ISCHEMIC STROKE / CLASSIFICATION AND ETIOPATHOGENSIS

Radiation-induced vasculopathy

Created 14/02/2022, last revision 07/11/2023

Patients after head and neck radiotherapy should be regularly monitored with ultrasound to detect carotid steno-occlusive disease

radiation therapy (RT) is an important part of the treatment of both primary and metastatic tumors
structures such as the brain, cranial nerves, spinal cord, and brain and heart vessels may be affected
radiation-induced vasculopathy (angiopathy) is a heterogeneous and poorly defined complex of vascular injuries attributable to radiation exposure
- both small and large vessels may be affected, manifesting as extracranial carotid stenosis, intracranial stenosis, and other vascular anomalies (e.g., cavernous malformations, aneurysms, moya-moya syndrome, etc.)
- vasculopathy is not limited to cerebral arteries, premature coronary artery disease (CAD) usually involves the ostium or proximal coronary arteries
- total dose, duration, and tissue type exposed play an important role
vasculopathy carries an increased risk of cardiovascular complications in the decades following the initial treatment
- occlusive vasculopathy may manifest years after initial radiotherapy (2-25 y) with an increased incidence due to improved oncological treatment and patient survival
- recognition of radiation vasculopathy is critical for initiating early therapeutic interventions

Etiopathogenesis

Vascular injury

acute radiation damage leads to impaired blood-brain barrier (BBB) integrity ⇒ vasogenic edema occurs
the late vascular complications are caused by endothelial damage. , manifesting as:
- telangiectasia
- aneurysm formation
- microangiopathy
- atherosclerosis affecting medium to large vessels
significant carotid vasculopathy (as a late complication of radiotherapy) is most frequently observed following ear, nose, and throat (ENT) radiotherapy

Glial and white matter injury

oligodendrocytes are more susceptible to radiation-induced damage compared to relatively resistant neurons
MRI shows brain atrophy and extensive leukoencephalopathy

Classification

Classification of post-radiation CNS injuries

Acute (< 14 days after radiation therapy)

the acute injury involves increased capillary permeability and vasodilation, leading to vasogenic edema
clinical presentation: headache, nausea, vomiting, fever, altered consciousness, or worsening of pre-existing focal symptoms
current protocols for administering corticosteroids to patients undergoing radiation therapy (RT) aim to reduce acute injury

Early delayed (> 2 weeks to several months)

both vasogenic edema and demyelination
clinical presentation: headache, nausea, vomiting, worsening of pre-existing focal symptoms
CT/MRI: edema in the irradiated area, hyperintense lesions on FLAIR/T2 sequences

Late (months to years)

late diffuse encephalopathy
- demyelination, atrophy, and necrotizing leukoencephalopathy
- cognitive dysfunction leading to progressive dementia, apraxia, and incontinence
- MRI shows atrophy and diffuse white matter changes
focal necrosis
- focal, usually progressive symptoms
- contrast-enhanced lesions with surrounding edema on brain MRI
  - differentiating these changes from tumor recurrence or metastasis can be challenging- biopsy or PET may assist in diagnosis
stroke-like migraine attacks after radiation therapy (SMART) syndrome
cranial nerve injury, ototoxicity, and endocrinopathy
cerebrovascular disease (radiation-induced vasculopathy)
- stenosis/occlusion of large and medium extra- and intracranial vessels due to accelerated atherosclerosis
  - typically after irradiation of tumors in the ENT region
  - asymptomatic x symptomatic (ischemic vascular events)
- moya-moya syndrome [Bitzer, 1995]
  - in young patients and children when tissues near the siphon are irradiated (e.g., in craniopharyngioma treatment)
- microangiopathy with subcortical ischemic lesions
- aneurysms

Diagnostic evaluation

Imaging findings of radiation vasculopathy exhibit a predictable location and time course. Acute injury occurs within several weeks of treatment, early delayed injury within several weeks to months, and late injury emerges months to years post-treatment

CT/MRI of the brain

specific finding: extensive leukoencephalopathy
CT – white matter hypodensities, vasogenic edema
T2/FLAIR – often symmetric hyperintense lesions
- hypointense lesions suggest vascular anomalies (e.g., cavernous malformations or telangiectasias)

Radiation-induced encephalopathy with extensive bifrontal lesions

Radiation-induced encephalopathy (FLAIR)

Neurosonology

significant bilateral common carotid artery (CCA) involvement is common
- especially after radiotherapy in the ENT region
radiation-induced stenoses tend to be severe and involve longer segments than the traditional atherosclerotic disease
non-calcified plaques with hypoechoic foci predominate in B-mode [Lam, 2012]

Severe carotid stenosis in a patient after radiotherapy for laryngeal carcinoma

CT/MR angiography

vascular imaging studies identify the above-stated vascular changes extra-/intracranially
- pathognomic is the focal presence of stenoses predominantly in the irradiated area and the absence of pathology in other segments
MRA/CTA/DSA may help to identify radiation-induced aneurysms or moyamoya revascularization patterns

Management

antiplatelet therapy
- in case of cancer-related thrombosis, LWHMs or DOACs are prescribed
vascular risk factors modification
- statins
- blood pressure monitoring and aggressive treatment of hypertension
- smoking cessation
follow-up is essential to detect premature carotid artery stenosis and CAD
- consider CEA or CAS if significant stenosis is identified
- vascular anatomy, surgical risk factors, and the patient’s prognosis must be taken into account
- both options share good short-term outcomes and similar perioperative complication rates; CEA probably offers more durable vessel patency
- CABG can be challenging in the presence of heavily calcified or friable internal mammary arteries
both open and endovascular treatment of intracranial radiation-induced aneurysms have been reported

CAS in patient with radiation-induced vasculopathy