Intracerebral haemorrhage — mechanisms, diagnosis and prospects for treatment and prevention

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Effective treatments for the acute stages of intracerebral haemorrhage are currently limited. In this Review, the authors consider advances in therapeutic strategies and neurosurgical procedures, including acute care bundles, that promise a new era of interventions.

Intracerebral haemorrhage (ICH) is a devastating condition associated with high mortality and substantial residual disability among survivors. Efective treatments for the acute stages of ICH are limited. However, promising fndings from randomized trials of therapeutic strategies, including acute care bundles that target anticoagulation therapies, blood pressure control and other physiological parameters, and trials of minimally invasive neurosurgical procedures have led to renewed optimism that patient outcomes can be improved. Currently ongoing areas of research for acute treatment include anti-infammatory and haemostatic treatments. The implementation of efective secondary prevention strategies requires an understanding of the aetiology of ICH, which involves vascular and brain parenchymal imaging; the use of neuroimaging markers of cerebral small vessel disease improves classifcation with prognostic relevance. Other data underline the importance of preventing not only recurrent ICH but also ischaemic stroke and cardiovascular events in survivors of ICH. Ongoing and planned randomized controlled trials will assess the efcacy of prevention strategies, including antiplatelet agents, oral anticoagulants or left atrial appendage occlusion (in patients with concomitant atrial fbrillation), and optimal management of long-term blood pressure and statin use. Together, these advances herald a new era of improved understanding and efective interventions to reduce the burden of ICH.

Diagnosing causes of intracerebral haemorrhage

• Main causes: cerebral small vessel disease (SVD), including cerebral amyloid angiopathy (CAA) and arteriolosclerosis

• Macrovascular causes (~10-20%): arteriovenous malformation, aneurysm, cavernous malformation, etc.

• Diagnostic work-up: brain parenchyma and intracranial vasculature imaging

• CT angiography as first step, intra-arterial digital subtraction angiography as reference standard

  
  

Neuroimaging markers of SVD

• CAA markers: cortical superficial siderosis, lobar cerebral microbleeds, enlarged perivascular spaces

• Arteriolosclerosis markers: deep ICH, periventricular white matter hyperintensities, deep cerebral microbleeds

• 'Mixed' pattern: presence of both CAA and arteriolosclerosis markers

Genetics and intracerebral haemorrhage

• APOE polymorphisms: ε2 and ε4 associated with increased ICH risk

• Other genetic variants associated with lobar and deep ICH

• Monogenetic conditions in young-onset CAA and SVD

Less common SVD subtypes

• CAA-related inflammation (CAA-ri)

• Iatrogenic CAA due to prion-like transmission of amyloid-β

Fluid biomarkers in diagnosis and prognosis of SVD

• Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) as potential blood biomarkers

• Cerebrospinal fluid (CSF) examination for CAA diagnosis

Current classifications for intracerebral haemorrhage aetiology

• SMASH-U and H-ATOMIC classifications

• CLAS-ICH and CADMUS classifications based on neuroimaging features

Advances and uncertainties in acute therapy

Therapeutic targets

• Primary injury: direct damage from ICH

• Secondary injury: haematoma expansion, inflammation, oedema

• Key treatment goals: preventing haematoma expansion and reducing secondary injury

Medical treatment for intracerebral haemorrhage

• Blood pressure management: target <140 mmHg within 1 h of ICH onset

• Antithrombotic reversal: stopping antiplatelet/anticoagulant medications

• Haemostatic agents: tranexamic acid, recombinant activated factor VIIa

• Anti-inflammatory treatments: under investigation

Surgical treatment of ICH

• Minimally invasive surgery showing promise in improving functional outcomes

• Ongoing trials investigating optimal surgical techniques and timing

• Decompressive craniectomy: potential benefit in selected cases

Advances in prevention measures

Recurrent intracerebral haemorrhage

• Higher recurrence risk in lobar ICH and CAA

• MRI markers of SVD help assess recurrence risk

Recurrent ischaemic stroke

• Annual risk similar to recurrent ICH (1-4%)

• Higher risk in arteriolosclerosis-related ICH

Long-term blood pressure control

• Key for secondary prevention in both deep and lobar ICH

• Ongoing trials investigating optimal blood pressure targets

Antiplatelet and anticoagulation therapy after intracerebral haemorrhage

• Antiplatelet therapy: RESTART trial showed no increased risk of ICH recurrence

• Anticoagulation: ongoing trials assessing safety and efficacy in atrial fibrillation patients

Utility of left atrial appendage occlusion

• Potential alternative to anticoagulation in ICH patients with atrial fibrillation

• Ongoing trials comparing LAAO with medical therapy

Statins and other lipid-lowering drugs

• Controversial use in ICH patients

• Ongoing SATURN trial investigating statin continuation vs. discontinuation after ICH

Disease-modifying therapies in cerebral small vessel diseases

• Intensive blood pressure management for arteriolosclerosis

• Potential therapies for CAA: anti-amyloid antibodies, RNA interference

• Anti-inflammatory approaches under investigation

Conclusions and future directions

• Advances in understanding ICH mechanisms and potential treatments provide optimism

• Improved classification of underlying aetiologies

• Ongoing trials in acute management and secondary prevention

• Need for implementation of integrated care pathways and organization of care

• Future studies based on improved understanding of ICH disease mechanisms and natural history