Original Paper Cerebrovasc Dis 1999;9:28–33 Received: June 25, 1997 Accepted: April 20, 1998 Thrombus in Vertebrobasilar Dolichoectatic Artery Treated with Intravenous Urokinase Michael De Georgia a John Belden a Linda Pao a Michael Pessin a Eddie Kwan b Louis Caplan a Departments of a Neurology and b Neuroradiology, New England Medical Center, Boston, Mass., USA Abstract Background: Vertebrobasilar dolichoectasia is often found in patients with posterior circulation ischemia. Brain ischemia is caused by abnormal flow in the dilated artery and obstruction of paramedian arteries or intraluminal thrombus with artery-to-artery embolism. We report a patient with vertebrobasilar dolichoectasia and luminal thrombus treated with intravenous urokinase who did well but died 2 months later of subarachnoid hemorrhage. Case Description: A 60-year-old man developed right-hand clumsiness, dysarthria and ataxia. Computed tomography showed vertebrobasilar dolichoectasia and thrombus in the basilar artery. Symptoms quickly resolved on heparin but recurred on warfarin and again resolved on heparin. Two weeks later, while on warfarin and aspirin 325 mg, he developed hand numbness, oscillopsia and ataxia. Symptoms again resolved on heparin. Angiography showed severe dolichoectasia of the distal right vertebral artery and basilar artery. A large mural thrombus was detected in the ventral part of the distal ABC © 1999 S. Karger AG, Basel 1015–9770/99/0091–0028$17.50/0 Fax + 41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Accessible online at: http://BioMedNet.com/karger basilar artery narrowing the lumen by 50%. He was treated with intravenous urokinase 4,400 units/kg as a bolus followed by 4,400 units/kg/h for 12 h. Repeat angiography showed almost complete recanalization and improved filling of basilar artery branches. He was maintained on warfarin and aspirin 81 mg and had no further ischemic episodes. He died 2 months later of rupture of the basilar artery and subarachnoid hemorrhage. Conclusion: Some patients with thrombosis of vertebrobasilar dolichoectactic arteries continue to have ischemic symptoms despite adequate anticoagulation. Intravenous thrombolysis may be effective in reducing the risk of stroke, but the risk/benefit ratio needs to be assessed in each patient. Introduction Arterial dolichoectasia has a predilection for the intracranial vertebral and basilar arteries [1]. The elongated dilated arteries may compress and distort the brainstem and the cranial nerves and can occasionally cause obstruction of the ventricular system [2–10]. Brain ischemia is also known to occur and the presumptive mechanisms of Dr. Michael De Georgia Department of Neurology State University of New York Health Science Center at Syracuse 750 East Adams Street, Syracuse, NY 13210 (USA) Tel. +1 315 464 5357, Fax +1 315 464 5006 Downloaded by: Chalmers University of 198.143.54.65 - 1/21/2016 7:41:25 AM Key Words Vertebrobasilar dolichoectasia W Aneurysm W Ischemic stroke W Thrombolysis stroke have been described [11–14]. Flow within the dilated dolichoectatic arteries, studied by transcranial Doppler ultrasound, is often abnormal with to and fro antegrade and retrograde passage of segments of the blood column [14–16]. The abnormal flow patterns and regions of stagnation within the dilated arteries can cause hypoperfusion and also promote intraluminal thrombus formation [11, 12]. The orifices of penetrating and circumferential branches of the intracranial vertebral and basilar arteries can be distorted or blocked by aneurysmal deformities, atheromatous plaques and intraluminal thrombus [11, 17]. Thrombi within the lumen can embolize distally [11, 12]. Dolichoectasia of the posterior circulation arteries is now readily diagnosed by computed tomography (CT) and magnetic resonance imaging (MRI) [5, 9, 15, 18–22]. These neuroimaging techniques can also sometimes show thrombi within the abnormal arteries. Little is known about the risks and benefits of various potential treatments for intraluminal thrombi within dolichoectatic arteries. We now report a patient with extensive thrombus within a dolichoectatic basilar artery in whom brain ischemia improved after lysis of the clot using intravenous urokinase. Unfortunately the patient died of dissection of the dolichoectatic artery 2 months after thrombolysis. Fig. 1. CT showing vertebrobasilar dolichoectasia with crescentshaped hyperdensity in the trunk of the basilar artery consistent with thrombus. Case Report A 60-year-old college professor developed right-hand clumsiness, slurred speech and ataxia on October 15, 1994. CT showed a dolichoectatic basilar artery with a crescent-shaped hyperdensity in the anterior part of the vessel consistent with thrombus (fig. 1). A reconstructed CT angiogram (spiral CT scan) confirmed the vertebrobasilar dolichoectasia (fig. 2) and he was anticoagulated with heparin. Within 20 min his symptoms resolved. He was discharged October 23, 1994 on warfarin but was readmitted 18 h later because of recurrence of ataxia, dysarthria and right-limb dysfunction. Shortly after beginning heparin his symptoms resolved. He was discharged October 31, 1994 on warfarin and aspirin 325 mg daily. November 7, 1994 he developed numbness of the left fingertips and toes, oscillopsia and ataxia. The international normalized ratio (INR) was subtherapeutic and he was again started on heparin and again had resolution of symptoms. November 21, 1994 he had a percutaneous lung biopsy because of a coin lesion seen on the admission chest X-ray. The heparin was discontinued for 4 h before the procedure during which time he developed tingling of his left arm and leg and dysarthria. Heparin was restarted and his symptoms resolved. A repeat CT angiogram showed narrowing of the basilar arterial lumen consistent with increased thrombus formation and he was transferred to the New England Medical Center for further management. He had a history of borderline hypertension and smoked a pipe until 10 years ago. His father died at age 64 of a subarachnoid hemorrhage (SAH) from a ruptured basilar artery aneurysm. The autopsy showed degeneration of the muscular and internal elastic layers of multiple arteries and no significant atherosclerosis. Physical examination revealed a blood pressure of 130/90. The general medical examination was normal. There were no neck or cranial bruits. He was alert and oriented. Eye movements were normal. There was mild downward rotatory nystagmus when looking to the right and small amplitude vertical nystagmus when looking up. Reflexes were brisk in all limbs and plantar responses were neutral. He had normal strength and sensation. There was slight dysmetria on finger-to-nose and heel-to-shin testing (left more than right) and rapid alternating movements were slightly clumsy on the left. His gait was wide-based with short, slow steps. Catheter angiography showed severe dolichoectasia of the distal right vertebral artery after the origin of the right posterior inferior cerebellar artery. The basilar artery was ectatic and looped to the left. There was a large mural thrombus in the ventral part of the basilar artery especially the distal two-thirds of the vessel. The diameter of the lumen was narrowed by at least 50% (fig. 3). Because of the size and layered appearance of the thrombus, local intra-arterial thrombolysis was not attempted. The patient was treated instead with an intravenous infusion of urokinase (Abbokinase®, Abbott Laboratories) similar to the protocol used in patients with pulmonary emboli [23]. He received an initial bolus of 4,400 units/kg over 10 min at 90 ml/h followed by a continuous infusion of 4,400 units/kg at a rate of 15 ml/h for 12 h. During the infusion, he had three transient epi- Thrombus in Vertebrobasilar Dolichoectatic Artery Treated with Intravenous Urokinase Cerebrovasc Dis 1999;9:28–33 Downloaded by: Chalmers University of 198.143.54.65 - 1/21/2016 7:41:25 AM 29 cle, right midbrain and a small area of the right cerebellar hemisphere. He was discharged on December 23, 1994 on warfarin (with the INR to be kept between 3 and 4) and aspirin 81 mg daily. The patient did well until February 11, 1995 when he developed a severe occipital headache, vomiting and coma. A repeat head CT scan showed a large SAH and hydrocephalus and the patient died. Neuropathology revealed dissection of the basilar artery. The artery was dilated to 2.0 cm at its mid-portion and was largely filled with clotted blood that dissected into the media of the vessel wall. The dissection extended approximately 1.0 cm rostral caudal from the mid-portion of the vessel. Microscopic examination of the basilar artery showed disruption of the internal elastic membrane and infiltration of the media by red blood cells. Discussion b Fig. 2a, b. CT angiography showing a dilated and tortuous basilar artery. sodes of left-sided weakness and dysarthria each lasting 5 min. Repeat angiography after the 12-hour infusion showed a significant decrease in the amount of mural thrombus. There was also improved filling of the left posterior cerebral artery and less stasis (fig. 4). He was maintained on heparin and aspirin 81 mg daily and had no further ischemic episodes. MRI done on December 5, 1994 showed infarctions of the pons bilaterally, the right middle cerebellar pedun- 30 Cerebrovasc Dis 1999;9:28–33 De Georgia/Belden/Pao/Pessin/Kwan/ Caplan Downloaded by: Chalmers University of 198.143.54.65 - 1/21/2016 7:41:25 AM a Dolichoectasia refers to widening and elongation of blood vessels. Synonyms include fusiform, circoid, or Sshaped aneurysm, dolichoectatic anomaly or malformation, vascular tortuosity, megadolichoectasia, and dilatative arteriopathy. Intracranial dolichoectasia is increasingly recognized with the wiedespread use of magnetic resonance angiography (MRA). The incidence ranges from 0.06% [3] to 5.8% [8] depending on how it is defined. The vertebral and basilar arteries are most frequently involved [1–3, 21]. Aichner et al. [20] reported the incidence of symptomatic vertebrobasilar dolichoectasia among 6,185 brain MRI examinations to be 0.25%. In a recent study using MRA, 12 of 70 (17%) consecutive patients with vertebrobasilar ischemia had dolichoectasia, 5 of whom had no other explanation for their ischemic symptoms [24]. The pathogenesis of vertebrobasilar dolichoectasia has not been well studied. Most patients are men older than 50 years with atherosclerosis and hypertension [4]. Dolichoectasia has also been described, however, in patients without atherosclerosis, and in children [1, 25, 26]. Pathological examination in young patients with dolichoectasia has shown deficiencies in the muscular and internal elastic layers with irregular thickness of the media and regions of fibrosis. At times, the intima is thickened and there is severe elastic tissue degeneration and an increase in the vasa vasorum. Read and Esiri [25] reported defects of the internal elastic lamina in an 11-year-old girl who died after rupture of a basilar artery aneurysm; necropsy showed that the artery had large gaps in the internal elastic lamina with only short segments of elastica remaining in some regions. Makos et al. [26] described 3 teenage siblings with basilar artery aneurysms and alpha-glucosidase deficiency, a glycogen storage disease. Postmortem examination showed loss of the internal elastic lamina and a a b b tasia of the basilar artery looping to the left. Large mural thrombus in the distal two thirds of the vessel, seen best on the lateral image, narrowing the arterial lumen by 50 %. Decreased filling of basilar branch vessels and left posterior cerebral artery. Thrombus in Vertebrobasilar Dolichoectatic Artery Treated with Intravenous Urokinase Fig. 4a, b. Postthrombolysis angiography showing a significant decrease in the amount of mural thrombus and improved filling of basilar branch vessels and left posterior cerebral artery. Cerebrovasc Dis 1999;9:28–33 31 Downloaded by: Chalmers University of 198.143.54.65 - 1/21/2016 7:41:25 AM Fig. 3a, b. Prethrombolysis angiography showing severe dolichoec- 32 Cerebrovasc Dis 1999;9:28–33 arterial rupture is that layered thrombus along the vessel wall may fortify it reducing the risk of rupture. SAH from vertebrobasilar dolichoectasia alone was not seen in large series of patients with dolichoectasia [3, 6, 7]. Whenever SAH occurred, a separate cause such as concomitant saccular aneurysm, carotid fusiform aneurysm, or uncontrolled hypertension was found. Recently, there has been renewed interest in thrombolytic therapy for acute thromboembolic stroke and several multicenter, randomized controlled trials have evaluated the safety and effectiveness of this therapy in the anterior circulation. Although a placebo-controlled study has not been done, thrombolytic therapy has been used successfully in patients with vertebral and basilar artery occlusions. In the two largest series, which included a total of 105 patients with basilar artery thrombosis, 83 (79%) were treated with thrombolytic agents [30, 31]. Hacke et al. [30] reported recanalization in 19 of 43 patients (44%) treated with intra-arterial urokinase or streptokinase. All patients without recanalization died but 14 of the 19 with recanalization survived (10 with a good outcome). In the other large series, von Kummer et al. [31] reported 40 patients with basilar artery occlusions treated with either intra-arterial (34) or intravenous thrombolytic agents (6). Recanalization occurred in 23 patients (58%). Mortality was high in those who did not recanalize after treatment (16 of 17 patients, 94%) compared with those who did recanalize (11 of 23 patients, 48%). Little is known about thrombolysis in those with vertebrobasilar dolichoectasia. Pessin et al. [11] reported 1 patient treated with intra-arterial streptokinase for a dilated and tortuous left vertebral and basilar artery with thrombus in the distal basilar artery. He became comatose and died in hospital after 36 h. Neuropathology showed the lumen of the basilar artery to be filled with thrombus. A recent hemorrhagic infarct was present in the left occipital cortex and a corresponding embolus occluded a branch of the left posterior cerebral artery. To our knowledge this is the only report of thrombolytic therapy in a patient with vertebrobasilar dolichoectasia. We chose an intravenous infusion of urokinase in this patient because of the large quantity of layered thrombus which had probably built up over several weeks. A continuous 12-hour infusion was thought to be better than a single-intra-arterial injection in safely and steadily removing a chronic thrombus. The stasis within a dolichoectatic vessel may ironically aid intravenous thrombolysis by concentrating the drug at the site of the thrombus. The risks of thrombolysis in this setting are not known. Although repeat angiography in our patient showed al- De Georgia/Belden/Pao/Pessin/Kwan/ Caplan Downloaded by: Chalmers University of 198.143.54.65 - 1/21/2016 7:41:25 AM vacuolation of the medial smooth muscle. Other authors have reported similar defects in older patients with ectatic basilar arteries [27–29]. There may be an interaction between variable degrees of congenital smooth muscle insufficiency and vascular risk factors. For example, lipid deposition beneath the intimal layer may cause disruption of the internal elastic lamina and muscular wall that is incompletely repaired because of congenital smooth muscle insufficiency [27]. The resultant atrophy of the elastic substance and musculature allows intravascular pressure to widen and elongate the artery [1, 27]. With increasing dilatation, blood flow velocity is reduced and thrombi build up in ring-shaped layers along the vessel wall. In our patient the structural anatomy of the vessel wall was disrupted by dissection but we suspect that he probably did have a defect in the internal elastic membrane and muscular layer like his father. Electron microscopy of a skin biopsy done during life also showed structural alterations of collagen fibrils and elastic fibers suggestive of an inherited connective tissue disorder. Atherosclerosis appeared to play little role in the development of ectasia in our patient and his father. The clinical features of vertebrobasilar dolichoectasia are quite variable. Patients may be asymptomatic but when symptoms occur they generally result from either compression of nearby structures as the artery thickens and expands our brainstem ischemia. The seventh cranial nerve is mainly affected although all cranial nerves have been reported. Compression of the posterior third ventricle and aqueduct can also cause hydrocephalus. More commonly, patients present with ischemia from focal narrowing, chronic deposition of intraluminal thrombus with local artery to artery embolism, or obstruction of paramedian penetrating arteries. Nishizaki et al. [6] studied 23 patients with vertebrobasilar dolichoectasia and found 5 (21%) with cranial nerve compression and 12 (52%) with brainstem ischemia. Echiverri et al. [7] found 4 (31%) with compressive symptoms and 10 (77%) with ischemic symptoms. One patient had both compressive and ischemic symptoms. Yu et al. [3] studied 17 patients and found 6 (35%) with compressive symptoms and 9 (53%) with brainstem ischemia. Finally, Pessin et al. [11] reported 7 patients with brainstem infarction. All patients had pontine infarcts and 1 also had a cerebellar infarct. Obstruction of pontine penetrating arteries and intraluminal thrombus resulted in unilateral pontine infarcts whereas basilar artery occlusion resulted in bilateral pontine infarcts. SAH has only rarely been reported as a complication of dolichoectasia. One possible explanation for the rarity of most complete recanalization of the artery, during the infusion he had three ischemic episodes which may have been from small emboli released from the dissolving thrombus. Whether thrombolysis contributed to the hemorrhagic infarction in the patient reported by Pessin et al. [11] is not clear. Our patient had no futher ischemic symptoms after intravenous thrombolysis. He died of dissection of the basilar artery and subarachnoid hemorrhage 2 months later. He was previously only mildly hypertensive but his blood pressure at the time of the rupture is not known and could have played a role. Although shortly before his death, the INR was therapeutic, it is possible that it was excessive at the time of the rupture. Finally, it is possible that thrombolysis, by removing built-up thrombus, reduced the risk of further ischemia but at the same time increased the risk of vessel wall rupture. In conclusion, some patients with thrombosis of vertebrobasilar dolichoectatic arteries continue to have ischemic symptoms despite adequate anticoagulation. Thrombolytic therapy may be effective in reducing the risk of stroke, but the risk/benefit ratio needs to be assessed in each patient. Similarly, long-term anticoagulation after thrombolysis in patients with vertebrobasilar dolichoectasia may be warranted to prevent reaccumulation of thrombus but, again the risk/benefit ratio needs to be individually assessed. 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