Cerebral Embolism, Marantic and Cancer Jon C.
Kooiker, MD; James M. MacLean, MD; Shuzo M. Sumi, MD
\s=d\ Two
subjects with cerebral
embolism
autopsy to have marantic (nonbacterial thrombotic) endocarditis (NBTE) and an unsuspected carcinoma. An additional 16 subjects with marantic were
Endocarditis,
found at
endocarditis and cancer were found on reviewing the autopsy records of 22 subjects with NBTE. Of these 18 subjects with NBTE and cancer, eight developed a
number of neurological syn¬ dromes may occur as manifesta¬ tions of "remote effects" of cancer.1·2 An overall incidence of 7% has been reported in patients with various types of cancers, and perhaps as high as 16% in men with lung cancer.1 These neurological manifestations may be the initial symptoms of malig¬ nant disease. The occurrence of nonbacterial thrombotic endocarditis (NBTE, ma¬ rantic endocarditis) in many chronic
A
Accepted
for publication March 25, 1975. From the Division of Neurology (Drs Kooiker and Sumi) and the Laboratory of Neuropathology (Dr Sumi), Department of Medicine, University of Washington School of Medicine, and the Section of Neurology, Virginia Mason Medical Center (Dr MacLean), Seattle. Reprint requests to Mail Stop RJ-05, Laboratory of Neuropathology, Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195 (Dr Sumi).
stroke during their illness, in five as the initial manifestation of cancer. Although the association of cancer and marantic endocarditis is generally well recognized, cerebral embolism from this source should be more seriously considered as one of the "remote effects" of cancer on the nervous system. (Arch Neurol 33:260-264, 1976)
diseases, including carcinoma, is well established. Cerebral embolism in NBTE is also well known. Of 20 patients with cancer and neurological symptoms, Reagan and Okazaki3 found 16 who had NBTE. Twelve of these 16 subjects had one or more acute neurological symptoms, and in 14, vascular occlusions or microinfarcts were found at autopsy. We recently studied two patients with signs of multiple cerebral emboli. Despite extensive search, a source of the emboli could not be found until autopsy, when they both were found to have marantic endocarditis and unsuspected carcinoma. This article presents the clinical and pathological findings in these two patients and reviews subjects with autopsy-con¬ firmed NBTE in our hospitals. Our experience confirms the observations of Reagan and Okazaki' concerning
frequent occurrence of NBTE and Although these authors men¬ tioned that the diagnosis of carcinoma may be preceded by neurologic symp¬ the
cancer.
toms, NBTE with cerebral embolism
as the initial manifestation of sys¬ temic cancer does not appear to have received the emphasis it deserves, despite reports noting the coinci¬ dental occurrence of cancer, NBTE, and cerebral embolism.4 " Even in patients with known carcinoma who have a "stroke," NBTE is rarely considered as a possible source of the embolus.
REPORT OF CASES Case 1.—Six weeks prior to admission, a 51-year-old woman was diagnosed as having thrombophlebitis of the left leg. She was admitted to Virginia Mason
Medical Center in Seattle because of confu¬ sion, "bizarre behavior," and right-sided weakness. She had a nonfluent aphasia and right-sided hemiparesis. General examina¬ tion, including cardiac evaluation, was unremarkable. Subsequently she had a generalized seizure, developed left-sided hemiplegia, and became decerebrate. Cerebral angio¬ grams showed complete occlusion of the right middle cerebral artery with delayed filling and emptying of several cortical vessels. The diagnosis was multiple cere¬ bral emboli. The patient deteriorated
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steadily and died three days after admis¬ sion. Laboratory findings are summarized in Table 1. The main general autopsy findings (Table 2) included a mucinous cystadenocarcinoma of the ovary that was locally invasive but without evidence of metasta¬ tic spread, and multiple, small, friable, reddish vegetations on the mitral valve (Fig 1) consisting largely of platelets with interspersed fibrin (Pig 2). There was swelling and hemorrhagic softening of almost the entire right cere¬ bral hemisphere, and a smaller area of softening in the midportion of the left postcentral gyrus (Fig 3). A whitish clot totally occluded the right middle cerebral artery out of its trifurcation (Fig 4). Multiple small clots also occluded the terminal branches of both middle cerebral arteries. Microscopically, the clot in the cerebral arteries consisted largely of platelets and fibrin similar to the vegeta¬ tions of the mitral valve. Case 2.—A 58-year-old man developed sudden left-sided weakness and dysarthria in August 1973. An asymptomatic "left lung infiltrate," which had been discovered on a routine chest roentgenogram in May 1972, had remained unchanged through the subsequent year. Examination revealed a mild left-sided
hemiparesis, homonymous hemianopsia on the left, and left-sided hyperreflexia. Spinal fluid was normal. Bilateral carotid arteriograms showed occlusion of a parie¬ tal branch of the right middle cerebral artery. The patient developed progressive
visual deterioration with "visual halluci¬ nosis and confabulation." His findings changed only in that bilateral Babinski signs became present. The patient was be¬ lieved to be cortically blind. Two purpuric lesions were found under the right thumb¬ nail. The patient died six weeks after the onset of his illness. Laboratory findings are summarized in Table 1. General autopsy findings (Table 2) included a firm, 4 5-cm mass and several small hilar nodes in the right lower lobe of the lung consisting of an undifferentiated carcinoma. A small plaque of tumor was present in the submucosa of the jejunum, and this was considered to be a primary undifferentiated epithelial carcinoma, probably arising from the small bowel. Marantic endocarditis involved the aortic valves. The left vertebral artery and the origin of the left posterior inferior cerebellar artery was occluded by a recent red throm¬ bus, and other thrombi were present in branches of the trifurcation of the right and left middle cerebral arteries. There were multiple infarcts of varying ages
Table
1.—Laboratory Findings Case 1
Erythrocyte sedimentation rate,
mm
Hematocrit, % Urinalysis Cerebrospinal fluid Prothrombin time, sec (normal, 14) Partial thromboplastin time, sec (normal, 35) Platelets/cu mm Thrombin time
Fibrinogen, mg (normal, 200-400)
20 31 Trace protein Xanthochromic
Case 2 40 26
Bloody
16 22
20 Normal
95,000
116,000
Normal Normal
91.5
Normal
Not examined.
Table
Case
2.—Autopsy Findings Other Embolie Involvement
Primary Carcinoma
Métastases? No
Brain Lesions Multiple infarcts
Multiple infarcts
Valve Involved Mitral
1
Ovary
2
Undifferentiated carcinoma
Pulmonary
3
Pancreas
Liver
Spleen, kidney Hemorrhagic in¬ farction, right hemisphere; agenesis, corpus
Mitral
4
Giant cell carcinoma Prostate
Yes
Large hemorrhagic None
Mitral
Heart, spleen, kidney Renal, splenic
Mitral
and
pericardial
callosum
5
infarct No
Right hemisphere
Pancreas
Yes Yes Yes
infarct Normal Normal Massive infarct, right cerebrum
Prostate
Yes
Right cerebrum,
6 7 8
Ovary Lung
9
both cerebellar
Heart
Mitral
Liver, spleen
Aortic Mitral Aortic
None
Liver, spleen, kidney Liver, spleen
Aortic
hemispheres 10 11 12 13 14 15 16
Pancreas
17
Prostate
Yes
frontal lobe Normal
None
18
Adenocarci-
No
Right cerebellar
None
Ovary Bronchogenic Pancreas Pancreas Bile duct Gallbladder
_noma, lung
Yes Yes Yes Yes Yes
Normal Not examined Not examined Normal Normal Normal
None
Yes
Infarct, occipital lobes and right
Kidney, spleen
Aortic
Tricuspid Tricuspid None None
infarct
Not mentioned.
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Aortic Aortic Mitral Mitral
Aortic and mitral Mitral
Table 3.—Clinical
Findings
Known
Case/Age, yr/Sex
Carci-
1/51/F
noma? No
Wasted? No
2/58/M
No
No
3/54/M
Yes
Yes
Neurologic Symptoms 1. Confusion, aphasia right-sided hemiplegia 2. Seizure, left-sided hemiplegia 1. Left-sided hemiplegia and hemianopsia 2. Cortical blindness and visual hallucinosis 3. Right-sided hemiplegia and obtundation Terminal left-sided
hemiplegia Right-sided hemiplegia and aphasia
Cardiac Murmur?
Other Evi¬ dence of Carcinoma? No
Neurologic
No
Other Signs of Embolism? No
Phle¬ bitis? Yes
No
Hematuria,
No
Abnormal chest roentgenogram
Embolism
No
No
Yes
No
Cerebral infarction
No
Hematuria
No
Tumor
skin petechiae
4/54/F
No
No
5/79/M
Yes
Yes
Transient ischemie attack followed by left-sided
No
No
6/54/F 7/70/M 8/68/M
Yes No No
Yes
None None
No No
No No
Diagnosis Embolism
Embolism
hemiplegia
Yes
Hilar
mass
Obtundation, left-sided
None None
Infarction,
hemiplegia
9/72/M
No
No
Ataxia, vertigo, hemi¬ plegia
No
No
Osteoblastic lesions
10/64/M 11/68/F 12/68/F 13/72/M 14/89/F 15/68/M 16/52/F
Yes No Yes Yes Yes Yes Yes
Yes
No No No No No No Yes
No No No
Yes No
Yes Yes Yes Yes Yes
No No No No
No No No
17/61/M 18/59/F
Yes No
Yes Yes
None None None None None None Transient amaurosis None None
No No
No No
Yes No
metastatic tumor Infarction
None None None None None None None None None
Not mentioned in chart.
involving both cerebral hemispheres. Many cortical blood vessels were occluded by thrombi in varying stages of organiza¬ tion.
tumor incidence of 75%. Of these 18
patients, eight Eight patients
were women.
had
neurologic
symptoms that could be attributed
METHODS
Twenty-two additional cases of autopsyproved NBTE were found from the review of autopsy files of the University of Wash¬ ington-affiliated hospitals (University Hospital, Harborview Medical Center, and Seattle Veterans Administration Hospital) and in two community hospitals (Virginia Mason Medical Center and Swedish Hospi¬ tal Medical Center), all in Seattle, making a total of 24 cases. Those cases with an associated cancer were studied and their clinical and pathological findings are sum¬ marized in Tables 2 and 3.
RESULTS
Of the 24 patients with NBTE, there was an associated malignant neoplasm in 18, which results in a
to
cerebral embolism. In four patients, the stroke was a preterminal event. In three of these patients, the diagnosis of cerebral embolism was made on the basis of evidence of multiple infarc¬ tions, either clinically or angiographically, and evidence of embolie involve¬ ment elsewhere (cases 1 and 2) or because of an acute neurologic deficit with initial recovery and a subsequent stroke (case 5). In all but one patient, the number, location, and estimated age of the infarctions correlated well with the clinical findings. In one patient with only transient amaurosis of the left eye (case 16), cystic infarctions of both occipital lobes and a more recent infarction of the right frontal lobe
were found. A cerebellar infarction with embolie occlusion of the right superior cerebellar artery was an unexpected finding in another patient who had had no neurological symp¬ toms. Thus, a total of nine patients had cerebral infarction. Arterial em¬ boli in the appropriate cerebral ar¬ teries were demonstrated in five pa¬ tients. In the others, cerebral embo¬ lism was inferred from multiple infarctions encountered in other or¬ gans. Although 12 patients were noted to be wasted, only one of the five patients with neurologic symptoms and previously undiagnosed carcino¬ ma was so described. In all but three patients with neurologic symptoms, metastatic involvement was found at autopsy. All three of these patients were among the five whose initial symptoms were those of a stroke.
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Fig 1.—Case 1: Mitral valve showing several large, friable vegetations.
Fig 2.—Portion of mitral valve (Va) and vegetation. Valve appears normal and vegetations consist of platelets and fibrin strands (hematoxylin-eosin, 60). These
COMMENT In a lecture to medical students in 1865 on the clinical differentiation between gastric carcinoma, benign gastric ulcers, and gastritis, Armand Trousseau pointed out that the diag¬ nosis was invariably carcinoma if the patient also had thrombophlebitis.7
The formation of thrombotic vegeta¬ tions on the heart valves in patients such as ours appears to have a similar
significance.
The association of thrombophlebitis and cancer has been well documented,8 although the incidence of cancer in patients with thrombophlebitis may be low. In one series, only 61 of 1,400 patients with thrombophlebitis had cancer.9 However, when present in patients with a stroke, thrombophle¬ bitis is most suggestive of cancer and NBTE, but this combination occurred in only two of our eight patients with neurologic symptoms. In other series, this association has been variable: six of 78 patients of MacDonald and Robbins,4 15 of 33 patients of Barron et al,5 and four of five of Aguayo's
patients.6
The incidence of associated malig¬ neoplasms in our 24 patients with NBTE was 75%, similar to the 85% of Barron et al5 and Aguayo." The most commonly associated tumors have been mucin-secreting adenocarcinomas. The primary tumors have involved lungs, breast, pancreas, gall¬ bladder, bile duct, kidney, prostate, and the alimentary tracts. Pancreas and lung were the commonest pri¬ mary sites in our patients, and there was no case of breast carcinoma. nant
thrombotic, noninflammato¬
vegetations on previously undam¬ aged cardiac valves have received many names, including marantic en¬ ry
docarditis, terminal endocarditis, endocardiosis, endocarditis simplex, and
Fig 3.—Case 1 : Coronal section of the cerebral hemisphere showing extensive recent softening and swelling in right middle cerebral artery territory (arrows) and small hemorrhagic infarct in left middle frontal gyrus (arrows).
nonbacterial thrombotic endocarditis. In an early classification of valvular vegetations, Libman10 concluded that NBTE had no clinical significance, occurring as a terminal or agonal event in a variety of wasting diseases. Gross and Friedberg11 reached a simi¬ lar conclusion from a study of 47 patients. However, later investigators noted a high incidence of cerebral and systemic embolism in such patients, with about one third having cerebral
embolism,3·6 to that in
frequency comparable patients. patients with NBTE and a
our
In our 18 cancer, three had clinical evidence of renal embolism, one of cutaneous
embolism, and eight of cerebral embo¬ lism. At autopsy, the incidence of embolism was much higher—renal infarction in six, splenic infarction in seven, myocardial infarction in two, hepatic infarction in two, and cerebral infarction in nine. The incidence of cerebral embolism in our patients was 50%.
Of the eight patients with acute neurologic symptoms, carcinoma had not been suspected in five when they
first seen, but metastatic carci¬ diagnosed in one on chest and skull roentgenograms (case 9). In case 8, carcinoma was suspected because of emaciation and diffuse abdominal pain, but the nature of the neoplasm was not ascertained until autopsy. In three subjects, the carciwere
noma was
Fig 4—Case 1: Right (R) middle cerebral artery with occlusion (arrow) extending into branches of trifurcation. Rule is in millimeters.
unexpected finding at our patients, a clinical diagnosis of cerebral embolism noma was an
autopsy. In three of
made but a definite source for embolism was not found. Barron et al5 and Aguayo6 each had two patients with cancer whose initial symptom was a stroke. As Adams12 noted, a stroke in cancer patients often proves to be an aseptic embolism rather than tumor emboli or cerebral metastasis. The vegetations in NBTE are gen¬ erally small and do not interfere with valve function, so that murmurs are absent in most patients. In our 18 patients with NBTE and cancer, a cardiac murmur was recorded only once, and this was not further charac¬ terized. The rarity of cardiac murmurs in such patients has already been was
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noted.7 Thus, the diagnosis of cerebral embolism was made, not because of a probable source of emboli was found, but because of the clinical presenta¬ tion-multiple sudden neurologic defi¬ cits, evidence of embolism elsewhere, characteristic angiographie findings or, in one case, a transient ischemie episode preceding the onset of a fixed neurologic deficit. As in our patients, the mitral valve is most frequently involved in NBTE. Both Reagan and Okazaki3 and MacDonald and Robbins4 found that the mitral valve was the site of vegeta¬ tions in 75% of their cases, with the aortic valve next in frequency. Although there was no definite predilection for men or women in those with cancer and NBTE, there was a noticeable preponderance of elderly patients. All our patients were over 50 years of age. Only five patients were younger than 55 years and 11 were older than 60. Others have noted a similar age distribution in patients with cancer.35 Which "stroke" patient should be suspected of having marantic endo¬ carditis and cancer? In any patient with cerebral embolism in whom a source of emboli cannot be found, NBTE should be suspected. If the
1. Croft
PB, Wilkinson M: Carcinomatous
Its incidence in patients with carcinoma of the lung and carcinoma of the breast. Lancet 1:184-188, 1963. 2. Posner JB: Neurological complications of systemic cancer. Med Clin North Am 55:625-646, 1971. 3. Reagan TJ, Okazaki H: The thrombotic syndrome associated with carcinoma: A clinical and neurological study. Arch Neurol 31:390-395,
neuromyopathy:
1974. 4. MacDonald RA, Robbins SL: The significance of non-bacterial thromboembolism: An autopsy and clinical study of 78 cases. Ann Intern Med 46:255-273, 1957. 5. Barron KA, Sequeira E, Hirano A: Cerebral embolism caused by non-bacterial thromboembolism. Neurology 10:391-397, 1960.
patient
is associated
over
60 years of age,
an
underlying carcinoma is a good possibility. In any patient with known carcinoma developing an acute stroke, NBTE must be seriously
considered. One might question the importance of establishing the diagnosis of NBTE and cancer, since seven of the eight patients who had neurologic symp¬ toms died of the complications of stroke, and this has been noted by others.13 However, in three of our patients, the tumor found at autopsy had not metastasized and was theoret¬ ically resectable. Even if the tumor is not resectable, it is still important to discover it, as palliative therapy may be available. In three patients there were re¬ peated episodes of cerebral embolism and the recognition of NBTE, and institution of anticoagulant therapy might have prevented further embolization and death. Reagan and Okaza¬ ki3 concluded that NBTE is one mani¬ festation of disseminated intravas¬ cular coagulation, a condition recently recognized to be a relatively common occurrence in patients with cancer.14 However, in our two patients in whom coagulation studies were done, the results were only suggestive of con-
References Aguayo AJ: Cerebral thrombo-embolism in malignancy. Arch Neurol 11:500-506, 1964. 7. Clinico-pathological conference: Prostatic carcinoma with pulmonary complication. Am J 6.
sumption coagulopathy. Coagulation patterns of the type
seen
in
our
first
patient are usually considered to indi¬ cate consumption, but the extremely short partial thromboplastin time sug¬ gested that the consumption may have occurred in vitro. In the second
patient, consumption coagulopathy was suggested by a low platelet count and low fibrinogen level. Studies of thrombotic vegetations on prosthetic valves1516 suggest that treatment with
antiplatelet agents such as dipyridamole and aspirin may also be effective in NBTE.14
This study was supported in part by National Institutes of Health training grants NS-05067 in Neurology and NS-05231 in Neuropathology. Donald Bauermeister, MD, Department of Pathology, Virginia Mason Medical Center, pro¬ vided the autopsy material from cases 1 and 2. The directors of the departments of pathology of the University Hospital, Harborview Medical Center, Seattle Veterans Administration Hospi¬ tal, and the Swedish Hospital Medical Center allowed us to review their files for the cases of marantic endocarditis included in this article. Laurence Harker, MD, and Richard Counts, MD, of the Division of Hematology, Department of Medicine, University of Washington School of Medicine, reviewed the hématologie findings.
Nonproprietary
Name
and Trademark of Drug
Dipyridamole-Persanime.
12. Adams RD: Case records of the Massachusetts general hospital: Case number 41491. N Engl J Med 253:1030-1036, 1955. 13. Ashenhurst EM, Cherkow G: Cerebral
Med 54:497-506, 1973. 8. Sproul EE: Carcinoma and venous thrombosis: The frequency of association of carcinoma in the body or tail of the pancreas with multiple venous thrombosis. Am J Cancer 34:566-585,
embolism from nonbacterial thromboembolism. Can Med Assoc J 86:313-317, 1962. 14. Merskey C: Pathogenesis and treatment of altered blood coagulability in patients with malignant tumor. Ann NY Acad Sc 230:289-293,
1938. 9. Lieberman
1974. 15. Sullivan JM, Harken DE, Gorlin R: Pharmacologic control of thromboembolic complications of cardiac valve replacement: A preliminary report. N Engl J Med 279:576-580, 1968. 16. Harker LA, Slichter SJ: Studies of platelet and fibrinogen kinetics in patients with prosthetic heart valves. Engl J Med 283:1302-1305, 1970.
JS,
Thrombophlebitis 545, 1961.
Barrero
and
J, Vdaneta E, et al:
cancer.
JAMA 117:542\x=req-\
10. Libman E: Characterization of various forms of endocarditis. JAMA 80:813-818, 1923. 11. Gross L, Friedberg C: Non-bacterial thrombotic endocarditis. Arch Intern Med 58:620-640, 1936.
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N
Kooiker, MD; James M. MacLean, MD; Shuzo M. Sumi, MD
\s=d\ Two
subjects with cerebral
embolism
autopsy to have marantic (nonbacterial thrombotic) endocarditis (NBTE) and an unsuspected carcinoma. An additional 16 subjects with marantic were
Endocarditis,
found at
endocarditis and cancer were found on reviewing the autopsy records of 22 subjects with NBTE. Of these 18 subjects with NBTE and cancer, eight developed a
number of neurological syn¬ dromes may occur as manifesta¬ tions of "remote effects" of cancer.1·2 An overall incidence of 7% has been reported in patients with various types of cancers, and perhaps as high as 16% in men with lung cancer.1 These neurological manifestations may be the initial symptoms of malig¬ nant disease. The occurrence of nonbacterial thrombotic endocarditis (NBTE, ma¬ rantic endocarditis) in many chronic
A
Accepted
for publication March 25, 1975. From the Division of Neurology (Drs Kooiker and Sumi) and the Laboratory of Neuropathology (Dr Sumi), Department of Medicine, University of Washington School of Medicine, and the Section of Neurology, Virginia Mason Medical Center (Dr MacLean), Seattle. Reprint requests to Mail Stop RJ-05, Laboratory of Neuropathology, Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195 (Dr Sumi).
stroke during their illness, in five as the initial manifestation of cancer. Although the association of cancer and marantic endocarditis is generally well recognized, cerebral embolism from this source should be more seriously considered as one of the "remote effects" of cancer on the nervous system. (Arch Neurol 33:260-264, 1976)
diseases, including carcinoma, is well established. Cerebral embolism in NBTE is also well known. Of 20 patients with cancer and neurological symptoms, Reagan and Okazaki3 found 16 who had NBTE. Twelve of these 16 subjects had one or more acute neurological symptoms, and in 14, vascular occlusions or microinfarcts were found at autopsy. We recently studied two patients with signs of multiple cerebral emboli. Despite extensive search, a source of the emboli could not be found until autopsy, when they both were found to have marantic endocarditis and unsuspected carcinoma. This article presents the clinical and pathological findings in these two patients and reviews subjects with autopsy-con¬ firmed NBTE in our hospitals. Our experience confirms the observations of Reagan and Okazaki' concerning
frequent occurrence of NBTE and Although these authors men¬ tioned that the diagnosis of carcinoma may be preceded by neurologic symp¬ the
cancer.
toms, NBTE with cerebral embolism
as the initial manifestation of sys¬ temic cancer does not appear to have received the emphasis it deserves, despite reports noting the coinci¬ dental occurrence of cancer, NBTE, and cerebral embolism.4 " Even in patients with known carcinoma who have a "stroke," NBTE is rarely considered as a possible source of the embolus.
REPORT OF CASES Case 1.—Six weeks prior to admission, a 51-year-old woman was diagnosed as having thrombophlebitis of the left leg. She was admitted to Virginia Mason
Medical Center in Seattle because of confu¬ sion, "bizarre behavior," and right-sided weakness. She had a nonfluent aphasia and right-sided hemiparesis. General examina¬ tion, including cardiac evaluation, was unremarkable. Subsequently she had a generalized seizure, developed left-sided hemiplegia, and became decerebrate. Cerebral angio¬ grams showed complete occlusion of the right middle cerebral artery with delayed filling and emptying of several cortical vessels. The diagnosis was multiple cere¬ bral emboli. The patient deteriorated
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steadily and died three days after admis¬ sion. Laboratory findings are summarized in Table 1. The main general autopsy findings (Table 2) included a mucinous cystadenocarcinoma of the ovary that was locally invasive but without evidence of metasta¬ tic spread, and multiple, small, friable, reddish vegetations on the mitral valve (Fig 1) consisting largely of platelets with interspersed fibrin (Pig 2). There was swelling and hemorrhagic softening of almost the entire right cere¬ bral hemisphere, and a smaller area of softening in the midportion of the left postcentral gyrus (Fig 3). A whitish clot totally occluded the right middle cerebral artery out of its trifurcation (Fig 4). Multiple small clots also occluded the terminal branches of both middle cerebral arteries. Microscopically, the clot in the cerebral arteries consisted largely of platelets and fibrin similar to the vegeta¬ tions of the mitral valve. Case 2.—A 58-year-old man developed sudden left-sided weakness and dysarthria in August 1973. An asymptomatic "left lung infiltrate," which had been discovered on a routine chest roentgenogram in May 1972, had remained unchanged through the subsequent year. Examination revealed a mild left-sided
hemiparesis, homonymous hemianopsia on the left, and left-sided hyperreflexia. Spinal fluid was normal. Bilateral carotid arteriograms showed occlusion of a parie¬ tal branch of the right middle cerebral artery. The patient developed progressive
visual deterioration with "visual halluci¬ nosis and confabulation." His findings changed only in that bilateral Babinski signs became present. The patient was be¬ lieved to be cortically blind. Two purpuric lesions were found under the right thumb¬ nail. The patient died six weeks after the onset of his illness. Laboratory findings are summarized in Table 1. General autopsy findings (Table 2) included a firm, 4 5-cm mass and several small hilar nodes in the right lower lobe of the lung consisting of an undifferentiated carcinoma. A small plaque of tumor was present in the submucosa of the jejunum, and this was considered to be a primary undifferentiated epithelial carcinoma, probably arising from the small bowel. Marantic endocarditis involved the aortic valves. The left vertebral artery and the origin of the left posterior inferior cerebellar artery was occluded by a recent red throm¬ bus, and other thrombi were present in branches of the trifurcation of the right and left middle cerebral arteries. There were multiple infarcts of varying ages
Table
1.—Laboratory Findings Case 1
Erythrocyte sedimentation rate,
mm
Hematocrit, % Urinalysis Cerebrospinal fluid Prothrombin time, sec (normal, 14) Partial thromboplastin time, sec (normal, 35) Platelets/cu mm Thrombin time
Fibrinogen, mg (normal, 200-400)
20 31 Trace protein Xanthochromic
Case 2 40 26
Bloody
16 22
20 Normal
95,000
116,000
Normal Normal
91.5
Normal
Not examined.
Table
Case
2.—Autopsy Findings Other Embolie Involvement
Primary Carcinoma
Métastases? No
Brain Lesions Multiple infarcts
Multiple infarcts
Valve Involved Mitral
1
Ovary
2
Undifferentiated carcinoma
Pulmonary
3
Pancreas
Liver
Spleen, kidney Hemorrhagic in¬ farction, right hemisphere; agenesis, corpus
Mitral
4
Giant cell carcinoma Prostate
Yes
Large hemorrhagic None
Mitral
Heart, spleen, kidney Renal, splenic
Mitral
and
pericardial
callosum
5
infarct No
Right hemisphere
Pancreas
Yes Yes Yes
infarct Normal Normal Massive infarct, right cerebrum
Prostate
Yes
Right cerebrum,
6 7 8
Ovary Lung
9
both cerebellar
Heart
Mitral
Liver, spleen
Aortic Mitral Aortic
None
Liver, spleen, kidney Liver, spleen
Aortic
hemispheres 10 11 12 13 14 15 16
Pancreas
17
Prostate
Yes
frontal lobe Normal
None
18
Adenocarci-
No
Right cerebellar
None
Ovary Bronchogenic Pancreas Pancreas Bile duct Gallbladder
_noma, lung
Yes Yes Yes Yes Yes
Normal Not examined Not examined Normal Normal Normal
None
Yes
Infarct, occipital lobes and right
Kidney, spleen
Aortic
Tricuspid Tricuspid None None
infarct
Not mentioned.
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Aortic Aortic Mitral Mitral
Aortic and mitral Mitral
Table 3.—Clinical
Findings
Known
Case/Age, yr/Sex
Carci-
1/51/F
noma? No
Wasted? No
2/58/M
No
No
3/54/M
Yes
Yes
Neurologic Symptoms 1. Confusion, aphasia right-sided hemiplegia 2. Seizure, left-sided hemiplegia 1. Left-sided hemiplegia and hemianopsia 2. Cortical blindness and visual hallucinosis 3. Right-sided hemiplegia and obtundation Terminal left-sided
hemiplegia Right-sided hemiplegia and aphasia
Cardiac Murmur?
Other Evi¬ dence of Carcinoma? No
Neurologic
No
Other Signs of Embolism? No
Phle¬ bitis? Yes
No
Hematuria,
No
Abnormal chest roentgenogram
Embolism
No
No
Yes
No
Cerebral infarction
No
Hematuria
No
Tumor
skin petechiae
4/54/F
No
No
5/79/M
Yes
Yes
Transient ischemie attack followed by left-sided
No
No
6/54/F 7/70/M 8/68/M
Yes No No
Yes
None None
No No
No No
Diagnosis Embolism
Embolism
hemiplegia
Yes
Hilar
mass
Obtundation, left-sided
None None
Infarction,
hemiplegia
9/72/M
No
No
Ataxia, vertigo, hemi¬ plegia
No
No
Osteoblastic lesions
10/64/M 11/68/F 12/68/F 13/72/M 14/89/F 15/68/M 16/52/F
Yes No Yes Yes Yes Yes Yes
Yes
No No No No No No Yes
No No No
Yes No
Yes Yes Yes Yes Yes
No No No No
No No No
17/61/M 18/59/F
Yes No
Yes Yes
None None None None None None Transient amaurosis None None
No No
No No
Yes No
metastatic tumor Infarction
None None None None None None None None None
Not mentioned in chart.
involving both cerebral hemispheres. Many cortical blood vessels were occluded by thrombi in varying stages of organiza¬ tion.
tumor incidence of 75%. Of these 18
patients, eight Eight patients
were women.
had
neurologic
symptoms that could be attributed
METHODS
Twenty-two additional cases of autopsyproved NBTE were found from the review of autopsy files of the University of Wash¬ ington-affiliated hospitals (University Hospital, Harborview Medical Center, and Seattle Veterans Administration Hospital) and in two community hospitals (Virginia Mason Medical Center and Swedish Hospi¬ tal Medical Center), all in Seattle, making a total of 24 cases. Those cases with an associated cancer were studied and their clinical and pathological findings are sum¬ marized in Tables 2 and 3.
RESULTS
Of the 24 patients with NBTE, there was an associated malignant neoplasm in 18, which results in a
to
cerebral embolism. In four patients, the stroke was a preterminal event. In three of these patients, the diagnosis of cerebral embolism was made on the basis of evidence of multiple infarc¬ tions, either clinically or angiographically, and evidence of embolie involve¬ ment elsewhere (cases 1 and 2) or because of an acute neurologic deficit with initial recovery and a subsequent stroke (case 5). In all but one patient, the number, location, and estimated age of the infarctions correlated well with the clinical findings. In one patient with only transient amaurosis of the left eye (case 16), cystic infarctions of both occipital lobes and a more recent infarction of the right frontal lobe
were found. A cerebellar infarction with embolie occlusion of the right superior cerebellar artery was an unexpected finding in another patient who had had no neurological symp¬ toms. Thus, a total of nine patients had cerebral infarction. Arterial em¬ boli in the appropriate cerebral ar¬ teries were demonstrated in five pa¬ tients. In the others, cerebral embo¬ lism was inferred from multiple infarctions encountered in other or¬ gans. Although 12 patients were noted to be wasted, only one of the five patients with neurologic symptoms and previously undiagnosed carcino¬ ma was so described. In all but three patients with neurologic symptoms, metastatic involvement was found at autopsy. All three of these patients were among the five whose initial symptoms were those of a stroke.
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Fig 1.—Case 1: Mitral valve showing several large, friable vegetations.
Fig 2.—Portion of mitral valve (Va) and vegetation. Valve appears normal and vegetations consist of platelets and fibrin strands (hematoxylin-eosin, 60). These
COMMENT In a lecture to medical students in 1865 on the clinical differentiation between gastric carcinoma, benign gastric ulcers, and gastritis, Armand Trousseau pointed out that the diag¬ nosis was invariably carcinoma if the patient also had thrombophlebitis.7
The formation of thrombotic vegeta¬ tions on the heart valves in patients such as ours appears to have a similar
significance.
The association of thrombophlebitis and cancer has been well documented,8 although the incidence of cancer in patients with thrombophlebitis may be low. In one series, only 61 of 1,400 patients with thrombophlebitis had cancer.9 However, when present in patients with a stroke, thrombophle¬ bitis is most suggestive of cancer and NBTE, but this combination occurred in only two of our eight patients with neurologic symptoms. In other series, this association has been variable: six of 78 patients of MacDonald and Robbins,4 15 of 33 patients of Barron et al,5 and four of five of Aguayo's
patients.6
The incidence of associated malig¬ neoplasms in our 24 patients with NBTE was 75%, similar to the 85% of Barron et al5 and Aguayo." The most commonly associated tumors have been mucin-secreting adenocarcinomas. The primary tumors have involved lungs, breast, pancreas, gall¬ bladder, bile duct, kidney, prostate, and the alimentary tracts. Pancreas and lung were the commonest pri¬ mary sites in our patients, and there was no case of breast carcinoma. nant
thrombotic, noninflammato¬
vegetations on previously undam¬ aged cardiac valves have received many names, including marantic en¬ ry
docarditis, terminal endocarditis, endocardiosis, endocarditis simplex, and
Fig 3.—Case 1 : Coronal section of the cerebral hemisphere showing extensive recent softening and swelling in right middle cerebral artery territory (arrows) and small hemorrhagic infarct in left middle frontal gyrus (arrows).
nonbacterial thrombotic endocarditis. In an early classification of valvular vegetations, Libman10 concluded that NBTE had no clinical significance, occurring as a terminal or agonal event in a variety of wasting diseases. Gross and Friedberg11 reached a simi¬ lar conclusion from a study of 47 patients. However, later investigators noted a high incidence of cerebral and systemic embolism in such patients, with about one third having cerebral
embolism,3·6 to that in
frequency comparable patients. patients with NBTE and a
our
In our 18 cancer, three had clinical evidence of renal embolism, one of cutaneous
embolism, and eight of cerebral embo¬ lism. At autopsy, the incidence of embolism was much higher—renal infarction in six, splenic infarction in seven, myocardial infarction in two, hepatic infarction in two, and cerebral infarction in nine. The incidence of cerebral embolism in our patients was 50%.
Of the eight patients with acute neurologic symptoms, carcinoma had not been suspected in five when they
first seen, but metastatic carci¬ diagnosed in one on chest and skull roentgenograms (case 9). In case 8, carcinoma was suspected because of emaciation and diffuse abdominal pain, but the nature of the neoplasm was not ascertained until autopsy. In three subjects, the carciwere
noma was
Fig 4—Case 1: Right (R) middle cerebral artery with occlusion (arrow) extending into branches of trifurcation. Rule is in millimeters.
unexpected finding at our patients, a clinical diagnosis of cerebral embolism noma was an
autopsy. In three of
made but a definite source for embolism was not found. Barron et al5 and Aguayo6 each had two patients with cancer whose initial symptom was a stroke. As Adams12 noted, a stroke in cancer patients often proves to be an aseptic embolism rather than tumor emboli or cerebral metastasis. The vegetations in NBTE are gen¬ erally small and do not interfere with valve function, so that murmurs are absent in most patients. In our 18 patients with NBTE and cancer, a cardiac murmur was recorded only once, and this was not further charac¬ terized. The rarity of cardiac murmurs in such patients has already been was
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noted.7 Thus, the diagnosis of cerebral embolism was made, not because of a probable source of emboli was found, but because of the clinical presenta¬ tion-multiple sudden neurologic defi¬ cits, evidence of embolism elsewhere, characteristic angiographie findings or, in one case, a transient ischemie episode preceding the onset of a fixed neurologic deficit. As in our patients, the mitral valve is most frequently involved in NBTE. Both Reagan and Okazaki3 and MacDonald and Robbins4 found that the mitral valve was the site of vegeta¬ tions in 75% of their cases, with the aortic valve next in frequency. Although there was no definite predilection for men or women in those with cancer and NBTE, there was a noticeable preponderance of elderly patients. All our patients were over 50 years of age. Only five patients were younger than 55 years and 11 were older than 60. Others have noted a similar age distribution in patients with cancer.35 Which "stroke" patient should be suspected of having marantic endo¬ carditis and cancer? In any patient with cerebral embolism in whom a source of emboli cannot be found, NBTE should be suspected. If the
1. Croft
PB, Wilkinson M: Carcinomatous
Its incidence in patients with carcinoma of the lung and carcinoma of the breast. Lancet 1:184-188, 1963. 2. Posner JB: Neurological complications of systemic cancer. Med Clin North Am 55:625-646, 1971. 3. Reagan TJ, Okazaki H: The thrombotic syndrome associated with carcinoma: A clinical and neurological study. Arch Neurol 31:390-395,
neuromyopathy:
1974. 4. MacDonald RA, Robbins SL: The significance of non-bacterial thromboembolism: An autopsy and clinical study of 78 cases. Ann Intern Med 46:255-273, 1957. 5. Barron KA, Sequeira E, Hirano A: Cerebral embolism caused by non-bacterial thromboembolism. Neurology 10:391-397, 1960.
patient
is associated
over
60 years of age,
an
underlying carcinoma is a good possibility. In any patient with known carcinoma developing an acute stroke, NBTE must be seriously
considered. One might question the importance of establishing the diagnosis of NBTE and cancer, since seven of the eight patients who had neurologic symp¬ toms died of the complications of stroke, and this has been noted by others.13 However, in three of our patients, the tumor found at autopsy had not metastasized and was theoret¬ ically resectable. Even if the tumor is not resectable, it is still important to discover it, as palliative therapy may be available. In three patients there were re¬ peated episodes of cerebral embolism and the recognition of NBTE, and institution of anticoagulant therapy might have prevented further embolization and death. Reagan and Okaza¬ ki3 concluded that NBTE is one mani¬ festation of disseminated intravas¬ cular coagulation, a condition recently recognized to be a relatively common occurrence in patients with cancer.14 However, in our two patients in whom coagulation studies were done, the results were only suggestive of con-
References Aguayo AJ: Cerebral thrombo-embolism in malignancy. Arch Neurol 11:500-506, 1964. 7. Clinico-pathological conference: Prostatic carcinoma with pulmonary complication. Am J 6.
sumption coagulopathy. Coagulation patterns of the type
seen
in
our
first
patient are usually considered to indi¬ cate consumption, but the extremely short partial thromboplastin time sug¬ gested that the consumption may have occurred in vitro. In the second
patient, consumption coagulopathy was suggested by a low platelet count and low fibrinogen level. Studies of thrombotic vegetations on prosthetic valves1516 suggest that treatment with
antiplatelet agents such as dipyridamole and aspirin may also be effective in NBTE.14
This study was supported in part by National Institutes of Health training grants NS-05067 in Neurology and NS-05231 in Neuropathology. Donald Bauermeister, MD, Department of Pathology, Virginia Mason Medical Center, pro¬ vided the autopsy material from cases 1 and 2. The directors of the departments of pathology of the University Hospital, Harborview Medical Center, Seattle Veterans Administration Hospi¬ tal, and the Swedish Hospital Medical Center allowed us to review their files for the cases of marantic endocarditis included in this article. Laurence Harker, MD, and Richard Counts, MD, of the Division of Hematology, Department of Medicine, University of Washington School of Medicine, reviewed the hématologie findings.
Nonproprietary
Name
and Trademark of Drug
Dipyridamole-Persanime.
12. Adams RD: Case records of the Massachusetts general hospital: Case number 41491. N Engl J Med 253:1030-1036, 1955. 13. Ashenhurst EM, Cherkow G: Cerebral
Med 54:497-506, 1973. 8. Sproul EE: Carcinoma and venous thrombosis: The frequency of association of carcinoma in the body or tail of the pancreas with multiple venous thrombosis. Am J Cancer 34:566-585,
embolism from nonbacterial thromboembolism. Can Med Assoc J 86:313-317, 1962. 14. Merskey C: Pathogenesis and treatment of altered blood coagulability in patients with malignant tumor. Ann NY Acad Sc 230:289-293,
1938. 9. Lieberman
1974. 15. Sullivan JM, Harken DE, Gorlin R: Pharmacologic control of thromboembolic complications of cardiac valve replacement: A preliminary report. N Engl J Med 279:576-580, 1968. 16. Harker LA, Slichter SJ: Studies of platelet and fibrinogen kinetics in patients with prosthetic heart valves. Engl J Med 283:1302-1305, 1970.
JS,
Thrombophlebitis 545, 1961.
Barrero
and
J, Vdaneta E, et al:
cancer.
JAMA 117:542\x=req-\
10. Libman E: Characterization of various forms of endocarditis. JAMA 80:813-818, 1923. 11. Gross L, Friedberg C: Non-bacterial thrombotic endocarditis. Arch Intern Med 58:620-640, 1936.
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N
