Carotid artery stenosis (CAS) is one of the major complications of external irradiation (radiotherapy, RT) for laryngeal carcinoma. Considering amaurosis fugax is often one of the first signs of significant CAS our focus was to determine weather patients with post-irradiation CAS also develop ocular microangiopathy as a result of insufficient ophthalmic circulation. In our study Carotid Duplex ultrasound scans revealed that 33.33% of patients had significant radiation–induced CAS. The majority (over 85.71%) of radiation-induced CAS had more than one atherosclerotic plaque including any degree of stenosis in the RT group, and had significantly more than that of the control group. Microangiopathic changes were documented only with the patients that have had an increased cerebrovascular risk (diabetes mellitus and arterial hypertension)

Božo Vojniković

Ines Strenja-Linić

Tea Čaljkušić-Mance

Strenja-Linić, Ines

Vojniković, Božo

Čaljkušić-Mance, Tea

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Focused High Risk – Population Screening for Carotid Stenosis and Retinal Microangiopathia after Radiotherapy for Laryngeal Carcinoma

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Coll. Antropol. 34 (2010) Suppl. 2: 49–52Original scientific paperFocused High Risk – Population Screening forCarotid Stenosis and Retinal Microangiopathiaafter Radiotherapy for Laryngeal CarcinomaInes Strenja-Lini}1, Bo`o Vojnikovi}2, Tea ^aljku{i}-Mance3, Robert Ti}ac4, David Bonifa~i}1 andDamir Kova~evi}31 Department of Neurology Rijeka University Hospital, Rijeka, Croatia2 Daily Eye Clinic »Dr. Bo`o Vojnikovi}«, Rijeka, Croatia3 Department of Ophthalmology, Rijeka University Hospital, Rijeka, Croatia4 Department of Otorhinolaryngology, Rijeka University Hospital, Rijeka, CroatiaA B S T R A C TCarotid artery stenosis (CAS) is one of the major complications of external irradiation (radiotherapy, RT) for laryn-geal carcinoma. Considering amaurosis fugax is often one of the first signs of significant CAS our focus was to deter-mine weather patients with post-irradiation CAS also develop ocular microangiopathy as a result of insufficient oph-thalmic circulation. In our study Carotid Duplex ultrasound scans revealed that 33.33% of patients had significantradiation–induced CAS. The majority (over 85.71%) of radiation-induced CAS hadmore than one atherosclerotic plaqueincluding any degree of stenosis in the RT group, and had significantly more than that of the control group. Micro-angiopathic changes were documented only with the patients that have had an increased cerebrovascular risk (diabetesmellitus and arterial hypertension).Key words: carotid artery stenosis, retinal microangiopathia, laryngeal carcinoma, radiotherapyIntroductionStroke is the third leading cause of death in the world,and also the leading cause of serious long-term disability,causing functional limitation in elderly population1,2.The clinical burden of stroke and transient ischemic at-tack now exceeds that of coronary heart disease1,3,4,7–10.Atherosclerosis accounts for up to one-third of allstrokes11–15. Approximately 50% of strokes occur in thedistribution of the carotid arteries and patterns of pro-gression of carotid stenosis is unpredictable, diseasesmay progress quickly or slowly, or remain stable formany years4–7,13. Carotid artery stenosis (CAS) can re-duce the risk of ipsilateral ischemic stroke in patientswith 70–99% symptomatic carotid stenosis, and in somepatients with 50–69% stenosis, if the stenosis is removedquickly5,8–11,15. Carotid stenosis greater than or equal to50% has been identified in 7% of men and 5% of womenolder than 65 years4,14. The annual stroke risk in patientswith carotid stenosis is most dependent on presence ofsymptoms as well as stenosis severity, but is also influ-enced by the presence of silent cerebral infarction,contralateral diseases, atherosclerotic risk factors, mor-phology of plaque and etc1–4,11,12. Stroke risk is the high-est immediately after the ischemic event.Carotid artery stenosis (CAS) is one of the major com-plications of external irradiation (radiotherapy, RT) forlaryngeal and neck carcinoma16–17. Prevalence of carotidarterial disease in patients with previous cervical radia-tion therapy is high enough to justify routine screeningfor carotid artery stenosis. The prevalence of critical CAstenosis in patients who have received radiation therapyfor head and neck cancer has been reported to be as highas 22%17. Irradiation may accelerate the development ofatherosclerosis, and this vascular injury involves all lay-ers of the vessel wall, with characteristic endothelial cellproliferation, media scarring, loss of smooth muscle andadventitial fibrosis.49Received for publication January 10, 2010The ophthalmic artery is the first major branch of thesupraclinoid portion of the internal carotid artery (ICA).Hemodynamically significant CAS can lead to diverse oc-ular complications, including transient monocular blind-ness, known as amaurosis fugax, retinal artery occlusionand the ocular ischemic syndrome (OIS)20. Anterior seg-ment fluorescein angiography (FAG) can be performed toevaluate hypoxic ocular conditions in the radiation-in-duced CAS. FAG characteristically reflects to the statusof chronic hypoperfusion of the chorioid and retina.Considering amaurosis fugax is often one of the firstsigns of significant CAS our focus was to determineweather patients with post-irradiation CAS also developocular microangiopathy as a result of insufficient oph-thalmic circulation16.Material and MethodsThe extracranial carotid arteries of 42 (33 male and 9female; mean age of 53.6 years) post-irradiation patientswith laryngeal carcinoma (International Classification-TNM: T3,T4) were examined with Color Doppler Ultra-sound by a vascular neurologist in a Neurosonology Lab-oratory, at the Department of Neurology, Rijeka Univer-sity Hospital. We applied Ultrasound screening protocolfor radiation-induced carotid stenosis originated in ourNeurological Laboratory (Figure 1).Also, for all of the patients flourescein angiography(FAG) was performed by an ophthalmologist at the De-partment of Ophthalmology, Rijeka University Hospital.All of the patients were divided into two groups: post-ir-radiation patients with and without CAS. Patients with-out CAS also represented the control group. The distri-bution of the CAS and the degree of stenosis were docu-mented.All of the patients with laryngeal carcinoma had beenundertaken to total laryngectomy with/without radicalneck dissection. The mean duration after radiotherapy inthe RT group was 5.2 years and the mean dosage of irra-diation was 6000 cGy in the neck area.Incidences of risk factors for arterial stenosis such astreated hypertension, smoking, treated diabetes and hy-percholesterolemia in these two groups were also moni-tored. The data was analyzed by the Fisher exact test.ResultsThe average age of patients in the study group withradiation-induced CAS was 53.6 years, and that of thecontrol group without CAS 66.8 years. The median followup since RXT was 5.2 years. Duplex ultrasound scans re-vealed that 14 (33.33%) of patients had significant radia-tion-induced CAS. Five patients (11.9%) had unilateralcarotid occlusion (Figure 2) and four patients (9.52%)have had stroke after radiation therapy. The majority(over 85.71%) of radiation-induced CAS had more thanone atherosclerotic plaque including any degree of steno-sis in the RT group, and had significantly more than thatof the control group (Figure 3). Male patients are signifi-cant more prevalent in CAS group than female (p>I. Strenja-Lini} et al.: Carotid Stenosis and Retinal Microangiopathia, Coll. Antropol. 34 (2010) Suppl. 2: 49–5250<50% STENOSIS50–69%STENOSIS70–99%STENOSIS100%STENOSISANNUAL FOLLOW UP FOLLOW UP 6 MONTHS MEDICAL RT ANDCONTRALATERAL ICASURVEILLANCECRITERIA:PSV >300 cm/sEDV >125 cm/sNEUROLOGICAL EVENT:TIA, STROKEANGIOGRAPHICEVALUATION/VERIFICATIONENDOVASCULARREPAIR (STENTING)VELOCITYCAS-carotid stent-assisted angioplasty, PSV-peak systolic velocity, ICA-internal carotidTIA- transient ishemic attack, RT-radiotherapy.artery,Fig. 1. Ultrasound screening protocol and patient managementfor radiation-induced carotid stenosis. Fig. 2. Radiation-induced occlusion of internal carotid artery.Fig. 3. Radiation-induced carotid stenosis.0.0154) (Table 1). Microangiopathic changes (performedFAG) were documented only with the patients that havehad an increased cerebrovascular risk (diabetes mellitusand arterial hypertension) and in both group of our pa-tients: with and without CAS. In this patients FAGshowed delayed chorioidal filling, delayed retinal arterialfilling and slow arteriovenous transit time.Discussion and ConclusionThe prevalence of carotid arterial disease in patientswith prior cervical radiation therapy is clinically signifi-cant and warrants aggressive screening as part of rou-tine pre-radiation and post-radiation care. Proposed me-chanism is a combination of direct vessel wall damage,with intimal proliferation, necrosis of media and also ac-celerated atherosclerosis and indirect effects as a resultof radiation-induced obliteration of the adventitial vasavasorum18,19,21. Our results support this thesis, becausethe majority of radiation-induced CAS has more than oneatherosclerotic plaque.This study has also shown that radiation could causesignificant carotid stenosis, but not ocular microangio-pathy.Changes in the domain of ocular microcirculation hadonly been documented with the patients with the usualcerebrovascular risk factors (diabetes mellitus and arte-rial hypertension). Yearly ultrasound examinations forRT patients are therefore necessary for screening andearly detection of carotid stenosis and to increase thepossibility of intervention for this late radiation-inducedcomplication17.Carotid artery disease that occurs as a result of radia-tion therapy or radical neck dissection is considered aclear indication for endovascular therapy and CA angio-plasty and stent placement has become an ultimate treat-ment strategy for this particularly challenging group ofindividuals16.R E F E R E N C E S1. ROTHWELL PM, COULL AJ, SILVER LE, Lancet, 366 (2005)1773. — 2. WARDLAW JM, STEVENSON MD, CHAPPELL F, ROTH-WELL PM, GILLARD J, YOUNG G, THOMAS SM, RODITI G, GOUGHMJ, Stroke, 40 (2009) 3511. — 3. ROTHWELL PM, ELIASZIW M, GUT-NIKOV SA, Lancet, 361 (2003) 107. — 4. ROTHWELL PM, MEHTA Z,HOWARD SC, GUTNIKOV SA, WARLOW CP, Lancet, 365 (2005) 256. —5. NORTH AMERICAN SYMPTHOMATIC CAROTID ENDARTEREC-TOMY TRIAL COLLABORATORS, N Engl J Med, 325 (1991) 445. — 6.BARNETT HJ, GUNTON RW, ELIASZIW M, FLEMING L, SHARPE B,GATES P, MELDRUMH, JAMA, 283 (2000) 1429. — 7. ROTHWELL PM,SLATTERY J, WARLOW CP, Stroke, 27 (1996) 260. — 8. BULAT C, AL-FIREVI] I, KORDA ZA, PROTRKA N, NOVKOSKI M, PREDRIJEVACM, Coll Antropol, 32 (2008) 209. — 9. DE SYO D, BJÖRN D, FRANJI],LOVRI^EVI] I, VUKELI] M, PALENKI] H, Coll Antropol, 29 (2005)627. — 10. BO[NJAK PA[I] M, VARGEK SOLTER V, [ERI] V, URE-MOVI] M, VIDRIH B, LISAK M, DEMARIN V, Coll Antropol, 29 (2005)623. — 11. VIDJAK V, HEBRANG A, BRKLJA^I] B, BRAJ[A M, KAR-LO N, ANTE B, Coll Antropol, 31 (2007) 723. — 12. VIDJAK V, HEB-RANG A, BRKLJA^I] B, BRAJ[A M, NOVA^I] K, BARADA A, CollAntropol, 31 (2007) 775. — 13. @UNTAR IN, VRKI] N, TOPI] E, KU-JUND@I] N, DEMARIN V, VUKOVI] V, Coll Antropol, 30 (2006) 871. —14. REINER-TEDESCHI E, REINER @, IVEKOVI] R, NOVAK-LAU[ K,PINTARI] I, Coll Antropol, 26 (2002) 615. — 15. ROBERT DE, DONO-VAN MT, HOPKINS NL, Neurosurg Focus, 18 (2005) 8. — 16. MORITZMW, HIGGINS RF, JACOBS JR, Arch Surg, 125 (1990) 1181. — 17.DUBEC JJ, MUNK PL, TSANG V, LEE MJ, JANZEN DL, BUCKLEY J,Br J Radiol, 71 (1998) 872. — 18. CARMODY BJ, ARORA S, AVENA R, JVasc Surg, 30 (1999) 1045. — 19. TAKAYUKI B, KYOKO I, RITSUKO T,TSUTOMU K, MOTOHIRO K, FUJIO N, Jpn J Ophthalmol, 43 (1999)546. — 20. FAJARDO LF, Cardiovasc Radiat Med, 1 (1999) 108.I. Strenja-Lini} et al.: Carotid Stenosis and Retinal Microangiopathia, Coll. Antropol. 34 (2010) Suppl. 2: 49–5251TABLE 1PATIENT CHARACTERISTICS AND COMORBIDITIESVariable (n=42) Significant stenosis No significant stenosis p valueNumber of patients 14 28 –Mean age (years) 53.6 66.8 –SexMale 14 19 0.0154Female 0 9Cumulative radiation dosage (cGy) 6,000 6,000 –Mean follow up since XRT 5.2 yrs 5.2 yrs –Combination surgery with XRT 14 28 –Stroke 4 5 0.220Current tobacco use 10 22 0.231Coronary artery desease 4 7 0.277Prior stent or surgical bypass graft mellitus 3 6 0.307Hypertension 10 19 0.271Diabetes mellitus 5 5 0.134Hyperlipidemia 5 8 0.244Chronic renal failure (creatinine >2) 1 2 0.461Atrial fibrilation 1 3 0.410I. Strenja-Lini}Department of Neurology, Rijeka University Hospital, Cambierieva 17/8, 51000 Rijekae-mail: medines4@yahoo.comCILJANI PROBIR VISOKORIZI^NE POPULACIJE ZA KAROTIDNU STENOZU I RETINALNUMIKROANGIOPATIJU NAKON RADIOTERAPIJE KARCINOMA LARINKSAS A @ E T A KStenoza karotidne arterije (KAS) jedna je od glavnih komplikacija radijacijske terapije (radioterapija, RT) larin-gealnog karcinoma. Uzimaju}i u obzir da je amaurosis fugax jedan od prvih znakova zna~ajne KAS, na{ cilj je bioutvrditi da li pacijenti sa postradijacijskom KAS razvijaju i o~nu mikroangiopatiju kao rezultat insuficijencije oftal-mi~ke cirkulacije. U na{oj studiji nalazi dobiveni u~injenom ultrazvu~nom doppler pretragom karotidnih arterija potvr-|uju da 33% pacijenata ima zna~ajnu postiradijacijsku KAS. Ve}ina (preko 85,71%) radijacijom induciranih KAS imalisu vi{e od jednog aterosklerotskog plaka uklju~uju}i razne stupnjeve stenoze u RT grupi, tako|er zna~ajno vi{e nego ukontrolnoj grupi. Mikroangiopatske promjene oka su dokumentirane samo kod pacijenata koji su imali pove}ani cere-brovaskularni rizik – {e}ernu bolest, te arterijsku hipertenziju.I. Strenja-Lini} et al.: Carotid Stenosis and Retinal Microangiopathia, Coll. Antropol. 34 (2010) Suppl. 2: 49–5252

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Focused High Risk – Population Screening for Carotid Stenosis and Retinal Microangiopathia after Radiotherapy for Laryngeal Carcinoma

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