Radiology Residents, Ain Shams University Hospitals Differentiation between Post-Thrombectomy Cerebral Hyperdensity (PCHD) and Hemorrhagic Transformation By Amgad M Moussa, MBBCh Sara W Tantawy, MBBCh Radiology Residents, Ain Shams University Hospitals

Learning Objectives After viewing this presentation, the reader should know: The burden of Stroke worldwide The growing role of endovascular treatment in Acute Ischemic Stroke The definition and proposed pathophysiology of PCHD How to differentiate between PCHD and Hemorrhage?

Stroke Stroke is the fifth leading cause of death in the United states, killing over 130,000 Americans each year; that is equivalent to one death every 4 minutes.[1] Ischemic stroke, in particular, is a leading cause of death and disability worldwide.[2] Much of the disability occurs in patients with acute large vessel occlusion, which often results in death or severe disability.[2]

Mechanical Thrombectomy Endovascular treatment of acute ischemic stroke in the anterior circulation due to large vessel occlusion is now the new standard of care.[3] It is safe and effective for achieving reperfusion and substantially reduces the degree of disability.[3] However, it is not without complications. One of the most dreaded complications is reperfusion hemorrhage.[4]

Stent retriever maneuvered in place Occluded Rt. MCA Stent Retreiver Total occlusion of the Rt Middle Cerebral Artery in a 21-year old female Stent retriever maneuvered in place Complete restoration of blood flow after retrieval

Post-Thrombectomy Cerebral Hyperdensity PCHD was first described by Komiyama et al in 1993.[5] The treating team noticed that two of their stroke patients who were treated by intra-arterial thrombinolysis showed hyper-dense lesions in the basal ganglia on the treated side on post-procedural CT imaging.[5] The measured density of the lesions was much higher than that of blood, and so they suggested that it was contrast extravasation.[5]

Post-Thrombectomy Cerebral Hyperdensity PCHD was then seen in patients who underwent mechanical thrombectomy, as documented by several studies.[6, 7] It was later defined as ‘Non-solid visually distinctive parenchymal hyperdense areas diagnosed within 4.5 hours after recanalisation, with a diameter of at least 0.1 cm2, and without a space occupying effect, and with an increased density of at least 5 Hounsfield Units compared to the unaffected contralateral.’[8] One of our patients showing extensive PCHD in the left basal ganglia

Post-Thrombectomy Cerebral Hyperdensity The incidence of PCHD ranges between 25% up to 84%.[7] Their significance has been controversial; sometimes associated with a higher risk of hemorrhagic transformation[7] and other times not[6]. One study even concluded that ‘areas of contrast staining were likely to infarct and unlikely to hemorrhage’.[9]

Subtle hyperdensity in the left basal ganglia Follow up CT showed hypodensity in the same region; a sign of infarction Subtle hyperdensity in the left basal ganglia

Pathophysiology The pathophysiology behind PCHD is not clearly understood.[9] Normally, the blood–brain barrier (BBB) is hardly permeable for iodinated contrast agents or red blood cells.[8] It has been postulated that brain tissue experiencing a high concentration of contrast, usually via direct intra-arterial injection past a thrombus, would be likely to stain secondary to a combination of breakdown of the BBB and the inherent toxic effects of contrast. [9]

Pathophysiology Opposers to this theory argue that we would see more cases of hemorrhagic transformation in patients with PCHD if the case was due to breakdown of the BBB.[9] They hypothesize that the lack of sufficient revascularization at the capillary level in the area of the infarct (even in cases of large vessel revascularization) causes decreased blood flow at the capillary level to ‘wash-out’ the contrast.[9]

Hemorrhagic Transformation The European Cooperative Acute Stroke Study I and II (ECASS I, II) classified hemorrhagic transformation into 4 subtypes: Parenchymal Hemorrhage types 1 and 2 as well as Hemorrhagic Infarction types 1 and 2.[8] Berger et al concluded that the only clinically significant hemorrhagic transformation in acute stroke patients is Parenchymal Hemorrhage type 2 (PH-2) which is defined as ‘Hemorrhage occupying greater than 30 % of the infarcted area with significant space-occupying effect’[10]

According to the ECASS classification, this would be a PH-2 One of our patients with a parenchymal hematoma involving a large portion of the infarcted left cerebral hemisphere with significant mass effect. According to the ECASS classification, this would be a PH-2

Hemorrhagic Transformation Experimental studies have shown that (PH-2) occurs when the integrity of the BBB and the basal lamina has been lost, which occurs after severe and prolonged ischemia.[6] Successful revascularization may preclude the loss of integrity of the BBB and basal lamina, thus decreasing the incidence of symptomatic hemorrhagic transformation. [6] This is supported by several clinical studies which have proven that severe hemorrhagic transformation is more common when recanalization has failed. [6]

PCHD vs. Hemorrhagic Transformation Differentiation between PCHD and hemorrhagic transformation is vital, as it will guide post-thrombectomy clinical management. [11] Komiyama et al suggested merely comparing the CT number to differentiate between blood and contrast, with contrast having a higher CT number.[5] However, more recent studies (as well as ourselves) found that to be difficult within the first 24 hours, the most crucial time, due to similar densities of iodine and blood.[11]

Patient with hyperdensity in the right basal ganglia with a CT number of 37-45 HU, suspected correctly to be hemorrhage Another patient with hyperdensity in the right basal ganglia, with slightly lower CT number, discovered later to be PCHD

PCHD vs. Hemorrhagic Transformation Nakano et al differentiated between PCHD and hemorrhage by defining hemorrhagic transformation as ‘intra-parenchymal hyperdense areas which did not resolve until more than 24 hours later’.[12] However, other studies concluded that contrast staining could persist beyond 24 hours adding to the confusion.[9]

PCHD vs. Hemorrhagic Transformation Other authors differentiated between PCHD and symptomatic hemorrhagic transformation by noticing that PCHD ‘conformed to the anatomic boundaries of normal structures, lacked surrounding edema and had no mass effect’[9] This method of differentiation proved most important, as symptomatic hemorrhagic transformation was the only type that affected long term survival and disability.[10]

Surrounding edema Hemorrhagic transformation in the right basal ganglia. Notice the surrounding hypodensity as well as the lack of conformation to anatomical borders. Patient with PCHD in the right cerebral hemisphere. Notice the absence of surrounding hypodensity, the lack of significant mass effect despite the large affected area and the conformation to anatomical borders.

PCHD vs. Hemorrhagic Transformation More recent studies have investigated the role of Dual Energy CT, which depends on differences between the photoelectric and Compton scattering components underlying the x-ray attenuation of hemorrhage and iodine, with promising results.[11, 13] It is hypothesized that since both phenomena rely on the x-ray photon energy, ,one can discriminate the pixel attenuation arising from these 2 effects by scanning at 2 different energy levels, such as 80kV and 140kV.[13]

PCHD vs. Hemorrhagic Transformation It is common knowledge among radiologists that blood appears hypointense on T2* weighted images due to the paramagnetic effects of blood degradation products, unlike iodine, which is diamagnetic.[14] A recent study concluded that, aside from some theoretical fears, Magnetic resonance imaging can be used to accurately differentiate between hemorrhage and PCHD.[14] Up to this day, to our knowledge, the current reference or gold standard used to differentiate between PCHD and hemorrhagic transformation is resolution of the contrast within 48 hours compared to hemorrhage which persists for days to weeks.[13]

Hyperdensity in the left basal ganglia, differentiation between PCHD and hemorrhage by CT would be difficult (no mass effect, mild surrounding edema, etc.) MRI was done. T2* weighted images show hypointense signal in the left basal ganglia consistent with hemorrhage

Illustrative Cases: Case 1 A 58 year old female presented with left sided weakness and disturbed consciousness level for the past 6 hours, CT brain was free and CT Angiography showed occlusion of the right MCA Mechanical Thrombectomy was done successfully.

Illustrative Cases: Case 1 Follow-up CT showed a hyperdense lesion in the right basal ganglia with mild mass effect and surrounding hypodensity, with a CT number closer to that of blood than of contrast; likely hemorrhage. Follow up CTs showed persistence of the hyperdensity with slow regression; confirming its nature.

Illustrative Cases: Case 2 A 64-year old male presented with right hemiplegia and aphasia for the past 5 hours. MRI was done revealing a small hyperacute area of diffusion restriction in the left frontal lobe with no hemorrhage, while the MRA showed total occlusion of the Left Internal Carotid Artery The decision was to arrange for Diagnostic Cerebral Angiography due to the acute onset of symptoms

Illustrative Cases: Case 2 Occluded Left ICA Recanalized Left ICA Diagnostic Cerebral Angiography showed total occlusion of the Left Internal Carotid Artery at its termination Mechanical Thrombectomy was done successfully and follow up CTs showed no hyperdense areas

Illustrative Cases: Case 3 A 24 year old male presented with left sided hemiparesis for the past 4 hours. CT brain was free and CT Angiography revealed occlusion of the Right MCA. Mechanical Thrombectomy was done successfully. Occluded Rt MCA

Illustrative Cases: Case 3 Follow-up CT brain 12 hours after thrombectomy showed diffuse hyperdensity in the vascular territory of the right MCA The hyperdensity showed no significant mass effect, had no surrounding hypodensity and had a CT number that was closer to contrast than to blood. PCHD was suspected Follow up CTs at 24 and 48 hours were not done due to rapid improvement of the patient’s condition with no deterioration

Illustrative Cases: Case 3 Follow up CT done 4 days later revealed persistent small hyperdense areas as seen above with resolution of the previously noted diffuse hyperdensity; likely explained by resolution of the PCHD followed by onset of hemorrhagic transformation. T2* weighted MR images confirmed the nature of the hyperdense lesions. At discharge, the patient had regained full motor power in the affected side and was functionally independent

Illustrative Cases: Case 4 A 64 year old male presented with right sided hemiplegia and distubred consciousness. CT brain was free and CT Angiography revealed total occlusion of the Left internal carotid artery in its cervical portion Thrombectomy was attempted and was successful after multiple attempts

Illustrative Cases: Case 4 A CT done after 24 hours showed resolution of the previously noted hyperdensity and replacement by hypodensity, a sign of infarction. This confirmed the previous diagnosis of PCHD No hemorrhage was noted Immediate post-procedure CT showed hyperdense area in the left cerebral hemisphere, with high CT number (120 HU), no surrounding hypodensity and no significant mass effect; picture suggestive of PCHD Mild clinical improvement was noted over the next 24 hours.

Illustrative Cases: Case 4 Two days later, the patient’s consciousness level deteriorated. CT was done revealing a hyperdense lesion in the left cerebral hemisphere with significant mass effect, surrounding hypodensity and CT number of blood; a picture of hemorrhagic transformation.

Conclusion Post-intervention Cerebral Hyperdensities have been documented repeatedly in the literature, but their significance and prognostic impact are still up for debate Differentiation between PCHD and symptomatic hemorrhagic transformation can be done by several ways with varying certainty Further studies need to be done to accurately differentiate them in the first 24 hours and integrate that into post-thrombectomy management protocols to achieve even better results.

References Centers for Disease Control and Prevention, National Center for Health Statistics. Underlying Cause of Death 1999-2013 on CDC WONDER Online Database, released 2015. Data are from the Multiple Cause of Death Files, 1999-2013, as compiled from data provided by the 57 vital statistics jurisdictions through the Vital Statistics Cooperative Program: http://wonder.cdc.gov/ucd-icd10.html Lavine SD et al. Training Guidelines for Endovascular Ischemic Stroke Intervention: An International Multi-Society Consensus Document. AJNR 2016 37:E31-E34, Zerna C et al. Imaging, Intervention and Work flow in Acute Ischemic Stroke: The Calgary Approach. AJNR (2016) 37:978-84 Palaniswami et al. Mechanical Thrombectomy Is Now the Gold Standard for Acute Ischemic Stroke: Implications for Routine Clinical Practice . Intervent Neurol 2015;4:18–29. DOI: 10.1159/000438774 Komiyama et al. Extravasation of Contrast Medium from the Lenticulostriate Artery Following Local Intracarotid Fibrinolysis. Surg Neurol (1993); 39:315-9 Parrilla et al. Hemorrhage/Contrast Staining Areas after Mechanical Intra-Arterial Thrombectomy in Acute Ischemic Stroke: Imaging Findings and Clinical Significance. AJNR (2012) 33:1791-96. Lummel et al. Hyperattenuated Intracerebral Lesions after Mechanical Recanalization in Acute Stroke. AJNR http://dx.doi.org/10.3174/ajnr.A3656 Nikoubashman et al. Clinical significance of post-interventional cerebral hyperdensities after endovascular mechanical thrombectomy in acute ischaemic stroke. Neuroradiology (2014) 56:41–50 Amans et al. Contrast Staining on CT after DSA in Ischemic Stroke Patients Progresses to Infarction and Rarely Hemorrhages. Interventional Neuroradiology (2014), 20: 106-115 - doi: 10.15274/INR-2014-10016 Berger et al. Hemorrhagic Transformation of Ischemic Brain Tissue: Asymptomatic or Symptomatic? Stroke (2001); 32: 1330-1335. Tijssen et al. The role of dual energy CT in differentiating between brain haemorrhage and contrast medium after mechanical revascularisation in acute ischaemic stroke. Eur Radiol (2014) 24:834–840 DOI 10.1007/s00330-013-3073-x Nakano et al. Parenchymal Hyperdensity on Computed Tomography After Intra-Arterial Reperfusion Therapy for Acute Middle Cerebral Artery Occlusion: Incidence and Clinical Significance. Stroke. (2001);32:2042-2048 Phan et al. Differentiation of Hemorrhage from Iodinated Contrast in Different Intracranial Compartments Using Dual-Energy Head CT. AJNR 2012 33:1088–94 Nikoubashman et al. MRI Appearance of Intracerebral Iodinated Contrast Agents: Is It Possible to Distinguish Extravasated Contrast Agent from Hemorrhage? AJNR 2016 37:1418 –2

Thank you for your attention Questions? amgadmoussa89@gmail.com