Inflammatory cerebral amyloid angiopathy

Inflammatory cerebral amyloid angiopathy is an uncommon cerebral amyloid deposition disease, closely related to the far more common non-inflammatory cerebral amyloid angiopathy, and can present as areas of vasogenic edema.

Terminology

The term "inflammatory cerebral amyloid angiopathy" can be used as an umbrella term encompassing two subtypes: cerebral amyloid angiopathy-related inflammation and amyloid β-related angiitis ^2,6. However, many authors interchange the terms "cerebral amyloid angiopathy-related inflammation" and "inflammatory cerebral amyloid angiopathy," either encompassing of amyloid β-related angiitis ⁸ or in distinction to it ³. Still others refer to only cerebral amyloid angiopathy-related inflammation alone ^1,4,5,10 or amyloid β-related angiitis alone ⁷ without mention of the other.

When the distinction is made, the difference lies in whether the inflammation is perivascular only (cerebral amyloid angiopathy-related inflammation or inflammatory cerebral amyloid angiopathy) or also involves and destroys the vessel wall (amyloid β-related angiitis).

This pathological distinction is not reliably predicted on imaging ². It may also be possible that, due to sampling error on biopsy, the pathological diagnosis does not reflect the global picture depicted on imaging ⁶. For these reasons, this article does not attempt to distinguish between subtypes and treats the terms interchangably.

Other synonyms used for this entity include cerebral amyloid inflammatory vasculopathy, amyloid angiopathy and granulomatous angiitis of the central nervous system, cerebral amyloid angiitis, primary angiitis of the central nervous system associated with cerebral amyloid angiopathy, and cerebral amyloid angiopathy associated with giant cell arteritis ⁹.

Additionally, although there is considerable overlap, inflammatory cerebral amyloid angiopathy should be distinguished from amyloid-related imaging abnormalities (ARIA) that are seen in the setting of treatment with novel amyloid-lowering therapies such as monoclonal antibodies ¹³. 

Epidemiology

The diagnostic criteria for possible or probable inflammatory cerebral amyloid angiopathy require age ≥40 years ⁴. In general, the same patient group affected by cerebral amyloid angiopathy is affected, and thus most patients are elderly, typically 60-80 years of age. However, the average patient is a little younger than in non-inflammatory cerebral amyloid angiopathy and older than those with non-amyloid primary cerebral angiitis ².

Diagnosis

A definite diagnosis requires pathologic demonstration (such as biopsy or autopsy). However, clinicoradiological diagnostic criteria have been proposed for cerebral amyloid angiopathy related inflammation ⁴.

Diagnostic criteria

Possible

1. age ≥40 years

2. at least one of these clinical features not directly attributable to an acute intracerebral hemorrhage:

   1. headache

   2. decrease in consciousness

   3. behavioral change

   4. focal neurological signs and seizures

3. MRI with white matter hyperintensities (unifocal or multifocal, corticosubcortical or deep) that extend to the immediately subcortical white matter

4. at least one of these corticosubcortical hemorrhagic lesions: cerebral macrobleed, cerebral microbleed, or cortical superficial siderosis

5. absence of neoplastic, infectious, or other cause

Probable

The same criteria as the possible category with the exception that the MRI white matter hyperintensities are also asymmetric, and that asymmetry is not due to past intracerebral hemorrhage.

Proposed changes

The addition of leptomeningeal enhancement on T1 C+ (Gd) and sulcal non-nulling on FLAIR have been proposed as additions to the MRI criteria, and are thought to increase its sensitivity ¹⁵.

Clinical presentation 

The clinical presentation is usually acute or subacute ^1,2, but may be chronic ⁴. The diagnostic criteria for possible or probable inflammatory cerebral amyloid angiopathy require at least one of the following clinical features that are not directly attributable to an acute intracerebral hemorrhage ⁴:

• headache

• decrease in consciousness

• behavioral change

• focal neurological signs and seizures

Acute or subacute cognitive decline is also a common clinical feature (and was the most common clinical feature in one meta-analysis ¹⁴) and some patients also present with hallucinations ². 

Radiographic features

Classically, CT and MRI demonstrate an area of vasogenic edema involving the subcortical white matter ¹. Lesions are usually unifocal but multifocal involvement is occasionally present at the time of diagnosis (~30%) ¹. It should be noted, however, that inflammatory cerebral amyloid angiopathy also involves leptomeningeal vessels and in some cases the majority of radiographic changes may be leptomeningeal rather than parenchymal ¹⁶.

Overall, MRI is the modality of choice in assessing patients with suspected inflammatory cerebral amyloid angiopathy as it is able to visualize the characteristic microhemorrhages and cortical superficial siderosis of cerebral amyloid angiopathy. 

CT

Subcortical white matter will demonstrate usually a solitary area of low density with localized mass effect ^1,2. 

Angiography (DSA)

Angiography does not reveal evidence of vasculitis involving the large- or medium-sized vessels ⁶.

MRI

White matter lesions

The diagnostic criteria for "probable" inflammatory cerebral amyloid angiopathy require white matter hyperintensities on T2-FLAIR that are asymmetric and extend to the immediately subcortical white matter ⁴. The asymmetry should not be due to past intracerebral hemorrhage to satisfy this criterion ⁴.

The presence of symmetric white matter lesions that extend to the immediately subcortical white matter would only meet the criteria for "possible" inflammatory cerebral amyloid angiopathy ⁴.

The white matter hyperintensity represents vasogenic edema, which may show localized mass effect. While changes are typically confined to the subcortical white matter, the involvement of the cortex is also encountered and predisposes to seizures ^1,2.

Hemorrhagic lesions

The diagnostic criteria for both probable and possible inflammatory cerebral amyloid angiopathy require at least one corticosubcortical hemorrhagic lesion ⁴, which is best demonstrated as signal loss on T2*-weighted sequences (susceptibility weighted or gradient echo):

• cerebral macrobleed (intraparenchymal hematoma)

• cerebral microbleeds (cerebral microhemorrhages)

  • present in ~90% of cases ^1,2

• cortical superficial siderosis

Leptomeningeal/vascular involvement

Leptomeningeal involvement may be detected through either leptomeningeal contrast enhancement on T1 C+ (Gd) and/or as sulcal non-nulling on FLAIR (i.e. subarachnoid FLAIR hyperintensity) ^1,2,15-17. Leptomeningeal contrast enhancement is seen in approximately half of patients ^1,2,15.

Occasional cases of pathologically-confirmed inflammatory cerebral amyloid angiopathy have been reported with prominent leptomeningeal involvement without the typical white matter or hemorrhagic lesions on imaging ^5,6,16. Cases of an isolated leptomeningeal process on imaging are more commonly categorized as amyloid β–related angiitis, within the limitations of variable terminology noted above ⁶.

MRA and vessel wall imaging may show medium-sized arteries involved with multifocal stenoses with wall thickening/enhancement ¹¹. Vessel wall enhancement, however, is not specific for inflammation and may be seen with noninflammatory amyloid angiopathy ¹².

Treatment and prognosis

A significant proportion of patients respond readily to treatment with corticosteroids, with or without another immunosuppressive medication (e.g. cyclophosphamide) ¹⁵, with improvement evident within a week or two of commencement of treatment. In fact, in a subgroup of patients, spontaneous remission is encountered ¹. In the remainder, which accounts for 60% of all affected individuals, even with treatment, severe disability or death are encountered ². Even with immunosuppression, approximately 25% of patients die within one year ¹⁵.

In patients who respond to treatment, imaging follow-up demonstrates regression of the aforementioned inflammatory findings. 

Differential diagnosis

The diagnosis of inflammatory cerebral amyloid angiopathy on clinicoradiologic grounds requires the exclusion of other causes:

• amyloid-related imaging abnormalities (ARIA) seen in patients treated with amyloid lowering therapies ¹³

• infection, such as progressive multifocal leukoencephalopathy (PML) or meningoencephalitis of various causes

• vascular pathologies, such as primary CNS vasculitis or posterior reversible encephalopathy syndrome (PRES)

• neoplasm, such as metastases