Radiation-induced arteriopathy of internal carotid artery — a rare cause of ischemic stroke

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Radiation-induced injury of neck arteries and intracranial vessels is a late complication of radiation therapy administered for head and neck cancers. The disease can develop at any age, including in children, directly depending on the timing of radiation therapy (RT). Stenoses of irradiated arteries and subsequent stroke typically manifest 5–10 years or more after treatment. Extracranially, carotid arteries are most commonly affected, likely due to their surrounding soft neck tissues lacking the bony canal protection characteristic of vertebral arteries. Intracranially, the arteries at the base of the brain are predominantly involved, most frequently the distal internal carotid artery (ICA) and middle cerebral artery [1–3]. Some patients, particularly children, develop moyamoya syndrome characterized by collateral network formation in the stenotic area [4].

Carotid system stenosis is detected in 18–38% of patients who underwent head and neck irradiation [5]. The risk of identifying hemodynamically significant stenosis (≥ 70%) is 8.5 times higher 5 years post-RT compared to the first 5 years [6].

The pathogenesis of radiation-induced arteriopathy remains insufficiently understood. Available evidence suggests accelerated atherosclerosis primarily in the ICA system. Radiation-induced inflammatory changes in arterial walls lead to endothelial damage, migration of smooth muscle cells from media to subendothelial space with subsequent proliferation, and macrophage infiltration into arterial walls. Macrophages absorb oxidized low-density lipoprotein cholesterol and migrate to subendothelial spaces forming foam cells that contribute to atherosclerotic plaque (ASP) [7, 8]. Radiation is also hypothesized to cause vasa vasorum occlusion and necrotic arterial wall changes followed by fibrosis [9]. Histological examination of radiation-induced ASPs in carotid arteries reveals changes similar to atherosclerosis. The distinction lies in lesion site exclusively to irradiated arteries and lower prevalence of vascular risk factors in these patients. Radiation-induced ASPs demonstrate substantial lipid accumulation, indirectly indicating the pathogenetic significance of lipid metabolism in their development [6, 10].

The morphological pattern of intracranial postradiation arteriopathy developing after cranial irradiation for head tumors are not described in the literature. Vascular wall changes detected by high-resolution MRI are not typical for atherosclerotic disease and manifest as prolonged stenosis due to concentric arterial wall thickening with contrast enhancement [3, 4, 11].

Clinical manifestations of ICA radiation-induced arteriopathy depend on the degree of stenosis and affected side. They include syncope, dizziness, and visual acuity reduction due to impaired blood flow in the ophthalmic artery branching from ICA, as well as cerebrovascular accidents [12–14]. Ten years after RT, the incidence of ischemic stroke increases exponentially [2, 14]. Long-term mortality from cerebrovascular diseases is significantly higher in patients who underwent RT compared to those treated solely with surgery for neck malignancies [15].

Computed tomography reveals thickening of the intima-media complex (IMC) in carotid arteries at early post-RT stages, which remains relatively stable for at least one year. One-third of patients demonstrate calcifications on CT scans, with no correlation to time elapsed after RT. Diabetes mellitus contributes to calcification [16, 17]. Atherosclerotic lesions in ICA are detected late after RT and progress over time. The degree of stenosis and increased IMC thickness show positive correlation with baseline cholesterol levels [16]. ICA patency is typically assessed using non-invasive angiography.

Treatment. It is necessary to eliminate and control all vascular risk factors, primarily smoking, arterial hypertension, and diabetes. Statin therapy is indicated, as clinical data show it reduces the degree of ICA stenosis [16, 18–20]. The effect of statin treatment does not depend on the initial degree of stenosis or baseline cholesterol levels [21]. The efficacy of statins is attributed to their protective effect on endothelial cells after radiation exposure. They reduce mitochondrial damage and inflammatory changes by inhibiting proinflammatory factors (monocyte chemoattractant protein-1, interleukin-6, interleukin-8, intercellular adhesion molecule-1) [22, 23].

In patients with symptomatic hemodynamically significant ICA stenoses (> 70%), carotid endarterectomy or stenting should be considered. Technical challenges during endarterectomy may arise due to fibrotic changes in the soft tissues of the neck [24]. The risk of perioperative cerebrovascular complications during endarterectomy and stenting is low. The frequency of late cerebrovascular accidents is higher in patients with stenting compared to endarterectomy. Restenosis may develop after stenting, necessitating dynamic follow-up [25].

In intracranial postradiation arteriopathy with middle cerebral artery involvement, including moyamoya syndrome, extracranial-intracranial anastomosis surgery is performed, which leads to cessation or significant reduction of transient cerebrovascular accident and headaches. Isolated conservative treatment with steroids and acetylsalicylic acid does not significantly affect the course of postradiation arteriopathy [4], although the use of low-dose steroid hormones (30 mg prednisone for 3 months) has been described [3].

The limited coverage in literature regarding postradiation ICA arteriopathy, diagnostic challenges in identifying the cause of associated stroke (particularly due to the long latency period between stroke onset and prior RT), served as the rationale for preparing this publication.

Clinical case report

Patient K., 26 years old, presented to the Russian Center of Neurology and Neurosciences in 2011. The patient provided informed consent for publication.

Complaints: clumsiness in the right extremities, mild word-finding difficulties, decreased vision in the left eye.

Medical history. In 2003, at age 18, laryngeal cancer was diagnosed, treated surgically followed by 2 courses of RT. The patient achieved complete remission and was discharged from oncology follow-up. In December 2010 (age 25), experienced a transient ischemic attack manifesting as brief numbness in the right arm. On October 6, 2011 (age 26), experienced transient loss of consciousness during daytime without preceding triggers, followed by right-sided limb weakness, speech impairment, and left eye vision loss upon recovery. Hospitalized at a local facility.

Brain MRI revealed infarction in the left cerebral hemisphere. Ultrasound examination (October 10, 2011): Left ICA occlusion with lumen filled by heterogeneous masses predominantly hypoechoic; right common carotid artery (CCA) stenosis 30%, right ICA stenosis 54%. Diffuse intimal thickening in both CCAs and ICAs. Peripheral arteries fully patent. ECG and echocardiography showed no abnormalities. Cholesterol 6.6 mmol/L, atherogenic index 7.3. Treatment: Cardiomagnyl, Plavix, Trental, Gliatilin, Solcoseryl, Cytoflavin. Statins were not prescribed. Speech and limb mobility nearly fully recovered; left eye vision impairment persisted.

In December 2011 outpatient MR angiography was performed to reveal left ICA occlusion, right ICA stenosis 70% (Fig. 1). Differential diagnosis included dissection due to increased T1-weighted fat-suppressed signal in the occluded left ICA lumen and “flame sign” at the left ICA ostium. Dissection was excluded due to absence of typical clinical manifestations (no headache/neck pain or triggering factors), unchanged left ICA diameter on MRI, and identification of atherosclerotic plaque in the proximal left ICA (Fig. 1, g, h).

 

Fig. 1. MRI of the brain and brachiocephalic arteries of patient K. a — infarction in the left cerebral hemisphere; T2-weighted wave, axial projection; b — stenosis of the common carotid artery and internal carotid artery (arrows); c, d, e — occlusion of the left internal carotid artery; d, i — aortic plaque of slightly increased MR signal intensity (hemorrhagic component?); g, h — aortic plaque at the orifice of the left internal carotid artery. Time-of-flight MR angiography: b, c — maximum intensity projection; e, h, g — axial projection. T1f/s: g — coronal projection; e, i — axial projection.

 

Considering medical history of neck radiation therapy, post-radiation arteriopathy was diagnosed with ASPs in both ICAs, occlusion of left ICA and stenosis of right ICA. Follow-up MRA in March 2012 showed no changes. Cholesterol level was 7.7 mmol/L. Recommended dose of 20 mg Atoris (atorvastatin) was taken only for 1 month.

On January 21, 2014, repeat MR angiography revealed progression of right ICA stenosis (Fig. 2). Cholesterol level was 7.7 mmol/L. Ophthalmological examination showed vascular-induced atrophy of left optic nerve disc. Statins and antiplatelet agents were recommended. No surgical intervention performed. During follow-up phone interview in August 2024, patient reported stable condition, employed, with reduced vision in left eye. No extracranial artery studies performed.

 

Fig. 2. Dynamic MRI of the brachiocephalic arteries of patient K. Increased aortic plaque size (b, c, d, f), right ICA stenosis (a, g), and left CCA stenosis (g, i, j, m) are indicated by arrows. The left ICA remains occluded, with thrombotic masses in the lumen of the ICA with slightly increased MR signal intensity in T1f/s and time-of-flight angiography (h, k)—no change during observation (dashed arrows). Time-of-flight MR angiography: a, d, g, j — maximum intensity projection; c, f, i, m — axial projection. T1f/s: b, d, h, k — axial projection.

 

Discussion

This paper presents a young patient who developed transient ischemic attack and stroke in the left middle cerebral artery territory 7 and 8 years after neck radiation therapy, respectively. The young age of the patient, no vascular risk factors and systemic atherosclerosis signs, along with unremarkable family history of vascular diseases, provided grounds for diagnosing late radiation therapy complication — post-radiation arteriopathy manifested by stenotic-occlusive lesions of both ICAs. Acute focal neurological symptoms, loss of consciousness in the acute phase despite mild focal neurological deficit, and localization of cerebral infarction in deep left hemisphere structures rather than borderzone areas suggest that the stroke occurred via an artery-to-artery embolism mechanism. The source was identified as thrombotic material in the lumen of the left ICA detected by ultrasound during the acute stroke phase, the formation of which was caused by atherosclerotic plaque. In this case, embolism occurred not only in the cerebral artery but also in the ophthalmic artery, causing ischemia of the optic nerve and its subsequent atrophy. Transient cerebrovascular accident and ischemic stroke developed 7–8 years after neck RT, which is fully consistent with data from other authors [2, 6, 14] and allows estimation of the rate of atherosclerotic ICA stenosis. Two years after stroke onset, with no statin therapy, progression of right ICA stenosis was observed (left ICA occlusion remained unchanged), while statin administration, according to literature data [16, 18–20], reduces stenosis severity. Subsequently, the patient did not monitor the condition of neck arteries. For 13 years following the stroke, the patient’s condition remained stable. No cerebrovascular events or transient ischemic attack occurred. The patient remains employed. The stable clinical course suggests that vertebral arteries, which provide cerebral blood supply, are not involved in the pathological process, likely due to their location within the bony canal that protects them from radiation damage and subsequent atherosclerotic changes.

The young age of the patient, increased signal from the occluded left ICA on initial MRI T1-weighted fat-suppressed (T1fs) imaging, and the “flame sign” at its origin formed the basis for differential diagnosis with ICA dissection, although clinical findings were not typical for this pathology [26, 27]. Comparison of MRI findings in our patient and those in ICA dissection revealed differential diagnostic features (Fig. 3). In post-radiation arteriopathy with atherothrombosis, the MR signal from thrombotic masses shows mildly increased intensity on T1fs and time-of-flight MR angiography, sometimes appearing isointense to surrounding soft tissues. By contrast, in the acute phase of dissection, the MR signal from intramural hematoma in these sequences is markedly enhanced due to paramagnetic properties of hemoglobin breakdown products, particularly extracellular methemoglobin. The external arterial diameter remains unchanged in atherothrombosis, while hematoma formation in the arterial wall during dissection causes its expansion. Furthermore, ASPs, as observed in our patient, are uncharacteristic of dissection. Finally, the signal from the arterial lumen in atherothrombosis remains stable over extended periods (several years), whereas dissection represents a dynamic process: the hematoma regresses and becomes undetectable on MRI within 3–6 months [28, 29].

 

Fig. 3. Comparative dynamics of MRI of the brachiocephalic arteries of patient K. (row 1) and a patient with left ICA dissection (row 2). Row 1: slight increase in MR signal intensity from the left ICA at the level of its occlusion, thrombotic masses in the lumen (arrow), the outer diameter of the artery is not enlarged (a, b). After 2 years, the MR signal from the artery remains unchanged (c). Row 2: marked increase in MR signal intensity from an intramural hematoma in the wall of the left ICA (arrows), the outer diameter of the artery is dilated, and the lumen is not visualized (d, e). After 2 years, the intramural hematoma is not detectable in the wall, the left ICA is occluded, with an isointense signal (e). a, g: time-of-flight MR angiography, axial projection. T1f/s: b, c, e, f — axial projection; a, b, d, e — examination 2 weeks after the onset of symptoms; c, f — after 2 years.

 

This case observation and literature data demonstrate the importance of comprehensive medical history analysis when determining causes of stenotic-occlusive lesions in cervical ICA. Following RT to the neck region, regular monitoring of neck arteries is essential for timely diagnosis of post-radiation arteriopathy and appropriate statin administration to prevent progression of carotid artery stenosis.

About the authors

Ludmila A. Kalashnikova

Russian Center of Neurology and Neurosciences

Author for correspondence.
Email: kalashnikovaNCN@yandex.ru
ORCID iD: 0000-0003-1142-0548

Dr. Sci. (Med.), Professor, principal researcher, 3^st Neurological department

Russian Federation, Moscow

Marina V. Dreval

Russian Center of Neurology and Neurosciences

Email: dreval-marina83@yandex.ru
ORCID iD: 0000-0002-7554-9052

Cand. Sci. (Med.), senior researcher, Radiology department

Russian Federation, Moscow

Rodion N. Konovalov

Russian Center of Neurology and Neurosciences

Email: krn_74@mail.ru
ORCID iD: 0000-0001-5539-245X

Cand. Sci. (Med.), senior researcher, Radiology department

Russian Federation, Moscow

Marina V. Krotenkova

Russian Center of Neurology and Neurosciences

Email: KalashnikovaNCN@yandex.ru
ORCID iD: 0000-0003-3820-4554

Dr. Sci. (Med.), Head, Radiology department

Russian Federation, Moscow

References

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