Case Report

Fibromuscular Dysplasia Complicated by Primary Thrombocythemia Presenting Recurrent Ischemic Cerebrovascular Accidents: A Case Report Kaori ABE, Satoru OHTA, Tadatoshi KOMIYA, Naotaka Sakamoto* and Yoshikuni Mizuno

A patient with fibromuscular dysplasia associated with primary thrombocythemia is reported. The patient, a 46-year-old female, had recurrent episodes of ischemic cerebrovascular accidents. Cranial CTscans revealed multiple low density areas in the right frontal and parietal lobes, and cerebral angiograms showed evidence of multiple . In addition, occlusion of the right internal carotid developed. Toour knowledge, this is the first report on fibromuscular dysplasia complicated by essential thrombocythemia. The pathogenesis of the severe thrombotic tendency is discussed. Key words: Fibromuscular dysplasia , Cerebral infarction, Transient ischemic attack, Carotid occlusion

Both essential thrombocythemia and fibro- bocytosis was noted at the time. From the summer muscular dysplasia are rare disorders in Japan. They of 1988 on, she had frequent episodes of headache can be considered as possible causes of in for which she required an ergot derivative for 6 younger persons. Wereport a patient with fibro- months. Also, in August 1988, she had an episode muscular dysplasia complicated by essential throm- of tingling sensation and weakness in her left hand. bocythemia. To our knowledge, such an association In January 1989 she felt a transient weakness on the has never been reported. The patient showed left side of her face and dysarthria upon waking up multiple cerebrovascular thrombo-embolicepisodes one morning. OnMarch 8, 1989 she noted weakness and complete occlusion of the right internal carotid in her upper and lower left extremities and was artery. The purpose of this report is to present the admitted to the Department of Radiology at first known case of fibromuscular dysplasia Juntendo University Medical Center the next day. associated with primary thrombocythemia and to A low density area was found in the right parieto- discuss the pathogenesis and the treatment of this occipital area by CT, and angiograms revealed disorder. irregularities in the right . Her symptoms improved during the next 3 weeks, and she CASE REPORT was discharged with a prescription of 200 mg/day The patient, a 46-year-old female, who was well ticlopidine. On April 4, she again had an episode until the end of December 1987, had a sudden onset of headache and felt weakness in her left arm. On of severe occipital headache, nausea and . April 7, weakness appeared in her left leg. She was She was admitted to a hospital where the neuro- re-admitted to the Department of Radiology. On the logical examination and cranial CT scan were 7th hospital day, she noted a visual field defect in reported to have been normal. However, throm- her right eye, and the neurology service was asked From Department of Neurology and *Radiology, Juntendo University School of Medicine, Tokyo Received for publication December 27, 1989; Accepted for publication July 24, 1990 Reprint requests should be addressed to Yoshikuni Mizuno, MD,Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113, Japan

548 Jpn J Med Vol 29, No 5 (September, October 1990) Fibromuscular Dysplasia and Thrombocythemia to see the patient. left extremity with pseudo-athetotic movements in Physical examination revealed a well-nourished the left hand. No cerebellar ataxia was present. Deep and well-developed Japanese female in no acute reflexes were slightly exaggerated in her upper left distress. Blood pressure was 130/70 mmHg,and the extremity. No pathological reflexes were noted. pulse rate 70/min and regular. No cervical was Superficial and vibration senses were normal. noted. There wasneither cardiac enlargement nor However, position, movement,stereotactic and two- heart murmur. The lungs were clear. No hepato- point discriminative sensations were diminished in splenomegaly was noted. her left hand. Neurological examination revealed an alert and The laboratory findings are summarized in Table intelligent female. Neither aphasia, apraxia nor 1. A marked increase in thrombocytes with giant agnosia was noted. Her visual acuity was 0.01 on platelets in the peripheral blood was noted (Fig. 1A). the right and 1.2 on the left. She showed a concentric Bleeding time was 1.5 min, PTT 37.9 s and PT 10.0 narrowing of the visual field bilaterally and a central s. The blood thromboxane B2 level was elevated to scotoma in her right eye. The optic fundi showed 78 pg/ml (normal: 14-50), and platelet factor 4 to occlusion of the right central retinal artery. Occular 49 ng/ml (20 >). These values were interpreted as movement,pupils and light reflex were normal. No suggesting the presence of a thrombotic tendency. nystagmus was seen. She showed left facial weakness Protein C, factor VIII, antithrombin III, fibrinogen, and deviation of the tongue to the left without FDP, oyplasmin and plasminogen inhibitor were atrophy. Other cranial nerves were intact. Her gait normal. The CSF findings were unremarkable. was normal. Slight weakness was noted in her upper Echocardiography and ECGwere normal. Ab-

Table 1. Laboratory data.

(Data on admission) RBC 442 x lO4/mm3 GOT 19 IU/1 (5-35) Hb 14.2 g/dl GPT 17 » (4-30) Ht 41.7% LDH 625 " (125-500) WBC 13800/mm3 ALP 5.5 KAU (1.6-9.9) Meta 1% BUN 1 1 mg/dl (8-17) Stab 6% Creatinine 0.7 » (0.6-1.2) Seg 72% Na 139 mEq/1 Lympho 10.5% K 3.7 " Mono 3% Cl ,104 " Eos 4.5% T 168 mg/dl (150-230) Baso 2.5% Triglycerides 89 » (37-150) PLT 824x l03/mm3 Phospholipids 179 » (150-250) Anti-cardiolipin antibody (-)

Mar3 Apr19 Apr25 May10 May20

PLT ( x lO3/mm3) 824 601 1072 1034 1268 Giant PLT + + + WBC ( /mm3) 13800 11400 12900 10100 11700 RBC ( x lOVmm3) 442 466 496 473 451 ESR (1 h/2 h) 4/12 5/ 7/18 9/24 CRP -

Mar14 Mar23 Apr20 May16 Platelet 40% 16% 28% 12% aggregation*

*ADP 2.3/uM (N: 40-70%)

Jpn J Med Vol 29, No 5 (September, October 1990) 549 Abe et al

Fig. 1. Giant platelets in the peripheral blood (A), and increase in megakaryocytes in the bone marrow (B). dominal CT scan and ultrasound examination Alow density area with scattered high density spots showedslight splenomegaly. Bone marrow examina- was seen in the right parieto-occipital area on March tion revealed mild generalized hyperplasia (Fig. IB), 9. Asimilar low density area was noted in the frontal including megakaryocytic hyperplasja. Neither lobe on April 10. Cerebral angiograms on March fibrosis nor leukemic cell infiltration was noted. The 9 (Fig. 3A) showed a narrowing in the right internal differential count of bone marrow cells was normal. carotid artery 2 cm above the bifurcation. The Chromosomeanalysis of a bone marrow aspirate appearance of the narrowing suggested "tubular wasnormal. Her neurophile alkaline phosphatase ." The left internal carotid artery showed score was 224 (240 ±60). multiple segmental narrowing and dilatation. Direct The serial cranial CT scans are shown in Fig. 2. right carotid angiograms on the same day (Fig. 4A,

Fig. 2. Cranial CT scans on March 9. A low density area with scattered high density spots is seen in the right parieto-occipital area (A), and a low density area in the frontal lobe on April 10 (B).

550 Jpn J Med Vol 29, No 5 (September, October 1990) Fibromuscular Dysplasia and Thrombocythemia

B) showed a filling defect along the wall of the right vical spine and extending into the intracranial internal carotid artery in its cavernous portion portion. The entire vascular lumen showed marked extending into the horizontal portion of the right irregular narrowing. Therenal werenormal middle cerebral artery. The terminal branches of the on the aortogram. The right carotid angiogram per- right middle cerebral artery showed multiple area of formed 10 days later (Fig. 6A) revealed no filling obstruction and narrowing, suggesting shower defect in the portion where the previous angiograms embolisms. The right vertebral angiograms on the had shown a marked filling defect. The digital sub- same day, March 9, (Fig. 5) showed segmental traction angiograms (DSA) on April 7 (Fig. 6B) narrowing originating at the level of the first cer- revealed a complete occlusion of the right internal carotid artery just above the bifurcation. Collateral circulations to the right internal carotid area were well visualized through the right ophthalmic artery and the right middle meningeal artery. She was treated with intravenous infusion of glycerol, and her weakness almost disappeared. The central scotomaand deep sensory loss of the left hand did not improve. She was then treated with a 160 mg dose of every other day and 0.75 mg carbocon daily, and was discharged on the May 24. Platelet count was 60 x lOVmm3,platelet factor 4 27 ng/ml and thromboxane B2 17 pg/ml upon discharge. For the past 6 months, since her discharge from our hospital, she has been doing well. DISCUSSION Fig. 3. The digital subtraction angiogram of cerebral We diagnosed this patient as having vessels on March 10. A narrowing (arrow) is seen in the fibromuscular dysplasia complicated by essential cervical portion of the right internal carotid artery (A), and thrombocythemia. The combination of these two multiple segmental stenoses and dilatations (arrow) in the cervical portion of the left internal carotid artery (B). disorders is rare. Essential thrombocythemia is

Fig. 4. The right carotid angiogram obtained on March 10. An irregular filling defect is seen from the cavernous portion of the internal carotid to the horizontal portion of the middle cerebral artery. Multiple occlusions are seen in the pre-central and the anterior parietal arteries (arrows), and stenoses in the posterior parietal and the angular arteries (arrowheads).

Jpn J Med Vol 29, No 5 (September, October 1990) 551 Abe et al

Fig. 5. The right vertebral angiogram obtained on March10. Segmental stenoses from the cervical to the intracranial portions, and generalized marked narrowing of the entire vessel are seen (A). Segmental stenoses are well visualized in the lateral view(B).

Fig. 6. The right carotid angiogram obtained on March 22 (A). The cavernous portion of the internal carotid and the horizontal portion of the middle cerebral artery are well visualized. The digital subtraction angiogram of the right carotid artery obtained on April 8 shows complete occlusion (arrow) of the internal carotid artery (B). characterized by an increase in thrombocytes, reported (3). The diagnostic criteria of this disorder bleeding from mucousmembranesand venous include: 1) history of bleeding or ; 2) thromboses of the extremities (1). Transient ischemic absence of asplenism, splenic atrophy or splenic attacks (2-4), amaurosis fugax (4, 5) and superior ; 3) RBC less than sagittal sinus thrombosis (6) are also not uncommon. 600x lOVmm3, Hb less than 18 g/dl, Ht less than Anabnormality in platelet aggregation has also been 54%, WBCless than 50,000/mm3 and platelets

552 Jpn J Med Vol 29, No 5 (September, October 1990) Fibromuscular Dysplasia and Thrombocythemia above 80 x lOVmm3;4) hyperplastic bone marrow summarized by Osborn and Anderson (7) as follows; and an increase in the number of megakaryocytes; 1) strings of beads (89%); 2) tubular stenosis (7%); and 5) absence of leukemic cell infiltration (1). Our and 3) diverticular outpouching (4%). Strings of case therefore fulfills the diagnostic criteria for beads usually involve the internal carotid artery at essential thrombocythemia. the level of the second cervical spine, that is, 1.5 to The abnormalities observed in the cerebral vessels 2 cm above the bifurcation (7, 12, 13). In the of this patient were remarkable: multiple segmental vertebral artery, the cervical portion is commonly narrowing and dilatation in the left internal carotid affected. The diagnosis of fibromuscular dysplasia artery; tubular stenosis of the right internal carotid is dependent upon the demonstration of the strings artery; and marked segmental narrowing and of beads in the angiogram (13, 14). To our irregularities in the vertebrobasilar artery. In a knowledge, the number of reported cases in Japan literature search, we could not find such vascular is only 20 (15). complications occurring in essential thrombocy- Concerning the pathogenesis of the neurological themia. The differential diagnoses of the vascular symptoms, tubular stenosis rather than strings of changes in our patient mayinclude fibromuscular beads is said to cause a disturbance in circulation dysplasia, , Takayasu's disease, (13, 16). It is rare to see complete occlusion of the vasospasm and stationary arterial wave. The latter internal carotid artery, as was seen in the present two conditions are considered to be functional; these case, in fibromuscular dysplasia (7, 9). In com- possibilities can be excluded because the same parison with marked vascular abnormalities, the abnormalities were seen in two separate angiograms clinical manifestations of this case wererelatively performed on different days. In Takayasu's disease, mild. The probable onset years before the vascular vascular changes are seen in the aorta, and in- changes maybe suggested from the development of flammatory responses are present in the blood. The collateral circulation. present case did not show such abnormalities. The Another interesting finding in the present case is site of predilection for atherosclerosis is the bifur- the transient filling defect in the right carotid artery cation of the external and the internal carotid arteries and multiple obstructions of the terminal branches (7). The bifurcation in this case was essentially observed on March 10. Stenosis may have been normal. In addition, the patient did not show any caused by a thrombus originating in the proximal risk factors of atherosclerosis, such as part of the right carotid artery, or a relatively fresh or . Since the patient is relatively thrombus formed in situ. Demonstration of angio- young, the possibility of atherosclerosis seems graphic evidence of shower embolisms has also unlikely. The pattern of alternating dilatation and rarely been achieved. stenosis, and tubular stenosis are characteristics of The bilateral concentric narrowing of the visual fibromuscular dysplasia. field in the present patient is further evidence of Fibromuscular dysplasia is characterized by pro- circulatory disturbance in the retina. Amarked liferation of the fibrous as well as the muscular thrombotic tendency is also supported by such tissues in the vascular wall. Although the laboratory data as an increase in thromboxaneB2 is most commonly involved, approximately 30% of and platelet factor 4. Neither of these disorders patients with fibromuscular hyperplasia show similar typically cause a severe thrombotic tendency. It may abnormalities in the extracranial parts of the inter- be that the combination of the two disorders resulted nal carotid and the vertebral arteries (8). Fibro- in these marked thrombo-embolic episodes. For muscular dysplasia may cause occurrence of instance, prostacycline formation in the diseased ischemic as well as hemorrhagic vascular events, vessels may not have prevented the thrombus including (9, 10). formation due to the increase in platelets. Asymptomatic cases have also been reported (1 1). The treatment consisted of aspirin and an Middle-aged females account for 80%of the cases alkylating agent, carbocon. While this treatment of fibromuscular dysplasia, which is usually bilateral appears to have been effective, the reason why (9, 12). Cerebral angiographic findings have been ticlopidine was not effective in alleviating thrombotic Jpn J Med Vol 29, No 5 (September, October 1990) 553 Abe et al episodes is not clear. Ticlopidine prevents platelet fugax. Int Med (Naika) 51: 984, 1983. 6) Iijima S, Nakamura S, Shio H, Kameyama M, Takeuchi aggregation by stimulating adenylate cyclase, but J. A case of superior sagittal sinus thrombosis with aspirin does so by inhibiting cyclooxygenase resulting primary thrombocythemia. Clin Neurol 20: 333, 1980. in the inhibition of thromboxane B2 formation. The 7) Osborn AG, Anderson RE. Angiographic spectrum of action of aspirin appears to be more direct in in- cervical and intracranial fibromuscular dysplasia. Stroke hibiting platelet aggregation. In fact, the throm- 8: 617, 1977. boxane B2 level remained elevated during 8) Mettinger KL. Fibromuscular dysplasia and the brain II. Current concept of the disease. Stroke 13: 53, 1982. ticlopidine administration, however it was normal 9) Mettinger KL, Ericson K. Fibromuscular dysplasia and whenaspirin and carbocon were used. In addition, the brain. Observations on angiographic, clinical and concomitant use of the alkylating agent may be genetic characteristics. Stroke 13: 46, 1982. another factor in the successful treatment of this 10) Monma S, Ohno K, Suzuki R. Coexistent fibromuscular patient. She has been free of symptoms since she was dysplasia of internal carotid arteries and intracavernous carotid - Case report. Clin Neurol 25: 1316, placed on this treatment. 1985. ll) Corrin LS, Sandok BA, House W. Cerebral ischemic ACKNOWLEDGEMENTS: We would like to thank events in patients with carotid artery fibromuscular Professor Yutaka Kuru and Associate Professor Hirotoshi dysplasia. Arch Neurol 38: 616, 1981. Sumie of the Department of Radiology, Juntendo University 12) So EL, Toole JF, Dalai P, Moody DM. Cephalic School of Medicine, for their permission to report this patient. fibromuscular dysplasia in 32 patients. Clinical findings Wealso thank Assistant Professor Yoshihisa Wakabayashi and radiologic features. Arch Neurol 38: 619, 1981. of the Department of Hematology and Dr. Naotake Sato of 13) Nishimoto S, Ueda K, Honma T. Fibromuscular the Department of Clinical Pathology, Juntendo University dysplasia of the head and the neck in Japan, in: Annual School of Medicine, for their valuable advice on essential Report of the Ministry of Health and Welfare Research thrombocythemia. Group on Cerebrovascular MoyamoyaDisease, Honda H, Ed. The Ministry of Health and Welfare, Tokyo, REFERENCES 1982, p.28. 14) Fukuuchi Y, Gotoh F. Fibromuscular dysplasia of 1) Ozer FL, Truax WE, Miesch DC, Levin WC. Primary cervico-cephalic arteries. Neurol Med(Tokyo) 19: 541 , hemorrhagic thrombocythemia. AmJ Med 28: 807, 1983. 1960. 15) Nishimoto S, Murota T, Niimi H, Kingasa K. A new 2) Levine J, Swanson PD. Idiopathic thrombocytosis. A case of fibromuscular dysplasia: Prognosis and a treatable cause of transient ischemic attacks. Neurology comment on encephalo-duro-arterio-myo-synangiosis 18: 711, 1968. (EDAMS) to cerebrovascular , 3) Saito T, Kaneko J, Mizuno Y, Yoshida M, SudaT. A in: Annual Report of the Ministry of Health and case of essential thrombocythemia with repeated Welfare Research Group on Cerebrovascular ischemic cerebrovascular accidents. Neurol Med MoyamoyaDisease, Honda H, Ed. The Ministry of (Tokyo) 16: 474, 1982. Health and Welfare, Tokyo, 1986, p.68. 4) Jabaily J, Harry JI, Laszlo J, et al. Neurologic 16) Yamamoto I, Kageyama N, Usui K, Yoshita J. manifestations of essential thrombocythemia. Ann Fibromuscular dysplasia of the internal carotid artery. Intern Med 99: 513, 1983. Unusual angiographic changes with progression of 5) Ishitsuka T, Fujishima M, Tomoda H, lino K, Omae clinical symptoms. Acta Neurochir 50: 293, 1979. T. A case of essential thrombocythemia with amaurosis

554 Jpn J Med Vol 29, No 5 (September, October 1990)