherosclerosis, increasing the risk of vascular stenosis or occlusion several to many years following radiation. However, intimal damage following irradiation may result earlier in thrombosis without stenosis. This report discusses three cases of carotid occlusion that occurred within 3 years of moderate dose irradiation. Angiographic studies showed that occlusion occurred in the absence of atherosclerotic stenosis. A review of the literature supports the conclusion that people who receive neck irradiation are at risk not only for the delayed development of diffuse atherosclerosis but also for thrombotic occlusion within months to several years. We suggest that patients who develop neurological symptoms or signs following neck irradiation, regardless of age, dose of radiation, or interval since radiation, should be evaluated for carotid or vertebra1 artery disease. Carotid occlusion, Thrombosis,
Radiation.
INTRODUCTION
METHODS AND MATERIALS
The chronic toxicity of ionizing radiation is directly related to the total dose of radiation and can include such diverse
Ch.w 1 A 3%year-old woman presented with supraclavicular and mediastinal adenopathy in June of 1984. Biopsy revealed nodular sclerosing Hodgkin’s disease. Staging laparotomy was positive for a single 4 mm focus of disease in the spleen, and she was pathologically staged as IIIAS. She was treated with total nodal irradiation, receiving 3926 cGy to the central axis midplane of the mantle field with 6 MV photons. Review of port films and carotid angiograms documented that the offending lesion was within the irradiated volume. Off axis calculations at a midplane depth in the left neck done during treatment give an estimated carotid artery dose of 4360 cGy in 20 fractions over 28 days (2 18 cGy per fraction). Compensators were not used to lower the daily risk dose. The right neck, the site of original disease, received an additional two fractions with an estimated carotid dose of 4760 cGy. She was clinically free of disease until August of 1986 when she developed recurrent disease in left pre-auricular and bilateral submandibular lymph nodes, possibly a
manifestations as transverse myelitis, brain necrosis, chronic enteritis, and subcutaneous fibrosis (I). These changes occur from months to years following therapeutic radiation and are thought to be caused by vascular damage (17). Small vessels are most frequently involved but delayed large vessel disease has been documented by study of pathology (9). Large vessel disease can occur within any vessel in the radiation port. The histologic changes are those of arteriosclerosis with a modest round cell infiltrate that most closely resemble atherosclerosis. Lesions generally become clinically apparent many years following therapeutic radiation and have been thought to occur almost exclusively in patients receiving doses greater than 4000 cGy (7). In this report we describe three patients in whom carotid artery occlusion occurred within 3 years of receiving moderate-dose radiation and whose clinical and angiographic patterns suggest that this was not caused by accelerated atherothrombosis.
* Department of Neurology. + Department of Radiology. * Division of Hematology-Oncology. BDivision of Radiation-Oncology. Reprint requests to: Dr. Call. Acknowledgements--We are indebted
assistance in preparation of the manuscript, to Drs. Harmon Eyre and Robert Stewart for their helpful comments, and to Dr. Luis Fajardo for providing us with a preprint of his comprehensive review of radiation damage. Accepted for publication 9 August 1989. to Marjory McKinney
for 635
636
I. J. Radiation
Oncology
0 Biology 0 Physics
marginal miss recurrence. She was started on chemotherapy consisting of nitrogen mustard, oncovin, procarbazine, and prednisone (MOPP) and had complete response after two courses. Therapy was complicated by phlebitis in the arms, attributed to vesicant drug administration. In November of 1986, after two cycles of MOPP chemotherapy, she had a IO-minute episode of tingling numbness in the left leg. A CT scan and EEG were both normal and no specific therapy was administered. Three weeks later, during the third course of MOPP. she was found on the floor unable to speak. In the hospital she was globally aphasic and had a dense right flaccid hemiplegia and hemihypesthesia. Laboratory studies showed an hematocrit of 36.9%. platelet count of 474,OOO/ul and white blood cell count of 98OO/ul. Prothrombin time (PT), partial thromboplastin time (PTT), and serum chemistries were all normal. The cholesterol was 200 mg/dl. An enzyme-linked immunosorbent assay test for antiphospholipid antibodies was negative. A lumbar puncture yielded clear colorless cerebrospinal fluid with two red blood cells and no white cells per ml: the protein was 4.5 mg/dl and the glucose was 75 mg/dl. An echocardiogram was normal. Five days following admission bilateral carotid angiography was performed. An irregular intraluminal filling defect was present at the bifurcation of the left common carotid which extended into and occluded the internal carotid at its origin (Fig. 1a and 1b). The aortic arch and other cervical and intracranial vessels appeared normal. with no evidence of atherosclerotic change. A repeat left carotid angiogram 1 week later showed a normal bifurcation with persistent occlusion of the internal carotid artery just distal to the bifurcation (Fig. lc and Id). A CT scan showed a large cortical and white matter low density lesion in the territory of the left middle cerebral artery. The patient was left with a profound aphasia, hemiplegia, and hemihypesthesia that has persisted for 2-f years. C’usr 2 A 42-year-old man was diagnosed as having mixed cellularity Hodgkin’s disease involving the left cervical and mediastinal lymph nodes in January 1982. Bone marrow biopsy, abdominal CT scan, and staging laparotomy were all negative for tumor and he was pathologically staged as IIA. He was treated with total nodal irradiation at an outside hospital with a 6 MV linear accelerator. The left neck was blocked when the mantle central axis midplane dose was 3780 cGy (2 1 fractions, 37 days). Irregular field off-axis dose calculations were not done. A radiation field setup photograph suggested that the left neck separation was less than the central axis separation: therefore, a dose higher than 3780 cGy to the left carotid artery can reasonably be assumed. The inferior left neck and supraclavicular fossa were boosted 2 months later during the inverted Y component of therapy with an additional I200 cGy in 6 fractions to the midplane with anterior and pos-
March
1990. Volume
IX. Number
3
terior opposed fields, the superior extent of which was below the carotid bifurcation. The patient did well until August of 1984 when he developed four episodes of right arm and leg numbness that lasted about 5 minutes each. He also had one additional brief episode of inability to write, although he did not note weakness or sensory change in the right hand. In September 1984 he developed numbness of the right arm and difficulty speaking. Examination at that time was notable for diminished sensation to all modalities in the right face, arm and leg, and mild dysarthria. Standard laboratory studies were normal. A cranial CT scan showed a small low density lesion in the left putamen. An echocardiogram showed minimal mitral valve prolapse. Cerebral angiography, performed 4 days after onset. was normal (Fig. 2a). The patient was treated with aspirin and dipyridamole: over several weeks he recovered almost completely. Six months later the patient abruptly developed more difficulty speaking and weakness of the right arm. He was readmitted to the hospital and on examination he was found to have a mild dysarthria and to make occasional paraphrasic errors. The sensory deficits noted 6 months earlier had persisted but were less pronounced. A mild right hemiparesis was detected with face and arm more affected than the leg. Complete blood count, differential and chemistries were again normal. The cholesterol was 225 mg/dl. Partial thromboplastin time was 25 seconds with a control of 39 seconds; prothrombin time was 1 1. I seconds with a control of 12.2 seconds. Antithrombin Ill. Protein C. and Protein S assays were all normal. Factor VlIIc activity was 3 18%) (normal range 50-200%). In the hospital the patient was treated with heparin but the dysarthria and paresis worsened. On the fifth hospital day. after the heparin was stopped in order to perform additional coagulation studies, he became completely mute with an inability to follow even simple commands, profoundly weak in the right lower half of the face and in the arm, and mildly weak in the right leg. One week later bilateral carotid and cerebral angiography were repeated and showed occlusion of the left internal carotid artery (Fig. 2b). The marked neurological deficit has persisted for 4 years. and the patient remains free of clinical evidence of recurrent Hodgkin’s disease. Ch.W 3 A 26-year-old woman was found to have a rhabdomyosarcoma of the right maxillary sinus in August of 1985. She received six cycles of vincristine, adriamycin, and cytoxan with excellent shrinkage of tumor. She was then treated with radiation therapy to the right maxilla and base of the skull. The dose was delivered with 6 MV X rays using an anterior and right anterior oblique wedged pair setup, 200 cGy per fraction to the 100% isodose line, to a total dose of 5000 cGy. The field size was reduced, and the dose boosted to 7000 cGy using the same beam
Carotid
thrombosis
0 G. K. CALL etul
637
Fig. 1. Case 1: The initial left carotid angiogram showed internal carotid occlusion with a common carotid intraluminal filling defect (white arrows. a and b). Angiography 1 week later showed resolution of the common carotid defect (white arrows, c and d).
arrangement and fractionation. In March 1986 a right maxillectomy was performed. After the procedure the patient developed a right-sided Horner’s syndrome. Several
months later maintenance therapy with vincristine, actinomycin D and cytoxan was begun. In September of 1986, while on maintenance chemo-
638
I. J. Radiation
Oncology
0 Biology 0 Physics
March
1990. Volume
IS. Number
Fig. 2. Case 2: (a) The original carotid angiogram 6 months prior to stroke was normal. occlusion at the time of the stroke (black arrow).
therapy, the patient developed transient visual changes in the right eye. These consisted of a greying out of vision, sometimes associated with a sensation of sparkling lights. which lasted for several minutes. Over the next 7 months she experienced approximately eight such spells. These were initially thought to be due to radiation retinopathy. On examination the patient had a persistent right Horner’s syndrome with ptosis and miosis. Standard laboratory studies were normal except for a cholesterol of 255 mg/dl. A cranial CT scan showed normal brain and surgical changes without evidence of disease recurrence. Bilateral carotid angiography in April of 1987 showed the right internal carotid artery to be occluded from its origin to a point just proximal to the origin of the ophthalmic artery (Fig. 3). The aortic arch and other cervical and intracranial vessels were normal. The patient was anticoagulated with warfarin for 6 months; no further symptoms have occurred in 32 months. Review of angiographic data and port verification films confirmed that the lesion was within the high dose volume.
RESULTS Three young people, aged 35, 42, and 26 years, developed carotid occlusion within the radiation port less than
3
(b) The internal
carotid
3 years following neck irradiation for cancer. In Case 1, an angiogram 1 week following the initial study showed resolution of the proximal intraluminal filling defect in the common carotid artery. There was no evidence of atherosclerosis or other angiopathy. This sequence of events suggests either embolus to the bifurcation or thrombosis of unknown cause (15). In this case, note should also be made of the episode of left leg numbness which occurred 3 weeks prior to left carotid occlusion and cerebral infarction. The sensory complaint on that occasion implicated the contralateral cerebral hemisphere, yet the right cerebral vessels were normal at the time of stroke. This would be consistent with a similar transient process in the contralateral vasculature which had an even higher radiation dose. In Case 2 a completely normal angiogram 6 months prior to internal carotid occlusion again speaks for embolism or inexplicable thrombosis. In Case 3 the internal carotid artery was occluded from its origin to the ophthalmic artery. There was no evidence of atherosclerosis or other angiopathy elsewhere. In each case the lack of atherosclerosis, the occurrence of carotid occlusion within the radiation port, and the temporal relation to radiation suggests an association between radiation therapy and carotid occlusion. In Cases 1 and 3, the acute events were concurrent with ongoing combination chemotherapy.
Carotid
thrombosis
639
0 G. K. CALL etal.
Table 1. Clinical data on patients with neck irradiation proven delayed stenosis or occlusion of cervical vertebral or carotid arteries
Source rt al. (1 I )
Levinson
Glick (6) Nardelli et al. (13) Rotman et al. (16) Osgood et al. (14) Hayward (8) McCready 6~ ul. (12) Silverberg
671al. ( 18)
Kearsley and Tattersall ( 10)
Fig. 3. Case 3: The stump of the occluded artery (black arrow).
right internal
carotid
DISCUSSION Multiple case reports have documented cervical carotid or vertebral stenosis or occlusion following neck irradiation (2, 6, 8, 10, 11, 12, 13, 14, 16, 18). Post-irradiation accelerated atherosclerosis is recognized by diffuse involvement of arteries in the radiation port. This contrasts strikingly with the focal or multifocal character of naturally occurring atherosclerosis. Table 1 lists the clinical characteristics of 18 patients reported in the literature who developed proven delayed stenosis or occlusion of cervical arteries following neck irradiation. In all instances the diffuse pattern of stenosis or occlusion was thought to be most consistent with irradiation change rather than naturally occurring disease. In most instances the interval from radiation exposure to neurologic symptoms was 15 years or more; there were four instances where symptoms developed between 6 and 8 years following radiation. The radiation dose was generally greater than 5000 cGy although in three it was between 4000 and 5000 cGy and in four instances it was not reported. The delayed development of cerebral ischemia following neck irradiation as documented by the cases in Table 1 has led to the suggestion that all such patients be followed by noninvasive carotid evaluation beginning 5 years following radiation exposure (3). However, in the three cases
Age/sex 74 54 68 54 32 38 27 55 44 24 67
M F F F M F F M M F M ? ? ? ? ? 3
64 M
Radiation dose (~GY)
and
Interval to symptoms (yrs)
7600 7200
25 34 32 15 27 36 15 27 7 24 17 6 30 7 24 8 14 17
”
6576 5400 ? 6000 6724 7500 ‘) 5500 4400 4600 4290 ? 6820 12,000 6600
considered here plus three others listed in the literature (Table 2) occlusion occurred within 3 years of radiation exposure. Our three cases also indicate that the process is not due to atherosclerotic stenosis. Recently, Feldman and Posner described 14 patients previously treated with radiation to the neck who presented with transient neurological deficits thought to be ischemic in nature (5). Five patients underwent arteriography and in four cases the vessels were normal. One patient had an isolated tight stenosis of the left internal carotid artery. A sixth patient had normal carotid doppler studies. These normal studies suggest a cause other than accelerated atherosclerosis as the etiology of the ischemia. However, Feldman and Posner did not specify the interval between radiation exposure and neurologic symptoms in every case, and in eight instances an evaluation of the cervical vessels was not carried out (5). Thus, we do not know how closely their cases resemble the three considered here. Table 2. Clinical data on patients with neck irradiation proven stenosis or occlusion of cervical vertebral or carotid arteries within 3 years
Present
and
Interval to symptoms (yrs)
Source
Age/sex
Radiation dose (~GY)
series
35 F 42 M 26 F ? ;
3926 3600 5000 5650 5500
1; 2
27 F
7200
2
Silverberg et a/. ( 13) Conomy and Kellermever (2)
2 3
I
1. J. Radiation
640
Oncology
0 Biology 0 Physics
The case of Conomy and Kellermeyer (2) closely resembles our three angiographically, particularly Case 1. Their case was studied at autopsy and showed carotid bifurcation thrombosis in the absence of stenosis. The microscopic changes consisted of myointimal fibrosis and disruption of the internal elastica with overlying thrombus. Although large arteries (greater than .5 mm in external diameter) are the least affected by ionizing radiation (4), the endothelial cells of these arteries can be damaged and myointimal proliferation has been documented clinically and experimentally. Such changes in the intima can lead to thrombosis in the absence of severe stenosis. The prognosis of patients who develop cerebral ischemit symptoms within a few years following neck irradiation can vary greatly. Our Cases 1 and 2 and those of Conomy and Kellermeyer developed devastating cerebral infarctions. Our Case 3 and the two from the Silvcrberg ct ~1. series (18) developed transient monocular blindness that resolved. We conclude that people who receive neck irradiation may be at risk not only for the delayed development of diffuse atherosclerosis but also for large artery thrombosis within months to several years. This can occur following a moderate radiation dose and the outcome can be a transient and apparently benign event, or a devastating cerebral infarction. The factors that predispose to carotid thrombosis following radiation may be multiple. Intimal damage within the radiation port probably occurs in all cases (4), yet clinically apparent large artery thrombosis is rare. This may be related to the high flow state of the
March
1990. Volume
1X. Number
3
cerebral vessels. Two of our cases may have had a hypercoagulable state; Case 1 had phlebitis associated with intravenous chemotherapy, and Case 2 had an elevated factor VIII concentration. Case 3 had hypercholesterolemia which may increase the risk of intimal damage and athcrosclerosis following radiation (4). In Cases 1 and 3. the acute events occurred during ongoing combination chemotherapy. for recurrent disease and in an adjuvant setting, respectively. These cases are sufficiently complex to suggest that thrombosis following irradiation is a multifactional process, and assignment of an etiology to radiation alone is unwarranted without further information. Our three patients all had warning events and the report by Feldman and Posner (5) indicates that this may be common. We suggest that patients who develop neurological symptoms or signs following neck radiation therapy, regardless of age. radiation dose, or interval following radiation. should be evaluated for carotid or vertebral artery disease. If the ischemic nature of the symptoms appear definite, antiplatelet agents could be tried even if vascular studies are negative. If symptoms persist, antithrombotic therapy with warfarin should be considered. After potentially curative antineoplastic therapy, efforts should be made to keep neck dose to less than 200 cGy per fraction. Irregular field off-axis dose calculations are mandatory in mantle radiation therapy because the neck routinely receives higher doses than the control axis. Brass sheet compensation is now routine at this institution during mantle field radiation therapy to keep the dose to the neck less than 200 cciy per fraction.
REFERENCES Anderson, R. E. Radiation injury. In: Kissane. J. M.. ed. Anderson’s pathology St. Louis: CV Mosby Co.: 1985.
2. Conomy.
I I. Levinson. S. A.; Close, M. B.: Ehrenfield. W. K.: Stoney. R. J. Carotid artery occlusive disease following external cervical irradiation. Arch. Surg. 107:395-397; 1973.
3.
12. McCready. R. A.: Hyde. G. L.; Bivins. B. A.; Mattingly, S. S.; Griffen, W. 0. Radiation-induced arterial injuries. Surgery 93:306-3 12; 1983.
I.
4. 5.
6. 7.
8. 9.
10.
J. P.; Kellermeyer, R. W. Delayed cerebrovascular consequences of therapeutic radiation. Cancer 36: I7021708; 1975. Elerding. S. C.; Fernandez, R. N.; Grotta, J. C. Carotid artery disease following external cervical irradiation. Ann. Surg. 194:609-615: 1981. Fajardo. L. F.: Berthrong, M. Vascular lesions following radiation. Path. Annu. Part I: June 1988. Feldman. E.: Posner. J. B. Episodic neurologic dysfunction in patients with Hodgkin’s disease. Arch. Neural. 43: 12271233: 1986. Click, B. Bilateral carotid occlusive disease. Arch. Pathol. 93:352-355; 1972. Graus. F.; Rogers, L. R.: Posner. J. B. Cerebrovascular complications in patients with cancer. Medicine 64: 16-35: 1985. Hayward, R. H. Arteriosclerosis induced by radiation. Surg. Clin. North Am. 52:359-366; 1972. Huvos, A. G.; Learning. R. H.; Moore. 0. S. Clinicopathologic study of the resected carotid artery. Am. J. Surg. 126: 570-574; 1973. Kearsley. J. H.: Tattersall, M. H. N. Cerebral embolism in cancer patients. Q. J. Med. 5 1(203):279-291: 1982.
13. Nardelli. E.; Fiaschi. F.; Ferrari. G. Delayed cerebrovascular consequences of radiation to the neck. Arch. Neural. 35: 53X-540: 1978. 14. Osgood, C. P.; Karunaratane, E. R.: Sandler, R.; Vandevander, P. A. Carotid occlusion in a 27 year old man. Neurosurgeq I X:459-460: 1986. 15. Pessin. M. S.; Abbott. B. P.: Prager. R. J.: Batson, R. A.: Scott. R. M. Clinical and angiographic features of carotid circulation thrombus. Neurology 36(4):5 18-523: 1986. 16. Rotman, M.; Seidenberg, B.; Rubin, I.; Botstein, C.; Bosniak. M. Aortic arch syndrome secondary to radiation in childhood. Arch. Intern. Med. 124:87-90: 1969. 17. Rottenberg. D. A.; Chernick. N. L.: Deck, M. D. Cerebral necrosis following radiotherapy of extracranial neoplasms. Ann. Neural. 1:339-357: 1977. 18. Silverberg. G. D.; Britt. R. H.: Goffinet. D. R. Radiationinduced carotid artery disease. Cancer 4 I : I30- 137; 1978.
0360-30 I6190 $3.00 + .Xl Copyright (c‘ 1990 Pergamon Press plc
l Brief Communication
CAROTID
THROMBOSIS
FOLLOWING
NECK IRRADIATION
GREGORY K. CALL, M.D.,* PATRICK F. BRAY, M.D.,* WENDY R. K. SMOKER, M.D.,’ SAUNDRA S. BUYS, M.D.$ AND JOHN K. HAYES, M.D.$ University
of Utah School of Medicine,
Salt Lake City, Utah 84 132
Therapeutic irradiation may accelerate atherosclerosis, increasing the risk of vascular stenosis or occlusion several to many years following radiation. However, intimal damage following irradiation may result earlier in thrombosis without stenosis. This report discusses three cases of carotid occlusion that occurred within 3 years of moderate dose irradiation. Angiographic studies showed that occlusion occurred in the absence of atherosclerotic stenosis. A review of the literature supports the conclusion that people who receive neck irradiation are at risk not only for the delayed development of diffuse atherosclerosis but also for thrombotic occlusion within months to several years. We suggest that patients who develop neurological symptoms or signs following neck irradiation, regardless of age, dose of radiation, or interval since radiation, should be evaluated for carotid or vertebra1 artery disease. Carotid occlusion, Thrombosis,
Radiation.
INTRODUCTION
METHODS AND MATERIALS
The chronic toxicity of ionizing radiation is directly related to the total dose of radiation and can include such diverse
Ch.w 1 A 3%year-old woman presented with supraclavicular and mediastinal adenopathy in June of 1984. Biopsy revealed nodular sclerosing Hodgkin’s disease. Staging laparotomy was positive for a single 4 mm focus of disease in the spleen, and she was pathologically staged as IIIAS. She was treated with total nodal irradiation, receiving 3926 cGy to the central axis midplane of the mantle field with 6 MV photons. Review of port films and carotid angiograms documented that the offending lesion was within the irradiated volume. Off axis calculations at a midplane depth in the left neck done during treatment give an estimated carotid artery dose of 4360 cGy in 20 fractions over 28 days (2 18 cGy per fraction). Compensators were not used to lower the daily risk dose. The right neck, the site of original disease, received an additional two fractions with an estimated carotid dose of 4760 cGy. She was clinically free of disease until August of 1986 when she developed recurrent disease in left pre-auricular and bilateral submandibular lymph nodes, possibly a
manifestations as transverse myelitis, brain necrosis, chronic enteritis, and subcutaneous fibrosis (I). These changes occur from months to years following therapeutic radiation and are thought to be caused by vascular damage (17). Small vessels are most frequently involved but delayed large vessel disease has been documented by study of pathology (9). Large vessel disease can occur within any vessel in the radiation port. The histologic changes are those of arteriosclerosis with a modest round cell infiltrate that most closely resemble atherosclerosis. Lesions generally become clinically apparent many years following therapeutic radiation and have been thought to occur almost exclusively in patients receiving doses greater than 4000 cGy (7). In this report we describe three patients in whom carotid artery occlusion occurred within 3 years of receiving moderate-dose radiation and whose clinical and angiographic patterns suggest that this was not caused by accelerated atherothrombosis.
* Department of Neurology. + Department of Radiology. * Division of Hematology-Oncology. BDivision of Radiation-Oncology. Reprint requests to: Dr. Call. Acknowledgements--We are indebted
assistance in preparation of the manuscript, to Drs. Harmon Eyre and Robert Stewart for their helpful comments, and to Dr. Luis Fajardo for providing us with a preprint of his comprehensive review of radiation damage. Accepted for publication 9 August 1989. to Marjory McKinney
for 635
636
I. J. Radiation
Oncology
0 Biology 0 Physics
marginal miss recurrence. She was started on chemotherapy consisting of nitrogen mustard, oncovin, procarbazine, and prednisone (MOPP) and had complete response after two courses. Therapy was complicated by phlebitis in the arms, attributed to vesicant drug administration. In November of 1986, after two cycles of MOPP chemotherapy, she had a IO-minute episode of tingling numbness in the left leg. A CT scan and EEG were both normal and no specific therapy was administered. Three weeks later, during the third course of MOPP. she was found on the floor unable to speak. In the hospital she was globally aphasic and had a dense right flaccid hemiplegia and hemihypesthesia. Laboratory studies showed an hematocrit of 36.9%. platelet count of 474,OOO/ul and white blood cell count of 98OO/ul. Prothrombin time (PT), partial thromboplastin time (PTT), and serum chemistries were all normal. The cholesterol was 200 mg/dl. An enzyme-linked immunosorbent assay test for antiphospholipid antibodies was negative. A lumbar puncture yielded clear colorless cerebrospinal fluid with two red blood cells and no white cells per ml: the protein was 4.5 mg/dl and the glucose was 75 mg/dl. An echocardiogram was normal. Five days following admission bilateral carotid angiography was performed. An irregular intraluminal filling defect was present at the bifurcation of the left common carotid which extended into and occluded the internal carotid at its origin (Fig. 1a and 1b). The aortic arch and other cervical and intracranial vessels appeared normal. with no evidence of atherosclerotic change. A repeat left carotid angiogram 1 week later showed a normal bifurcation with persistent occlusion of the internal carotid artery just distal to the bifurcation (Fig. lc and Id). A CT scan showed a large cortical and white matter low density lesion in the territory of the left middle cerebral artery. The patient was left with a profound aphasia, hemiplegia, and hemihypesthesia that has persisted for 2-f years. C’usr 2 A 42-year-old man was diagnosed as having mixed cellularity Hodgkin’s disease involving the left cervical and mediastinal lymph nodes in January 1982. Bone marrow biopsy, abdominal CT scan, and staging laparotomy were all negative for tumor and he was pathologically staged as IIA. He was treated with total nodal irradiation at an outside hospital with a 6 MV linear accelerator. The left neck was blocked when the mantle central axis midplane dose was 3780 cGy (2 1 fractions, 37 days). Irregular field off-axis dose calculations were not done. A radiation field setup photograph suggested that the left neck separation was less than the central axis separation: therefore, a dose higher than 3780 cGy to the left carotid artery can reasonably be assumed. The inferior left neck and supraclavicular fossa were boosted 2 months later during the inverted Y component of therapy with an additional I200 cGy in 6 fractions to the midplane with anterior and pos-
March
1990. Volume
IX. Number
3
terior opposed fields, the superior extent of which was below the carotid bifurcation. The patient did well until August of 1984 when he developed four episodes of right arm and leg numbness that lasted about 5 minutes each. He also had one additional brief episode of inability to write, although he did not note weakness or sensory change in the right hand. In September 1984 he developed numbness of the right arm and difficulty speaking. Examination at that time was notable for diminished sensation to all modalities in the right face, arm and leg, and mild dysarthria. Standard laboratory studies were normal. A cranial CT scan showed a small low density lesion in the left putamen. An echocardiogram showed minimal mitral valve prolapse. Cerebral angiography, performed 4 days after onset. was normal (Fig. 2a). The patient was treated with aspirin and dipyridamole: over several weeks he recovered almost completely. Six months later the patient abruptly developed more difficulty speaking and weakness of the right arm. He was readmitted to the hospital and on examination he was found to have a mild dysarthria and to make occasional paraphrasic errors. The sensory deficits noted 6 months earlier had persisted but were less pronounced. A mild right hemiparesis was detected with face and arm more affected than the leg. Complete blood count, differential and chemistries were again normal. The cholesterol was 225 mg/dl. Partial thromboplastin time was 25 seconds with a control of 39 seconds; prothrombin time was 1 1. I seconds with a control of 12.2 seconds. Antithrombin Ill. Protein C. and Protein S assays were all normal. Factor VlIIc activity was 3 18%) (normal range 50-200%). In the hospital the patient was treated with heparin but the dysarthria and paresis worsened. On the fifth hospital day. after the heparin was stopped in order to perform additional coagulation studies, he became completely mute with an inability to follow even simple commands, profoundly weak in the right lower half of the face and in the arm, and mildly weak in the right leg. One week later bilateral carotid and cerebral angiography were repeated and showed occlusion of the left internal carotid artery (Fig. 2b). The marked neurological deficit has persisted for 4 years. and the patient remains free of clinical evidence of recurrent Hodgkin’s disease. Ch.W 3 A 26-year-old woman was found to have a rhabdomyosarcoma of the right maxillary sinus in August of 1985. She received six cycles of vincristine, adriamycin, and cytoxan with excellent shrinkage of tumor. She was then treated with radiation therapy to the right maxilla and base of the skull. The dose was delivered with 6 MV X rays using an anterior and right anterior oblique wedged pair setup, 200 cGy per fraction to the 100% isodose line, to a total dose of 5000 cGy. The field size was reduced, and the dose boosted to 7000 cGy using the same beam
Carotid
thrombosis
0 G. K. CALL etul
637
Fig. 1. Case 1: The initial left carotid angiogram showed internal carotid occlusion with a common carotid intraluminal filling defect (white arrows. a and b). Angiography 1 week later showed resolution of the common carotid defect (white arrows, c and d).
arrangement and fractionation. In March 1986 a right maxillectomy was performed. After the procedure the patient developed a right-sided Horner’s syndrome. Several
months later maintenance therapy with vincristine, actinomycin D and cytoxan was begun. In September of 1986, while on maintenance chemo-
638
I. J. Radiation
Oncology
0 Biology 0 Physics
March
1990. Volume
IS. Number
Fig. 2. Case 2: (a) The original carotid angiogram 6 months prior to stroke was normal. occlusion at the time of the stroke (black arrow).
therapy, the patient developed transient visual changes in the right eye. These consisted of a greying out of vision, sometimes associated with a sensation of sparkling lights. which lasted for several minutes. Over the next 7 months she experienced approximately eight such spells. These were initially thought to be due to radiation retinopathy. On examination the patient had a persistent right Horner’s syndrome with ptosis and miosis. Standard laboratory studies were normal except for a cholesterol of 255 mg/dl. A cranial CT scan showed normal brain and surgical changes without evidence of disease recurrence. Bilateral carotid angiography in April of 1987 showed the right internal carotid artery to be occluded from its origin to a point just proximal to the origin of the ophthalmic artery (Fig. 3). The aortic arch and other cervical and intracranial vessels were normal. The patient was anticoagulated with warfarin for 6 months; no further symptoms have occurred in 32 months. Review of angiographic data and port verification films confirmed that the lesion was within the high dose volume.
RESULTS Three young people, aged 35, 42, and 26 years, developed carotid occlusion within the radiation port less than
3
(b) The internal
carotid
3 years following neck irradiation for cancer. In Case 1, an angiogram 1 week following the initial study showed resolution of the proximal intraluminal filling defect in the common carotid artery. There was no evidence of atherosclerosis or other angiopathy. This sequence of events suggests either embolus to the bifurcation or thrombosis of unknown cause (15). In this case, note should also be made of the episode of left leg numbness which occurred 3 weeks prior to left carotid occlusion and cerebral infarction. The sensory complaint on that occasion implicated the contralateral cerebral hemisphere, yet the right cerebral vessels were normal at the time of stroke. This would be consistent with a similar transient process in the contralateral vasculature which had an even higher radiation dose. In Case 2 a completely normal angiogram 6 months prior to internal carotid occlusion again speaks for embolism or inexplicable thrombosis. In Case 3 the internal carotid artery was occluded from its origin to the ophthalmic artery. There was no evidence of atherosclerosis or other angiopathy elsewhere. In each case the lack of atherosclerosis, the occurrence of carotid occlusion within the radiation port, and the temporal relation to radiation suggests an association between radiation therapy and carotid occlusion. In Cases 1 and 3, the acute events were concurrent with ongoing combination chemotherapy.
Carotid
thrombosis
639
0 G. K. CALL etal.
Table 1. Clinical data on patients with neck irradiation proven delayed stenosis or occlusion of cervical vertebral or carotid arteries
Source rt al. (1 I )
Levinson
Glick (6) Nardelli et al. (13) Rotman et al. (16) Osgood et al. (14) Hayward (8) McCready 6~ ul. (12) Silverberg
671al. ( 18)
Kearsley and Tattersall ( 10)
Fig. 3. Case 3: The stump of the occluded artery (black arrow).
right internal
carotid
DISCUSSION Multiple case reports have documented cervical carotid or vertebral stenosis or occlusion following neck irradiation (2, 6, 8, 10, 11, 12, 13, 14, 16, 18). Post-irradiation accelerated atherosclerosis is recognized by diffuse involvement of arteries in the radiation port. This contrasts strikingly with the focal or multifocal character of naturally occurring atherosclerosis. Table 1 lists the clinical characteristics of 18 patients reported in the literature who developed proven delayed stenosis or occlusion of cervical arteries following neck irradiation. In all instances the diffuse pattern of stenosis or occlusion was thought to be most consistent with irradiation change rather than naturally occurring disease. In most instances the interval from radiation exposure to neurologic symptoms was 15 years or more; there were four instances where symptoms developed between 6 and 8 years following radiation. The radiation dose was generally greater than 5000 cGy although in three it was between 4000 and 5000 cGy and in four instances it was not reported. The delayed development of cerebral ischemia following neck irradiation as documented by the cases in Table 1 has led to the suggestion that all such patients be followed by noninvasive carotid evaluation beginning 5 years following radiation exposure (3). However, in the three cases
Age/sex 74 54 68 54 32 38 27 55 44 24 67
M F F F M F F M M F M ? ? ? ? ? 3
64 M
Radiation dose (~GY)
and
Interval to symptoms (yrs)
7600 7200
25 34 32 15 27 36 15 27 7 24 17 6 30 7 24 8 14 17
”
6576 5400 ? 6000 6724 7500 ‘) 5500 4400 4600 4290 ? 6820 12,000 6600
considered here plus three others listed in the literature (Table 2) occlusion occurred within 3 years of radiation exposure. Our three cases also indicate that the process is not due to atherosclerotic stenosis. Recently, Feldman and Posner described 14 patients previously treated with radiation to the neck who presented with transient neurological deficits thought to be ischemic in nature (5). Five patients underwent arteriography and in four cases the vessels were normal. One patient had an isolated tight stenosis of the left internal carotid artery. A sixth patient had normal carotid doppler studies. These normal studies suggest a cause other than accelerated atherosclerosis as the etiology of the ischemia. However, Feldman and Posner did not specify the interval between radiation exposure and neurologic symptoms in every case, and in eight instances an evaluation of the cervical vessels was not carried out (5). Thus, we do not know how closely their cases resemble the three considered here. Table 2. Clinical data on patients with neck irradiation proven stenosis or occlusion of cervical vertebral or carotid arteries within 3 years
Present
and
Interval to symptoms (yrs)
Source
Age/sex
Radiation dose (~GY)
series
35 F 42 M 26 F ? ;
3926 3600 5000 5650 5500
1; 2
27 F
7200
2
Silverberg et a/. ( 13) Conomy and Kellermever (2)
2 3
I
1. J. Radiation
640
Oncology
0 Biology 0 Physics
The case of Conomy and Kellermeyer (2) closely resembles our three angiographically, particularly Case 1. Their case was studied at autopsy and showed carotid bifurcation thrombosis in the absence of stenosis. The microscopic changes consisted of myointimal fibrosis and disruption of the internal elastica with overlying thrombus. Although large arteries (greater than .5 mm in external diameter) are the least affected by ionizing radiation (4), the endothelial cells of these arteries can be damaged and myointimal proliferation has been documented clinically and experimentally. Such changes in the intima can lead to thrombosis in the absence of severe stenosis. The prognosis of patients who develop cerebral ischemit symptoms within a few years following neck irradiation can vary greatly. Our Cases 1 and 2 and those of Conomy and Kellermeyer developed devastating cerebral infarctions. Our Case 3 and the two from the Silvcrberg ct ~1. series (18) developed transient monocular blindness that resolved. We conclude that people who receive neck irradiation may be at risk not only for the delayed development of diffuse atherosclerosis but also for large artery thrombosis within months to several years. This can occur following a moderate radiation dose and the outcome can be a transient and apparently benign event, or a devastating cerebral infarction. The factors that predispose to carotid thrombosis following radiation may be multiple. Intimal damage within the radiation port probably occurs in all cases (4), yet clinically apparent large artery thrombosis is rare. This may be related to the high flow state of the
March
1990. Volume
1X. Number
3
cerebral vessels. Two of our cases may have had a hypercoagulable state; Case 1 had phlebitis associated with intravenous chemotherapy, and Case 2 had an elevated factor VIII concentration. Case 3 had hypercholesterolemia which may increase the risk of intimal damage and athcrosclerosis following radiation (4). In Cases 1 and 3. the acute events occurred during ongoing combination chemotherapy. for recurrent disease and in an adjuvant setting, respectively. These cases are sufficiently complex to suggest that thrombosis following irradiation is a multifactional process, and assignment of an etiology to radiation alone is unwarranted without further information. Our three patients all had warning events and the report by Feldman and Posner (5) indicates that this may be common. We suggest that patients who develop neurological symptoms or signs following neck radiation therapy, regardless of age. radiation dose, or interval following radiation. should be evaluated for carotid or vertebral artery disease. If the ischemic nature of the symptoms appear definite, antiplatelet agents could be tried even if vascular studies are negative. If symptoms persist, antithrombotic therapy with warfarin should be considered. After potentially curative antineoplastic therapy, efforts should be made to keep neck dose to less than 200 cGy per fraction. Irregular field off-axis dose calculations are mandatory in mantle radiation therapy because the neck routinely receives higher doses than the control axis. Brass sheet compensation is now routine at this institution during mantle field radiation therapy to keep the dose to the neck less than 200 cciy per fraction.
REFERENCES Anderson, R. E. Radiation injury. In: Kissane. J. M.. ed. Anderson’s pathology St. Louis: CV Mosby Co.: 1985.
2. Conomy.
I I. Levinson. S. A.; Close, M. B.: Ehrenfield. W. K.: Stoney. R. J. Carotid artery occlusive disease following external cervical irradiation. Arch. Surg. 107:395-397; 1973.
3.
12. McCready. R. A.: Hyde. G. L.; Bivins. B. A.; Mattingly, S. S.; Griffen, W. 0. Radiation-induced arterial injuries. Surgery 93:306-3 12; 1983.
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J. P.; Kellermeyer, R. W. Delayed cerebrovascular consequences of therapeutic radiation. Cancer 36: I7021708; 1975. Elerding. S. C.; Fernandez, R. N.; Grotta, J. C. Carotid artery disease following external cervical irradiation. Ann. Surg. 194:609-615: 1981. Fajardo. L. F.: Berthrong, M. Vascular lesions following radiation. Path. Annu. Part I: June 1988. Feldman. E.: Posner. J. B. Episodic neurologic dysfunction in patients with Hodgkin’s disease. Arch. Neural. 43: 12271233: 1986. Click, B. Bilateral carotid occlusive disease. Arch. Pathol. 93:352-355; 1972. Graus. F.; Rogers, L. R.: Posner. J. B. Cerebrovascular complications in patients with cancer. Medicine 64: 16-35: 1985. Hayward, R. H. Arteriosclerosis induced by radiation. Surg. Clin. North Am. 52:359-366; 1972. Huvos, A. G.; Learning. R. H.; Moore. 0. S. Clinicopathologic study of the resected carotid artery. Am. J. Surg. 126: 570-574; 1973. Kearsley. J. H.: Tattersall, M. H. N. Cerebral embolism in cancer patients. Q. J. Med. 5 1(203):279-291: 1982.
13. Nardelli. E.; Fiaschi. F.; Ferrari. G. Delayed cerebrovascular consequences of radiation to the neck. Arch. Neural. 35: 53X-540: 1978. 14. Osgood, C. P.; Karunaratane, E. R.: Sandler, R.; Vandevander, P. A. Carotid occlusion in a 27 year old man. Neurosurgeq I X:459-460: 1986. 15. Pessin. M. S.; Abbott. B. P.: Prager. R. J.: Batson, R. A.: Scott. R. M. Clinical and angiographic features of carotid circulation thrombus. Neurology 36(4):5 18-523: 1986. 16. Rotman, M.; Seidenberg, B.; Rubin, I.; Botstein, C.; Bosniak. M. Aortic arch syndrome secondary to radiation in childhood. Arch. Intern. Med. 124:87-90: 1969. 17. Rottenberg. D. A.; Chernick. N. L.: Deck, M. D. Cerebral necrosis following radiotherapy of extracranial neoplasms. Ann. Neural. 1:339-357: 1977. 18. Silverberg. G. D.; Britt. R. H.: Goffinet. D. R. Radiationinduced carotid artery disease. Cancer 4 I : I30- 137; 1978.
