Cerebral Amyloid Angiopathy

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Learning objectives

  • Understand the aetiology and risk factors for CAA
  • Be able to recognise the clinical presentation of CAA
  • Discuss diagnostics and treatment strategies

Introduction

Cerebral amyloid angiopathy (CAA) is a common cause of intracranial haemorrhage in the elderly or in younger patients with rare inherited forms. CAA is a distinct cerebral process alone and is unrelated and should not be confused with the systemic amyloidosis deposition diseases. There is a rare but treatable form of inflammatory amyloid disease which all should be aware of, which responds well to immunosuppressive therapy.

Aetiology

CAA has been found commonly in those with Alzheimer disease, but only a minority of those with CAA develop Alzheimer disease. There is an increased risk of dementia in those with ICH. There is a genetic association with apolipoprotein E gene epsilon 2 and 4 alleles. Hereditary forms of CAA are generally familial (rare), more severe and earlier in onset. These are

  • Dutch type: late middle age. ICH. Amyloid deposition. Some get dementia. Defect in amyloid protein precursor protein (APP) gene on chromosome 21.
  • Icelandic type: Presents young adults with ICH. Dementia is seen. It may involve the brainstem and cerebellum too. There may be a mutation of the cysteine protease inhibitor cystatin C.

Pathology

Cerebral amyloid angiopathy is a major cause of haemorrhagic stroke. There is localised amyloid deposition which increases vessel wall fragility which leads to increased bleeding risk. Suspect amyloid if lobar bleeds are seen in those over age > 70 without evidence of pre-existing hypertension. By lobar, we are referring to the cortex and subcortical white matter in distinction to the deep hypertensive bleeds affecting putamen, thalamus and pons. CAA bleeds are slightly commoner in temporal and occipital lobes rather than frontal and parietal lobes. The main differentials of a lobar bleed will be an extension from a large putaminal haemorrhage, Haemorrhagic transformation of an infarct, arteriovenous malformation (AVM) or a haemorrhagic tumour. Histological examination reveals the deposition of amyloid in the media and adventitia of small and mid-sized arteries (and, less frequently, veins) of the cerebral cortex and the leptomeninges. There is a rare variant of suspected inflammatory amyloid angiopathy. This responds well to immunosuppressive therapy. This has been in the past and often nowadays is diagnosed by biopsy but criteria have been developed to help with the diagnosis.

Clinical

Clinically the course can be recurrent as there is a predisposition to further bleeds. Bleeds may be brought on by falls or trivial trauma. Some cases can be relentless with reoccurring bleeds which follow an initial event, a sort of 'primary progressive' pattern. These are then followed over a year or so by further anatomically related and unrelated lobar bleeds for which little can be done other than to stop all anticoagulants and look at falls risk and manage any co-existing blood pressure which may coexist. As soon as the patient gets over one episode they come back with a further. Patients with CAA can simply have transient neurology with a TIA-like syndrome or focal seizure type episode. A real concern when many of us do TIA clinics with limited access to MRI and an assumption that such episodes are most likely thrombotic. CT is unlikely to pick up small especially non-acute microbleeds especially as the presentation to the TIA clinic may be after days or even weeks.

Boston Criteria for CAA

DefinitionDetails
Definite cerebral amyloid angiopathy a full post-mortem examination reveals lobar, cortical, or cortical / sub-cortical haemorrhage and pathological evidence of severe cerebral amyloid angiopathy.
Probable cerebral amyloid angiopathy with supporting pathological evidence :

clinical data and pathological tissue (evacuated haematoma or cortical biopsy specimen) demonstrate a haemorrhage as mentioned above and some degree of vascular amyloid deposition. Doesn't have to be post-mortem

Probable cerebral amyloid angiopathy Pathological confirmation not required. Patient older than 55 years. Appropriate clinical history. MRI findings demonstrate multiple haemorrhages of varying sizes/ages with no other explanation.
Possible cerebral amyloid angiopathy Patient older than 55 years with appropriate clinical history. MRI findings reveal a single lobar, cortical, or cortical / sub-cortical haemorrhage without another cause, multiple haemorrhages with a possible but not a definite cause, or some haemorrhage in an atypical location.

The Boston criteria were first proposed to standardise the diagnosis of cerebral amyloid angiopathy. They comprise of combined clinical, imaging and pathological parameters. They provide a useful list of criteria for research and comparing similar groups of patients. Using these criteria in most cases without post-mortem or brain biopsy we can therefore only suggest that our patients have Probable or Possible CAA.

==Cerebral amyloid angiopathy-related inflammation (CAA-ri)

Diagnostic Criteria for Cerebral amyloid angiopathy-related inflammation (CAA-ri)[4]
1Presentation with a variable combination of acute or subacute onset of headache, decrease in consciousness or behavioral change, focal neurological deficits, and seizures.
2MRI with patchy or confluent T2-weighted or fluid-attenuated inversion recovery (FLAIR) lesions, usually asymmetric, with or without mass effect and with or without leptomeningeal or parenchymal enhancement
3Multiple lobar microhaemorrhages and recent or past lobar intracerebral haemorrhage (ICH); and
4the absence of neoplastic, infectious, or other cause.

Imaging

  • Basic stroke Investigations: for haemorrhage
  • CT Brain: acutely this will show a single or possibly more than one lobar haemorrhage in a superficial location. There may be local extension to the subarachnoid space or into the ventricles. As time passes there may be an accumulation of bleeds. Bleeds tend to be more common in the frontal and parietal lobes both cortically and subcortical. Posterior structures including cerebellum and deep nuclei can be affected but usually, the traditional sites for hypertensive bleeds such as putamen, thalamus and pontine are avoided.
  • MRI Brain: using the Gradient echo or T2* sequences is very sensitive at detecting haemosiderin a breakdown product of blood and therefore indicating evidence of old bleeds. A new entity known as Brain Microbleeds has been discovered which may suggest subclinical CAA. They are seen in 5-20% of the population depending on the population studied and radiological techniques in their imaging diagnosis [Rosand J et al. 2000]. These have been defined radiologically as homogeneous, round foci, < 10 mm diameter (no minimum size was specified), of low signal intensity on GRE T2*-weighted MRI. They need to be differentiated from lesions compatible with an infarct with haemorrhagic transformation [Cordonnier et al. 2009]. Microbleeds are commoner in those taking anti-thrombotic agents. Note that Inflammatory amyloid may be seen and there is greater evidence of oedema and swelling in the brain due to CAA-related inflammation is patchy and asymmetrical.
  • CTA/MRA/CTV: may be needed when other aetiologies are being considered.
  • PET brain imaging: is very much a research tool
  • Genetic studies: if needed in those with suspected familial disease
  • Brain Biopsies: taken at surgery or post-mortem the brain will show amyloid with Congo red staining. It has also been done to justify immunosuppression for the inflammatory form of the disease but attempts are being made to use radiological findings.

Possible Complications

There may well be repeated episodes of bleeding in the brain which is usually intraparenchymal but may at times be convexity subarachnoid blood. Bleeding into the ventricular system may precipitate Hydrocephalus. Focal and generalised seizures may occur. Over time repeated injury can lead to a progressive disability, dementia and death.

Management

  • Avoid antiplatelets and antithrombotics and thrombolysis
  • Immunosuppression for inflammatory form may be considered.
  • Standard care for Haemorrhagic stroke including surgery
  • Falls prevention is useful
  • Good management of hypertension and vascular risks
  • Long term dementia and seizure care

References