Spontaneous ICH: the issue of perihemmorhagic edema

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1 4 rd Congress of the European Academy of Neurology Lisbon, Portugal, June 16-19, 2018 Teaching Course 13 New concepts in critical care of stroke patients - Level 3 Spontaneous ICH: the issue of perihemmorhagic edema Dimitre Staykov Eisenstadt, Austria dimitre.staykov@bbeisen.at

2 Disclosure statement: The author has no conflict of interest in relation to this manuscript Introduction Spontaneous intracerebral hemorrhage (ICH) accounts for 10-15% of all strokes.[1, 2] With an annual incidence of per population, ICH affects approximately 2 million patients worldwide every year.[3] While incidence of ICH is comparable between white, black and Hispanic people, it is about two times higher in eastern and south-eastern Asians.[4] Older people are at higher risk to suffer ICH. With every additional age decade, incidence of ICH increases almost twice. It comprises only 1.9 per person-years for people younger than 45, 36.5 for year-olds and 196 per person-years for people older than 85.[4] Considering the trends of current demographic development and the increasingly ageing population in the western world, ICH is expected to gain further importance as a public health problem in the future.[5] Up to 70-90% of ICH are caused by rupture of small vessels chronically damaged by hypertension. Typically, such primary hypertensive ICH are located in the basal ganglia (28-42%) and the thalamus (10-26%). [6, 7] Lobar ICH, as well as cerebellar and brainstem ICH are less frequent. [7] Secondary ICH are associated with vascular malformations, aneurysms, tumors, secondary hemorrhagic transformation of ischemic areas, amyloid angiopathy (especially in older patients), drug abuse, or disturbances of coagulation, including patients treated with oral anticoagulants (up to 20% 1

3 of all ICH).[7, 8] According to their variable etiology, such bleedings are often atypically located. Prognosis of ICH is worse as compared to ischemic stroke, including a higher mortality reaching approximately 40% within the first 30 days after the bleeding, and a higher morbidity.[4] Only approximately 20% of ICH patients are functionally independent at 6 months.[9] A recent analysis of the Global Burden of Disease Study focusing on the neurological field confirmed the important role of so called hemorrhagic strokes (a term including ICH and SAH) as the cause of the highest mortality and morbidity as compared to all other diseases from the neurological spectrum.[10] Looking at Disability-Adjusted Life-Years (DALY), hemorrhagic strokes are the number one DALY cause (35.7% of DALY caused by any neurological diseases), followed by ischemic stroke with 22.4%, migraine (12.7%), epilepsy (9.9%), dementia (6.4%). Diseases like Parkinson s disease (1.1%) or multiple sclerosis (0.6%) cause a comparatively low burden of DALY. For better understanding a DALY can be described as the loss of one healthy year of one s life. Clinical studies have identified multiple factors associated with higher mortality and worse outcome in ICH. Older age and lower Glasgow coma scale (GCS) score at presentation have been almost uniformly reported as independent negative prognostic predictors.[11-14] Other important factors independently associated with unfavourable outcome are ICH volume,[11] hematoma growth,[15] intraventricular hemorrhage (IVH)[16-18], hydrocephalus [18, 19], and perihemorrhagic edema.[20] In a simplified representation pathophysiological mechanisms acting in ICH can be divided in acute and delayed: 2

4 Acute ICH causes immediate damage to the affected brain tissue by disruption and compression of surrounding structures. Hemmorhage growth, which most frequently occurs in the first hours and days after symptom onset, can exert an additional negative effect. Release of blood breakdown products and a cascade of secondary damaging mechanisms lead to the development of perihemorrhagic brain edema (PHE) that can lead to secondary deterioration and even to a considerable spaceoccupying effect and herniation in larger ICH.[21] Considering the fact that the volume of a sphere is calculated using the cube of the radius, only a small additional edema rim around a hemorrhage, as seen on a CT scan, can lead to a multiplication of the initial lesion volume, as shown in the following illustration: 3

Mechanisms of development of perihemorrhagic edema after ICH The pathophysiological cascades after ICH that lead to the development of PHE inlcude several different mechanisms of damage.

5 Mechanisms of development of perihemorrhagic edema after ICH The pathophysiological cascades after ICH that lead to the development of PHE inlcude several different mechanisms of damage.[3] After immediate initial mechanical tissue disruption, compression and oligemia of the brain tissue surrounding the hematoma, in the first minutes after the event, glutamate release and excitotoxicity play an important role. This leads to calcium influx, mitochondrial failure, necrosis and cytotoxic edema. Hematoma retraction occurring within the first hour after ICH also contributes to the volume of the perihematomal lesion. The release of thrombine and halotransferrin are involved in the genesis of PHE starting from the first minutes after ICH up to several days thereafter. The inflammatory cascades initiated by those blood constituents are usually further enhanced by erythrocytolysis (typically occurring after 3 days) and release of iron, hemin and heme degradation products. Further processes include microglia activation, release of free radicals, activation of matrix 4

metalloproteinases, complement activation and release of inflammatory transmitters leading to disruption of the blood brain barrier and further inflammation.

6 metalloproteinases, complement activation and release of inflammatory transmitters leading to disruption of the blood brain barrier and further inflammation. The illustration below shows a schematic representation of the most important procecess leading to the development of PHE. (from [3]) The next figure shows the different pathophysiological mechanisms of PHE development on a time axis: 5

Assessment of PHE by CT and MRI imaging PHE is best characterized by MRI imaging because of the good contrast of edema against non-affected brain tissue on T2 /FLAIR sequences.

7 Assessment of PHE by CT and MRI imaging PHE is best characterized by MRI imaging because of the good contrast of edema against non-affected brain tissue on T2 /FLAIR sequences. Several studies have been published, where MRI assessment has been used to quantify PHE after ICH.[22-25] There are, however, difficulties using MRI as a standard tool for longitudinal follow-up of PHE in ICH patients. MRI has a more limited availability, the investigation lasts longer and may pose a challenge in more severely affected and uncooperative patients. Computed tomography (CT) is more widely available, however, the contrast between PHE and non-affected tissue is less well distinguishable and represents a source of error when exact quantification of PHE is required. This difficulty has been overcome by the development of computer assisted semi-automatic PHE volumetry methods allowing the use of standard CT scan images for investigator-independent quantification of PHE. One good example of semi-automatic CT based PHE volumetry validated against MRI has been developed by Volbers et al. using threshold based limits for the assessment of edema (ranging 6

8 between 5-33 Hounsfield units).[25] Reliable assessment of edema has meanwhile allowed better comparability between studies conducted by different workgroups. Meanwhile it has been well documented that PHE is dose dependent and larger ICH produce larger PHE.[20] The colinearity of those factors and the strong influence of ICH volume on outcome has posed some difficulties in the investigation of the actual independent effect of PHE on clinical outcome and mortality. The use of relative PHE, defined as the amount of PHE per ml of the initial ICH size, has been propagated by some authors, however, recent studies have shown that relative PHE is inversely proportional to ICH volume, thereby underestimating the effect of PHE in larger as compared to smaller ICH. The recently described parameter edema extension distance [26] (see figure below from Parry-Jones & al Stroke 2015) seems to overcome the shortcuts of absolute and relative PHE and represent a better tool for assessment of the prognostic effects of PHE.[27] 7

9 Edema and clinical outcome after ICH As shown above, the different detrimental mechanisms of PHE after ICH have been well studied in the experimental setting and there is no doubt that PHE is a surrogate parameter for delayed damage of perihematomal brain tissue [28]. Nevertheless, the association of PHE and clinical outcome in ICH patients has been difficult to elucidate. With the development of PHE assessment methods for CT imaging the role of perihemorrhagic edema as a negative prognostic predictor after ICH becomes clearer, as data from recent larger studies performed by different workgroups convincingly show.[27, 29-31] Therefore, PHE appears to be a legitimate treatment target in patients with ICH. Treatment approaches to PHE Osmotherapy The use of osmotic agents for treatment of cerebral edema is based on the assumption that osmotically active substances could facilitate the transfer of water from the interstitium into the bloodstream thereby reducing the space-occupying effect of perihemorrhagic edema. Osmotic agents routinely used in neurocritical care include mannitol, glycerol, hypertonic saline. To date there are no high quality data in support of those treatment options in patients with ICH. A smaller clinical study showed that continuous hypertonic saline may reduce edema and improve outcome in patients with ICH treated on a neurological ICU [32]. A posthoc analysis of the INTERACT 2 trial showed no convincing effects of mannitol on the clinical course after ICH [33]. 8

10 Hypothermia Hypothermia has been subject of research in experimental ICH models in the recent past and several rodent studies have reported reduction in inflammation, oxidative damage, blood brain barrier disruption and perihemorrhagic edema using prolonged therapeutic hypothermia.[34-36] The clinical application of mild therapeutic hypothermia (35 C for up to 10 days) in patients with large ICH has been investigated by one research group from Erlangen, Germany [37, 38]. The authors of those studies describe a marked reduction of perihemorrhagic edema evolution and a lower mortality in treated patients as compared to historical controls. Hypothermia in ICH is currently being further investigated in ongoing trials [39]. Deferoxamine As iron toxicity plays an important role in perilesional brain damage and PHE formation after ICH, it represents a logical treatment target with a strong pathophysiological background. Until now, there is extensive experimental evidence showing, that deferoxamine, an iron chelator, can reduce hemoglobin-induced neurotoxicity after ICH.[40] This has been demonstrated in rat ICH models, where deferoxamine could reduce PHE formation and improve functional outcome.[41, 42] First clinical data have been published from a phase I study investigating the safety and tolerability of deferoxamine.[43] The results of the ongoing phase II IDEF trial are expected in 2018 (clinicaltrials.gov NCT ). Antiinflammatory treatment approaches Especially at later stages of edema development inflammatory processes represent a major part of the detrimental pathways acting in the 9

11 perihemorrhagic area. Most of the available research addressing antiinflammatory treatments for PHE have been performed in animal studies. A recent small Chinese study reports reduced PHE in ICH patients treated with fingolimod, as compared to controls.[44] Decompressive craniectomy Decompressive craniectomy is a well-established treatment for large hemispheric infarction. The concept of decompressive craniectomy without hematoma evacuation in larger ICH has been recently tested in smaller case series.[45-47] Based on those proof-of-concept data, a Swiss workgroup has initiated a larger randomized controlled trial (Swiss trial of decompressive craniectomy versus best medical treatment of spontaneous supratentorial intracerebral hemorrhage -SWITCH) aiming to investigate this treatment method. SWITCH recruits patients aged 18-75, with larger ICH (30-100ml), a GCS 8-13 within 72h from symptom onset. Meanwhile 66 out of the planned total number of 300 patients have been recruited ( accessed on Feb ). 10

12 References 1. Qureshi, A.I., et al., Spontaneous intracerebral hemorrhage. N Engl J Med, (19): p Labovitz, D.L., et al., The incidence of deep and lobar intracerebral hemorrhage in whites, blacks, and Hispanics. Neurology, (4): p Qureshi, A.I., A.D. Mendelow, and D.F. Hanley, Intracerebral haemorrhage. Lancet, (9675): p van Asch, C.J., et al., Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol, Lovelock, C.E., A.J. Molyneux, and P.M. Rothwell, Change in incidence and aetiology of intracerebral haemorrhage in Oxfordshire, UK, between 1981 and 2006: a population-based study. Lancet Neurol, (6): p Brott, T., K. Thalinger, and V. Hertzberg, Hypertension as a risk factor for spontaneous intracerebral hemorrhage. Stroke, (6): p Thrift, A.G., G.A. Donnan, and J.J. McNeil, Epidemiology of intracerebral hemorrhage. Epidemiol Rev, (2): p Flaherty, M.L., Anticoagulant-associated intracerebral hemorrhage. Semin Neurol, (5): p Staykov, D., et al., Novel approaches to the treatment of intracerebral haemorrhage. Int J Stroke, (6): p Chin, J.H. and N. Vora, The global burden of neurologic diseases. Neurology, (4): p Broderick, J.P., et al., Volume of intracerebral hemorrhage. A powerful and easy-to-use predictor of 30-day mortality. Stroke, (7): p Daverat, P., et al., Death and functional outcome after spontaneous intracerebral hemorrhage. A prospective study of 166 cases using multivariate analysis. Stroke, (1): p Lisk, D.R., et al., Early presentation of hemispheric intracerebral hemorrhage: prediction of outcome and guidelines for treatment allocation. Neurology, (1): p Tuhrim, S., et al., Validation and comparison of models predicting survival following intracerebral hemorrhage. Crit Care Med, (5): p Davis, S.M., et al., Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology, (8): p Steiner, T., et al., Dynamics of intraventricular hemorrhage in patients with spontaneous intracerebral hemorrhage: risk factors, clinical impact, and effect of hemostatic therapy with recombinant activated factor VII. Neurosurgery, (4): p ; discussion Tuhrim, S., et al., Volume of ventricular blood is an important determinant of outcome in supratentorial intracerebral hemorrhage. Crit Care Med, (3): p

13 18. Bhattathiri, P.S., et al., Intraventricular hemorrhage and hydrocephalus after spontaneous intracerebral hemorrhage: results from the STICH trial. Acta Neurochir Suppl, : p Diringer, M.N., D.F. Edwards, and A.R. Zazulia, Hydrocephalus: a previously unrecognized predictor of poor outcome from supratentorial intracerebral hemorrhage. Stroke, (7): p Staykov, D., et al., Natural Course of Perihemorrhagic Edema After Intracerebral Hemorrhage. Stroke, Zazulia, A.R., et al., Progression of mass effect after intracerebral hemorrhage. Stroke, (6): p Olivot, J.M., et al., MRI profile of the perihematomal region in acute intracerebral hemorrhage. Stroke, (11): p Venkatasubramanian, C., et al., Natural History of Perihematomal Edema After Intracerebral Hemorrhage Measured by Serial Magnetic Resonance Imaging. Stroke, Aksoy, D., et al., Magnetic resonance imaging profile of blood-brain barrier injury in patients with acute intracerebral hemorrhage. J Am Heart Assoc, (3): p. e Volbers, B., et al., Semi-automatic volumetric assessment of perihemorrhagic edema with computed tomography. Eur J Neurol, Parry-Jones, A.R., et al., Edema Extension Distance: Outcome Measure for Phase II Clinical Trials Targeting Edema After Intracerebral Hemorrhage. Stroke, (6): p. e Wu, T.Y., et al., Natural History of Perihematomal Edema and Impact on Outcome After Intracerebral Hemorrhage. Stroke, (4): p Xi, G., R.F. Keep, and J.T. Hoff, Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol, (1): p Yang, J., et al., Prognostic Significance of Perihematomal Edema in Acute Intracerebral Hemorrhage: Pooled Analysis From the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial Studies. Stroke, Murthy, S.B., et al., Perihematomal Edema and Functional Outcomes in Intracerebral Hemorrhage: Influence of Hematoma Volume and Location. Stroke, Volbers, B., et al., Impact of Perihemorrhagic Edema on Short-Term Outcome After Intracerebral Hemorrhage. Neurocrit Care, Wagner, I., et al., Effects of continuous hypertonic saline infusion on perihemorrhagic edema evolution. Stroke, (6): p Wang, X., et al., Mannitol and Outcome in Intracerebral Hemorrhage: Propensity Score and Multivariable Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2 Results. Stroke, Fingas, M., D.L. Clark, and F. Colbourne, The effects of selective brain hypothermia on intracerebral hemorrhage in rats. Exp Neurol, (2): p

14 35. Kawanishi, M., et al., Effect of delayed mild brain hypothermia on edema formation after intracerebral hemorrhage in rats. J Stroke Cerebrovasc Dis, (4): p MacLellan, C.L., et al., The influence of hypothermia on outcome after intracerebral hemorrhage in rats. Stroke, (5): p Kollmar, R., et al., Hypothermia reduces perihemorrhagic edema after intracerebral hemorrhage. Stroke, (8): p Staykov, D., et al., Mild prolonged hypothermia for large intracerebral hemorrhage. Neurocrit Care, (2): p Kollmar, R., et al., Cooling in intracerebral hemorrhage (CINCH) trial: protocol of a randomized German-Austrian clinical trial. Int J Stroke, (2): p Selim, M., Deferoxamine mesylate: a new hope for intracerebral hemorrhage: from bench to clinical trials. Stroke, (3 Suppl): p. S Nakamura, T., et al., Deferoxamine-induced attenuation of brain edema and neurological deficits in a rat model of intracerebral hemorrhage. J Neurosurg, (4): p Okauchi, M., et al., Effects of deferoxamine on intracerebral hemorrhageinduced brain injury in aged rats. Stroke, (5): p Selim, M., et al., Safety and Tolerability of Deferoxamine Mesylate in Patients With Acute Intracerebral Hemorrhage. Stroke, (11): p Fu, Y., et al., Fingolimod for the Treatment of Intracerebral Hemorrhage: A 2-Arm Proof-of-Concept Study. JAMA Neurol, (9): p Ramnarayan, R., et al., Decompressive hemicraniectomy in large putaminal hematomas: an Indian experience. J Stroke Cerebrovasc Dis, (1): p Fung, C., et al., Decompressive Hemicraniectomy in Patients With Supratentorial Intracerebral Hemorrhage. Stroke, Heuts, S.G., et al., Decompressive hemicraniectomy without clot evacuation in dominant-sided intracerebral hemorrhage with ICP crisis. Neurosurg Focus, (5): p. E4. 13

UPSTATE Comprehensive Stroke Center. Neurosurgical Interventions Satish Krishnamurthy MD, MCh

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