Journal of the Neurological Sciences 352 (2015) 122–124
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Fatal intracerebral haemorrhage following intravenous thrombolysis for acute ischaemic stroke: A hidden role for cerebral amyloid angiopathy? Keywords: Intracerebral haemorrhage CT Cerebral amyloid angiopathy Thrombolysis t-PA
after thrombolysis, the GCS dropped to 8/15 with profound left hemiparesis and increasing agitation. An urgent brain CT scan (Fig. 1B) revealed a right frontal, parietal and temporal lobe ICH which extended into the right lateral ventricle and subarachnoid space with surrounding oedema and midline shift. Neurosurgical intervention was not recommended and in consultation with the family, the patient was symptomatically managed for shortness of breath, agitation and nausea with cyclizine/morphine sulphate/midazolam by continuous infusion subcutaneous pump. Death occurred 62 h after the onset of stroke symptoms. 2. Neuropathology
Dear Editor, Thrombolysis with recombinant tissue plasminogen activator (rt-PA) is currently the only approved therapy for acute ischemic stroke. However, intracerebral haemorrhage (ICH) remains the most feared and devastating complication of intravenous thrombolysis [1]. We report a case of a patient who suffered a catastrophic haemorrhage following intravenous thrombolysis for stroke, related to previously unsuspected severe cerebral amyloid angiopathy (CAA) found on autopsy. 1. Case report A 75-year-old woman with a history of hypertension, type II diabetes mellitus and hypercholesterolemia, presented to the emergency department within 51 min of acute onset left arm weakness, left facial droop and speech disturbance. Medications included aspirin 75 mg daily, bisoprolol 2.5 mg daily, perindopril 5 mg daily, furosemide 20 mg daily, levemir and novorapid insulins. On examination, her blood pressure (BP) was 170/80 mm Hg, heart rate (HR) 75 beats per minute (bpm) and regular, and Glasgow Coma Scale (GCS) 15/15. The patient was dysarthric with left upper limb power of 0/5 and 4+/5 in the left lower limb. The National Institute of Health Stroke Scale (NIHSS) score was 7/42. An urgent non-contrast CT of the brain (within 44 min of admission) showed an evolving right middle cerebral artery infarct (Fig. 1A). The electrocardiogram showed normal sinus rhythm. Blood indices showed: haemoglobin of 13.2 g/d L, platelets 295 × 109/L, prothrombin time 13.2 s, international normalized ratio 0.98, serum glucose 12.8 mmol/L with normal urea, electrolytes and liver function tests. The patient consented to treatment with IV t-PA which was started 69 min after presentation (i.e. 120 min from symptoms onset). At the end of the treatment infusion, BP was 180/75 mm Hg, GCS 15/15 and there was no change in the NIHSS score. Two hours and ten minutes after intravenous thrombolysis (250 min after first symptoms) the patient complained of mild headache which was relieved by paracetamol. Left upper limb power had improved from 0 to 2/5 and GCS was still 15/15. Her BP had gradually decreased to 140/50 mm Hg. Ten hours
http://dx.doi.org/10.1016/j.jns.2015.03.030 0022-510X/© 2015 Elsevier B.V. All rights reserved.
At autopsy, a large area of infarction in the distribution of the right middle cerebral artery was confirmed and accompanied by haemorrhagic transformation as well as subarachnoid haemorrhage. On routine haematoxylin-eosin staining there was eosinophilic material deposited within the vessel walls of small arteries, which were thickened. On immunohistochemistry, there was intense positivity for vascular amyloid-β (Fig. 1C and D) involving both leptomeningeal and intraparenchymal vessels in all areas of the cortex examined, supporting a diagnosis of severe CAA. 3. Discussion Severe CAA likely played an important role in the development of this patient's catastrophic post t-PA ICH due to haemorrhagic transformation of a small, acute, embolic middle cerebral artery territory infarct. CAA is a common small vessel disease of the brain characterised by progressive amyloid-β deposition in the walls of small to medium sized arteries, arterioles and capillaries in the cortex and leptomeninges and is a major cause of spontaneous symptomatic lobar ICH and cognitive impairment in the elderly [2]. In the present case, neuropathology showed previously clinically unsuspected severe CAA involving leptomeningeal and intraparenchymal vessels with intense transmural amyloid-β immunopositivity, associated with intraparenchymal bleeding and subarachnoid haemorrhage. Post-thrombolysis ICH is a complex pathophysiological process – known predictors currently include increasing age, early ischaemic CT changes, clinical stroke severity, high blood pressure, hyperglycaemia, large baseline diffusion lesion volume and leukoaraiosis [1]. The presence of these established risk factors might be confounding the relationship between CAA and post-t-PA ICH. However, it seems plausible that CAA, causing the blood vessel walls to become fragile, may interact with some of the factors which increase bleeding risk after t-PA such as hyperglycaemia and hypertension [3] as were present in this patient, lowering the threshold for a life-threatening post-thrombolysis ICH. A small number of autopsy cases also support a role of pre-existing CAA with thrombolysis-related ICH [4,5]; but in most of these cases thrombolysis was administered for cardiac disease rather than stroke. Given the potential risks that CAA confers on a patient for life threatening ICH following t-PA in acute ischaemic stroke, better identification
Letter to the Editor
123
Fig. 1. Brain CT on admission (A), and repeated CT scans (B and C) at the time of clinical deterioration with low Glasgow Coma Scale. (D) Haematoxylin-eosin staining showing thick-walled hyalinised cortical vessels with loss of smooth muscle cells. (E) Immunohistochemical detection of amyloid-β showing dense amyloid deposition which spans the entire vessel wall of cortical arterioles. Also shown are diffuse BA4 plaques adjacent to vessels.
of such patients might be important in the future. A recent positron emission tomography study using non-invasive amyloid imaging with Pittsburgh Compound B (PiB), demonstrated that neocortical PiB retention was higher among patients with post-thrombolysis intracerebral haemorrhage compared with patients without and normal controls, supporting underlying CAA as a predisposing factor for rt-PA-related intracerebral haemorrhage [6]. Structural MRI can also detect the consequences of CAA, including multiple lobar cerebral microbleeds, a putative biomarker of the disease and a risk factor for ICH recurrence [2]. In recent meta-analyses it has not been possible to definitively demonstrate that the presence of microbleeds on MRI is associated with an increased risk of ICH following t-PA [7,8]. However, the studies analysed had methodological limitations and further research is required to clarify if the risk of developing ICH outweighs the benefits of t-PA in a subgroup of acute ischaemic stroke patients with multiple lobar cerebral microbleeds suggestive of CAA. Our case adds to the evidence that CAA may be related to thrombolysis-related ICH, but well-designed studies are essential to clarify its exact independent role (including neuropathological and MRI examinations in acute ischaemic stroke). Emerging imaging biomarkers for CAA and ICH risk, including lobar microbleed number, cortical superficial siderosis and posterior white matter hypointensities may become increasingly useful for outcome endpoints in clinical trials and patient risk stratification [9]. However, in the absence of systematic data current evidence does not support pre-treatment MRI as a significant component of thrombolysis decision making, which might risk worse outcomes from delay of a proven treatment.
Funding and disclosures The authors report no disclosures relevant to this work.
References [1] Derex L, Nighoghossian N. Intracerebral haemorrhage after thrombolysis for acute ischaemic stroke: an update. J Neurol Neurosurg Psychiatry 2008;79:1093–9. [2] Charidimou A, Gang Q, Werring DJ. Sporadic cerebral amyloid angiopathy revisited: recent insights into pathophysiology and clinical spectrum. J Neurol Neurosurg Psychiatry 2012;83:124–37. [3] Mazya M, Egido JA, Ford GA, Lees KR, Mikulik R, Toni D, et al. Predicting the risk of symptomatic intracerebral hemorrhage in ischemic stroke treated with intravenous alteplase: safe implementation of treatments in stroke (SITS) symptomatic intracerebral hemorrhage risk score. Stroke 2012;43:1524–31. [4] McCarron MO, Nicoll JA. Cerebral amyloid angiopathy and thrombolysis-related intracerebral haemorrhage. Lancet Neurol 2004;3:484–92. [5] Mattila OS, Sairanen T, Laakso E, Paetau A, Tanskanen M, Lindsberg PJ. Cerebral amyloid angiopathy related hemorrhage after stroke thrombolysis: case report and literature review. Neuropathology 2015;35:70–4. [6] Ly JV, Rowe CC, Villemagne VL, Zavala JA, Ma H, O'Keefe G, et al. Cerebral betaamyloid detected by Pittsburgh compound B positron emission topography predisposes to recombinant tissue plasminogen activator-related hemorrhage. Ann Neurol 2010;68:959–62. [7] 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 Psychiatry 2013;84:277–80. [8] Shoamanesh A, Kwok CS, Lim PA, Benavente OR. Postthrombolysis intracranial hemorrhage risk of cerebral microbleeds in acute stroke patients: a systematic review and meta-analysis. Int J Stroke 2013;8:348–56. [9] Greenberg SM, Salman RA, Biessels GJ, van Buchem M, Cordonnier C, Lee JM, et al. Outcome markers for clinical trials in cerebral amyloid angiopathy. Lancet Neurol 2014;13:419–28.
Authors and their individual contributions to the manuscript O. Ntlholang: data collection, write up, and critical revisions. M. Farrell: data collection, pathological analysis, and critical revisions. I. Noone: data collection and critical revisions. A. Charidimou: write up and critical revisions. M. Crowe: data collection, write up, and critical revisions.
Onte Ntlholang Department of Medicine for the Elderly, St Vincent's University Hospital, Dublin, Ireland Michael Farrell Department of Neuropathology, St Vincent's University Hospital, Dublin, Ireland
124
Letter to the Editor
Imelda Noone Department of Medicine for the Elderly, St Vincent's University Hospital, Dublin, Ireland
Morgan Crowe Department of Medicine for the Elderly, St Vincent's University Hospital, Dublin, Ireland
Andreas Charidimou UCL Institute of Neurology, The National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom Corresponding author at: 175 Cambridge Street, Suite 300, Boston, MA 02114, USA. Tel.: +1 617 643 3941. E-mail address: [email protected].
13 February 2015
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Fatal intracerebral haemorrhage following intravenous thrombolysis for acute ischaemic stroke: A hidden role for cerebral amyloid angiopathy? Keywords: Intracerebral haemorrhage CT Cerebral amyloid angiopathy Thrombolysis t-PA
after thrombolysis, the GCS dropped to 8/15 with profound left hemiparesis and increasing agitation. An urgent brain CT scan (Fig. 1B) revealed a right frontal, parietal and temporal lobe ICH which extended into the right lateral ventricle and subarachnoid space with surrounding oedema and midline shift. Neurosurgical intervention was not recommended and in consultation with the family, the patient was symptomatically managed for shortness of breath, agitation and nausea with cyclizine/morphine sulphate/midazolam by continuous infusion subcutaneous pump. Death occurred 62 h after the onset of stroke symptoms. 2. Neuropathology
Dear Editor, Thrombolysis with recombinant tissue plasminogen activator (rt-PA) is currently the only approved therapy for acute ischemic stroke. However, intracerebral haemorrhage (ICH) remains the most feared and devastating complication of intravenous thrombolysis [1]. We report a case of a patient who suffered a catastrophic haemorrhage following intravenous thrombolysis for stroke, related to previously unsuspected severe cerebral amyloid angiopathy (CAA) found on autopsy. 1. Case report A 75-year-old woman with a history of hypertension, type II diabetes mellitus and hypercholesterolemia, presented to the emergency department within 51 min of acute onset left arm weakness, left facial droop and speech disturbance. Medications included aspirin 75 mg daily, bisoprolol 2.5 mg daily, perindopril 5 mg daily, furosemide 20 mg daily, levemir and novorapid insulins. On examination, her blood pressure (BP) was 170/80 mm Hg, heart rate (HR) 75 beats per minute (bpm) and regular, and Glasgow Coma Scale (GCS) 15/15. The patient was dysarthric with left upper limb power of 0/5 and 4+/5 in the left lower limb. The National Institute of Health Stroke Scale (NIHSS) score was 7/42. An urgent non-contrast CT of the brain (within 44 min of admission) showed an evolving right middle cerebral artery infarct (Fig. 1A). The electrocardiogram showed normal sinus rhythm. Blood indices showed: haemoglobin of 13.2 g/d L, platelets 295 × 109/L, prothrombin time 13.2 s, international normalized ratio 0.98, serum glucose 12.8 mmol/L with normal urea, electrolytes and liver function tests. The patient consented to treatment with IV t-PA which was started 69 min after presentation (i.e. 120 min from symptoms onset). At the end of the treatment infusion, BP was 180/75 mm Hg, GCS 15/15 and there was no change in the NIHSS score. Two hours and ten minutes after intravenous thrombolysis (250 min after first symptoms) the patient complained of mild headache which was relieved by paracetamol. Left upper limb power had improved from 0 to 2/5 and GCS was still 15/15. Her BP had gradually decreased to 140/50 mm Hg. Ten hours
http://dx.doi.org/10.1016/j.jns.2015.03.030 0022-510X/© 2015 Elsevier B.V. All rights reserved.
At autopsy, a large area of infarction in the distribution of the right middle cerebral artery was confirmed and accompanied by haemorrhagic transformation as well as subarachnoid haemorrhage. On routine haematoxylin-eosin staining there was eosinophilic material deposited within the vessel walls of small arteries, which were thickened. On immunohistochemistry, there was intense positivity for vascular amyloid-β (Fig. 1C and D) involving both leptomeningeal and intraparenchymal vessels in all areas of the cortex examined, supporting a diagnosis of severe CAA. 3. Discussion Severe CAA likely played an important role in the development of this patient's catastrophic post t-PA ICH due to haemorrhagic transformation of a small, acute, embolic middle cerebral artery territory infarct. CAA is a common small vessel disease of the brain characterised by progressive amyloid-β deposition in the walls of small to medium sized arteries, arterioles and capillaries in the cortex and leptomeninges and is a major cause of spontaneous symptomatic lobar ICH and cognitive impairment in the elderly [2]. In the present case, neuropathology showed previously clinically unsuspected severe CAA involving leptomeningeal and intraparenchymal vessels with intense transmural amyloid-β immunopositivity, associated with intraparenchymal bleeding and subarachnoid haemorrhage. Post-thrombolysis ICH is a complex pathophysiological process – known predictors currently include increasing age, early ischaemic CT changes, clinical stroke severity, high blood pressure, hyperglycaemia, large baseline diffusion lesion volume and leukoaraiosis [1]. The presence of these established risk factors might be confounding the relationship between CAA and post-t-PA ICH. However, it seems plausible that CAA, causing the blood vessel walls to become fragile, may interact with some of the factors which increase bleeding risk after t-PA such as hyperglycaemia and hypertension [3] as were present in this patient, lowering the threshold for a life-threatening post-thrombolysis ICH. A small number of autopsy cases also support a role of pre-existing CAA with thrombolysis-related ICH [4,5]; but in most of these cases thrombolysis was administered for cardiac disease rather than stroke. Given the potential risks that CAA confers on a patient for life threatening ICH following t-PA in acute ischaemic stroke, better identification
Letter to the Editor
123
Fig. 1. Brain CT on admission (A), and repeated CT scans (B and C) at the time of clinical deterioration with low Glasgow Coma Scale. (D) Haematoxylin-eosin staining showing thick-walled hyalinised cortical vessels with loss of smooth muscle cells. (E) Immunohistochemical detection of amyloid-β showing dense amyloid deposition which spans the entire vessel wall of cortical arterioles. Also shown are diffuse BA4 plaques adjacent to vessels.
of such patients might be important in the future. A recent positron emission tomography study using non-invasive amyloid imaging with Pittsburgh Compound B (PiB), demonstrated that neocortical PiB retention was higher among patients with post-thrombolysis intracerebral haemorrhage compared with patients without and normal controls, supporting underlying CAA as a predisposing factor for rt-PA-related intracerebral haemorrhage [6]. Structural MRI can also detect the consequences of CAA, including multiple lobar cerebral microbleeds, a putative biomarker of the disease and a risk factor for ICH recurrence [2]. In recent meta-analyses it has not been possible to definitively demonstrate that the presence of microbleeds on MRI is associated with an increased risk of ICH following t-PA [7,8]. However, the studies analysed had methodological limitations and further research is required to clarify if the risk of developing ICH outweighs the benefits of t-PA in a subgroup of acute ischaemic stroke patients with multiple lobar cerebral microbleeds suggestive of CAA. Our case adds to the evidence that CAA may be related to thrombolysis-related ICH, but well-designed studies are essential to clarify its exact independent role (including neuropathological and MRI examinations in acute ischaemic stroke). Emerging imaging biomarkers for CAA and ICH risk, including lobar microbleed number, cortical superficial siderosis and posterior white matter hypointensities may become increasingly useful for outcome endpoints in clinical trials and patient risk stratification [9]. However, in the absence of systematic data current evidence does not support pre-treatment MRI as a significant component of thrombolysis decision making, which might risk worse outcomes from delay of a proven treatment.
Funding and disclosures The authors report no disclosures relevant to this work.
References [1] Derex L, Nighoghossian N. Intracerebral haemorrhage after thrombolysis for acute ischaemic stroke: an update. J Neurol Neurosurg Psychiatry 2008;79:1093–9. [2] Charidimou A, Gang Q, Werring DJ. Sporadic cerebral amyloid angiopathy revisited: recent insights into pathophysiology and clinical spectrum. J Neurol Neurosurg Psychiatry 2012;83:124–37. [3] Mazya M, Egido JA, Ford GA, Lees KR, Mikulik R, Toni D, et al. Predicting the risk of symptomatic intracerebral hemorrhage in ischemic stroke treated with intravenous alteplase: safe implementation of treatments in stroke (SITS) symptomatic intracerebral hemorrhage risk score. Stroke 2012;43:1524–31. [4] McCarron MO, Nicoll JA. Cerebral amyloid angiopathy and thrombolysis-related intracerebral haemorrhage. Lancet Neurol 2004;3:484–92. [5] Mattila OS, Sairanen T, Laakso E, Paetau A, Tanskanen M, Lindsberg PJ. Cerebral amyloid angiopathy related hemorrhage after stroke thrombolysis: case report and literature review. Neuropathology 2015;35:70–4. [6] Ly JV, Rowe CC, Villemagne VL, Zavala JA, Ma H, O'Keefe G, et al. Cerebral betaamyloid detected by Pittsburgh compound B positron emission topography predisposes to recombinant tissue plasminogen activator-related hemorrhage. Ann Neurol 2010;68:959–62. [7] 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 Psychiatry 2013;84:277–80. [8] Shoamanesh A, Kwok CS, Lim PA, Benavente OR. Postthrombolysis intracranial hemorrhage risk of cerebral microbleeds in acute stroke patients: a systematic review and meta-analysis. Int J Stroke 2013;8:348–56. [9] Greenberg SM, Salman RA, Biessels GJ, van Buchem M, Cordonnier C, Lee JM, et al. Outcome markers for clinical trials in cerebral amyloid angiopathy. Lancet Neurol 2014;13:419–28.
Authors and their individual contributions to the manuscript O. Ntlholang: data collection, write up, and critical revisions. M. Farrell: data collection, pathological analysis, and critical revisions. I. Noone: data collection and critical revisions. A. Charidimou: write up and critical revisions. M. Crowe: data collection, write up, and critical revisions.
Onte Ntlholang Department of Medicine for the Elderly, St Vincent's University Hospital, Dublin, Ireland Michael Farrell Department of Neuropathology, St Vincent's University Hospital, Dublin, Ireland
124
Letter to the Editor
Imelda Noone Department of Medicine for the Elderly, St Vincent's University Hospital, Dublin, Ireland
Morgan Crowe Department of Medicine for the Elderly, St Vincent's University Hospital, Dublin, Ireland
Andreas Charidimou UCL Institute of Neurology, The National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom Corresponding author at: 175 Cambridge Street, Suite 300, Boston, MA 02114, USA. Tel.: +1 617 643 3941. E-mail address: [email protected].
13 February 2015
