Case Report

intravenous thrombolysis in a patient with known cavernous malformation: a first case report

Abstract

The presence of a cerebral cavernous malformation (CM) is generally not regarded as an exclusion criterion to the use of intravenous tissue plasminogen activator (tPA). However, there is a conceivable risk of hemorrhaging with an intracerebral CM, which may dissuade clinicians from treating stroke patients with systemic tPA in the presence of a CM. The case of a 79-year-old man with acute ischemic stroke treated with systemic tPA in the setting of known CM is presented. The patient tolerated intravenous thrombolysis well and remained clinically stable throughout the observa- tion period. This is the first reported case (to our knowl- edge) supporting the notion that systemic thrombolysis is safe in presence of a previously clinically silent CM.

Even now a decade after its initial approval, intravenous

(IV) application of tissue plasminogen activator within 3 hours of stroke onset remains the only approved therapy for acute ischemic stroke . Contraindications to treatment are numerous and as the use of and experience with tPA increases, stroke neurologists are often challenged with situations in which the safety of thrombolysis remains unknown. The presence of an intracranial arteriovenous malformation is often considered such as contraindication to

IV thrombolysis due to the concern for symptomatic intracranial hemorrhage [1]. However, successful, deliberate off-label systemic thrombolysis has been described [2]. Conversely, absence of a listed contraindication may not always provide a straightforward answer about the treat- ment’s safety in particular settings. For example, the presence of a cerebral cavernous malformation (CM), another type of cerebral vascular malformation, is not specifically listed as an exclusion criterion to the use of IV tPA. However, its histopathologic hallmark consists of small hemorrhages within the lesion, and it has the potential to extensively hemorrhage [1,3]. Therefore, the conceivable, yet unknown, risk of thrombolysis-precipitated rupture of an intracerebral CM may dissuade clinicians from treating AIS patients with tPA in the presence of a CM. Here, we report the first case of an AIS patient with known CM who was successfully treated with tPA, with complete resolution of

neurologic deficits and without other sequelae, providing evidence that systemic thrombolysis in patients with known CM may indeed be safe.

A 79-year-old right-handed man noted an acute word finding difficulty. Within the next hour, he became severely aphasic and developed right hemiparesis.

Medical history and review of systems: He had hyperten- sion, dyslipidemia, Sleep apnea, coronary artery bypass graft secondary to dissection of his right coronary artery after cardiac catheterization, atrial fibrillation status post cardio conversion (in Sinus bradycardia at time of presentation), and a stable, asymptomatic intracerebral CM (Fig. 1A-C). He had a remote smoking history and no alcohol or illicit drug use. Review of systems was otherwise unremarkable.

Examination: The patient had severe expressive aphasia, a right facial paresis, and a right brachiofacially predominant hemiparesis. On admission, his National Institutes of Health Stroke Scale score was 11.

Imaging findings and clinical course: The initial computed tomography (CT) of the head demonstrated a left-sided hyperdense Middle cerebral artery sign (Fig. 1D), and CT angiography confirmed complete occlusion of the left middle cerebral artery at its M1-M2 junction (Fig. 1E). Perfusion CT demonstrated a significant cerebral blood volume-mean transit time mismatch (ie, penumbra\) in the left insula and inferior frontal regions (not shown). The patient subsequently received intravenous tPA at 2.3 hours after symptom onset. His condition started to improve within the following 1.5 hours. Perfusion CT at 15 hours after presentation demonstrated almost complete resolution of the previously noted ischemic area (not shown), and neurologic examination on poststroke day 1 was normal. Magnetic resonance imaging (MRI) 30 hours after tPA treatment showed 2 punctuate areas with restricted diffusion in the left temporal and parietal lobes, respectively (Fig. 1F). There was no evidence of intracranial hemorrhage or expansion of the known CM when compared to a pretreatment MRI.

Cavernous malformations comprise 5% to 13% of intracranial vascular malformations and can be found in every region of the brain and the brainstem [3]. Although CM may cause potentially fatal hemorrhaging, their annual risk for clinically significant bleeding is relatively low at 0.25% to 6% [3], likely owing to low flow and pressure within the malformation. However, an individual patient’s hemorrhage risk is difficult to project [3-5]. Risk factors for

0735-6757/$ – see front matter (C) 2010

117.e2 Case Report

Fig. 1 A, Axial T2-weighted MRI demonstrating a small left temporal lobe CM before treatment with tPA. B, Detail from A. C, multiplanar gradient recalled-weighted MRI from the same region as shown in B. D, Unenhanced CT of the head demonstrating focal hyperDense middle cerebral artery sign (arrow). E, Coronal CT angiogram indicating M1-M2 junction occlusion (arrowhead). F, Diffusion- weighted axial MRI demonstrating small punctate Ischemic infarct in the left temporal lobe at 30 hours after thrombolysis. Asterisks denote CM on pretreatment MRI.

bleeding include family history, previous hemorrhage, CM growth, de novo appearance, extensive calcifications, pregnancy, and possibly age and anatomical location. One study suggested that endogenous tPA might be a mediator of symptomatic CM hemorrhage [4,6]. Heparin may increase endogenous tPA activity, and heparin induced rupture of cavernous malformations has been described [7,8]. However, there are no studies or case reports regarding the use of thrombolytics in the setting of a present CM [1,9]. Despite these daunting facts, we believe that the decision to offer thrombolysis to AIS patients with CM should be carefully considered. Each year, only about 2% of the 615 000 patients experiencing a new or recurrent ischemic stroke in the United States receive treatment with tPA. A significant proportion of eligible patients remain untreated because of presumed contraindications because safety and efficacy data are lacking for particular clinical circumstances [1,9,10]. Given the estimated population prevalence of 0.2% to 0.6% for CM [3,11], it is conceivable that many other patients carrying an occult CM have inadvertently received thrombolysis without complication. Although the actual risk of thrombolysis-associated intra- cranial hemorrhage is unknown, we believe it is low in the setting of a previously clinically silent CM in patients without other purported risk factors for bleeding. Given the lack of published data regarding tPA-associated bleeding risk in presence of CM, an individualized decision to provide thrombolysis appears justified.

Nils Henninger MD

Nabil Ahmad Jane G. Morris Department of Neurology

University of Massachusetts Medical Center

Worcester, MA 01655, USA E-mail address: [email protected]

doi:10.1016/j.ajem.2009.04.008

References

1. De Keyser J, Gdovinova Z, Uyttenboogaart M, et al. intravenous alteplase for stroke: beyond the guidelines and in particular clinical situations. Stroke 2007;38:2612-8.
2. Sumner CJ, Golden JA, Hemphill III JC. Should thrombolysis be contraindicated in patients with cerebral arteriovenous malformations? Crit Care Med 2002;30:2359-62.
3. Raychaudhuri R, Batjer HH, Awad IA. Intracranial cavernous angioma: a practical review of clinical and biological aspects. Surg Neurol 2005;63:319-28 [discussion 328].
4. Maiuri F, Cappabianca P, Gangemi M, et al. Clinical progression and familial occurrence of cerebral cavernous angiomas: the role of angiogenic and growth factors. Neurosurg Focus 2006;21:e3.
5. Maraire JN, Awad IA. Intracranial cavernous malformations: lesion behavior and management strategies. Neurosurgery 1995;37:591-605.
6. Frim DM, Zec N, Golden J, et al. Immunohistochemically identifiable tissue plasminogen activator in cavernous angioma: mechanism for re- hemorrhage and lesion growth. Pediatr Neurosurg 1996;25:137-41 [discussion 141-2].

Case Report 117.e3

1. Zhao BQ, Ikeda Y, Ihara H, et al. Essential role of endogenous tissue plasminogen activator through matrix metalloproteinase 9 induction and expression on heparin-produced cerebral hemorrhage after cerebral ischemia in mice. Blood 2004;103:2610-6.
2. Pozzati E, Zucchelli M, Marliani AF, et al. Bleeding of a familial cerebral cavernous malformation after prophylactic anticoagulation therapy. Case report. Neurosurg Focus 2006;21:e15.
3. Aleu A, Mellado P, Lichy C, et al. hemorrhagic complications after off-label thrombolysis for ischemic stroke. Stroke 2007;38:417-22.
4. Hills NK, Johnston SC. Why are eligible thrombolysis candidates left untreated? Am J Prev Med 2006;31:S210-6.
5. Soderman M, Andersson T, Karlsson B, et al. Management of patients with brain arteriovenous malformations. Eur J Radiol 2003;46: 195-205.