bs_bs_banner

Neuropathology 2015; 35, 70–74

doi:10.1111/neup.12152

Cas e Rep o r t

Cerebral amyloid angiopathy related hemorrhage after stroke thrombolysis: Case report and literature review Olli S. Mattila,1,4,5 Tiina Sairanen,1 Elina Laakso,1 Anders Paetau,2 Maarit Tanskanen3 and Perttu J. Lindsberg1,4,5 Departments of 1Neurology and 2Pathology, Helsinki University Central Hospital, Helsinki, 3Department of Pathology, Kanta-Häme Central Hospital, Hämeenlinna, 4Research Program of Molecular Neurology, Research Programs Unit, and 5 Department of Clinical Neurosciences, University of Helsinki, Helsinki, Finland

Cerebral amyloid angiopathy (CAA) predisposes to symptomatic intracerebral hemorrhage (sICH) after combined thrombolytic and anticoagulant treatment of acute myocardial infarction. However, the role of CAA in stroke thrombolysis has not been established. Here, we describe a confirmed case of CAA-related hemorrhage in a patient receiving thrombolysis for acute ischemic stroke. On autopsy, immunohistochemistry revealed amyloid-β positive staining in thickened cortical and meningeal arteries at sites of hemorrhage. Further research is urgently needed to determine the hemorrhage risk related to CAA in stroke thrombolysis and develop better diagnostic tools to identify CAA in the emergency room. Key words: cerebral amyloid angiopathy, intracerebral hemorrhage, ischemic stroke, subarachnoid hemorrhage, thrombolysis.

INTRODUCTION Symptomatic intracerebral hemorrhage (sICH) after stroke thrombolysis is unpredictable and often represents a catastrophe for both the patient and the treating physician.1 While there are numerous known risk factors2 and clinical scores for recognizing patients at high risk, the majority of sICH occurs in patients with only a few identifiable risk factors.3 Underlying cerebrovascular pathology is a likely predisposing element, especially when the hemorrhage occurs outside the ischemic territory, reported in ∼3% of thrombolyzed stroke patients.4,5 Theo-

Correspondence: Olli S. Mattila, MD, Biomedicum Helsinki 1, Haartmaninkatu 8, 00290, Helsinki, Finland. Email: olli.s.mattila@ helsinki.fi Received 5 May 2014; revised and accepted 1 August 2014; published online 6 November 2014.

© 2014 Japanese Society of Neuropathology

retically, one such pathology could be cerebral amyloid angiopathy (CAA), defined as gradual deposition of amyloid-β protein around capillaries and arterioles of the cortex and meninges. Prevalence of CAA increases with age, estimated to be 20%, 30% and 40–60% in 60–69, 70–79 and 80–97 yearolds, respectively, based on autopsy studies.6 Advanced CAA entails a specific vasculopathy that gives rise to cerebral microbleeds (CMB) and microscopic infarctions,7 or most devastatingly, to CAA-associated intracerebral hemorrhage (CAAH). Importantly, experimental studies have shown that amyloid protein has local protease-enhancing, profibrinolytic and anticoagulant properties which predispose to hemorrhage.6 CAAH comprises 5–10% of spontaneous ICH, and is typically: (i) multifocal; (ii) lobar; and (iii) extends to subarachnoidal and subdural spaces. CAA has been associated with sICH after combined thrombolytic and anticoagulant treatment of acute myocardial infarction (AMI)8 but the role of CAA has not been defined in stroke thrombolysis. Here, we report clinical and neuropathological findings of a patient with multifocal sICH after stroke thrombolysis, showing a clear spatial relation between CAA pathology and sites of hemorrhage.

CLINICAL AND PATHOLOGICAL FINDINGS A 71-year-old woman was admitted to our neurological emergency department due to sudden onset aphasia. Her medical history included a non-Q myocardial infarction 10 years earlier, she was a smoker (>10 cigarettes/day) and her medication comprised of aspirin (100 mg), simvastatin (20 mg), bisoprolol (10 mg) and citalopram (20 mg). At the time of symptom onset she had an upper respiratory tract infection together with slight headache.

Thrombolysis-associated hemorrhage in CAA

71

On admission the physical examination was normal except for moderate aphasia, scoring 3 points on the NIH stroke scale. The brain CT showed no signs of early infarction, bleeding or dense intracranial vessels, but demonstrated moderate periventricular vascular degeneration (Fig. 1A). Point-of-care international normalized ratio was 1.3, blood pressure 142/86 mmHg, glucose 140 mg/dL and body temperature 38.1°C. She therefore scored 0 points on the SEDAN score (blood Sugar, Early ischaemic changes, hyperDense artery sign, Age, and NIH Stroke Scale (NIHSS) score), used for estimating probability of thrombolysis-related sICH, with 0 points indicating lowest possible risk.3 Thrombolysis was started 81 min after symptom onset (11 min after hospital arrival) with a 50 mg total dose of intravenous recombinant tissue plasminogen activator (rtPA), for a body weight of 56 kg. Activated partial thromboplastin time was 25 s, tromboplastin time 15 s, platelets 213 E9/L, and hemoglobin 133 g/L. CRP and leukocyte counts were elevated, 109 mg/L and 14.9 E9/L respectively. Chest X-ray did not show any infiltrates, while ECG

A

showed sinus rhythm with a ventricular rate of 94/min and signs of left ventricular hypertrophy. Blood pressure remained at 140/80 mmHg during thrombolysis. At the end of thrombolysis the patient developed an intense headache and her aphasia worsened. A new CT scan taken 1 h after rt-PA infusion showed cortical ICH in the left temporal lobe and right parietal and frontal lobes, also extending to the subarachnoid space, together with small bilateral subdural hemorrhages (Fig. 1B). Her level of consciousness declined further, and propofol sedation and intubation were required. Fresh frozen plasma (650 mL) and tranexamic acid (1 g) were administered, and cefuroxime treatment (4.5 g/day) was started. After 18 h she developed anisocoria and a follow-up CT scan showed enlargement of the hemorrhages and edema, together with subfalcine herniation (Fig. 1C). By the second morning CRP was 320 mg/L, hemoglobin 92 g/L and thrombocytes 115 E9/L. Streptococcus pneumoniae was detected in blood cultures taken on admission. Despite the discontinuation of sedation the patient remained comatose and died 6 days after admission.

B

C

Fig. 1 Radiological findings. (A) The admission brain CT showed moderate periventricular vascular degeneration, but no other pathological findings. (B) The follow-up brain CT obtained after neurological deterioration showed CAA-type lobar intracerebral hemorrhage (ICH) in the left temporal lobe, and right frontal and parietal lobes. Blood was also seen bilaterally in the subarachnoid and subdural spaces. (C) Another follow-up brain CT obtained 20 h after symptom onset showed further enlargement of hemorrhage and edema, midline shift and subfalcine herniation.

© 2014 Japanese Society of Neuropathology

72

OS Mattila et al.

A

B

C

D

Fig. 2 Neuropathological findings. (A) Ischemic pycnotic red neurons in the underlying right frontal cortex. HE, scale bar = 50 μm. (B) Subarachnoid hemorrhage (SAH) in the right frontal middle cerebral artery region, displaying a typical thickened meningeal amyloid angiopathic arteriole. HE, scale bar = 100 μm. (C) Amyloid-β positive vessels in connection with the lobar intracerebral hemorrhage (ICH) in the left temporal lobe. Amyloid-β IHC, scale bar = 200 μm. (D) Amyloid-β positive ruptured vessel in the left temporal lobar ICH. Amyloid-β IHC, scale bar = 50 μm.

Neuropathological evaluation revealed a brain weighing 1611 g, with subarachnoid hemorrhage (SAH), multifocal ICH and herniation at previously mentioned sites. Diffuse acute infarction was seen in the right frontal lobe (Fig. 2A). Microscopy showed thickening of arteries in the subarachnoid space (Fig. 2B) and cortex bilaterally, also at the sites of hemorrhage, with widespread positivity in Congo red staining and strong immunoreactivity for amyloid-β protein (Fig. 2C,D), indicating the presence of extensive CAA. There was also cracking of blood vessels with fibrinoid necrosis centered on the hemorrhage sites. In addition, there were early signs of Alzheimer’s disease, with a Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) B level of senile plaques, and a Braak IV stage of neurofibrillary tangles.

DISCUSSION We describe a case of neuropathologically confirmed CAA as a predisposing factor for sICH after stroke thrombolysis, showing severe CAA pathology at sites of hemorrhage. Our report appears in parallel with a matching case study by Felling et al.,9 together highlighting a new role for CAA as a hemorrhage risk factor in stroke thrombolysis.

We could not determine the definite etiology of initial aphasia in our patient, as autopsy did not reveal infarction in corresponding brain areas. Initial ischemia may have been reversed by early thrombolysis. Alternatively, aphasia could have been an acute transient focal neurological episode (TFNE) known to associate with CAA,10 but the admission CT scan did not reveal any blood in cortical sulcal spaces, a finding which is often associated with these episodes. Based on follow-up imaging studies and symptom development, infarction in the right frontal lobe was likely initiated later, as a consequence of hemorrhage and herniation. CAA in our patient was widespread and severe, corresponding to grade 4 in the hemorrhagic regions when graded after Greenberg and Vonsattel.11 Moreover, the amyloid-laden blood vessels were situated directly in the hemorrhage areas. These findings refer CAA to be causative for hemorrhage in our patient.11 However, there are several other factors that may have also contributed to hemorrhage formation and development. Our patient had a streptococcal infection with associated fever, bacteremia and leukocytosis that could increase bleeding risk, but the importance of these risk factors is uncertain.2 The possibility of infective endocarditis was ruled out on autopsy. Prior © 2014 Japanese Society of Neuropathology

© 2014 Japanese Society of Neuropathology

Based on reported activated partial thromboplastin time (APTT) values. AMI, acute myocardial infarction; SAH, subarachnoid haemorrhage; IVH, intraventricular haemorrhage. †

Multifocal lobar hemorrhage, IVH, SAH Two hematomas, SAH Multifocal lobar hemorrhage Multifocal lobar hemorrhage + IVH Multifocal lobar hemorrhage Multifocal lobar hemorrhage, SAH Multifocal lobar hemorrhage, SAH Wijdicks and Jack15 Pendlebury et al.16 Sloan et al.8 Sloan et al.8 Sloan et al.8 Felling et al.9 Mattila et al.

AMI AMI AMI AMI AMI Acute ischemic stroke Acute ischemic stroke

Streptokinase Alteplase Alteplase Alteplase Alteplase Alteplase Alteplase

Yes Yes Yes Yes Yes No No

8 h from start of thrombolysis Onset time unclear, CT scan 18 h from start of thrombolysis 12 h from thrombolysis 6 h from start of thrombolysis 11.8 h from start of thrombolysis 7.5 h from start of thrombolysis 9.5 h from start of thrombolysis Immediately after thrombolysis Immediately after thrombolysis Yes† Yes Streptokinase Streptokinase AMI AMI Subdural hemorrhage, multifocal lobar hematomas Single lobar hematoma, SAH Ramsay et al.13 Leblanc et al.14

Onset of ICH symptoms Heparin treatment Thrombolytic drug Indication for thrombolysis Hemorrhage type Publication

use of antiplatelets and leukoaraiosis are both known to increase hemorrhage risk, but are not contraindications for thrombolysis.2 Finally, anemia and thrombocytopenia during follow-up, and low low-density lipoprotein levels, may have contributed to hematoma expansion.12 Despite these relative risk factors, the decision to administer thrombolytics followed our institutional guidelines, and was further supported by the short onset-to-treatment time. Our case study, and that of Felling et al.,9 contrast with earlier reports connecting CAA and sICH after thrombolytic treatment (Table 1). First, earlier cases have occurred in the setting of AMI, without initial symptomatic cerebral lesions. Second, these patients were treated with a combination of both thrombolytic and adjuvant anticoagulant drugs.14 Finally, in all AMI cases sICH occurred several hours after the infusion of thrombolytics. Literature on sICH after thrombolysis of AMI largely emphasizes the negative effects of thrombolytics, listing systemic hypofibrinogenemia (especially with streptokinase treatment) and local pro-proteolytic effects of plasminogen activators as key mediators. In the case of CAA, these direct effects are supported by data on APP23 transgenic CAA mice, which develop microhemorrhages, and even ICH, after rt-PA administration.17 However, anticoagulation with heparin seems to be more significant in enlargement of microhemorrhages to symptomatic parenchymal hematomas: in mouse models of laser-induced cortical microhemorrhage and collagenase-induced ICH, anticoagulation led to significantly larger hemorrhage volumes, while tPA administration had no such effects.18 Because of adjuvant anticoagulation, CAA may be a more significant risk factor in thrombolysis of AMI as opposed to stroke thrombolysis. There are no guidelines on how CAA should be taken into account when administering thrombolytics.At present, a definite diagnosis of CAA can only be established by neuropathological analysis. The most common surrogate marker is identification of CMBs in typical corticosubcortical positions by T2*-weighted MRI. A recent meta-analysis investigating CMBs as a risk factor for thrombolysis-associated sICH only found a trend toward increased risk, although the studies did not focus on patients with CAA-type CMB findings.19 Similarly, although the ApoE ε4-allele is associated with increased risk for developing CAA,20 no connection has been found between ApoE ε4 and thrombolysis-related sICH risk. MRI images or ApoE genotype were not acquired in our patient case, which is a limitation of our case study. Robust radiological or point-of-care biomarkers of CAA should be developed to characterize the bleeding risk associated with CAA during stroke thrombolysis. Neuropathological registries of victims of fatal thrombolysis-

73 Table 1 Characteristics of reported patients with fatal symptomatic intracerebral hemorrhage after thrombolytic treatment together with neuropathologically confirmed cerebral amyloid angiopathy

Thrombolysis-associated hemorrhage in CAA

74

OS Mattila et al.

related sICH are needed to identify the prevalence and role of underlying cerebrovascular pathology, and to retrospectively validate hypotheses arising from experimental and clinical registry studies. 9.

DISCLOSURES The authors report no disclosures. None of the authors took part in the acute treatment of the patient.

10.

ACKNOWLEDGMENTS TS is supported by research funding from the Maire Taponen Foundation. PJL is supported by research grants from the Helsinki University Central Hospital governmental subsidiary funds for clinical research, the Finnish Academy, the Sigrid Jusélius Foundation, the Maire Taponen Foundation, and the Paavo Nurmi Foundation.

11.

12.

REFERENCES 1. Strbian D, Sairanen T, Meretoja A et al. Patient outcomes from symptomatic intracerebral hemorrhage after stroke thrombolysis. Neurology 2011; 77 (4): 341– 348. 2. Whiteley WN, Slot KB, Fernandes P, Sandercock P, Wardlaw J. Risk factors for intracranial hemorrhage in acute ischemic stroke patients treated with recombinant tissue plasminogen activator: a systematic review and meta-analysis of 55 studies. Stroke 2012; 43 (11): 2904–2909. 3. Strbian D, Engelter S, Michel P et al. Symptomatic intracranial hemorrhage after stroke thrombolysis: the SEDAN score. Ann Neurol 2012; 71 (5): 634–641. 4. Wahlgren N, Ahmed N, Dávalos A et al. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in StrokeMonitoring Study (SITS-MOST): an observational study. Lancet 2007; 369 (9558): 275–282. 5. Mazya MV, Ahmed N, Ford GA et al. Remote or extraischemic intracerebral hemorrhage – an uncommon complication of stroke thrombolysis: results from the safe implementation of treatments in StrokeInternational Stroke Thrombolysis Register. Stroke 2014; 45 (6): 1657–1663. 6. McCarron MO, Nicoll JAR. Cerebral amyloid angiopathy and thrombolysis-related intracerebral haemorrhage. Lancet Neurol 2004; 3 (8): 484–492. 7. Vinters HV, Wang ZZ, Secor DL. Brain parenchymal and microvascular amyloid in Alzheimer’s disease. Brain Pathol 1996; 6 (2): 179–195. 8. Sloan MA, Price TR, Petito CK et al. Clinical features and pathogenesis of intracerebral hemorrhage after

13.

14.

15.

16.

17.

18.

19.

20.

rt-PA and heparin therapy for acute myocardial infarction: the Thrombolysis in Myocardial Infarction (TIMI) II Pilot and Randomized Clinical Trial combined experience. Neurology 1995; 45 (4): 649–658. Felling RJ, Faigle R, Ho CY, Llinas RH, Urrutia VC. Cerebral amyloid angiopathy: a hidden risk for IV thrombolysis? J Neurol Transl Neurosci 2014; 2 (1): 1034. Charidimou A, Peeters A, Fox Z et al. Spectrum of transient focal neurological episodes in cerebral amyloid angiopathy: multicentre magnetic resonance imaging cohort study and meta-analysis. Stroke 2012; 43 (9): 2324–2330. Greenberg SM, Vonsattel JP. Diagnosis of cerebral amyloid angiopathy. Sensitivity and specificity of cortical biopsy. Stroke 1997; 28 (7): 1418–1422. Cucchiara B, Tanne D, Levine SR, Demchuk AM, Kasner S. A risk score to predict intracranial hemorrhage after recombinant tissue plasminogen activator for acute ischemic stroke. J Stroke Cerebrovasc Dis 2008; 17 (6): 331–333. Ramsay DA, Penswick JL, Robertson DM. Fatal streptokinase-induced intracerebral haemorrhage in cerebral amyloid angiopathy. Can J Neurol Sci 1990; 17 (3): 336–341. Leblanc R, Haddad G, Robitaille Y. Cerebral hemorrhage from amyloid angiopathy and coronary thrombolysis. Neurosurgery 1992; 31 (3): 586–590. Wijdicks EF, Jack CR. Intracerebral hemorrhage after fibrinolytic therapy for acute myocardial infarction. Stroke 1993; 24 (4): 554–557. Pendlebury WW, Iole ED, Tracy RP, Dill BA. Intracerebral hemorrhage related to cerebral amyloid angiopathy and t-PA treatment. Ann Neurol 1991; 29 (2): 210–213. Winkler DT, Biedermann L, Tolnay M et al. Thrombolysis induces cerebral hemorrhage in a mouse model of cerebral amyloid angiopathy. Ann Neurol 2002; 51 (6): 790–793. Foerch C, Rosidi NL, Schlunk F et al. Intravenous tPA therapy does not worsen acute intracerebral hemorrhage in mice. PLoS ONE 2013; 8 (2): e54203. Charidimou A, Kakar P, Fox Z, Werring DJ. Cerebral microbleeds and the risk of intracerebral haemorrhage after thrombolysis for acute ischaemic stroke: systematic review and meta-analysis. J Neurol Neurosurg Psychiatr 2013; 84 (3): 277–280. Rannikmäe K, Samarasekera N, Martínez González NA, Al-Shahi Salman R, Sudlow CLM. Genetics of cerebral amyloid angiopathy: systematic review and meta-analysis. J Neurol Neurosurg Psychiatr 2013; 84 (8): 901–908. © 2014 Japanese Society of Neuropathology

Cerebral amyloid angiopathy related hemorrhage after stroke thrombolysis: case report and literature review.

Cerebral amyloid angiopathy (CAA) predisposes to symptomatic intracerebral hemorrhage (sICH) after combined thrombolytic and anticoagulant treatment o...
567KB Sizes 2 Downloads 11 Views