”VICTOR BABEȘ” UNIVERSITY OF MEDICINE AND PHARMACY TIMIȘOARA DOCTORAL SCHOOL MEDICINE Habilitation thesis PROF. JIANU DRAGOȘ CĂTĂLIN DEPARTMENT VIII… [311398]
”VICTOR BABEȘ” UNIVERSITY OF MEDICINE
AND PHARMACY TIMIȘOARA
DOCTORAL SCHOOL
MEDICINE
Habilitation thesis
PROF. [anonimizat] – NEUROSCIENCES
DISCIPLINE of NEUROLOGY
“VICTOR BABEȘ” UNIVERSITY OF MEDICINE AND PHARMACY
TIMIȘOARA
2020
”VICTOR BABEȘ” UNIVERSITY OF MEDICINE AND
PHARMACY TIMIȘOARA
DOCTORAL SCHOOL
MEDICINE
Habilitation thesis
AN INTEGRATED APPROACH TO THE ROLE OF NEUROSONOLOGY IN THE DIAGNOSIS OF CEREBROVASCULAR AND ASSOCIATED DISEASES
PROF. [anonimizat]-NEUROSCIENCES
DISCIPLINE of NEUROLOGY
“VICTOR BABEȘ” UNIVERSITY OF MEDICINE AND PHARMACY
TIMIȘOARA
2020
Table of contents
Abstract of the habilitation thesis……………………………………….……………………3
Rezumatul tezei de abilitare …………………………………………………………………………..6
1. ACADEMIC, PROFESSIONAL, AND SCIENTIFIC ACHIIEVEMENTS
1.1. Academic achievements…………………………………………………………………..9
1.2. Professional achievements………………………………………………………………12
1.3. Scientific achievements…………………………………………………………………15
1.3.1. Publications……………………………………………………………………………….15
1.3.2. Personal research………………………………………………….……….………….21
1.3.3. Data from the literature. Personal contributions
1.3.3.1. The role of the extracranial Doppler ultrasonography in the diagnosis of cerebrovascular and associated diseases.
1.3.3.1.1. [anonimizat]……………………………………………23
1.3.3.1.2. [anonimizat]…………………………………..28
1.3.3.1.3. TransIent Perivascular Inflammation of the Carotid artery-(TIPIC) syndrome. Data from the literature. Personal contributions………………………………….…………………….31
1.3.3.1.4. Tipic syndrome: Beyond the Myth of Carotidynia, a new distinct unclassified entity…………………………………………………………………………………………………………33
1.3.3.1.5. Carotid body paragangliomas. Data from the literature. Personal contributions…………………………………………….………………….…………………….. 41
1.3.3.1.6. An evaluation on multidisciplinary management of carotid body paragangliomas: a report of seven cases……………………………………..…………….43
1.3.3.1.7. Anatomical considerations on carotid and vertebral arteries. Congenital variations. Data from the literature. Personal contributions……………………………………………………..51
1.3.3.1.8. Multiple congenital anomalies of carotid and vertebral arteries in a patient with an ischemic stroke in the vertebrobasilar territory. Case report and review of the literature…………………..…………………………………………………….……………55
1.3.3.1.9. Large Giant Cell Arteritis with Eye Involvement. Data from the literature. Personal contributions………………………………………………………………………………………………………………62
1.3.3.1.10. Color Doppler imaging features in patients presenting central retinal artery occlusion with and without giant cell arteritis………………………………………………………74
1.3.3.1.11. Clinical and ultrasonographic features in anterior ischemic optic neuropathies…………………………………………..……………..……………………………..78
1.3.3.2. The role of the transcranial Doppler ultrasonography in the diagnosis of cerebrovascular and associated diseases.
1.3.3.2.1. Transcranian Doppler (TCD) [anonimizat] (TCCS)-Background…………………………………………….…………………………………………..85
1.3.3.2.2. Vascular aphasias. Data from the literature. Personal contributions……………………90
1.3.3.2.3. Extra and transcranial color-coded sonography findings in aphasics with internal carotid artery, and/or left middle cerebral artery stenosis or occlusion……………………………………………………………………………………….98 1.3.3.2.4. Cerebral vessels endothelial dysfunction. Diabetic microangiopathy. The relation between chronic kidney disease and cerebrovascular disease in diabetic patients. Data from the literature. Personal contributions…………………………………………………………………..99
1.3.3.2.5. Cerebrovascular reactivity is impaired in patients with non-insulin-dependent diabetes mellitus and microangiopathy………………………..…….……………………105
1.3.3.2.6. Glycated peptides are associated with the variability of endothelial dysfunction in the cerebral vessels and the kidney in type 2 diabetes mellitus patients: a cross-sectional study……………………………..…………………………………………….……111
1.3.3.3. Concluding remarks…………………………….……………………………………….119
First Appendix-Tabels……………………………………….…………………………….122
Second Appendix-Figures…………………………………………………………………129
2. PLANS FOR CAREER DEVELOPMENT
2.1. Development of academic career………….………….………………………………136
2.2. Development of professional career………………….………………………………137
2.3.Plans for further scientific achievements (Fields of research, Research projects)….138
REFERENCES……………………………………………………………………………..144
Abstract
The first part of my habilitation thesis presents the relevance and originality of my achievements.
My academic career has been based on two essential components: ongoing self-improvement to obtain the professional skills required by the progress of neurology, and the transmission of knowledge to all those interested. I completed my PhD in 2001 as an assistant Professor.
My medical career Since 2001, I have been senior consultant neurologist. In 2005, I obtained a certificate in Neurosonology. Since 2018, I have been the Secretary of the National Commission of Neurology of the Romanian Health Ministry.
My scientific achievements are represented by 7 books as single or first author (one published abroad as single author), 5 chapters (as first author) in 5 treaties published abroad, and 465 scientific papers. I published 24 full-text articles in ISI indexed journals (total IF of 36.069); 8 as a first author, 6 as a principal author (total IF of 16.497). The Hirsch index (Web of Science) is 7. I received 6 scholarships. I took part in 6 grants awarded following a competition (2 as Director).
My scientific achievements covered different research topics:
1) ischemic stroke 2) neuro-ophthalmology 3) vascular aphasias 4) vascular cognitive impairment (VCI).
My fields of scientific research have focused on two main areas:
A. The role of the extracranial Doppler ultrasonography in the diagnosis of cerebrovascular (CVD) and associated diseases.
50% of all ischemic strokes are due to thromboembolic events (from cardiac origin or from large vessels disease), while 25% of them are caused by small vessels disease.
Extracranial Doppler ultrasonography analyzes extracranial vessel wall anatomy and detects parietal anomalies. It can rule out both stenosis and occlusion in the carotid bulb and can assess the arterial blood flow characteristics.
My main contributions in this field are the following:
1. Transient Perivascular Inflammation of the Carotid artery (TIPIC) syndrome should be considered in the differential diagnosis of neck pain. We propose four major criteria: a) presence of acute pain overlying the carotid artery, which may or may not radiate to the head, b) eccentric perivascular infiltration (PVI) on imaging, c) exclusion of another vascular or nonvascular diagnosis with imaging, d) improvement within 14 days either spontaneously or with anti-inflammatory treatment.
2. Carotid body paragangliomas, which are hyper vascularized tumours of the carotid body are represented by a painless latero-cervical mass. Duplex ultrasound helps define vascularity of the tumour, and precise its location at carotid bifurcation.
3. In the case of multiple congenital anomalies of carotid and vertebral arteries, their diagnosis is based on combined use of duplex ultrasound and CT-A.
4. Large vessels GCA. Duplex ultrasound has a high sensitivity to detect the “dark halo” sign in this disease.
5. GCA with eye involvement. It consists in arteritic anterior ischemic optic neuropathy or central retinal artery occlusion, with abrupt, painless, and severe loss of vision of the involved eye. Because Duplex ultrasound data of temporal arteries do not correlate with eye complications, Color Doppler imaging of the orbital vessels is of critical importance, in order to quickly differentiate the mechanism of eye involvement (arteritic, versus non-arteritic); the former should be treated promptly with systemic corticosteroids to prevent further visual loss of the fellow eye.
B. The role of the transcranial Doppler (TCD) ultrasonography in the diagnosis of CVD and associated diseases.
TCD combines in real-time intracranial blood flow patterns and velocity modifications with arterial diameter in the stenotic vessels.
My main contributions in this field are the following:
1. Vascular aphasias and Doppler ultrasound. Aphasia represents a central disorder of language that impairs a person's ability to understand and produce spoken and written language. Vascular aphasias (aphasias in stroke) have not typically corresponded to linguistic domains because lesions involve vascular territories, rather than being restricted to the dorsal fronto-parietal language or the ventral temporal language networks. Doppler ultrasonography is a reliable method for the evaluation of the intracranial arteries stenosis/occlusions and helps identify the intracranial hemodynamic impairment in the cervical ICAs diseases causing vascular aphasias.
2. In type 2 DM, endothelial dysfunction in the cerebral vessels appears before the endothelial impairment at the glomerular level, thus explaining why these patients may develop cerebral vessels modifications while remaining normoalbuminuric. At brain level, the plasma levels of a biomarker of endothelial dysfunction (asymmetric dimethyl-arginine) correlated with the cerebral hemodynamic indices, evaluated by TCD.
3. In normoalbuminuric patients with type 2 DM, proximal tubule (PT) dysfunction may precede the stage of microalbuminuria. The increase in biomarkers for PT dysfunction in incipient diabetic nephropathy and diabetic cerebral microangiopathy preceded the increase in the urine albumin: creatinine ratio (UACR), thus supporting this statement.
4. In our studies we found that plasma glycated peptides (AGEs) are directly involved in the endothelial dysfunction in the brain vasculature, and are associated with the PT dysfunction in normoalbuminuric type 2 DM patients.
5. Cerebrovascular microangiopathy has a high prevalence in normotensive type 2 DM patients and has a predictive value for the concomitant development of diabetic nephropathy. The reverse is also valid, because it may also occur in normoalbuminuric type 2 DM patients.
6. TCD is a sensitive and a reliable tool in the detection of cerebral microangiopathy in DM patients.
7. Cerebrovascular reactivity (CVR) is impaired in normoalbuminuric type 2 DM patients. The cerebral vasodilator capacity is diminished during hypercapnia induced by the breath-holding test. These cerebral haemodynamic changes correlate significantly with duration of DM, endothelial dysfunction, parameters of inflammation, AGEs, UACR, cystatin C, and glomerular filtration rate in these patients.
The second part of my thesis is dedicated to career development plans. The major short-term objective in terms of academic career development is getting my habilitation in order to be able to supervise PhD students in the field of Neurology. Because interdisciplinary studies are the basis for new projects and relevant publications, I will continue to participate in multi-disciplinary research teams, both Romanian and foreign.
I propose the following research directions, focusing on cerebrovascular and associated diseases: a) cerebral and renal impairment in patients with type 2 DM, b) neuro-ophthalmology, c) Vascular Cognitive Impairment, and vascular aphasias, d) cerebral venous thrombosis.
Rezumat
Prima parte a tezei de abilitare prezintă relevanța și originalitatea realizărilor mele.
Cariera academică s-a bazat pe două componente esențiale: auto-perfecționarea continuuă, necesară pentru obținerea abilităților profesionale solicitate de progresul neurologiei și transmiterea cunoștiințelor acumulate tuturor celor interesați. Din 2001 sunt doctor în medicină, fiind atunci asistent universitar.
Cariera medicală Din 2001 sunt medic primar neurolog. În 2005 am obținut competența în Ultrasonografie Doppler Cerebralî. Din 2018 sunt secretarul Comisiei Naționale de Neurologie a Ministerului Sănătății.
Realizările științifice constau în: 7 monografii în calitate de unic sau prim autor (una publicată în străinătate, autor unic), 5 capitole (prim autor) în 5 tratate publicate în străinătate și c) 465 lucrări științifice. Am publicat 24 articole în extenso în reviste indexate ISI (FI cumulat: 36,069), dintre care 8 în calitate de prim autor și 6 de autor principal (FI cumulat: 16,497). Indexul Hirsch (Web of Science) este 7. Am primit 6 premii. Am participat la 6 granturi (2 în calitate de Director de Proiect).
Realizările mele științifice sunt în următoarele domenii de cercetare:
1) Infarctul cerebral 2) Neuro-oftalmologia 3) Afaziile vasculare 4) Deteriorarea cognitivă vasculară.
Domeniile mele de cercetare științifică s-au concentrat pe 2 arii principale:
A Rolul Ultrasonografiei Doppler extracraniene în diagnosticul bolilor cerebrovasculare și asociate.
50% dintre infarctele cerebrale sunt produse prin mecanism tromboembolic (embolii cardiace sau arterio-arteriale), iar 25% sunt consecința microangiopatiei cerebrale. Ultrasonografia Doppler extracraniană analizează anatomia peretelui vascular și detectează anomaliile parietale. Poate exclude stenozele și ocluziile de la nivelul bulbului carotidian.
Principalele mele contribuții se referă la:
1 Sindromul de inflamație perivasculară tranzitorie a arterei carotide trebuie luat în considerare la diagnosticul diferențial al durerii regiunii gâtului. Propunem 4 criterii de diagnostic: a) prezența unei dureri acute pericarotidiene, care poate sau nu să iradieze spre cap, b) infiltrația excentrică perivasculară evidențiată imagistic, c) excluderea imagistică a unei alte afecțiuni vasculare sau nonvasculare, d) ameliorarea în decurs de 14 zile fie spontan, fie sub tratament antiinflamator.
2 Paraganglioamele de corpuscul carotidian sunt tumori hipervascularizate ale acestuia, reprezentate de o formațiune laterocervicală indoloră. Ultrasonografia Doppler relevă vascularizația și localizarea tumorii la nivelul bifurcației carotidiene.
3 Diagnosticul anomaliilor congenitale multiple ale arterelor carotide și vertebrale utilizează ultrasonografia Doppler și CT-A.
4 Arterita cu celule gigante (forma cu afectarea vaselor mari). Ultrasonografia Doppler prezintă o sensibilitate mare în detectarea semnului „halo-ului întunecat”.
5 Arterita cu celule gigante cu afectare oculara. Afectarea constă în neuropatie optică anterioarî ischemică arteritică sau în ocluzie de arteră centrală a retinei, cu scăderea marcată, bruscă si indoloră a acuității vizuale a ochiului implicat. Întrucât datele oferite de ultrasonografia Doppler a arterelor temporale nu se corelează cu afectarea oculară, ultrasonografia Doppler a vaselor oculare este esențială, permițând diferențierea rapidă a mecanismului arteritic sau nonarteritic de afectare a arterelor oculare, primul necesitând inițierea rapidă a corticoterapiei, pentru a preveni pierderea vederii la ochiul congener.
B Rolul Doplerului transcranian (TCD) in diagnosticul bolilor cerebrovasculare și asociate
TCD combină în timp real modificările velocimetrice cu diametrul stenozelor arteriale.
Principalele mele contribuții se referă la:
1 Afaziile vasculare și ultrasonografia Doppler. Afazia este o tulburare dobândită de expresie și de recepție a limbajului vorbit și scris, produsă de o leziune cerebrală. Afaziile vasculare (afaziile din accidentele vasculare cerebrale) nu au un corespondent tipic la nivelul domeniilor lingvistice, întrucat leziunile care le determină implică teritorii vasculare care nu se suprapun exact pe rețelele limbajului. TCD este o metoda fiabila, care permite evaluarea stenozelor/ocluziilor arterelor endocraniene și care ajută la identificarea modificărilor hemodinamice intracraniene produse de stenozele/ocluziile porțiunii cervicale a ACI, care determină infarctele cerebrale soldate cu afazii.
2 În DZ tip 2, disfuncția endotelială la nivelul vaselor cerebrale precede afectarea endoteliului glomerular, explicând de ce acești pacienți pot dezvolta modificări la nivelul vaselor cerebrale ramânând normoalbuminurici. La nivel cerebral, nivelul plasmatic al unui biomarker al disfuncției endoteliale denumit dimetil-arginina asimetrica s-a corelat cu indicii hemodinamici cerebrali evaluați prin TCD.
3 La pacienții normoalbuminurici cu DZ tip 2, disfuncția tubulului proximal poate precede stadiul de microalbuminurie. Creșterea nivelului biomarkerilor urinari pentru disfuncția tubulară proximală în nefropatia diabetica incipientă și în microangiopatia cerebrală diabetică a precedat creșterea raportului: albumină/creatinină din urină (UACR), argumentând această afirmație.
4 În studiile noastre, produșii terminali de glicozilare avansata (AGEs) sunt implicați direct în disfuncția endotelială a vaselor cerebrale și sunt asociați cu disfuncția tubulară proximală la pacienții normoalbuminurici cu DZ tip 2.
5 Microangiopatia cerebrala are o prevalență ridicată la pacienții diabetici normotensivi, având o valoare predictivă importantă pentru dezvoltarea concomitentă a nefropatiei diabetice. Reversul este valabil.
6 TCD este o metodă sensibilă și fiabilă pentru detectarea microangiopatiei cerebrale la pacienții diabetici.
7 Reactivitatea cerebrovasculară este afectată la pacienții normoalbuminurici cu DZ tip 2. Capacitatea vasodilatatorie cerebrala este diminuată în timpul hipercapniei induse de testul de monitorizare TCD la apnee. Aceste modificări hemodinamice cerebrale se corelează semnificativ cu durata DZ, disfuncția endotelială, parametrii inflamației, AGEs, UACR, cistatina C și cu rata filtrării glomerulare.
A doua parte a tezei de abilitare este dedicată planurilor de dezvoltare a carierei.
Obiectivul major pe termen scurt al dezvoltării mele academice constă în obținerea certificatului de atestare, ceea ce mi-ar permite să coordonez doctoranzi. Întrucât studiile interdisciplinare sunt baza unor proiecte și a unor articole relevante, voi continua să particip la echipe de cercetare multidisciplinară din țară și din străinătate.
Propun următoarele domenii de cercetare, focalizate pe bolile cerebrovasculare și asociate: a) afectarea cerebrală și renală la pacienții cu DZ tip 2, b) neuro-oftalmologia, c) deteriorarea cognitivă vasculară și afaziile vasculare, d) flebotrombozele cerebrale.
1. ACADEMIC, PROFESSIONAL AND SCIENTIFIC ACHIEVEMENTS
The first part of my habilitation thesis reveals a synthesis of my academic (didactic), professional (medical), and scientific evolution from my graduation from the University of Medicine and Pharmacy Timisoara, in the year 1991, up to my:
Current position:
Professor at “Victor Babes” University of Medicine and Pharmacy, Timisoara, Department of Neurosciences, Discipline of Neurology, MD, PhD, Senior Consultant in Neurology, Certificate in Neurosonology, Certificate in the Management of Health Services, Head of the First Department of Neurology, Clinical County Emergency Hospital Timișoara, Romania, Secretary of the National Commission of Neurology of the Romanian Health Ministry.
1.1. Academic achievements
I have developed my academic (didactic-teaching) career alongside my professional (medical) pursuits, with a particular emphasis on interaction with both students and residents.
Academic course
In February 1992, I started my academic career, obtaining through competition a co-assistant professor position in the Discipline of Neurology at “Victor Babes” University of Medicine and Pharmacy Timisoara. In 1995, I was promoted through exam to the degree of assistant professor in the same discipline.
I completed my doctoral thesis (PhD degree) entitled “Contributions to the semiology of expressive disturbances in aphasias”in 2001, as an assistant professor. In 2003, I obtained a lecturer position through competition, thereafter, advancing to associate professor (2008), and finally, professorship (2017).
In January 2015, I was appointed by the university’s senate as one of the two coordinators of the training program of resident physicians in the specialty of Neurology for the “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania. The main didactic activities and responsibilities
During my didactic activity, I have been teaching students, helping them in the beginning (pre-2003) during their practical activities and subsequently, through the courses I have taught.
I delivered lectures and conducted clinical workshops in Romanian for Romanian students (from the Faculty of Medicine – both the General Medicine section and the Physiotherapy one) and for residents (junior neurologists) (from the Faculty of Medicine), and in French for foreign students (from the Faculty of Medicine).
For more than 27 years (since February 1992) my academic career has been based on two aspects: a). continuing self-improvement to obtain the professional skills required by the evolution of neurology, and b). the transmission of knowledge to all those interested: students, residents, and young collaborators from my discipline, so that data can be easily understood.
I strive to ensure a good quality of the information provided by updating yearly the presentations according to recent international and, in particular, European guidelines; I have constantly introduced new approaches in education, including evidence-based medicine. I have always tried to be a model for my students and residents; I paid special attention to the fact that teacher-student/resident dialogue should be based on mutual respect. My teaching approach is student- and resident-centered, and I encourage hands-on participation by both students and residents during clinical rounds, in neurosonology, etc., integrating them in the daily activity, thus promoting a greater awareness of their responsibilities, particularly with respect to the care of patients. Emphasis is also put on training in emergency neurology. I have tried, both during courses and during labs, to encourage them to get actively involved in the examination, diagnosis, and treatment of patients. Thus, through all these activities, I have thought to develop the medical thinking of the students and residents, in order to acquire the skills required to become good practitioners.
Learning materials
I provided learning materials in both printed and electronic format for both Romanian and French courses, which are updated continuously with medical information selected from international databases (PubMed, Medline, UpToDate, etc.).
As part of my teaching activity, I edited or contributed to the editing of five courses for students and resident neurologists.
These are:
1. Neurology (course for the students of the Faculty of Medicine), University of Medicine and Pharmacy Timisoara, 2000;
2. Aphasiology (course for resident neurologists, for neurologists, and for senior neurologists), University of Medicine and Pharmacy Timisoara, 2002;
3. Neurological Syndromes (course for the students of the Faculty of Medicine), University of Medicine and Pharmacy Timisoara, 2005;
4. Neurological Syndromes. Neurological Pathology (course for the students of the Faculty of Medicine), Mirton Publishing House, Timișoara, Romania, 2007;
5. Elements of Neurology (course for the students of the Faculty of Medicine), Mirton Publishing House, Timișoara, Romania, 2015.
Diploma theses and scientific circles
In November 2012, I established the scientific circle for students entitled “Actualities in ischemic stroke”. I have supervised 18 diploma theses, all of them highly rated by the examination boards, from which extracts have been drawn to provide information at medical student conferences in the shape of posters and other free media formats. Two of these diploma thesis are now the basis for two PhD theses of two of my young collaborators, concerning cerebral vein and dural sinus thrombosis, and vascular aphasias, respectively.
Since 2005, in order to complement my academic activity, I have organized nine postgraduate courses in Neurology at "Victor Babeș" University of Medicine and Pharmacy-Discipline of Neurology, entitled “Actualities in ischemic stroke”, concerning updates in cardio-embolic ischemic stroke, extra and transcranial Doppler ultrasonography and large arteries disease (LAD) ischemic stroke, diagnosis of symptomatic intracranial atherosclerotic disease, vascular cognitive impairment, vascular aphasias, cerebral vein and dural sinus thrombosis, diagnosis and treatment of inflammatory arterial stenosis, concerning especially giant cell arteritis with eyes involvement, and Color Doppler imaging of retrobulbar (orbital) vessels, etc.
My participation as a lecturer in different national postgraduate courses has to be mentioned as part of my didactic activity.
The most important courses in which I took part as a speaker are: 1). International School of Neurology, 8th European Teaching Course on Neuro-Rehabilitation– RoNeuro Brain Days, June 29-July 1, 2018, Eforie Nord, Romania. This meeting has been endorsed by WFNR (World Federation for Neuro-Rehabilitation), EFNR (The European Federation of Neuro-Rehabiliation Societies), EAN (the home of Neurology).
2). International School of Neurology, 7th European Teaching Course on Neuro-rehabilitation– RoNeuro Brain Days, June 30-July 2, 2017, Eforie Nord, Romania. 3). International Summer School of Neurology, July 15-July 18, 2010, Eforie Nord, Romania. This meeting has been endorsed by the Society for the Study of Neuroprotection and Neuroplasticity (SNNN).
Since 2015, under my supervision and of the SNNN, four residents in Neurology have received yearly scholarships to attend the International Summer School of Neurology and the European Teaching Course on Neuro-Rehabilitation (RoNeuroBrain Days) at Eforie Nord, Romania.
In July 2018, two of my young collaborators won the first two places of the annual competition. Between May 2017 and May 2019, two of my young colleagues, which are now PhD students, were involved in the research activities of the international project “Improved health care in neurology and psychiatry – longer life” IHC-RORS-9 INTERREG-IPA CBC Romania-Serbia Program. I was Director of this project.
In 2010, I was a scientific reviewer (referent) in two committees for rendering the doctoral degree (PhD thesis) in medicine (Discipline of Neurology, “Victor Babes” University of Medicine and Pharmacy, Timisoara), and health management (West University, Timisoara), respectively.
Commissions for the Admission to the “Victor Babes” University of Medicine and Pharmacy, Timisoara/ Committees for rendering academic degrees
Since 1992, I have been a member of the Commission for the Admission to the Faculty of Medicine, specialization General Medicine.
Since 2012, I have been a member in five committees for rendering academic degrees: a). member of the commission for the position of assistant professor (three commissions, at “Victor Babes” University of Medicine and Pharmacy, Timisoara); b).member of the commission for the position of lecturer (one commission, at “Vasile Goldis” West University Arad, Faculty of Medicine); c).member of the commission for the position of associate professor (one commission, at the University of Brasov, Faculty of Medicine).
Different Councils, Commissions and Committees
I was a member of the working committee for the elaboration of the questions (neurology) for the residency contest (2012, 2017).
Between 2013 and 2016, I was a member of the Committee of Evaluation and Assurance of Educational Quality of the “Victor Babeș” University of Medicine and Pharmacy Timișoara, Faculty of Medicine. Since January 2019, I have been a member of the Medical Committee of the “Victor Babeș” University of Medicine and Pharmacy Timișoara.
Between 2012 and 2016, I was an Academic Counsellor of the Rector of our University. Since 2007, I have been a member of the Jury for the oral examination of the Diploma of French Medical (Institut Francais de Roumanie, Timișoara). Therefore, I examined different candidates, including some colleagues from our University, who, after the exam, delivered lectures and conducted clinical workshops in French for foreign students (from the “Victor Babeș” University of Medicine and Pharmacy, Timișoara).
Between 2005 and 2012, I was a consultant within the Research Base with Multiple Users-The center of modeling the prosthesis and the surgery on the human skeleton – at the Polytechnic University Timisoara. My main role in the center’s team was examining the patients and the creation of neuromotor retrieval protocols.
1.2. Professional (Medical) achievements
Professional course
Professional degrees
In 1984, I graduated from “Tudor Vladimirescu” High-school in Târgu-Jiu, the department of mathematics-physics (first of the candidates).
I attended the courses of the Faculty of Medicine of the University of Medicine and Pharmacy of Timisoara in 1984 (second of the candidates). After that, I accomplished nine months of required military training (1984-1985). Throughout my university (1985-1991), I had as main objectives to learn as much theoretical information as possible, and to acquire practical skills, as well, both during the clinical internships and the summer practice periods. I sustained my Diploma Thesis entitled „Neurostimulation in lower-back pain”.
I obtained my MD in year 1991 (first of the candidates, overall mark: 10, from a maximum of 10). Between November 1991 and January 1992, I worked for 3 months as an intern at the Department of Neurology, Clinical Emergency County Hospital from Timisoara.
Subsequently, I was admitted to the neurological specialty (February 1992). Between the years 1992 and 1996, I was a resident physician in the specialty of Neurology at the Clinical Emergency County Hospital from Timisoara. I consider that this period of my clinical work was extremely useful for the development of my medical thinking and for my ability to communicate to the patient.
Following a national exam in October 1996 (Department of Neurology, University of Medicine and Pharmacy, Cluj-Napoca) (second of the candidates), I obtained the title of specialist physician in neurology.
I have been working as a neurologist in the Neurology Clinic of the Clinical Emergency County Hospital in Timisoara between July 1997 and 2001. I further advanced my medical career by obtaining the title of senior neurologist, after passing a national exam in 2001 (Department of Neurology, “Carol Davila” University of Medicine and Pharmacy, Bucharest) (first of the candidates). I have been working as a senior consultant neurologist in the First Neurology Clinic of the Clinical Emergency County Hospital from Timisoara since January 2002.
Different certificates
In 2005, I obtained a certificate in neurosonology, after passing a national exam at the Department of Neurology, “Carol Davila” University of Medicine and Pharmacy, Bucharest.
In 2018, I obtained a certificate in the Management of Health Services, after passing a regional exam at the Department of Public Health and Health Management, University of Medicine and Pharmacy, Timisoara.
Courses and stages
During my professional (medical) career, my efforts were oriented not only to the clinical activity, but also to my scientific development. Thus, during this period of time, I have participated in various postgraduate courses, stages, congresses, conferences, and symposiums in the country and abroad.
In order to broaden my professional skills, I graduated two neurosonology courses organized by the Department of Neurology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, in 2000 (three weeks), and 2004 (one month), respectively.
In 2004, I completed a 3-month specialization internship at Centre Hospitalier Regional et Universitaire de Caen, France, where I benefited from a scholarship offered by our University. There, I was a Visiting Research Fellow in LUnite dexplorations vasculaires du Service de Chirurgie Thoracique et Cardiovasculaire (Perfecting stage of duplex imaging of extracranial arteries and transcranial Doppler ultrasound – TCD).
In 2005, I completed a 1-month specialization internship at Fondation Ophtalmologique “Adolphe de Rothschild”, Paris, France. There, I was Visiting Research Fellow in Le Service d´Imagerie Medicale: Echographie, Radiologie, Scanner, IRM (Perfecting stage of duplex imaging of extracranial arteries, transcranial color Doppler ultrasonography – TCCD, and Color Doppler imaging of retrobulbar –orbital vessels).
In September 2017, I was Visiting Research Fellow in Fondation Ophtalmologique “Adolphe de Rothschild”, Paris, France (Perfecting stage of Transcranial color Doppler ultrasonography-TCCD, computer tomography-CT, computer tomography angiography-CT-A, magnetic resonance imaging-MRI, magnetic resonance angiography-MR-A, and Stroke-Unit: thrombolysis and thrombectomy).
In 2017-2018, I followed a course in the Management of Health Services, organized by the Department of Public Health and Health Management Neurology, University of Medicine and Pharmacy of Timisoara.
The interest I have shown for neurology has led me to graduate from a series of courses organized by the Department of Neurology, University of Medicine and Pharmacy of Timisoara:
1. Vascular Dementia and Alzheimer Disease (1 week) 2002.
2. Clinical implications of intracranial arteries anomalies (3 months) 2003.
3. Cortical dysfunctions in neurologic diseases (3 months) 2004.
I participated at 83 international congresses/conferences/symposiums and numerous national congresses/conferences/symposiums, where I graduated 65 international courses and numerous national courses, the majority during: the ESNCH (European Society of Neurosonology and Cerebral Hemodynamics) conferences, EAN (European Academy of Neurology) congresses, or ESO (European Stroke Organization) conferences.
Activities in National Commissions of the Romanian Health Ministry
In 2017, I was appointed as a member of the National Commission of Neurology of the Romanian Health Ministry.
Since 2018, I have been the Secretary of the National Commission of Neurology of the Romanian Health Ministry.
Activities in Professional Commissions of the Romanian Health Ministry.
The results obtained in the professional, and didactic activity have been recognized by my appointment in 28 professional commissions: (member of the commissions for the degree of specialist physician in neurology, Timisoara; member of the commissions for the degree of senior physician in neurology, Timisoara; chair or member of the commissions for the position neurologist, senior neurologist, physiotherapist, psychologist, Timisoara; member of the commission for the post of Medical Director, Municipal Hospital, Lugoj, Timis).
Recognitions elements of professional activity
Head of the First Department of Neurology of the Clinical Emergency County Hospital, Timisoara In 2014, I became Head of the First Department of Neurology of the Clinical Emergency County Hospital, Timisoara (main activities and responsibilities: managerial activity) through competition.
In August 2019, after passing another exam, I continued as Head of the First Department of Neurology of the Clinical Emergency County Hospital, Timisoara.
Moreover, I am a member of several scientific societies:
Affiliation to national organizations or societies
1. Romanian Society of Neurology-affiliated to the Word Federation of Neurology) (since 1992).
2. Romanian National Association of Stroke-affiliated to the ESO (European Stroke Organization), and WSO (International Stroke Society-World Stroke Organization) (since 1999).
3. Scientific Association “Timișoara Medicală” (since 1992).
4. Medico-Surgical Neurological Society, Timișoara (founding member/secretary) (1996– 2006).
5. Multidisciplinary Research Association from the West Zone of Romania (1998 – 2006).
6. SRUMB (Romanian Society of Ultrasonography in Medicine and Biology), affiliated to the (EFSUMB) European Federation of the Societies of Ultrasound in Medicine and Biology, and to the (WFUMB) World Federation of Ultrasound in Medicine and Biology. (2006 – 2008).
Affiliation to international organizations or societies
1. ESO (European Stroke Organization) (since 2011)
2. ISS-WSO (International Stroke Society-World Stroke Organization) (since 2007)
3. ESNCH (European Society of Neurosonology and Cerebral Hemodynamics) (since 2018)
4. EAN (European Academy of Neurology) (since 2015)
5. SSNN (Society for the Study of Neuroprotection and Neuropasticity) (since 2005). Clinical Study Experience
Since 2003, the professional skills I have acquired have allowed me to participate in 16 international multicentre clinical trials: 10 as principal investigator and 6 as co-investigator. This offered me the opportunity to learn the basic principles in conducting research on human subjects, principles that I applied in my own scientific activity. Between December 2003 – December 2005, I was a co-investigator in the REACH (Reduction of atherothrombosis for continued health) Registry. This large, international, contemporary database shows that classic cardiovascular risk factors are consistent and common but are largely under-treated and under-controlled in many regions of the world. (1000 citations/Jan 2020) (JAMA. 2006 Jan 11;295(2):180-9. DOI:10.1001/ jama. 295. 2. 180).
Clinical Study Experience: 16
(Name/Indications/Sponsor/ Phase/Role/Period)
1. Agatha/Stroke/Sanofi – Aventis/IV/ Sub-Investigator /March 2002 – Feb 2003
2. Reach registry/Stroke/Sanofi – Aventis//IV/ Sub-Investigator /Dec 2003 – Dec 2005
3. Stroke/ Society for the Study of Neuroprotection and Neuroplasticity-SSNN/ IV/ Principal Investigator/Sep 2005-Sep 2006
4. Stroke/ CSC Pharmaceuticals/ IV/Principal Investigator/ Nov 2005 – May 2006
5. Stroke/ Novartis/ IV/SubInvestigator/ Feb 2003 – Feb 2004
6. Epilepsy/Novartis/ IV/SubInvestigator/Jun 2006-Jan 2008
7. Cars/ Stroke/Ever Pharma Austria/II/ Co-Investigator/ Jul 2007-Jul 2009
8. Demences/Lunbeck/ IV/SubInvestigator/Jul 2009-Jun 2010
9. Peripheral Neuropathic Pain/ Astellas UK/IV/Principal Investigator/Nov 2010-Nov 2013
10. Mild Cognitive Impairment/ Ipsen Beaufour/ IV/ Principal Investigator/ Sep 2010-Sep 2014
11. Peripheral Neuropathic Pain/ Astellas UK/ IV/ Principal Investigator/ Mar 2012-Sep 2013
12. Observe-PD, protocol no10537/ Parkinson/ Abbvie/ IV/ Principal Investigator/Jul-Dec 2015
13. DUOGLOBE P14-494 /Parkinson//Abbvie/IV/ Principal Investigator/Sep 2016-Dec 2017
14. CREGS EVER –GB-0514/ Stroke/Ever/ IV/ Principal Investigator/Dec 2015-Dec 2016
15. COSMOS/ Parkinson//Abbvie/ IV/ Principal Investigator/Sep 2017-Dec 2016.
16. C-Regs 2 (EVER-AT-0717) EVER Neuro Pharma Gmbh, Austria//IV/Principal Investigator/ July 2019-ongoing.
1.3. Scientific achievements
1.3.1. Publications
Results of the scientific and research activities
Field of research
In 1991, I elaborated my license thesis entitled “Neurostimulation in lower-back pain”, highly rated by the examination board.
In 2001, I defended my PhD thesis entitled “Contributions to the semiology of expressive disturbances in aphasias”. This was the first doctoral thesis in Romanian concerning the domain of aphasias. It allowed the drawing of conclusions with practical applicability on diagnosis and treatment of vascular aphasias, and was also materialized by papers published in scientific journals and a monograph.
My scientific achievements covered different areas: neurology, nephrology, diabetes, nutrition and metabolic diseases, ophthalmology, and anatomy.
In my research activity, I have collaborated with colleagues both from abroad (France-Paris) and Romania (Cluj-Napoca, Bucuresti, and Timisoara, including other disciplines from “Victor Babes” University of Medicine and Pharmacy, such as: nephrology, diabetes, nutrition and metabolic diseases, ophthalmology, and anatomy).
Research topics
From a practical standpoint, I have had a fundamental influence on the implementation of following research topics in my department:
1) Ischemic stroke: Large arteries diseases: (extracranial and intracranial arterial stenosis/occlusions, extra and transcranial Doppler sonography), cerebral venous thrombosis, small arteries diseases (cerebral and renal impairment in patients with diabetes mellitus-DM: cerebral vessels endothelial dysfunction in DM, and the relation between kidney disease and cerebrovascular disease in diabetic patients).
2) Neuro-ophthalmology: anterior ischemic optic neuropathies, central retinal artery occlusion, giant cell arteritis with eye involvement, Color Doppler ultrasound of retrobulbar (orbital) vessels.
3) Disorders of speech and language: vascular aphasias, assessment of aphasias with WAB-Western Aphasia Battery-Romanian version.
4) Vascular cognitive impairment, Mild Cognitive Impairment
Leader of different research groups
I am the leader of the research group in Neurosonology, and of the research group in Disorders of speech and language/aphasias, respectively, at the Discipline of Neurology, University of Medicine and Pharmacy “Victor Babeș”, Timișoara, (2005– ongoing). My scientific achievements paralleled my academic and professional career leading to the elaboration and publication of seven books as single or first author, of five chapters (as first author in five treaties published abroad) and of 465 scientific papers (appearing in international or national journals):
Books and chapters
a). five monographs as single author:
– one monograph published abroad:
1. Diagnosis of symptomatic intracranial atherosclerotic disease (Scholars’Press,
OmniScriptum), Saarbrucken, Germany, 2015.
– four books published in Romania:
1. Elements of Aphasiology. (Mirton Publishing House), Timișoara,2001.
2. Neurological Syndromes. Neurological Pathology. (Mirton Publishing House), Timișoara, 2007.
3. Management of Romanian aphasics with ischemic stroke of brain. (Mirton Publishing
House. Medica Collection), Timișoara, 2011.
4. Elements of Neurology. (Mirton Publishing House), Timișoara, 2015.
b). two monographs as first author published in Romania:
1. Color Doppler Echography. Ophthalmological and neurological interferences. (Mirton Publishing House. Medica Collection), Timișoara, 2010.
Authors: Dragoș Cătălin Jianu, Silviana Nina Jianu.
This book was awarded the’’Carol Davila” prize for Medicine- IIIrd edition, prize of the
Great National Lodge of Romania and of the Romanian Academy (June 2013).
2. Vascular cognitive Impairment. (Mirton Publishing House), Timișoara, Romania, 2017.
Authors: Dragoș Cătălin Jianu, Claudia Bârsan, Sorin Ursoniu.
c). five chapters in five treaties published abroad.
1. Chapter 16 – Large Giant Cell Arteritis with Eye Involvement.
Authors: Dragos Catalin Jianu, Jianu Silviana Nina, Petrica Ligia and Serpe Mircea.
In: Advances in the Diagnosis and Treatment of Vasculitis – Luis M Amezcua-Guerra (Ed.)
InTech, Rijeka, Croatia, 2011.
2. Chapter 5 – Giant Cell Arteritis and arteritic anterior ischemic optic neuropathies
Authors: Dragos Catalin Jianu, Jianu Silviana Nina.
In: Updates in the diagnosis and treatment of vasculitis –Lazaros Sakkas and Christina Katsiari (Ed.). In Tech, Rijeka, Croatia, 2013.
3. Chapter 3-Cerebral Vein and Dural Sinus Thrombosis
Authors: Dragoș Cătălin Jianu, Silviana Nina Jianu, Georgiana Munteanu, Flavius Traian Dan, Claudia Bârsan.
In: Ischemic Stroke of Brain – Pratap Sanchetee (Ed), Intech Open, London, UK.
4. Chapter – Clinical presentation of Myastenia Gravis. [Online First],
Authors: Dragoș Cătălin Jianu, Silviana Nina Jianu, Claudia Bârsan. In: Tymus – Nima Rezaei, (Ed), IntechOpen, London, UK.
DOI: http://dx.doi.org/10.5772/intechopen.86566.
https://www.intechopen.com/online-first/clinical-presentation-of-myasthenia-gravis
5. Chapter-Diagnosis of symptomatic intracranial atherosclerotic disease. [Online First],
Authors: Dragoș Cătălin Jianu, Silviana Nina Jianu, Georgiana Munteanu, Flavius Traian Dan, Claudia Bârsan. In: Cerebrovascular Diseases- Patricia Bozzetto, (Ed). IntechOpen, London, UK.
https://www.intechopen.com/online-first/diagnosis-of-symptomatic-intracranial-atherosclerotic-disease
Scientific papers
Currently, I have published 465 scientific papers, appearing as full text articles (162) or in abstract form articles (303);
They covered different areas: neurology, ophthalmology, nephrology, diabetology, or internal medicine.
A. 162 full text articles:
1). 24 articles in ISI indexed journals (total impact factor of 36.069)
a). 8 as a first author, 6 as a principal author (total impact factor of 16.497) b). 10 as a co-author (total impact factor of 19.572).
Alongside these, there are:
2). 5 articles in journals indexed in PubMed (2 as a first author, 3 as a co-author),
3). 14 articles in journals indexed in other international databases (7 as a first author, 7 as a co-author),
4). 13 articles in national journals certified by the National Council of the Higher Education’s Scientific Research (CNCSIS), category B (7 first author, 6 co-author).
5). 106 articles in other national journals with ISSN (52 first author, 54 co-author).
B. 303 abstract form articles:
1). 133 papers (110 with ISSN) presented at international congresses of neurology, nephrology, ophthalmology, etc. (58 published in ISI journals, or in non-ISI journals indexed in international databases, or in abstract books); 76 as a first author, and 57 as a co-author), etc., and
2). 170 papers (114 with ISSN) presented at national congresses of neurology, nephrology, ophthalmology, diabetology, or internal medicine, etc., (39 as a first author, 131 as a co-author).
Elements of recognition of scientific and research activities
Citations
By the time this thesis was written (January 2020), I had 82 appearances in the Web of Science system, my papers had 145 citations, which means 1.77 citations per paper and a Hirsch index of 7 reported by the Thomson Web of Science Core Collection. The article that has accumulated the highest number of citations (25) is:
Proximal tubule dysfunction is dissociated from endothelial dysfunction in normoalbuminuric patients with type 2 diabetes mellitus: a cross-sectional study. Nephron Clin. Pract. 2011; volume 118: Issue 2 pages: c155-c164.
Authors: Petrica Ligia, Petrica M, Vlad A, Jianu DC, Gluhovschi Gh, Ianculescu C, Firescu C, Dumitrascu V, Giju S, Gluhovschi C, Bob F, Gadalean F, Ursoniu S, Velciov S, Bozdog Gh, Milas O.
Scholarships and awards: 6
The results of my scientific research activity were appreciated by different societies and committees:
1. 4-th place at the First edition of Grand Prix Beaufour Ipsen, Bucharest, Romania (Oct 2000), with the paper entitled: „Topographic and clinical correlations in transcortical aphasias” Author: Dragoș Cătălin Jianu
2. Best Poster at the IXth Congress of the Romanian Society of Neurology, Bucharest, Romania (Oct 2003), with thepaperentitled:” Primary progresive aphasia” Author: Dragoș Cătălin Jianu
3. First prize at the XIIth Conference of the Romanian Association of Stroke, Cluj-Napoca, Romania (Sep 2009), withthepaperentitled:”The role of ultrasonography in thestudy of theocular ischemic syndrome”. Authors: Dragoș Cătălin Jianu, Silviana Nina Jianu
4. Best Poster at the Joint Congress of SOE (European Society of Ophthalmology) – AAO (American Academy of Ophthalmology), Geneva, Switzerland (June 2011), with the paper entitled :„EP-NEO-426: Color Doppler Imaging of retrobulbar vessels findings in large giant cell arteritis with eye involvement”. Authors: Silviana Nina Jianu, Dragoș Cătălin Jianu
5.’’Carol Davila” prize for Medicine- IIIrd edition-The Great National Lodge of Romania and Romanian Academy (June 2013), with the monography entitled: „Color Doppler Echography. Ophthalmological and neurological interferences”. (Mirton Publishing House), Timișoara, Romania, 2010. Authors: Dragoș Cătălin Jianu, Silviana Nina Jianu.
6. Prize UEFISCDI (code: PN-II-RUPRECISI-2015-9-10647), (2015), with the paper entitled:” Glycated peptides are associated with the variability of endotelial dysfunction in the cerebral vessels and the kidney in type 2 diabetes mellitus patients: a cross-sectional study. J Diabetes Complications, March 2015, Volume 29, Issue 2, pg 230-237. Authors: Petrica Ligia, Vlad A, Gluhovschi Gh, Gadalean F, Dumitrascu V, Vlad D, Popescu R, Velciov S, Gluhovschi C, Bob F, Ursoniu S, Petrica M, Jianu DC.
Member of the editorial board
The experience gained in the scientific activity is also recognized by my appointment as a member of the editorial board of the:
1. “Medico-Surgical Neurology”, Timișoara (1996-2003)
2. „Acta Neurologica Transilvaniae”, Cluj-Napoca (2005-ongoing)
3. „ Romanian Journal of Aphasiology, Cluj-Napoca (2016-ongoing)
4. „Journal of Physiotherapy in neurological diseases, Cluj-Napoca (2016-ongoing),
Peer-reviewer
I activate as a peer-reviewer for
1. “Ophthalmic Plastic and Reconstructive Surgery, (Official Journal of the American Society for Ophthalmic Plastic and Reconstructive Surgery, ISI journal), (USA).
2. Clinical Ophthalmology (An international, peer reviewed, open access journal covering all subspecialties within ophthalmology), (NZ).
2. Journal of US-China Medical Science (USA).
3. Journal of Case Reports and Studies (JCRS), (USA).
4. „Acta Neurologica Transilvaniae”, Cluj-Napoca.
5. „Romanian Journal of Aphasiology, Cluj-Napoca.
6. „Journal of Physiotherapy in neurological diseases”. Cluj-Napoca.
Organization Committees of Conferences/Symposiums
In addition, I was a member/head of the organizing team of several conferences or symposiums, some of which are:
1. ”Clinic of Neurology Timisoara-50 years”Conference, 7-8 October 1999, Timișoara, Romania.
2. The VIIIth International Symposium “Young People and Multidisciplinary Research”. Association for Multidisciplinary Research of the West Zone of Romania).11-12 May 2006, Timișoara, Romania.
3. “Improved health care in neurology and psychiatry-longer life”-IHC-RORS-9
INTERREG-IPA CBC Romania-Serbia Programme. – Head of the Organizing Committee for 6 symposiums in Timisoara (May 2017-May 2019). – Head of the Organizing Committee for 3 round tables in Lugoj, Caransebes, Drobeta Turnu Severin (May 2017-May 2019).
Scientific Committees of Congresses/Conferences/Symposiums/ International School of Neurology/European Teaching Courses
1. International School of Neurology, 8th European Teaching Course on Neuro-Rehabilitation– RoNeuro Brain Days, June 29-July 1, 2018, Eforie Nord, Romania,
2. International School of Neurology, 7th European Teaching Course on Neuro-Rehabilitation– RoNeuro Brain Days, June 30-July 2, 2017, Eforie Nord, Romania
3. The IX Regional Conference of Ophthalmology with International participation- Actualities in Diagnosis and Treatment in Ophthalmology, Timisoara, Romania, April,23-25, 2015.
4-12. Stroke National Conferences with international participation (2011-2019). (1-12. Member of the Scientific Committee)
13. “Improved health care in neurology andpsychiatry-longerlife” -IHC-RORS-9
INTERREG-IPA CBC Romania-Serbia Programme
Grants/Scientific projects awarded by competition
The scientific activity I have mentioned could not have been possible without the financing of the research, which were realized mainly by the grants allocated in the six research projects to which I took part (in two of them I was Director for the project):
Director Grants/Scientific projects awarded by competition: 2
1. “Improved health care in neurology and psychiatry-longer life” (acronymIHC)-RORS-9
INTERREG-IPA CBC Romania-Serbia Program
1: Employment promotion and basic services strengthening for an inclusive growth 1-2: Health and social infrastructure
Project Director: Professor Dragos Catalin Jianu.
Budget 238.035,00 EUR (Partner 2- University of Medicine and Pharmacy Timisoara)
May 2017- May 2019 (24 months).
The overall objective of the project was an improvement of the diagnosis, treatment and quality of life in border region in patients with vascular cognitive impairment (VCI). VCI reflects the complex interactions between vascular etiologies, risk factors (VRFs), and morphological changes within the brain and their effects on cognition. It includes the whole spectrum of cognitive alterations which can be attributed to a vascular cause. We emphasized that VCI can be prevented by a careful diagnosis of stroke and associated cognitive alterations (memory, attention, etc.,), and also by lowering stroke risk with the appropriate therapy.
2.“Diagnosis and rehabilitation of aphasics with mother tongue Romanian after ischemic stroke”.
Code CPV 79315000-5. Subproject, ”Technology Cares”, financed by the Program People, the Program for Interregional Co-operation INTERREG IVC, (UK, Spain, Poland, Romania).
Director of the Romanian research subproject: Assoc Prof Dragos Catalin Jianu
Budget 12609 EUR (University of Medicine and Pharmacy Timisoara, Romania).
September 2010- March 2011 (7 months)
The overall objective of the project was an improvement of the diagnostic and recovery of Romanian aphasics with ischemic stroke.
Member Grants/Scientific projects awarded by competition: 4
1. “Platform of implantology, intelligent prosthetics and biomechanical rehabilitation” CNCSIS 2006. Cod CNCSIS 43-Romanian Ministry of Education and Research,
Project Director Prof.Dr.Ing.Doina Drăgulescu-Politehnica University Timisoara,
Member of the research team. Lecturer: Jianu DC (Department of Neurology–University of Medicine and PharmacyTimisoara, Romania).
Budget: 8.805.600 RON; 2006-2008 (24 months).
My main role was the neurological exam of the patients, the creation of neuromotor retrieval protocols, and data analysis.
2. „The treatment of the peripheric vascular complications in diabetus mellitus and in nondiabetic arteriopathies, using the angiogenic gene theraphy”(acronym AARTGEN)
PC Project/Health-Romanian Ministry of Education,
Project Director Prof.Andrei Anghel-University of Medicine and Pharmacy Timisoara. Member of the research team. Assoc Prof: Jianu DC (Department of Neurology).
Budget: 2.105.000 RON; 2007- 2009 (33 months).
My main role was the neurological exam of the patients and data analysis.
3. “Detection and validation of new molecular markers for early diagnosis of diabetic nephropathy” (acronym NEPHROMOL)
Program III-C1-PCFI, 2015/2016 University of Medicine and Pharmacy Timisoara, Romania
Project Director: Prof.Ligia Petrica, University of Medicine and Pharmacy Timisoara.
Member of the research team. Assoc Prof: Jianu DC(Department of Neurology). Budget 135.000 RON; 2015-2016 (24 months).
The specific objectives of the project included the evaluation of the endothelial dysfunction at glomerular and cerebrovascular levels by specific biomarkers, and pulsatile index, resistance index, and cerebral vascular reactivity, respectively)
This project led to the publication of six articles in ISI journals with a cumulative impact factor of 12.029.
4.“Translational study from innovative fundamental research to clinical practice regarding genetic, epigenetic and protein markers of chronic diabetic kidney disease diagnosis (Acronym: GEN-DIAB”).
Program III-C5-PCFI-2017/2018, University of Medicine and Pharmacy Timisoara, Romania. Project Director: Prof. Ligia Petrica-University of Medicine and Pharmacy,Timisoara.
Member of the research team. Prof. Jianu DC (Department of Neurology)
Budget 135.000 RON; 4 January 2017-31 December 2018 (months)
This project won the Internal Competition organized by "Victor Babeș" University of Medicine and Pharmacy Timișoara, P III – C5 – PCFI – 2017/2018.
The specific objectives of the project included the evaluation of endothelial dysfunction at glomerular and neuronal level through specific pro-inflammatory cytokines, and PI, RI and cerebrovascular reserve, respectively). This project led to the publication of seven articles in ISI journals with a cumulative impact factor of 16.036.
1.3.2. Personal research
My fields of research have focused on two main areas, the role of the extracranial Doppler ultrasonography, and of the Transcranial Doppler ultrasonography, respectively, in the diagnosis of cerebrovascular and associated diseases.
A. The role of the extracranial Doppler ultrasonography in the diagnosis of cerebrovascular and associated diseases.
I studied: a). the TransIent Perivascular Inflammation of the Carotid artery (TIPIC) syndrome, syndrome which should be consider in the differential diagnosis of neck pain; b). the carotid paragangliomas (CBPGLs), which are hypervascularized tumors of the carotid body; c). the congenital anomalies of the supra-aortic arteries and their branches as potential risk factors for ischemic stroke; d) large Giant Cell Arteritis with Eye Involvement;
The results of these studies have been published in full text articles in 8 ISI-indexed journals (6 first author, 1 principal author, and 1 co-author)
1. TIPIC Syndrome: Beyond the Myth of Carotidynia, a New Distinct Unclassified Entity.
2. An evaluation on multidisciplinary management of carotid body paragangliomas: a report of seven cases.
3. Multiple congenital anomalies of carotid and vertebral arteries in a patient with an ischemic stroke in the vertebrobasilar territory. Case report and review of the literature
4. Left internal carotid artery agenesis associated with communicating arteries anomalies. A case report.
5. Color Doppler imaging features of two patients presenting central retinal artery occlusion with and without giant cell arteritis.
6. Clinical and color Doppler imaging features of one patient with occult giant cell arteritis presenting arteritic anterior ischemic optic neuropathy.
7. Clinical and ultrasonographic features in anterior ischemic optic neuropathies.
8. Giant cell arteritis with arteritic anterior ischemic optic neuropathy.
In addition, with regard to the same issue, I am the author of :
a). one monography as first author published in Romania:
1. Color Doppler Echography. Ophthalmological and neurological interferences.
b). two chapters as first author in two international treaties published abroad.
1. Chapter 16 – Large Giant Cell Arteritis with Eye Involvement. in: Advances in the Diagnosis and Treatment of Vasculitis.
2. Chapter 5 – Giant Cell Arteritis and arteritic anterior ischemic optic neuropathies. in: Updates in the diagnosis and treatment of vasculitis
c). numerous abstract form articles, indexed in ISI-quoted or other international data bases journals, and
d). numerous full text articles indexed in other international databases journals.
B. The role of the transcranial Doppler ultrasonography in the diagnosis of cerebrovascular and associated diseases.
I studied: a) the vascular aphasias (aphasias in ischemic stroke) and the role of Duplex ultrasound as a reliable method for the evaluation of large arteries disease (LAD) – ischemic stroke, b). cerebral vessels endothelial dysfunction in patients with type 2 diabetes mellitus, c). the complexity of the relation between kidney disease and cerebrovascular disease in diabetic patients.
The results of these studies have been published in full text articles in 8 ISI-indexed journals (2 principal author, 6 co-author).
1. Glycated peptides are associated with the variability of endotelial dysfunction in the cerebral vessels and the kidney in type 2 diabetes mellitus patients: a cross-sectional study 2. MiRNA Expression is Associated with Clinical Variables Related to Vascular Remodeling in the Kidney and the Brain in Type 2 Diabetes Mellitus Patients
3. Cerebral microangiopathy in patients with non-insulin-dependent diabetes mellitus 4. Cerebrovascular reactivity is impaired in patients with non-insulin-dependent diabetes mellitus and microangiopathy
5. Nephro- and neuroprotective effects of rosiglitazone versus glimepiride in normoalbuminuric patients with type 2 diabetes mellitus: a randomized controlled trial
6. Does chronic kidney disease define a particular risk pattern of cerebral vessels modifications in patients with symptomatic ischemic cerebrovascular disease
7. Proximal tubule dysfunction is dissociated from endothelial dysfunction in normoalbuminuric patients with type 2 diabetes mellitus: a cross-sectional study.
8. Pioglitazone delays proximal tubule dysfunction and improves cerebral vessels endothelial dysfunction in normoalbuminuric patients with type 2 diabetes mellitus
In addition, with regard to the same issue, I am the author of:
a). Four monographs
– one book published abroad as single author:
Diagnosis of symptomatic intracranial atherosclerotic disease
– two books published in Romania as single author:
1. Elements of Aphasiology.
2. Management of Romanian aphasics with ischemic stroke of brain.
– one book published in Romania as first author:
1. Vascular Cognitive Impairment
b). one chapter in a treaty published abroad, as first author:
Chapter – Diagnosis of symptomatic intracranial atherosclerotic disease: in Cerebrovascular diseases.
c). numerous abstract form articles, indexed in ISI-quoted or other international
databases journals, including:
1. Extra and transcranial color-coded sonography findings in aphasics with internal carotid artery, and/or left middle cerebral artery stenosis or occlusion
d). numerous full text articles indexed in other international databases journals Moreover, I participated as a director or a member in four research grants/scientific projects awarded by competition in this field of research
Director of international Grants/Scientific projects awarded by competition: 2
1. “Improved health care in neurology and psychiatry-longer life” (acronym IHC)-RORS-9
2.“Diagnosis and rehabilitation of aphasics with mother tongue Romanian after ischemic stroke".
Member Grants/Scientific projects awarded by competition: 2
1. “Detection and validation of new molecular markers for early diagnosis of diabetic nephropathy” (acronym NEPHROMOL)
2. “Translational study from innovative fundamental research to clinical practice regarding genetic, epigenetic and protein markers of chronic diabetic kidney disease diagnosis (acronym : GEN-DIAB”).
1.3.3. Data from the literature. Personal contributions
1.3.3.1. The role of the extracranial Doppler ultrasonography in the diagnosis of cerebrovascular and associated diseases.
1.3.3.1.1. Cerebrovascular disease forms-Background
Cerebrovascular disease (CVD) ranks among the most important causes of disease in the world [1,2]. The most common form of CVD is ischemic stroke, accounting for about 70-80% of all strokes in developed countries [3,4]. A cerebral infarction is an area of brain parenchyma characterized by the presence of tissue necrosis secondary to ischemia. [5] CVD may be grouped under large- and small- vessel domains. [6-8] It was suggested that 50% of all ischemic strokes are due to thromboembolic events (from cardiac origin or from large-vessel disease), while 25% of them are caused by small-vessel disease (SVD). [7,9]
a). Macrovascular disease
Cortical, subcortical, cerebellar, or brainstem ischemic lesions which are larger than 1.5 cm on CT/MRI are usually considered to be large ischemic brain lesions. [8,10] They may be consequences of embolic events from cardiac origin or from large-vessel disease (LVD) due to atherosclerosis, plaque rupture, intraplaque hemorrhage, thrombotic occlusion, dissection and dolichoectasia, which can also follow hemodynamic events, causing border-zone or watershed lesions. [7,8] The term “large vessels” will be used referring to the large arteries of the neck, the intracranial arteries that form the circle of Willis and the vessels which arise from it (i.e. the anterior, middle, and posterior cerebral arteries). [5] LVD usually manifest itself in the form of ischemic stroke, causing a wide spectrum of clinical syndromes. [6,8,9] The proportion of ischemic strokes attributable to large artery atherosclerosis (LAA) varies between 9% and 35% of all ischemic strokes depending on the classification used to define stroke mechanisms, the thoroughness of the workup to rule out alternative causes and the populations studies. [11-15]
Atherosclerosis is a systemic process that affects the supplying arteries of most important organs, the brain, the hearth and the kidneys. Areas that are considered “prone to develop atherosclerosis include the arterial bifurcations, mostly the wall of daughter arteries opposed to flow dividers [16]. This includes the wall of the internal carotid arteries (ICAs), the middle cerebral arteries (MCAs), as well as the middle segment of the basilar artery (BA) [15,17-19].
Atherosclerosis causes a progressive hardening of vessels walls in the deep white matter (WM) and basal ganglia in response to blood flow oscillatory shear stress and loss of auto regulation through chronic damage of the perivascular nerves. [7,20] The core lesion at the basis of atherosclerosis is the atheromatous plaque. By definition, atherothrombotic strokes occur when enlarged atherosclerotic plaques produce a considerable stenosis of the vascular lumen or cause its occlusion through a superimposed thrombus. Also, atherosclerotic plaques may release embolic materials (artery-to-artery embolism) leading to major cerebrovascular events. [5,9]
Atherosclerosis, although widely prevalent, is not a process of normal aging. Vascular risk factors are among the most important determinants of atherosclerosis. Among them, diabetes, high low-density lipoprotein cholesterol, hypertension and smoking are the most modifiable risk factors for atherosclerosis. [21-23] These risk factors affect vascular beds in different fashions. For example, diabetes and metabolic syndrome are more important predictors of intracranial LAA than of extracranial LAA [24,25]. In contrast, smoking and hypertension are predictors of extracranial LAA [26,27]. More studies are needed to understand the mechanistic pathways of atherosclerosis for each vascular bed, in different race–ethnic groups as well as gene-environment determinants of atherosclerosis in order to advance the current knowledge and treatments for this widely prevalent disorder. [9,28]
b). Microvascular disease
Small vessel disease (SVD) is a systemic condition referring to a group of pathological processes which affect small arteries, arterioles and capillaries. [29,30] It increases with age, is accelerated by vascular risk factors, and causes clinically significant lesions to multiple organs affecting the heart, brain, kidney, and retina [9,28]. Small-vessel alterations in the brain include arteriolosclerosis, wall thickening by lipohyalinosis, fibrinoid necrosis, microatheromas, and cerebral amyloid angiopathy. [5,7,8,28] Although SVD is not usually attributable to atherosclerosis, some evidence suggests that lacunar infarctions, as defined by size, location and clinical syndromes, can also be caused by LAA, underscoring even further the importance of atherosclerosis in relation to stroke mechanisms [15,31]. The most important consequence of SVD is the decrease of both cerebral blood flow and blood volume in affected areas leading to a significant reduction of vasodilatory response and thus interfering with the hemodynamic reserve. [5,9]
The vascular changes described in SVD cause a chronic ischemia of the cerebral tissue behind it and, as a result: ischemic demyelination, low-grade tissue infarction, dilatation of perivascular spaces and, ultimately, disruption of cortico-cortical connections. [5,32] SVD may also determine edema and damage of the blood-brain barrier (BBB) with chronic leakage of fluid and macromolecules in the white matter usually resulting in cerebral microbleeds. [5,9,28]
Parenchymal lesions that are associated with these vessel abnormalities include lacunar strokes, border zone (watershed) infarctions, diffuse white matter (WM) changes (subcortical leuko-encephalopathy or leukoaraiosis) and cerebral microbleeds, mainly in the basal ganglia and fronto-temporal WM. [5,7,8,33] We want to emphasize that cerebral atrophy, which is often seen as a neurodegeneration mark, can also occur as a consequence of the vascular disease. [34] For example, hippocampal neurons are particularly vulnerable to disturbances in the cerebral blood flow or hypoxia caused by vascular disease. [7] Thus, it was reported that SVD may lead to hippocampal and brain atrophy, these pathological changes being found in >50% of cases. [35] Over recent years cerebral SVD has become increasingly recognized as a major contributor to age related motor and cognitive decline, being seen as the most important cause of vascular cognitive impairment (VCI). [8,30,32] Clinically, cerebral SVD is characterized by the insidious onset of cognitive decline (which encompasses impaired executive function, apathy, and mood disturbance [6,32] associated with gait abnormalities (small shuffling steps and poor balance), urinary incontinence, dysarthria, and dysphagia. [9,32]
The lacunar state
Lacunes (or empty spaces) are formed from remnants of small infarcts (50 –500 µm diameter) and can be easily quantified by neuroimaging methods, especially MRI. Most lacunar infarcts are found in the territory of the deep penetrating arteries [5]. Several studies have found a significantly high rate of lacunes on imaging, some as high as 20%. [21,36] The lacunar infarcts are referred as silent because, usually there is no clinical history of a stroke. However, it was demonstrated that patients with silent infarcts had greater cognitive decline compared with those with no such pathological changes. [38] Lacunar infarcts are associated with a poor outcome in the elderly with vascular dementia (VaD). [35] Among these, the neocortical microinfarcts and to a lesser extent periventricular demyelination predict a progressively unfavorable evolution of cognitive impairment. [7,9]
Diffuse white matter (WM) changes, also called subcortical leukoencephalopathy or leukoaraiosis, are commonly encountered in SVD and in VaD. This pathological entity results from a chronic hypoxic state determined by vascular insufficiency (oligemia). Subcortical leukoencephalopathy is attributed to myelin loss and axonal abnormalities, being associated with disruption of cortico-cortical pathways, especially in the frontal lobe. [7] O’Brien et al., stated that the frequency of WM changes is increased not only in patients with CVD, but also in those with arterial hypertension, cardiovascular disease and diabetes mellitus. [39] WM changes seen in SVD are usually accompanied by vacuolization and widening of the perivascular spaces (PVS). [7] PVSs are normal anatomical structures defined as fluid-filled space following the course of brain vessels through grey or white matter. Due to their small diameter (≤ 2mm) normal PVSs cannot be detected by low- resolution MR or CT scans, but it is suggested that a generalized enlargement of PVS associated with other markers of SVD may be relevant to vascular cognitive impairment (VCI). [8,9,34]
In very rare cases, cognitive decline may be related to hemodynamic disturbances caused particularly by unilateral or bilateral occlusion of carotid arteries. [40] It was reported that chronic ischemia without stroke in the carotid territory can result in widespread or multifocal infarction in regions including the association areas, leading ultimately to dementia. It is important to mention that this type of dementia is reversible after correction of the hemodynamic impairment. [9]
Imaging assessment of cerebral SVD
a). CT scanning
The characteristic findings on brain CT suggesting cerebral SVD include patchy low-density periventricular abnormalities (WM low attenuation or leukoaraiosis) and lacunar microinfarcts. It is important to mention that WM changes are visible on brain CT in less than 4% of healthy elderly individuals. In contrast, leukoaraiosis is found in almost all patients who are thought to have a clinically relevant vascular component to their cognitive impairment. However, brain CT has limitations in its sensitivity to visualize small-vessel ischemic lesions (eg. Lacunar infarcts). [7,9,32]
b). Brain MRI
Magnetic resonance imaging (MRI) has become the most valuable imaging technique for identifying and mapping cerebral SVD in vivo. [29] The typical MRI findings associated with vascular disease in the brain (especially parenchymal lesions linked to SVD) are frequent and are also clearly correlated with dementia risk. [28] The characteristic manifestations of SVD (lacunes and leukoaraiosis) are seen on MRI FLAIR and T2/ proton density- weighted images as periventricular WM hyperintensities (WMH). [8,29,32] The WM changes seen on MRI represent areas of demyelination, enlarged perivascular spaces, and occasionally infarctions. [36] Their age-related frequency also increases in the presence of long-term high blood pressure and diabetes. [5] It is important to emphasize that, according to several MRI studies, white-matter abnormalities are present in about a third of older people, including patients with cognitive decline or a history of cerebrovascular events. [32] Although WMH are commonly seen in AD, the presence on brain MRI of confluent, “diffuse and extensive” hyperintensities on T2 weighted images and vascular-like lesions on T1 weighted images suggests that the cognitive impairment etiology has an important vascular part. It was reported that older people with more extensive WMH are more likely to have cerebrovascular risk factors, to have cognitive impairment or to experience cognitive decline in the future. [6] Particularly, WMH seems to be associated with decline in speed of information-processing and executive function. According to population-based cross-sectional as well as longitudinal studies, older patients without dementia, but with severe periventricular WMLs have a more than twofold increased risk of dementia. [5,32,41,42] Thus, currently WMH is considered to be an independent predictor of cognitive decline, even more suggestive than the presence of lacunar infarcts. [36]
In conclusion, in daily practice, cerebrovascular SVD is diagnosed on brain computed tomography (CT) or magnetic resonance imaging (MRI). On brain imaging, the characteristic manifestations associated with SVD include small subcortical infarcts, white matter MRI hyperintensities (WMH), enlarged perivascular spaces (PVS) and cerebral microbleeds (CMBs). Imaging standards for cerebral SVD as they were established by an international working group – STandards for ReportIng Vascular changes on nEuroimaging (STRIVE) criteria – are used exclusively in research studies. [8,9,34]
c). Positron emission tomography (PET) scanning
PET scanning is a sensitive imaging technique used to assess the cerebral perfusion and metabolism. It was demonstrated that normal aging is associated with a decreased cerebral metabolic rate of oxygen, but with no change in the oxygen extraction ratio and a normal WM blood flow. In contrast, demented subjects with leukoaraiosis on brain CT present a reduced cerebral blood flow associated with an increased oxygen extraction ratio, suggesting a state of “misery perfusion” not only in the deep WM but in the whole cerebral cortex. [9,32,34]
The major risk factors for CVD which are also associated with cognitive decline include [32,43]:
– Hypertension is an established risk factor for all forms of ischemic cerebrovascular damage, coronary heart disease and dementia. [32,44] Currently, hypertension is the strongest predictor of cognitive impairment, being seen as a common denominator for a variety of neurodegenerative conditions. [44,45] Chronically elevated blood pressure promote cerebral SVD, increases the amounts of senile plaques and NFTs and is also linked to brain atrophy progression. [46] In addition, there was found a positive association between long-standing hypertension and severity of WMLs on brain MRI. Interestingly, several studies suggested that mid-life, but not late-life hypertension is associated with an increased risk of dementia in elderly. [32,47] It is also important to mention that a number of large prospective studies have shown that antihypertensive drugs reduces the rate of incident dementia. [36] Also, a meta-analysis of 14 studies of individuals with no cognitive impairment confirmed that those under anti-hypertensive therapy has a lower incidence of both VaD and all-cause dementia. [48] On the other hand, low systolic blood pressure (<130 mmHg) has also been associated with cerebral hypoperfusion and exacerbation of WM ischemia, leading to an increased incidence of leukoaraiosis. [9,32]
– Hyperlipidemia. There is a significant link between high mid-life total cholesterol and an increased risk of late-life dementia. It was suggested a possible role of lowering cholesterol level by use of statins in decreasing dementia risk, but this has not yet been proven by clinical trials. [5,9,47,49]
– Diabetes. Long-term diabetes mellitus (DM) is an important risk factor for cardiovascular and cerebrovascular disease. It was also shown that diabetes increases the risk of both vascular and degenerative types of dementia. It seems to exist a link between the cognitive decline and the glycemic control, with significant cognitive deficits in acute hypoglycemia and milder deficits in hyperglycemic states. Also, patients with long-term illness, greater incidence of complications or increased frequency of hypoglycemic episodes, present a more severe cognitive dysfunction. [5,9,43,49]
– Cardiovascular disease, smoking, alcohol consumption aging, diet, physical inactivity, mid-life obesity, the metabolic syndrome, hyperhomocysteinemia (HHy), apolipoprotein E (APOE for gene; apoE for protein) represent other major risk factors for CVD. [9]Top of Form
1.3.3.1.2 Extracranial Color-coded duplex sonography-Background
According to Del Sete, extracranial Color-coded duplex sonography is usually the first study performed by physicians to rule out carotid disease. It is a safe, noninvasive, reliable, widespread available, and low-cost bedside screening imaging technique with excellent spatial display, and unique capacity to study real-time hemodynamics of extracranial arteries. It is capable to analyze vessel wall anatomy and to detect both parietal anomalies (hypoechoic plaques, clotting and parietal hematoma) and the external diameter of the artery; it can rule out both stenosis and occlusion in the carotid bulb. It can monitor the development of extracranial carotid atherosclerotic lesions from early asymptomatic changes to the morphological changes associated with the unstable carotid artery plaque. On the other hand, the use of a color-coded Doppler flow imaging technique improves the study of arterial and venous blood flow characteristics, which plays an important role in the distribution of atherosclerotic plaques and provides information on smaller arteries with low flow. [50-52]
Reutern noted that since publications of the results of the carotid surgery trials [53,54] treatment of symptomatic patients with internal carotid artery (ICA) stenosis depends primarily on the degree of stenosis. Therefore, the reliability of diagnostic ultrasound in grading a stenosis has a strong impact on the acceptance and general clinical usefulness of ultrasonic methods. Their advantage is to combine morphologic and hemodynamic criteria. By combining all available sonographic information, it is possible not only to grade a stenosis but to provide a complex description of the disease. [55]
Olah asserted that for ultrasound imaging of extracranial vessels different modes are used:
B-mode (brightness mode)
The strength of the echo is recorded as a bright dot, while the location of different gray dots corresponds to the depth of the target. [56]
The duplex image
Associates a B-mode gray-scale image with pulse-wave (PW) Doppler flow velocities measurements. The B-mode image represents the anatomical localization of the vessels, indicating the zone of interest where a Doppler sample volume should be placed and where the velocities are measured. The Doppler angle can be measured correctly when the blood flow is parallel to the direction of the vessel. [56]
Color Doppler flow imaging
Measure mean frequency shift in each sample volume. It represents color–coded velocity information, which is superimposed as a color flow map on a B-mode image. In each sample volume, the color reflects the blood flow velocity in a semi quantitative manner, as well as the flow direction relative to the transducer. Blood flowing toward or away from the transducer is shown by different colors (red and blue). Moreover, fast flow is indicated by a lighter hue and slow flow by a deeper one. The color flow map indicates the position and orientation of the vessels, as well as the site of turbulent flow or stenosis. Since color flow mapping is based on flow velocity measured by PW technology, aliasing occurs if the frequency shift is higher than half of the pulse repetition frequency (PRF). [56]
Power Doppler mode
Uses the signal intensity of the returning Doppler signal instead of frequency shift. Power (intensity) of the signal is displayed as a color map superimposed on a B-mode image. Since the Doppler power is determined mainly by the volume rather than the velocity of moving blood, power Doppler imaging is free from aliasing artifacts and much more sensitive to detect flow, especially in the low-flow regions. However, PTM does not contain information about the flow direction or flow velocity. [56]
Technical settings
Linear phase array probes with frequencies ranging from 5 to 13 MHz should be used. The higher the frequency used, the better the definition that will be obtained. The Doppler waveform should be obtained with an angle of insonation < 60 degrees. [56]
According to Guttierez, all systemic arteries are composed of three histological layers: the intima, the media and the adventia. A linear concentration of elastic fibers called the internal elastic lamina separates the intima from the media, and in the majority of the arteries, a second, less well-developed layer of elastic tissue separates the adventitia from the media, this is called the external elastic lamina. [3,57,58]
He noted that important differences in blood flow patterns and wall pathology are described among arteries from different vascular beds; the more conspicuous example of different histological arterial characteristics is seen in the brain arteries. These arteries are exposed to low flow, they lack an external elastic lamina and their muscularis (i.e., media) appears thinner compared to other arteries [57,59]. These arteries, unlike the rest of the vasculature, have a complex collateral network exemplified by the circle of Willis, but also aided but at least seven other types of collateral flow from inside and outside the skull that confers its unique pathophysiology [3,58]. Coronary arteries have a ticker media compared to brain arteries and they age prematurely compared to the middle cerebral artery or radial arteries [60]. Arguably, a stronger thicker media is able to help the coronary arteries withstand the higher wall sheer-stress of a non-stop, highly muscular pump compared to the fixed pressure found in the intracranial space that can partially dampen the oscillations induced by the cardiac cycle [61]. These evidences argue for a match between the microscopic arterial characteristics with the needs of the tissue they supply. This coupling of physiology and anatomy is perhaps one of the most fundamental relationships to understand when studying atherosclerosis [3]
Atherosclerosis is a chronic inflammatory process, characterized by the progressive thickening and derangement of the intima and media layers of the artery wall [62]. It is defined by the hardening of arteries in the setting of increased collagenous tissue. A fundamental feature of atherosclerosis in histopathology sections is the presence of a lipid core. The best example of this is the atheroma or type IV lesion (the lipid core is identified as a relatively well-defined area at the bottom of the plaque). [51,63]
The initial stages of atherosclerosis include intima thickening that in some cases can regress and normalize. However, it can also progress and turn pathological when more fibrotic tissue is incorporated. [64] The lipid core represents a focal accumulation of cholesterol. [3] In 2004, an international group of researchers with experience in ultrasonography met in Manheim, Germany, with the goal of standardizing the protocols for carotid wall imaging and facilitating comparisons across studies. [3]
The two most common measures of atherosclerosis in the carotid wall are the carotid intima-media thickness (cIMT) and carotid plaque (CP), although other characteristics such as plaque composition (i.e., necrosis vs. hemorrhage), lumen irregularities and calcifications can be reliably identified using ultrasound. [65-68] The predictive power of IMT and carotid plaque (CP) depends on standardization of ultrasound definitions and techniques used. [51,69]
Carotid intima-media thickness (cIMT)
Represents the distance between the luminal-intimal interface and the media-adventitial interface of the carotid arteries. [70]. It is a double-line pattern visualized by brightness mode (B-mode) ultrasound on carotid artery’s wall in a longitudinal plane. These interfaces appear as parallel lines bordering the lumen in the luminal surface and the outer margin of the hypoechoic layers that constitute the media and are limited externally by the hyperechoic layer corresponding to the adventicia. [51,71]
The Mannheim Consensus recommends that at minimum cIMT is obtained from the distal 2 cm of the CCA, proximal to the bifurcation, and preferably in a wall region free of plaque [66], even if the IMT from the ICA seems to better correlate with cerebrovascular events compared to the IMT from the CCA [72]. Arguments in favor of this location include the relatively parallel and predictable course of the CCA among adults compared to the ICA course, which can vary more often among individuals [73]. For an accurate and reproducible measure of IMT, automated methods are available on new-generation instruments. [51]
The cIMT varies with age, sex, race-ethnicity and body surface area [74,75]. The average cIMT in population-based studies increases from 0.5 mm in young individuals to 0.80 mm in the elderly [76-79] and, for the age group usually evaluated in stroke prevention, it is considered normal below 1.0 mm, and increased between 1.0 and 1.4 mm. For values equal to 1.5 mm or higher, the parallel course of intima-media and adventitia layers is often lost, and the IMT turns into a plaque [51].
Carotid intima-media thickness (cIMT) and risk of stroke
Del Sete noted that multiple epidemiological studies have shown the importance of cIMT as a surrogate marker in the prediction of stroke and other vascular events. [80-84]. In one of the largest population-based studies, the Atherosclerosis Risk in Communities (ARIC), among 13123 participants with a mean follow-up of 8 years, the absolute annual stroke risk associated with cIMT greater than 1.0 mm was 0,5% for both men and women [85]. The cIMT was a better predictor of nonlacunar stroke than lacunar stroke or hemorrhages [86].
The value of cIMT has been confirmed in a large meta-analysis of the PROG-IMT collaborative project that included 36984 participants with two consecutive ultrasound measurement of Cimt [87]. Baseline cIMT as well as the repeated ultrasound cIMT was associated with cardiovascular risk including stroke (combined adjusted outcome hazard ratio 1.16 [95% confidence interval (CI) 1.10-1.22)]. However, cIMT progression, defined as thicker cIMT from baseline to subsequent visit, was not significantly associated with the risk of vascular events [51].
According to Del Soto, cIMT may represent pathological changes of arterial medial hypertrophy or intimal thickening in the absence of atherosclerosis, in which case cIMT does not represent atherosclerosis [51].
However, because cIMT and atherosclerosis share common underlying mechanisms and atherosclerosis starts by intima thickening, cIMT may be a less specific but more sensitive indicator of overall vascular disease [68].
Carotid plaque (CP)
Is defined as a focal extrusion into the arterial lumen of at least 50% more in thickness than the surrounding cIMT value, or an absolute thickness greater than 1.5 mm when measured in the same fashion as cIMT [69]. It represents an increase of the internal layers of the vessel wall, encroaching on the arterial lumen [70]. CP confers an increased risk of cardiovascular disease (CVD). In subjects with CP identified by ultrasound, no additional value is obtained from studying the cIMT [51,80,88,89].
In the following pages, I will present the five papers, published in ISI journals, to which I was first author (4 papers), or coauthor (1 paper), respectively.
1.3.3.1.3. TransIent Perivascular Inflammation of the Carotid artery-(TIPIC) syndrome. Data from the literature.
Carotidynia was a clinical entity described by Fay in 1927, characterized by tenderness and pain at the level of the carotid bifurcation. [90] Initially classified as an idiopathic neck pain syndrome in the first International Classification of Headache Disorders in 1988, [91] it was subsequently removed as a distinct entity in 2004. [92] Indeed, the 2 clinical signs of carotidynia were neither specific nor constant, and other causes of neck pain might have the same clinical presentation. Biousse and Bousser [93] described these controversial aspects in 1994 and considered carotidynia a myth
However, since 2000, a few case reports have described imaging abnormalities in patients presenting with tenderness and pain at the level of the carotid bifurcation. Imaging techniques like ultrasonography (US), [94,95] MR imaging, [96] CT angiography, [97] F fluorodeoxyglucose positron-emission tomography, [98,99] or associated modalities [100] showed abnormal soft tissue surrounding the carotid artery and a thickened carotid wall, especially near its bifurcation. Differential diagnoses of carotid pain such as carotid dissection, thyroiditis, vasculitis, head and neck inflammation or mass, sialadenitis, or cervical arthrosis were excluded. Hence, the authors suggested that a distinct entity of idiopathic carotid inflammation seemed to exist after all. [101]
The goal of our study [101] was to improve the clinico-radiologic description of this unclassified entity among patients presenting with acute neck pain and strikingly similar perivascular and vascular abnormalities during diagnostic imaging.
Personal contributions
Clinical and Imaging Characteristics
This entity was relatively rare in our study, with an estimated prevalence of 2.8% (18/654) among patients with acute neck pain in the first center. However, we can presume that this particular cluster of symptoms is underestimated because of the relatively mild clinical symptoms and the quick relief of pain and decrease of imaging abnormalities within 13 days.
We believe that this entity should be added to the International Classification of Headache Disorders-III. [102]
We propose 4 major criteria as follows:
1). Presence of acute pain overlying the carotid artery, which may or may not radiate to the head
2). Eccentric perivascular infiltration (PVI) on imaging
3). Exclusion of another vascular or nonvascular diagnosis with imaging
4). Improvement within 14 days either spontaneously or with anti-inflammatory treatment. Additionally, a minor criterion could be the presence of a self-limited intimal soft plaque.
We suggest a suitable name to describe this entity: TransIent Perivascular Inflammation of the Carotid artery (TIPIC) syndrome. [101]
Changes in Current Practice
We believe that clinicians should think about the TIPIC syndrome in the differential diagnosis of neck pain. They could set a precise diagnosis with adequate imaging modalities, to exclude other entities in the differential diagnosis and propose adequate treatment. Recognition of this syndrome would be cost-effective and avoid unnecessary, additional diagnostic examinations. US appears to be a suitable examination for screening because it can detect PVI with high accuracy, similar to other imaging methods, but without any exposure to radiation, high magnetic fields, or the administration of intravenous contrast agents. It is affordable and easily accessible, and it has excellent inter-reader concordance. Imaging diagnosis should be performed without delay because these abnormalities decrease very quickly. Follow-up could be made with US to assess PVI decrease and control lumen narrowing or soft intimal plaque. [94,101]
1.3.3.1.4. American Journal of Neuroradiology, May 2017 (the Official Journal of the American Society of Neuroradiology),Vol.38, Issue 7, 1 Jul 2017, 1391-1398.
TIPIC Syndrome: Beyond the Myth of Carotidynia, a New
Distinct Unclassified Entity
Authors: Lecler A, Obadia M, Savatovsky J, Picard H, Charbonneau F, Menjot de Champfleur N, Naggara O, Carsin B, Amor-Sahli M, Cottier JP, Bensoussan J, Auffray-Calvier E, Varoquaux A, De Gaalon S, Calazel C, Nasr N, Volle G, Jianu DC, Gout O, Bonneville F, Sadik JC.
Carotidynia was a clinical entity described by Fay in 1927, characterized by tenderness and pain at the level of the carotid bifurcation. [90] Initially classified as an idiopathic neck pain syndrome in the first International Classification of Headache Disorders in 1988, [91] it was subsequently removed as a distinct entity in 2004. [92] Indeed, the 2 clinical signs of carotidynia were neither specific nor constant, and other causes of neck pain might have the same clinical presentation. Biousse and Bousser [93] described these controversial aspects in 1994 and considered carotidynia a myth. However, since 2000, a few case reports have described imaging abnormalities in patients presenting with tenderness and pain at the level of the carotid bifurcation. Imaging techniques like ultrasonography (US), [94,95] MR imaging, [96] CT angiography, [97] F fluorodeoxyglucose positron-emission tomography, [98,107] or associated modalities [99] showed abnormal soft tissue surrounding the carotid artery and a thickened carotid wall, especially near its bifurcation. Differential diagnoses of carotid pain such as carotid dissection, thyroiditis, vasculitis, head and neck inflammation or mass, sialadenitis, or cervical arthrosis were excluded. Hence, the authors suggested that a distinct entity of idiopathic carotid inflammation seemed to exist after all.
The goal of our study was to improve the clinico-radiologic description of this unclassified entity among patients presenting with acute neck pain and abnormal carotid and pericarotidian tissues on imaging.
MATERIALS AND METHODS
Research Design
We conducted a retrospective multicenter systematic chart review in centers specialized in head-and-neck and neurologic diseases. This study was approved by the institutional research ethics boards. All patients were contacted and given the opportunity to express their refusal to have their medical records used. This study follows the Strengthening the Reporting of Observational Studies in Epidemiology guidelines. [100]
Patients
Two physicians, a senior neuroradiologist and a neurologist, both of whom are specialized in neurovascular diseases with 30 years of experience each (J.C.S. and M.O.), screened the clinical and radiologic files of all adult patients from 10 centers who presented from January 2009 through April 2016 with acute cervical pain and with at least 1 diagnostic image (MR imaging, CT, or US) including a dedicated vessel analysis. Among patients fulfilling these criteria, they excluded cases with inadequate or incomplete vessel exploration, cases with no vascular abnormality, and those in which a clearly identified and classified vascular disease was found. The final number of patients from these centers was 47, who all had symptomatology appropriate for the diagnosis of carotidynia and represent the study group.
Review of Clinical and Biologic Charts
Patient charts were systematically reviewed, and we collected the following clinical data: the date that pain began; the presence of major cardiovascular risk factors; medical history; medications; unilateral or bilateral cervical pain (as well as location, side, and pain scale score); a cervical swelling or a palpable abnormality over the carotid bifurcation; the presence of lymphadenopathy; the presence of associated head, neck, neurologic, or ophthalmologic symptoms; the treatment administered and its duration; the duration of pain; report of ≥1 relapse during follow-up; and the total duration of follow-up. All relevant biologic data on admission and during follow-up were collected. The following relevant biologic data were recorded on admission and during follow-up for all patients in the first center (A. Rothschild Foundation’s Department of Radiology): erythrocyte sedimentation rate; C-reactive protein level; complete blood count; herpes simplex virus, varicella zoster virus, Epstein-Barr virus, chlamydia, mycoplasma, influenza, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, Lyme disease, type 1 human T-cell lymphotropic virus, and syphilis serologies, including immunoglobulin-M and immunoglobulin-G; renal function; electrolyte level; glycemia; serum cholesterol level; comprehensive hepatic workup; coagulation test; serum protein electrophoresis; thyroid hormone level; autoimmune markers; angiotensin-converting enzyme level; and antineutrophil cytoplasmic antibody. The minimal biologic data recorded in the other centers included erythrocyte sedimentation rate, C-reactive protein level, complete blood count, renal function, electrolytes, glycemia, serum cholesterol level, comprehensive hepatic work-up, and coagulation test.
Diagnostic and Follow-Up Imaging Modalities
US was performed with Logic E9 (GE Healthcare, Milwaukee, Wisconsin) and Xario XG (Toshiba, Tokyo, Japan) machines. Cervical and intracranial vessels were examined in B-mode and color-coded duplex with spectrum analysis. CTA examinations were performed with a Discovery 750 HD 64-section scanning system (GE Healthcare) in the first center, and with Discovery 750 HD 64-section or LightSpeed VCT 32-section (GE Healthcare) or Somatom 16-section (Siemens, Erlangen, Germany) scanners in the other centers. MR imaging examinations were performed with a 3T Ingenia or a 1.5T Achieva imager (Philips Healthcare, Best, the Netherlands) with a 32-channel head coil covering the bifurcation in the first center and with 3T Skyra, 1.5T Avanto, 1.5T Sonata, 3T Verio (Siemens, Erlangen, Germany), 1.5T Signa Excite (GE Healthcare), or 3T Achieva (Philips Healthcare) scanners in the other centers.
Technical data are provided for the first center in On-line Tables 1.1. and 1.2.
Imaging Reading Criteria
Two neuroradiologists (A.L. and F.C. with 7 and 12 years of experience, respectively) independently analyzed the datasets in random order. The readers were blinded to the clinical and biologic data. Discrepancies were resolved by consensus.
For each diagnostic and follow-up imaging technique, the readers assessed the abnormalities as the following:
The presence of a perivascular infiltration (PVI) was defined as soft amorphous tissue replacing the fat surrounding the carotid artery, with a hazy aspect of the fat; its precise location; its dimensions (including largest axial diameter and span); its preferential side; the percentage of vessel circumference involvement; and the confidence in detecting the abnormalities (0 = very low level of confidence, 1 = relatively high confidence, 2 = extremely high confidence).
The presence of vascular abnormalities, such as an intimal soft plaque, defined as a well-delineated intimal plaque, hypoechogenous without posterior acoustic shadowing in US, hypodense or hypointense compared with a normal-sized lymph node on CT or MR imaging, respectively; or a calcified plaque, defined as a hyperechogenous intimal plaque with posterior acoustic shadowing on US, isodense to the bone in CT, with no signal on MRimaging; or the presence of a lumen caliber narrowing, and its quantification by using the North American Symptomatic Carotid Endarterectomy Trial criteria. [103]
For US, the readers assessed the presence of a vascularization of the PVI in Doppler or power Doppler mode and the presence of cervical carotid or intracranial vessel hemodynamic changes.
For MR imaging results, the readers assessed the fat-suppressed T1- and T2-weighted imaging signal intensity of the PVI compared with a contralateral normal-sized lymph node (1 = less intense, 2 = as intense, 3 = more intense) and the presence of cerebral ischemic lesions with diffusion-weighted imaging and fluid-attenuated inversion recovery sequences.
For CTA and MR imaging, the readers assessed the enhancement of the PVI compared with a contralateral normal-sized lymph node (0 = no enhancement, 1 = less enhancement, 2 = same enhancement, 3 = more enhancement) and the presence of inflammation of the pharyngeal or laryngeal mucosa.
Statistical Analysis
Results of systematic reviews were encoded on a spreadsheet and subsequently analyzed by a senior medical biostatistician (H.P.) with the R statistical package. [104] Due to the descriptive design of this study, the analysis was focused on the description of patients’ sociodemographic, clinical, biologic, and imaging characteristics. Interobserver agreement was assessed with no weighted κ statistics, by using the Landis and Koch interpretation. [105] Whenever quantitative imaging variables were measured with different imaging modalities, Bland-Altman plots were used to look for an intermodality measurement bias. A linear regression was conducted to evaluate the correlation between the symptom-to imaging delay and the following parameters: the percentage of arterial circumference involved, the presence of a lumen caliber narrowing and its severity, the PVI median largest diameter and median span, and the presence of a soft intimal plaque. A P value below .05 was considered significant.
RESULTS
Demographic, Clinical, and Biologic Characteristics
Forty-seven patients presented with cervical pain, including 45 with unilateral pain and 2 with bilateral pain. The mean patient age was 48 years, and the female/male ratio was 1.5:1. Twenty-two patients (47%) had at least 1 vascular risk factor. Eight patients (17%) had associated neurologic symptoms: transient dizziness and vertical diplopia with extrinsic ipsilateral oculomotor cranial nerve palsy in 1 patient, a contralateral-sided dysesthesia in 4 patients, a contralateral transient motor deficit in 1 patient, and an ipsilateral peripheral facial palsy in 2 patients. Two patients had fever. Eight patients (17%) had a clinical history of autoimmune disease: Two had ankylosing spondylarthritis, 1 had Hashimoto thyroiditis, 1 had Graves’ disease, 1 had systemic lupus erythematosus, 1 had Sjӧgren syndrome, and 2 had rheumatoid arthritis. Three patients overall (6%) had elevated erythrocyte sediment ratios or C-reactive protein levels but normal blood counts. Two of eighteen (11%) had elevated serum immunoglobulin-M antibodies: against herpes simplex virus for 1 patient and against type B-influenza for the other. No other patients presented with an elevation in inflammatory markers (Table 1.1).
Diagnostic Imaging
The median delay between the onset of symptoms and the first imaging was 5 days. All patients except 4 presented with a PVI at the level of the carotid bifurcation, most often in a posterior and lateral location (Fig 1.1). Two patients presented with bilateral carotid abnormalities. The median largest axial diameter of the PVI ranged from 4 to 5 mm, and the median PVI span ranged from 15 to 28 mm. Self-assessed confidence in investigator detection was high in all examinations performed with US or MR imaging and in 69% of the CT reviews. An intimal soft plaque was observed in 14 US reviews (58%), 6 CT reviews (46%), and 12 MR imaging reviews (27%) (Fig 1.2). A mild lumen caliber narrowing was observed in US reviews of 9 patients (38%), CT reviews of 4 patients (31%), and MR imaging reviews of 12 patients (27%). No hemodynamic change was observed in color duplex Doppler. No cerebral parenchymal ischemia was seen with MR imaging. Diagnostic imaging data are presented in Table 1.2.
Follow-Up
The mean follow-up duration was 3 months. All patients had a full clinical recovery, with a median delay of 13 days. Thirty-four patients received anti-inflammatory treatment, and 3 received steroids. Ten patients did not receive any treatment. Nine (19%) patients had a clinical relapse with exactly the same clinical and imaging abnormalities. Seven of these patients had a clinical history of autoimmune disease, and they presented with a simultaneously acute exacerbation of their autoimmune disease. All laboratory test results were within normal ranges during follow-up.
Twenty-five patients (53%) had follow-up imaging. Eleven (44%) had US, and 23 (92%) had MR imaging. No CTA was performed. All patients presented with a decrease or disappearance of the PVI; a residual PVI was noted in all patients with US and 15 patients (65%) with MR imaging (Fig 1.3). Eight patients had complete disappearance of PVI on MR imaging. The median PVI diameter and span decrease ranged from 55% to 61% and 50% to 62%, respectively. Soft intimal plaque was persistent in 4 and 3 patients with US and MR imaging, respectively, and disappeared in 4 patients with US and 6 with MR imaging. Lumen caliber narrowing was persistent in 2 patients with US and 1 patient with MR imaging, respectively (Fig 1.4). Follow-up imaging data are presented in Table 1.3.
Interobserver Agreement
Overall interobserver agreement was perfect (κ=1) for the detection of a PVI, excellent for the PVI largest diameter or lumen caliber narrowing with US or MR imaging (κ= 0.9 and 0.83, respectively), and good for the detection of soft intimal plaque (κ=0.75). CT showed a smaller interobserver agreement for lumen caliber narrowing and the presence of soft intimal plaque (κ=0.6 and 0.71, respectively).
Associations with Symptom-to-Imaging Delay
There was a significant correlation between a longer symptom-to imaging delay and a lower PVI median span (P = .02 and P = .04) and a lower PVI median largest diameter (P = .04) on sonography and a lower PVI median span (P=.04) on MR imaging. There was no significant correlation between the symptom-to-imaging delay and the presence of a lumen caliber narrowing or a soft intimal plaque or the percentage of the arterial circumference involved.
DISCUSSION
We report a multicenter series of 47 patients presenting with acute neck pain and strikingly similar unclassified perivascular and vascular abnormalities seen on imaging. These findings strongly support the existence of an as yet unclassified clinico-radiologic entity classically diagnosed as “carotidynia” in the literature dated before 2004.
Clinical and Imaging Characteristics
This entity was relatively rare in our study, with an estimated prevalence of 2.8% (18/654) among patients with acute neck pain in the first center. However, we can presume that this particular cluster of symptoms is underestimated because of the relatively mild clinical symptoms and the quick relief of pain and decrease of imaging abnormalities within 13 days. This entity has been previously reported on in a few small series as carotidynia, but we present the largest series published so far with 3 distinct imaging modalities and follow-up data.
Clinically, all our patients presented with acute pain directly around the level of the carotid bifurcation. Eight patients presented with previously undescribed, transient neurologic symptoms, which lacked explanation despite a brain parenchyma MR imaging. After imaging, the presence of a unilateral eccentric PVI at the level of bifurcation was the most striking feature described. [95,96,99] Two patients presented with bilateral carotid involvement, [98] though most were unilateral. [95,96] PVI imaging characteristics were similar to those found in the literature, with a median diameter of 5 mm and a median span of 20 mm. [96,106]
Some patients had a mild associated narrowing of the lumen, [95,107] though most patients had no luminal change [96,99] or any hemodynamic abnormality. We report the presence of a self-limited, intimal soft plaque in half of our patients, which has been described in previous reports. [95,108] These intimal changes might be induced by the healing phase of the carotid inflammatory process.
Nonsteroidal anti-inflammatory agents and high doses of aspirin were the most frequent treatment in our population and in the literature, with a complete median delay of pain relief in 13 days. [94-96] Some authors reported full recovery with clopidogrel [107] or without any treatment at all. [96] All patients had complete clinical resolution during follow-up. Nine patients presented with ≥1 relapse with intervals ranging from 1 to 6 months, similar to what is found in the literature. [97]
Although early case reports described the complete disappearance of clinical and imaging abnormalities, [96] more recent case reports showed a persistence of imaging abnormalities, similar to our findings. [95,108,109] It could be explained by the development of early fibrosis associated with low-grade chronic active inflammation, as described in the only histologic study found during the literature review. [110]
Possible Pathophysiologic Mechanisms
Most case reports and small studies hypothesized that observed vascular and perivascular changes were consistent with inflammation. [98,109] Clinical findings support this hypothesis, with ipsilateral lymph node enlargement and/or contiguous pharyngo-laryngeal inflammation, [111] as well as biologic findings, with a mild increase of the erythrocyte sedimentation rate or C-reactive protein. [98,107,112,113] In our series, only 3 patients had a mild increase of the erythrocyte sedimentation rate or C-reactive protein levels. Eight patients had an autoimmune disease such as rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylarthritis, Graves’ disease, Sjӧgren syndrome, or Hashimoto thyroiditis. Most interesting, 7 over these 8 patients presented with several simultaneous clinical relapses of the perivascular inflammation of the carotid artery and of their autoimmune disease, suggesting a link between the diseases. One study reported a case of fluoxetine-induced carotidynia, presumably explained by the inflammatory modulation induced by the antidepressants. [114] Some studies reported an increased activity corresponding to the region of soft-tissue thickening within the carotid sheath with FDGPET- CT, [98,107,115] though these findings were not specific for inflammation. Other hypotheses were discussed, such as vasculitis. [116] However, PET-CT with abnormally increased activity in neither the remainder of the body nor the vessels was described. [98,107] In our center, none of the patients with biopsy-proved giant cell arteritis presenting with acute neck pain or tenderness had abnormalities of the carotid bulb on imaging, and no relationship between the 2 entities was reported in literature. Spontaneous resolution excludes neoplastic processes. Finally, 1 study reported histologically proved findings of chronic inflammation in 1 patient with pathologic changes consisting of vascular and fibroblast proliferation and predominantly lymphocytic low-grade chronic active inflammation. [110] Therefore, given that the pathogenesis remains unknown, this entity may be an inflammatory process of unknown origin or part of an autoimmune process.
Proposition for a New Entity
In 2004, carotidynia was removed from the International Classification of Headache Disorders. [92] Causes of acute neck pain are numerous, [117] and we agree that the term “carotidynia” is confusing and should not be used anymore. [93] However, our study strongly suggests the existence of a clinical entity that was formerly poorly described (often under the “carotidynia” label) with very consistent clinical and imaging characteristics. In our study, the attempt to label this entity was shown to be dysfunctional and confusing among the different centers with at least 4 distinct labels used to describe the same entity (“carotidynia,” “carotidodynia,” “carotidobulbia,” or “carotiditis”). In the past, some authors proposed terms such as “idiopathic carotiditis” [109] or “carotid periarteritis,” [98] but these terms were not accurate because vascular and perivascular abnormalities occur simultaneously.
Consequently, we strongly support the need for a new label, and we suggest an acronym most apt for this entity: TransIent Perivascular Inflammation of the Carotid artery (TIPIC) syndrome. This acronym was chosen by consensus of the neurologists, radiologists, internists, and vascular physicians working at the different centers that collaborated on this project. We believe that this entity should be added to the International Classification of Headache Disorders-III. [102] We propose 4 major criteria as follows:
1) Presence of acute pain overlying the carotid artery, which may or may not radiate to the head
2) Eccentric PVI on imaging
3) Exclusion of another vascular or nonvascular diagnosis with imaging
4) Improvement within 14 days either spontaneously or with anti-inflammatory treatment.
Additionally, a minor criterion could be the presence of a self-limited intimal soft plaque.
Limitations of the Study
Our study has some limitations. First, it was a retrospective, descriptive study with a small number of patients, thus limiting its scope mostly in the descriptive and exploratory fields. Second, a non-negligible number of patients were probably not selected during the screening process because of a lack of diagnostic imaging or a delayed order for diagnostic imaging. Third, our median follow-up duration was short, and we could not say whether follow-up imaging would eventually show the complete disappearance of the PVI, relapses, or development of atherosclerosis. Fourth, because of the benign course of the disease, adding details from pathology is difficult and not feasible; thus, better comprehension of the physiopathology has been stalled for the moment.
Changes in Current Practice
We believe that clinicians should think about the TIPIC syndrome in the differential diagnosis of neck pain. They could set a precise diagnosis with adequate imaging modalities, to exclude other entities in the differential diagnosis and propose adequate treatment. Recognition of this syndrome would be cost-effective and avoid unnecessary, additional diagnostic examinations. US appears to be a suitable examination for screening because it can detect PVI with high accuracy, similar to other imaging methods, but without any exposure to radiation, high magnetic fields, or the administration of intravenous contrast agents. It is affordable and easily accessible, and it has excellent interreader concordance. Imaging diagnosis should be performed without delay because these abnormalities decrease very quickly. Follow-up could be made with US to assess PVI decrease and control lumen narrowing or soft intimal plaque. [94]
Our study raised concerns about 2 major issues. First, the neurologic risk may not be as low as previously reported in the literature because 8 of our patients had neurologic events. We do not have a convincing explanation regarding the possible relationship between this entity and the neurologic events encountered. The lumen caliber narrowing was mild, and there were no local or distal hemodynamic changes with cervical or transcranial US. Brain MR imaging performed at the time of the neurologic events did not show any acute brain abnormality with diffusion or FLAIR-weighted imaging. Therefore, the hypothesis of a brain ischemia linked to the carotid artery narrowing, either due to distal embolism or low-flow, is unlikely. An inflammatory hypothesis involving both the carotid artery and intracranial arteries at the same time might be considered, but our imaging protocol was not designed to detect intracranial vessel wall inflammation.
Second, the persistence of vascular wall abnormalities, including an intimal soft plaque with imaging, suggest the hypothesis of a secondary development of atherosclerosis in these patients, therefore justifying a longer follow-up.
Recognition of this entity favors further, large prospective studies to answer these major questions and to elucidate the prevalence, pathophysiologic mechanisms, risk factors, etiologic processes, and potential therapies for this condition.
CONCLUSIONS
We describe more precisely a currently unclassified clinico-radiologic entity in patients presenting with acute cervical pain and strikingly similar perivascular and vascular abnormalities during diagnostic imaging. We suggest a suitable name to describe this entity: TransIent Perivascular Inflammation of the Carotid artery (TIPIC) syndrome.
1.3.3.1.5. Carotid body paragangliomas: Data from the literature.
Carotid body paragangliomas (CBPGLs), which are hypervascularized tumors of the carotid body [118-122], constitute the most common form (50%) of head and neck paragangliomas [120,123-126]. Usually, CBPGLs are represented by a painless cervical mass, with no functional or bilateral neck tumors.
As direct biopsy is not suitable for the diagnosis of CBPGLs (they are tumors with no clear histological features of malignancy), the use of different types of imaging techniques can provide correct preoperative diagnosis in most cases with satisfactory sensitivity and specificity [128-132]. The Joint Vascular Research Group (JVRG), in their meta-analysis study [133], recommend that duplex ultrasound be the primary diagnostic investigation in carotid body tumors. Also used for their preoperative assessment are digital subtraction angiography (DSA), computed tomography (CT), CT angiography (CT-A), magnetic resonance imaging (MRI) and MR-angiography (MR-A) [129,133,134].
Duplex ultrasound helps define vascularity of the tumor (data regarding blood flow in the mass itself), and precise tumor location at carotid bifurcation [135,136]. Thus, the tumor is represented by a highly vascularized (intralesional abundant blood flow signals) hypoechoic mass in the area of the carotid bifurcation, which usually causes wide splaying of the bifurcation and separation of the internal carotid artery and external carotid artery [120,123,135-137]. Consequently, based on the two main characteristics of the lesion: vascularity and location, duplex ultrasound is helpful in differentiating CBPGLs from other solid, non-hypervascular masses [120,123,135-140]. Duplex ultrasound is also suitable for classification of cervical paragangliomas as carotid body, vagal or jugular paraganglioma based on the topographic relation to the carotid arteries and internal jugular vein [135,136]. Visualization of the intrinsic tumor vasculature proved an additional distinguishing criterion upon duplex ultrasound [135,136]. This technique completely depicts CBPGLs but fails to delineate the high cervical portion of vagal and jugular paragangliomas [135,136]. Anterior displacement of both carotid arteries and posterior displacement of the internal jugular vein can be found in vagal paragangliomas [135,136]. The caudal tumor extension of the jugular paragangliomas can be recognized within the expanded lumen of the internal jugular vein [135,136]. On duplex ultrasound, intratumoral flow is directed cranially in CBPGLs and inferiorly in vagal and jugular paragangliomas. [135,136]
In addition to the diagnosis and differential diagnosis of CBPGLS, duplex ultrasound can provide information on carotid body tumor size, blood supply of the tumor, and coexistent carotid artery disease, which is useful in forming a treatment plan and assessing the risk of surgery [135,136].
On the other hand, Duplex ultrasound has a limited ability to identify complex blood supply to a large carotid body tumor [135], and to measure the tumor exactly [135,136].Finally, duplex ultrasound may be useful in screening for familial CBPGLs, and in the follow-up, where it can be a particularly valid first-line tool, thereby reserving second-line techniques such as MRI and CT for selected cases, where it is important to know the accurate dimensions of the lesions [134,136,141].
MRI and MR-A are considered as the gold standard imaging techniques for the evaluation of carotid space tumors, as they allow a multiplane approach which is very important in the preoperative study [120,121,123,140,142,143]. These techniques are more effective non-invasive imaging modalities compared to with duplex ultrasound, especially for small tumors (diameter <3 cm) [129,135,136,140,141,143-148]. Unfortunately, MRI/MR-A do not provide data about the potential for malignancy and postoperative early recurrence because the tumors are too small in terms of the MRI/MR-A’s resolution power [134,144].
The main purpose of our study [134] was to establish a better-standardized proceeding in the diagnosis (clinical and imaging characteristics) and surgical treatment of these tumors, in our Departments in order to provide the best outcome of such patients.
Changes in Current Practice in our Departments
Taking into consideration the practicability and invasiveness of these investigations, as well as the risks and costs involved [120,126,128,131,139,140], we propose that the imaging techniques for diagnosis of CBPGLs be performed in the following sequence: (a) duplex ultrasound, (b) MRI, and (c) MR-A.
Relatively early evaluation of CBPGL can be possible using multidisciplinary management (including radiologists, surgeons, otolaryngologists, anesthesiologists, and neurologists). Their early diagnosis, and complete surgical excision are imperative (only Shamblin group II tumors), minimizing the known risk of complications associated with large CBPGLs (Shamblin group III) [134].
1.3.3.1.6. Romanian Journal of Morphology and Embryology, 2016, Volume 57, Number 2 Suppl, Rom J Morphol Embryol 2016, 57 (2 Suppl):853-859.
An evaluation on multidisciplinary management of carotid body paragangliomas: a report of seven cases
Authors: Dragos Catalin Jianu, Silviana Nina Jianu, Andrei Gheorghe Marius Motoc, Traian Flavius Dan, Marioara Poenaru, Sorina Taban, Octavian Marius Cretu
Introduction
Macroscopically, the carotid body is a well circumscribed, round, reddish-brown highly specialized organ. Its measurements are approximately 5×3×2 mm and it is located in the adventitia of the carotid bifurcation [135]. Its feeding vessels run primarily from the ascending pharyngeal artery (a branch of external carotid artery– ECA), but may receive branches from the internal carotid artery (ICA) bulb, and innervated through the IX (glossopharyngeal) and X (vagus) nerves [118,119,123,124]. Microscopically, the tumors are highly vascular; between the many capillaries are clusters of cells, including supporting cells and chief cells [135]. Cytochemical techniques usually demonstrate epinephrine, norepinephrine and serotonin in these cells [135]. The function of the carotid body is related to the autonomous control of the respiratory and cardiovascular systems, as well as blood temperature [118,119,124]. It is a chemoreceptor organ that is stimulated by hypercapnea, hypoxia, and acidosis, which controls the autonomous control drive by increasing the sympathetic flow [118,119,124].
Carotid body paragangliomas (CBPGLs) are relatively rare tumors arising from paraganglionic cells of the carotid body, which develop from both mesodermal elements of the third branchial arch and neural elements originating from the neural crest ectoderm [120,123-126]. Van Haller, in 1743, first described the carotid body while the term “paraganglia” was introduced by Kohn in the early XXth century [135,144].
The main purpose of our study is to establish a better-standardized proceeding in the diagnosis (clinical and imaging characteristics) and surgical treatment of these tumors, in our Departments in order to provide the best outcome of such patients.
Case presentations
This is a retrospective analysis of the medical records of all cases diagnosed with CBPGLs and operated on in our Departments between March 2009 and December 2012. There were seven patients (five women, two men with mean age of 54.7 years, with an overall age ranging from 41 to 69 years). All the preoperative, operative and postoperative data were studied for each case and the follow-up by the medical records. All patients were given a medical history questionnaire. Familial disease was initially determined by pedigree analysis. All cases underwent a complete head and neck examination, through clinical neurological, ear nose throat (ENT: preoperative and postoperative laryngoscopy as well as phoniatric evaluation), surgical, anesthesiologist, and ophthalmological practices. The clinical characteristics of the CBPGLs were represented by: site, size, consistency, and pulsatility of the neck mass, and the possible preoperative complications (craniofacial involvement, etc.). All patients were examined for possible functional tumors (typical symptoms such as flushing, palpitations, or headaches). Before surgery, all cases with a presumed CBPGL underwent combined imaging techniques in order to classify the type of tumor and plan the proper treatment. All patients have been evaluated by the first author of this study, by duplex ultrasound as first step (with a 7.5–10 MHz linear array transducer, combining B mode and color Doppler/pulsed-wave Doppler ultrasound).
All cases underwent a second examination, represented by magnetic resonance imaging – MRI (1.5 T), and magnetic resonance angiography (MR-A). The characteristic findings on MRI and MR-A were studied for lesion shape, margin, signal intensity, angle of common carotid artery (CCA) bifurcation, and the relationship between the great vessels and the carotid space mass. All lesionswere classified using the MRI measurements into three groups according to the latero-lateral diameter of the tumor: group I (<3 cm), group II (3–5 cm), and group III (>5 cm).
All patients were operated by the same team (one ENT and one surgeon). We analyzed surgical treatment modalities used. All interventions were performed under general anesthesia. The tumors were confirmed on histopathology and immunohistochemistry, and were screened for malignancy. The main criteria of malignancy were obtained from operative notes, e.g., lymph node metastases and aggressive local infiltration of adjacent tissues.
We examined surgical complications and outcome. Major outcomes included peri-operative mortality, stroke/transient ischemic attack (TIA), and cranial nerve injury as well as recurrences. All patients were followed-up clinically every three months for the first year, and twice/year for the next two years, with yearly duplex ultrasound.
Clinical presentation
All unilateral CBPGLs were discovered upon patient self-examination. The main clinical data are shown in Table 1.4.
Physical examination revealed in all seven cases an unilateral painless palpable pulsatile neck mass, laterally mobile but vertically fixed, located just anterior to the sternocleidomastoid muscle at the level of the hyoid bone, and below the angle of the mandible. The neck masses were firm and incompressible, and were suspected of the tumor due to the transmitted pulsation. There was no evidence of clinically functioning tumors (with none of the patients having signs of increased catecholamine secretion: flushing, or palpitations), and no bilateral involvement of carotid bifurcation in any of the cases.
No neurological abnormalities caused by vagal or hypoglossal nerve involvement (dysphagia/dysphonia), or by cervical sympathetic nerve impingement (Horner’s syndrome) were reported before surgical excision.
The first patient had a family history for CBPGL, and two different localizations (the second one was a glomus tumor of the right prelachrymal sac).
Imaging diagnostics
All patients have been evaluated by duplex ultrasound as the first step, followed by a second group of examinations, represented by MRI and MR-A.
Duplex ultrasound characteristics
The topographic relation of the tumors to the carotid arteries and the internal jugular vein and the patterns of vascularization were assessed in all seven cases:
a) B-scan imaging revealed in all cases a well-defined, solid, inhomogeneous, hypoechoic mass, located at the carotid bifurcation that pushed the carotid arteries apart.
b) Pulsed Doppler analysis of blood flows indicated in all tumors low-resistance flow patterns [with a low resistance index (RI), and a high diastolic component], obtained from multiple sites within the mass of the tumor. An arterio-venous shunt could be seen in all cases, with accelerate and turbulent flow in the vessels of the tumor.
c) The color Doppler imaging revealed in all patients a characteristic broadening (wide splaying) of the carotid bifurcation by a hyper-vascular mass (the highly vascularized tumor), with shifting of both the ICA and the internal jugular vein posterior and laterally and of the ECA anterior and medially. The hypervascularity of the CBPGLs appeared in all these cases as an abundant flow signal (irregular color signals) with flow direction being predominantly upward (according to the direction of tumor growth and vascular supply). All seven carotid body tumors could be assessed to their full extent (Fig. 1.5).
d) Power Doppler ultrasonography demonstrated in all cases the intra-tumoral increased vasculature as an abundant flow, characterized as an intense blush pattern, throughout the entire tumor, mainly in small blood vessels. The ECA and ICA were noted to surround the highly vascularized tumor. Consequently, all our CBPGLs appeared on duplex ultrasound as a hypoechoic, inhomogeneous, well defined and highly vascularized mass arising at the carotid bifurcation between the ICA and ECA, widening the bifurcation without infiltrating it.
MRI/MR-A characteristics
a) MRI showed a densely enhanced tumor at a widened carotid bifurcation in all patients. On the MR images of three CBPGLs, the lesions were of intermediate intensity on T1-weighted images and slightly hyperintense on T2-weighted images (Fig. 1.6.).
MRI indicated the full extent of the tumors and provided information about the absence of infiltration of adjacent structures in all cases, allowing us to assess the entire extent of all CBPGLs.
b) MR-A confirmed the diagnosis, demonstrating a hypervascularized tumor in the carotid bifurcation. The typical feature was splaying of the carotid bifurcation, with the ECA displaced anteriorly and the ICA and internal jugular vein located posteriorly. All CBPGLs derived their blood supply from the ECA (Fig. 1.7).
Using the preoperative imaging techniques, all neck tumors were classified into group II (3–5 cm) according to their diameter. No lymph node metastasis was found at preoperative imaging in any of the cases.
Surgical treatment
No preoperative embolization of the feeding vessels by superselective carotid artery angiography or fine needle aspiration of the tumor were performed before surgery in any case.
All interventions were realized under general anesthesia. All patients were operated through a longitudinal cervical incision made along the anterior border of the sternocleidomastoid muscle; the internal jugular vein was identified and the common facial vein ligatured. The CCA was dissected to obtain proximal control. Intra-operatively, on exploration of the neck, all seven patients showed CBPGLs group II Shamblin (tumors of medium size, with a latero-lateral diameter between 3 and 5 cm that partially surrounded the carotid vessels or adherent to them). Therefore, we proceeded to a complete subadventitial resection of the tumor in all cases. No lymph node involvement was found intra-operatively in any patient.
Macroscopically, all CBPGLs resected were well circumscribed, rubbery and reddish brown. Histological examination The CBPGL was confirmed in each case on histopathology (Fig. 1.8.) and immunohistochemistry, where all the tumor cells tested positive for synaptophysin and chromogranin, negative for cytokeratin. It showed no signs of malignancy in any of the seven tumors. All resected lymph nodes resulted negative for metastasis at histological examination.
Surgical complications and outcomes
There was no operative mortality, and no peri-operative stroke/TIA or severe bradycardia or hypotension were observed. No revision was needed for bleeding (no major bleeding/vascular injury were noted). The operating time was 123±20 minutes. No post-operative complications (respiratory failure, hematoma, infection, or cranial nerve injury) were noted in six cases. The seventh patient presented a transient ipsilateral vague nerve deficit (the tumor was tightly adherent to the neighboring vagus and was successfully resected sparing the nerve, but postoperatively the patient complained of dysphonia). Complete recovery was seen in her case after three months. During the third year follow-up, it was observed that none of our seven patients developed local, regional or distant metastases (recurrence rate was null).
Discussion
CBPGLs, which are hypervascularized tumors of the carotid body [118-122], constitute the most common form (50%) of head and neck paragangliomas [120,123-126]. Sometimes, they are multi-center tumors (4%) [120,123], just like our first case (with an additional glomus tumor of the right prelachrymal sac), being more common in patients with a familial history (7–10% of all CBPGLs) [120,123-126], like in our first patient. The incidence of bilateral CBPGLs is approximately 5–10% [118,124,149], but none of our cases was bilateral. On the other hand, sex prevalence is controversial [145]. In the literature [120,121,123-127,142,149,150], the mean age of clinical onset in patients with CBPGLs is 40 years, with a high frequency between 30 and 60 years [121]; all our seven cases fell within this age range.
Initially, due to its slow growth, the tumor is generally asymptomatic. In few cases, it is functional (secretes vasoactive substances) [128,129,135,141,144-146]. We had no clinical symptoms associated with catecholamine production (such as uncontrolled fluctuating hypertension, blushing, and palpitations) in any of the cases.
Then CBPGLs are clinically manifested as palpable painless (non-tender) lateral neck masses (all our seven cases), like vagal paragangliomas [120,126], located just anterior to the sternocleidomastoid muscle at the level of the hyoid bone [118,124]. All our seven neck tumors were mobile in the lateral plane, but their mobility was limited vertically, like in other studies [118,124]. Occasionally, the tumor mass may transmit the carotid pulse: our patients showed unilateral palpable pulsatile neck masses [137]. The presence of vascular murmur near the mass is rare, but it may be a sign of severe carotid artery compression [135,144] (none of our patients).
In time, the tumor grows and causes external compression, and/or involvement of the surrounding anatomical structures (carotid arteries plus the sympathetic chain, IX–XII cranial nerves, etc.), and manifesting as Horner’s syndrome, dysphagia, etc. [129,135,136,141,144-148]. None of our cases presented these symptoms before surgery. Jugular paragangliomas present skull base extension, with symptomatic relief [130] (none of our cases).
Other differential diagnosis of CBPGLs is with vagal paragangliomas, thyroid nodules, lymphadenopathy, brachial cysts, carotid artery aneurysms, and salivary gland tumors [130,131].
Due to the hypervascularization of these tumors, and the proximity to different nervous and vascular structures, fine-needle aspiration biopsy as a preoperative diagnostic tool is not advised as it may cause massive hemorrhage, pseudoaneurysm formation and carotid thrombosis [135,145]. This procedure also presents a risk of dissemination [135,145]. On the other hand, cytological evaluation cannot differentiate benign from malignant lesions [128,130,131]. We did not use this technique in any of our cases.
As direct biopsy is not suitable for the diagnosis of CBPGLs (they are tumors with no clear histological features of malignancy), different imaging modalities are essential in their preoperative diagnosis [129-131,135,136,141,144-148].
The use of different types of non-invasive imaging techniques can provide correct preoperative diagnosis in most cases with satisfactory sensitivity and specificity [127-132]. The Joint Vascular Research Group (JVRG), in their meta-analysis study [133], recommend that duplex ultrasound be the primary diagnostic investigation in carotid body tumors. Also used for their preoperative assessment are digital subtraction angiography (DSA), computed tomography (CT), CT angiography (CT-A), MRI and MR-A [129,133].
Duplex ultrasound helps define vascularity of the tumor (data regarding blood flow in the mass itself), and precise tumor location at carotid bifurcation [135,136]. Thus, the tumor is represented by a highly vascularized (intralesional abundant blood flow signals) hypoechoic mass in the area of the carotid bifurcation, which usually causes wide splaying of the bifurcation and separation of the ICA and ECA [120,123,125-137]. All these signs were identified in our seven patients.
Consequently, based on the two main characteristics of the lesion: vascularity and location, duplex ultrasound is helpful in differentiating CBPGLs from other solid, non-hypervascular masses [120,123,135-140]. Duplex ultrasound is also suitable for classification of cervical paragangliomas as carotid body, vagal or jugular paraganglioma based on the topographic relation to the carotid arteries and internal jugular vein [135,136]. Visualization of the intrinsic tumor vasculature proved an additional distinguishing criterion upon duplex ultrasound [135,136]. This technique completely depicts CBPGLs but fails to delineate the high cervical portion of vagal and jugular paragangliomas [135,136]. Anterior displacement of both carotid arteries and posterior displacement of the internal jugular vein can be found in vagal paragangliomas [135,136]. The caudal tumor extension of the jugular paragangliomas can be recognized within the expanded lumen of the internal jugular vein [135,136]. On duplex ultrasound, intratumoral flow is directed cranially in CBPGLs and inferiorly in vagal and jugular paragangliomas. However, there are difficulties with other entities, like ganglion’s metastasis of thyroid or breast cancer [135,136].
In addition to the diagnosis and differential diagnosis of carotid body tumors, duplex ultrasound can provide information on carotid body tumor size, blood supply of the tumor (feeding arteries) and coexistent carotid arterydisease, which is useful in forming a treatment plan and assessing the risk of surgery [135,136]. On the other hand, Duplex ultrasound has a limited ability to identify complex blood supply to a large carotid body tumor [135], and to measure the tumor exactly [135,136].
Finally, duplex ultrasound may be useful in screening for familial CBPGLs (like in our first case), and in the follow-up, where it can be a particularly valid first-line tool, thereby reserving second-line techniques such as MRI and CT for selected cases, where it is important to know the accurate dimensions of the lesions [136,141]. This technique is inexpensive, safe, accurate, readily available, and it is the non-invasive choice for the primary diagnosis of CBPGLs based on its vascularity and location [120,135-140].
MRI shows characteristic imaging features of CBPGLs that are helpful for their differential diagnosis (“salt and pepper” pattern) [120]. This classic imaging appearance of these lesions on MRI-T2 weighted images, where the “pepper” refers to the low signal flow voids and the “salt” refers to high signal foci of hemorrhage and/or slow flow [144]. This imaging appearance was identified in three of our cases. MRI is better in differentiating of CBPGLs from other paraganglioma [144].
MRI and MR-A with contrast medium administration of the neck are sensitive to assess the presence of tumor at the carotid bifurcation (additional information about the exactly tumor size) (all our cases). They also identify the relationship of the tumor with the adjacent structures (splaying of the carotid bifurcation) [130,135,136,144] (all our cases), and an eventual vascular encasement [145] (any patient). MR-A provides that CBPGL displace the ICA, but do not cause obstruction of this vessel [124] (all our cases). MR-A leads, sometimes, to the identification of an afferent vessel of the tumor (all cases), which could be selective embolized (any patient) [123].
MRI and MR-A are considered as the gold standard imaging techniques for the evaluation of carotid space tumors, as they allow a multiplane approach which is very important in the preoperative study [120,121,123,133,140,142,143]. These techniques are more effective non-invasive imaging modalities compared to with duplex ultrasound, especially for small tumors (diameter <3 cm) [129,135,136,140,141,143-148].
Unfortunately, MRI/MR-A do not provide data about the potential for malignancy and postoperative early recurrence because the tumors are too small in terms of the MRI/MR-A’s resolution power [144].
Moreover, both duplex ultrasound and MRI can predict the Shamblin classification, according to several authors [144]. Therefore, both modalities were ordered for all our seven patients.
Digital subtraction angiography (DSA) confirms the diagnosis of CBPGLs demonstrating a hypervascularized tumor in the carotid bifurcation [widening of the carotid bifurcation by a well-defined tumor blush (“lyre sign”), which is classic path gnomonic angiographic finding] [118,122,129,135,136,141,144-148]. The DSA demonstrates accurate the tumor blood supply (it can identify the feeding vessels of the tumor, usually originating from the pharyngeal artery, or CEA). This technique has to be used only in selected cases, to detect the vascular anatomy of large tumors, with identification of an afferent vessel of the BPGL, followed by preoperative selective embolization of the tumor [145,146]. For evident reasons, we did not used DSA in any case.
Taking into consideration the practicability and invasiveness of these investigations, as well as the risks and costs involved, and last, but not least, the international literature [120,126,128,131,139,140], we propose that the imaging techniques for diagnosis of CBPGLs be performed in the following sequence: (a) duplex ultrasound, (b) MRI, and (c) MR-A.
In consequence, the localization of the tumor within the carotid bifurcation, splaying of the bifurcation, and profuse vascularity are important in the imagistic diagnosis of carotid body tumors [129,135,136,141,144-148].
The selection of treatment depends on the biological activity, size, volume, location, anatomical relationships of the tumor to neighboring structures, such as carotid vessels, craniofacial nerves, the angle of the jaw and the vertebral bodies, as well as the overall fitness of the patient [144].
When the tumor is considered functional, careful clinical evaluation before surgery, measurement of serum catecholamine, treatment with adrenergic blockers, and gentle manipulations during the excision are essential for optimal results [27] (no functional tumor was found in any of our cases).
Given that the natural history of CPPGLs is believed to be unpredictable, immediate surgical removal is recommended. Complete surgical excision remains the golden standard of therapy, as the tumor has a 5% or greater incidence of metastases; radiation therapy and chemotherapy are unsatisfactory [127,135,144]. General anesthesia is routine for safe CBPGLs surgery [128], and we used it in all our cases.
The surgical treatment depends on multiple factors, the proper preoperative classification of CBPGLs being imperative for optimal management [129,135,136,141,144-148,151].
Based on the relationship to the carotid arteries, Shamblin et al. divided carotid body tumors into three groups [147,151]. The size of the tumor is positively correlated with the Shamblin classification (the relationship to the carotid arteries), because CBPGLs become more adherent to carotid vessels as they become larger [129,135,136,141,144-148,151]. They classified as group I the small tumors, which do not involve the carotid vessels and that can be easily dissected away from the vessels. Group II included CBPGLs of medium size that partially surrounded the vessels or were adherent to them, but could be separated with careful sub adventitial dissection (all our seven patients). Group III consisted of tumors that were large and typically encased the carotid artery, thus requiring partial or complete vessel resection and replacement (ligation of ECA and ICA reconstruction with resection of the tumor) [151].
Luna-Ortiz et al. [151] considered that the Shamblin classification predicts only vascular morbidity without remarking on the neurological morbidity and reflects only the surgeon’s experience in dissecting the tumor. Consequently, they modified the Shamblin grouping as follows: group I – less than 4 cm in size with no surrounding or infiltrating the carotid and excision done without difficulty, group II – more than 4 cm in size with partial surrounding or infiltrating the carotid and excision done with difficulty (all our patients). Group III includes tumors with infiltration to any carotid vessel, more than 4 cm in size, and intimately infiltrating or surrounding the carotid vessels, requiring vascular repair, sacrifice or vessel replacement [133,147,148].
Different surgical techniques are used to reduce adverse outcomes and to achieve optimal results as well [129,135,136,141,144-148,151].
Careful dissection of the neighboring nerves is essential [144]. Boscarino et al. asserted that the risk of intraoperative cranial nerve injury proportionally increases with the size and extension of tumor (like in our seven patients, which presented the greatest tumor from our seven cases) [145,146]. For this reason, it is mandatory to assess the preoperative status of neighboring cranial nerves (vagus nerve, hypoglossal nerve, and the superior laryngeal nerve) that are potentially at risk of intraoperative injury [145]. Also, accurate dissection with excision of the tumor should be performed along the subadventitial plane or “white line” suggested by Gordon-Taylor [144-146] in order to separate the tumor from the surrounding vessels (all our patients).
The surgical procedure must include regional lymph nodes with enlarged size, suspicious morphology, or closely adherent to the tumor [144-146]. No malignancy was detected in our cases.
Resection of large CBPGLs – group III Shamblin (none of our cases) can be difficult to perform because of their site, size, carotids adherence, local cranial nerve involvement, and hypervascularity, with possible excessive blood loss [127]. A combined therapeutic approach, with eventually preoperative selective embolization followed by surgical resection by an experienced team, offers a safe and effective method for complete excision of such tumors, with a reduced morbidity rate [127,130,142,143]. Embolization is recommended in a few selected cases (size >5 cm, Shamblin’s type III, or significant cranial extension) to decrease the vascularity of the tumor and lower operative blood loss thereby reducing technical difficulty [145,146]. However, preoperative embolization is still controversial as it may cause ICA thrombosis [135]. No preoperative embolization was performed in our patients. Histologically, carotid body paraganglioma resemble the normal architecture of the carotid body. The tumors are highly vascular, and between the many capillaries are clusters of cells called zellballen [145,146] (all our cases).
Concerning postoperative outcomes, surgery has been associated with several complications such as stroke, cranial nerve injury, and bleeding; the risk of postoperative stroke in CBPGLs resection is now less than 5% [118,133,145,151,152] (no stroke occurred in our cases). However, the incidence of cranial nerve injury remains strikingly high, ranging from 20% to 50%, with larger tumor of Shamblin III variety [118]. Speech and swallowing difficulties could be produced in the immediate postoperative period [144]. In 20% of patients, the neurological deficits are permanent [118]. Postoperatively, we found only one case of transient vague nerve damage. A serious problem during tumor excision is bleeding, which sometimes can be massive. Different authors have recommended standardized ICA shunting during CBPGL excision in order to exclude the vascular supply of ECA, reduce the size of the tumor, and guide the resection in difficult cases [118,132,151,152]. We did not use this technique in any case.
Recurrence after complete resection occurs in approximately 6% of patients [118]; in our study, however, there were no recurrences for three years.
Limitations of our study include: (a) the small number of cases presented (all Shamblin II group), (b) the follow-up period after surgery does not permit long-term conclusions regarding the recurrence of such tumors.
Conclusions
Multidisciplinary management (including radiologists, surgeons, otolaryngologists, anesthesiologists, and neurologists) of patients with CBPGLs is essential. Their early diagnosis (with duplex ultrasound, associated with MRI, and MRA), and complete surgical excision are imperative, like we proceeded in all our seven cases.
1.3.3.1.7. Anatomical considerations on carotid and vertebral arteries. Congenital variations – Data from the literature.
Encephal blood supply depends on four main vessels, two carotid arteries and two vertebral arteries in the majority of cases. Agenesia or hypoplasia of any of these vessels is infrequent. Common Carotid artery (CCA)
Usually, the right common carotid and the right subclavian arteries have origin in the brachio-cephalic trunk which is the first branch in the aortic arch. The left CCA, and the left subclavian arteries (SCAs) come directly from the aorta (the vertebral artery-VA is a branch of the SCA). However, according to Jorda, up to 8% of cases may show some variations in these patterns. The CCA ascends through the neck, without branching, up to the thyroid cartilage (C4-C5), where it usually divides into two major branches, the internal carotid artery (ICA) and the external carotid artery (ECA) [153]
The presence of concomitant CCA and ICA hypoplasia suggests the congenital character of the process [154]. It is important to know that patients with distal ICA dissection may show a similar Color-coded carotid duplex sonography pattern, but the reductions in the ICA and CCA calibers and augmentation in collateral flow from the VA are usually less pronounced than those found in the cases of congenital hypoplasia [52,154].
Internal carotid artery (ICA)
At the bifurcation, the CCA widens and the dilatation continues into the origin of the ICA, forming what is called the carotid bulb. Usually the ICAs are located in a dorsolateral position with respect to the ECA, but variations are quite frequent. From there on, the ICA ascends toward the base of the skull without branching, while the ECA shows branches emerging in its very first segments. The diameter of the ICA ranges normally between 4 mm and 5 mm, and changes along the course, the bulb being in general one-third larger than the distal diameter. [153]
Internal carotid artery (ICA) hypoplasia
ICA is one of the most stable arteries and its congenital anomalies are an infrequent occurrence [155-158]. They have been categorized by Lie into three groups: a). agenesis (absence of the entire artery and its bony canal) [159], b). aplasia (a vestige of ICA is present, as well as the carotid canal) and c). hypoplasia (both the artery and the carotid canal are small but with a normal structure) [160,161]. The left ICA dysgenesis cases are three times more frequent that those concerning the right one. [52,154]
ICA hypoplasia – arterial narrowing along its entire course because of incomplete development the carotid– is a very rare anomaly occurring in 0.079% of individuals [154,160,162]. It may be unilateral or, more rarely, bilateral [52,163] The diagnosis of ICA hypoplasia is based on neuroimaging and includes: color-coded carotid duplex sonography (CCDS) followed by angiography – CT/MRA or DSA [52,154,164].
The CT of the skull base will help to differentiate the congenital from the acquired narrowing of the ICA [155]. The presence of a small bony carotid canal on CT imaging at the level of the left petrous ICA, demonstrates the diagnosis of ICA hypoplasia, excluding the hypothesis of ICA acquired stenosis and respectively of ICA agenesis. [52]
Color-coded carotid duplex sonography (CCDS) is usually the first study performed by physicians to rule out carotid disease. Among the limitations of CCDS, the most important one is the impossibility to exam the ICA in its high cervical, intrapetrous and intracranial segments and also, it is especially difficult to describe a deep cervical variant of this artery. [52,154,155] According to Chen et al., there are direct and indirect CCDS signs suggesting ICA hypoplasia [154]. Direct findings are a long segmental small-caliber (about 50% smaller than the size of the unaffected contralateral artery) lumen accompanied by a significant reduced flow volume (13% of the normal side) in the affected vessel, but without important atherosclerosis, a false lumen, or notable wall thickening. Indirect signs encompass a significantly augmented total flow volume in the bilateral VAs (augmented by over 130% of the normal value), anterograde ipsilateral ophthalmic arterial flow, a diminishing artery diameter, and higher flow resistance in the ipsilateral CCA. [52,154,155]. However, MR/CTA is the best noninvasive method to assess narrowed ICA, collateral circulation and possible associated intracranial aneurysms [52,154,155,164].
Clinical aspects of ICA hypoplasia
Although most of the cases of ICA hypoplasia remain asymptomatic, some patients present ischemic or hemorrhagic cerebral events secondary to cerebral hypo- perfusion or bleeding from aneurysms or dilated collaterals [52].
Vertebral artery (VA)
The VA is the largest and most constant stem of the ipsilateral SCA [165-167]. This artery is typically divided into four sections: the first segment (V1 – preforaminal) starts from its origin (V0 – ostium) on the SCA to the C6 transverse process; the second (V2 – foraminal) from C6 to C2 transverse process; the third (V3 – atlantic): from C2 to the foramen magnum; and the fourth (V4 – intracranial) from the foramen magnum to the vertebrobasilar junction [167-169].The VA has a normal diameter of 3–5 mm. It has important anatomical relationships with the ipsilateral ICA and hypoglossal nerve (CN XII) and represents the primary blood supply for the infratentorial brain structures [52,168,170]. Visualization of VA and its eventual pathological modifications is possible by using CCDS or some sort of angiography techniques, such as DSA, CT/MRA [52,171,172].
Limitations of ultrasound assessment of the VA
Nowadays, CCDS is the first test used in the assessment of extracranial segment of VA [171,173]. The Doppler waveform, which corresponds to VAs, is monophasic with prominent diastolic flow and spectral broadening [174]. The CCDS assessment of the VA includes the measurement of the arterial diameter (4.6 mm in average), the peak systolic velocity (PSV) (56 cm/s in average) and end diastolic velocity (EDV) (17 cm/s in average), the RI (0.69 in average) and the net vertebral flow volume (200 mL/min in average) [52,174-176]. According to Baltgaile, an ultrasound examination of VAs is more challenging as compared with the insonation of the ICA. This is due to the anatomical position, variation of course and diameter, deeper location of the VA and its course through transverse processes of cervical vertebrae. [165,170,177].
MRA and CTA assessment of the VA
Baltgaile noted that MRA and CTA confirm the higher sensitivity of contrast-enhanced MRA (CE-MRA) and CTA in diagnosing VAs stenosis than color duplex. The specificities for CTA, CE-MRA and color duplex were very similar: 95.2%, 94.8% and 97.7%, respectively. Specificities for CE-MRA and color duplex demonstrated significant heterogeneity [177,178].
Congenital variations of Vas
The VA is subject to numerous anatomical variations [52,166,179,180].
Aortic arch origin of VA
The abnormal arising of VA from the aortic arch (about 6% of the population) is the consequence of an error that occurs during the human embryonic development [181]. It was reported that the left VAs originating from the aortic arch are frequently hypoplastic and go into the foramen transversarium at a different level (C5 instead of C6) [52,168,173,181].
Hypoplasia of Vas
The two VAs are usually unequal in size, the right being smaller than left in most cases. Congenital variations in the arrangement and size of the VAs are frequent, ranging from asymmetry of both VAs to severe hypoplasia of one VA. A hypoplastic VA was defined as a lumen diameter of <2 mm or < 3mm, but there is no consensus on this value, because the majority of studies were not conducted on healthy subjects or the sample size was small [52,182]. The reported frequency of unilateral VA depends on the definition used from hypoplasia and varies from 2% to up 12% [101,177,183-185].
Color-coded carotid duplex sonography (CCDS)
The hemodynamic consequences of VA hypoplasia revealed by CCDS include: a cut-off point of< 2 or 2.5 mm (measured in the entire course of the artery) determined for hypoplasia of VA. This is based on significant hemodynamic changes as an increase in ipsilateral flow resistance (resistance index >0.75), contralateral diameter (side-to-side diameter difference>0.12 cm) and a reduction of flow volume (side-to-side flow volume ratio>5) that is, below 30-40ml/min by CCDS [177,184,167].
We have to mention that this method is not useful in the assessment of the exact trajectory of this artery and it may not be enough in order to differentiate VA hypoplasia from aplasia, occlusion or dissection. CT/MRA usually confirms the diagnosis [52,173,187].
MRA
The frequency of VA hypoplasia defined as a diameter < 2 mm by MRA was found to be as high as 26.5 % in normal subjects. This may had resulted from measurement differences (MRA vs. CCDS). [101,177]. Hypoplasia of both VAs is encountered in 0.3% in sonographically and angiographically studied patients [177,184,188].
Clinical aspects of VA hypoplasia
The absence of vb insufficiency symptoms among people with hypoplastic VA, indicates that even marked VA asymmetry is a normal variation [170,183,184,186,189]. Although it must be mentioned that some studies demonstrated a high association of VA territory ischemic stroke with ipsilateral hypoplasia of the VA [177,179]. In the past years, it was suggested that an ipsilateral hypoplastic VA represents a risk factor for ischemic stroke in the vertebrobasilar territory – particularly for ischemic events in the posterior inferior cerebellar artery (PICA) and lateral medullary territories [52,162,170]. At the moment, the hypoplastic VA is not seen as an independent risk factor for stroke, however it is important to know that, if associated with other risk factors, it may induce ischemic stroke in the posterior circulation territories [172,189].
Personal contributions
The congenital anomalies of the supra-aortic arteries and their branches as potential risk factors for cerebrovascular insufficiency are not yet fully investigated and understood.
For this reason, our report [52] describes the case of a 68-year-old man with an acute ischemic stroke in the vertebrobasilar territory (unilateral pontine infarct) demonstrated by brain MRI. CCDS and CT-A revealed a combination of congenital anomalies of the neck arteries: left CCA hypoplasia, left ICA hypoplasia, right VA hypoplasia and the emergence of the left VA directly from the aortic arch.
The aim of our article was to emphasize the value of CCDS as an accurate, non-invasive method of assessing the neck arteries and, also, the importance of the morphological anomalies of the carotid and vertebral arteries in the cerebral hemodynamics. [173] In our case, the ICA hypoplasia was an incidental diagnosis – none of the symptoms accused, as neither the imaging lesion found being consistent with the vascular territory of this artery.
Our diagnosis – multiple congenital anomalies of carotid and vertebral arteries – was based on CCDS and CTA, knowing that the combined use of these methods allows a non-invasive and precise assessment of the neck vessels and their pathology. It was shown that the ICA and VA dysgenesis, in coexistence with other risk factors for stroke may be involved in cerebral ischemic events and respectively in the vertebrobasilar ischemic stroke pathogenesis. [52] Therefore, we can assume that the presence of the right hypoplastic VA (associated to other vascular anomalies in a hypertensive patient) may have played a role in the cerebral ischemic event presented in our case. [52]
1.3.3.1.8. Romanian Journal of Morphology and Embryology, Volume 59, Number 4, 1279-1285, 2018, Romanian Academy Publishing House, Rom J Morphol Embryol 2018, 59(4):1279-1285
Multiple congenital anomalies of carotid and vertebral arteries in a patient with an ischemic stroke in the vertebra-basilar territory. Case report and review of the literature
Authors: Dragos Catalin Jianu, Silviana Nina Jianu, Gratian Dragoslav Miclaus, Georgiana Munteanu, Traian Flavius Dan, Claudia Barsan, Mihnea Munteanu, Horia Tudor Stanca, Andrei Gheorghe Marius Motoc, Octavian Marius Cretu
Introduction
The congenital anomalies of the supra-aortic arteries and their branches as potential risk factors for cerebrovascular insufficiency are not yet fully investigated and understood.
The internal carotid artery (ICA) is one of the most stable arteries and its congenital anomalies (agenesis, aplasia, or hypoplasia) are an infrequent occurrence [155-158]. Hypoplasia is characterized by ICA narrowing along its entire course because of incomplete development. The anomaly has a prevalence of 0.079% and may be unilateral or, more rarely, bilateral [163]. Despite the significantly altered vascular anomaly, the majority of patients are asymptomatic due to the extensive collateral flow on the affected side [154,163,178]. However, ICA dysgenesis is associated with a higher prevalence of cerebral aneurysms and has important implications during carotid endarterectomy or trans-sphenoidal pituitary surgery [164,190]. The vertebral artery (VA) usually originates as the first branch of the subclavian artery being its largest and most constant stem [165,174]. However, it was shown that the anatomical features of VAs are quite diverse [166,170]. In 6% of the population (usually asymptomatic patients), the left VA arises directly from the aortic arch, while VA hypoplasia has frequently been recognized among healthy individuals [170,174,179]. Nevertheless, it has been suggested that VA hypoplasia involves an increased probability of ischemic stroke in the vertebrobasilar circulation territory [167,170].
The diagnosis of ICA and VA hypoplasia is usually incidental [164]. Extracranial and transcranial color-coded duplex sonography (CCDS) followed by angiography – including computed tomography angiography (CTA), magnetic resonance angiography (MRA), or digital subtraction angiography (DSA) – are the most important methods of assessing these vascular anatomic abnormalities [154,173]. Also, a hypoplastic carotid canal observed on CT of the skull base and sometimes, a decrease in ipsilateral common carotid artery (CCA) lumen diameter are considered hallmarks of congenital ICA hypoplasia [155,164].
We present here the case of an old man diagnosed in our clinic with an acute ischemic stroke in the vertebrobasilar territory (unilateral pontine infarct) and a rare combination of morphological abnormalities of the neck arteries: left ICA hypoplasia, left CCA hypoplasia, right VA hypoplasia and the emergence of the left VA from the aortic arch. These findings were demonstrated by brain CT, brain magnetic resonance imaging (MRI), CCDS, and CTA.
In this article, we want to emphasize the value of CCDS as a valuable diagnostic tool for assessing the neck arteries and the practical neurological importance of recognizing the anatomical variants and anomalies of the carotid and vertebral arteries [173].
Case presentation
We describe the case of a 68-year-old man (S.V.) examined in the Emergency Room (ER) Department of “Pius Brînzeu” Emergency County Hospital, Timișoara, Romania, in 23.02.2018, for vertigo, gait disturbances, and right latero-pulsion. The symptoms described had a sudden onset on the day of presentation. Therefore, the patient was admitted in the First Department of Neurology (File No. 9367), with the presumptive diagnosis of stroke in the vertebrobasilar territory. From the patient past medical history, we knew that he was hypertensive under antihypertensive and antiplatelet therapy; the latter one was stopped seven days before the symptom’s onset.
At the time of admission, the patient was clinically stable – afebrile, with normal blood pressure (BP) 120/80 mmHg and oxygen saturation of the arterial blood (SpO2 96%). His heart was regular [heart rate (HR) 72 beats/min], with normal heart sounds and no audible murmur, rubs, or gallops. His lungs were clear to auscultation, without wheezes or rhonchi. His abdomen was benign with normoactive bowel sounds. His peripheral pulses were full and there were no edema or rash on the skin.
On the neurological examination, we observed gait disturbances with right latero-pulsion and a wider base, evidence of right dysmetria; tendon reflexes were 2+ and symmetrical throughout, while the plantar responses where flexors on both sides; there were no meningeal signs nor evidence for intracranial hypertension; the patient had a normal tone in all four extremities and no motor deficits; the sensation was found to be intact to light touch, pinprick, proprioception, vibration and temperature throughout; cranial nerves tests were normal and the speech was fluent, with no errors in comprehension or repetition.
During the admission, several investigations were performed including: non-enhanced brain CT (with no pathological findings concerning the brain, but the CT axial image at the level of the left petrous ICA showed a small left carotid canal to the skull base), brain MRI (Fig. 1.9), CTA neck/carotids (Fig. 1.10) and brain (circle of Willis), and extracranial (Fig. 1.11) and transcranial CCDS. These tests had led to discovery of an acute (over 12 hours after onset of symptoms) ischemic lesion localized in the pons (unilateral, and paramedian), and of several vascular abnormalities: left ICA hypoplasia, left CCA hypoplasia, right VA hypoplasia and the emergence of the left VA from the aortic arch. Other paraclinical tests were performed: laboratory blood tests [complete blood count (CBC), renal and liver function tests, electrolyte assessment, erythrocyte sedimentation rate (ESR), coagulation tests], electrocardiogram (ECG), abdominal echography and chest X-ray – none of them showing relevant pathological changes.
Other causes (vasculopathies, such as arteritis or tubular fibromuscular dysplasia) able to determine the symptoms accused by our patient were excluded by the imaging tests listed above.
Under antiplatelet (Clopidogrel), lipid control with statins and antihypertensive therapies [angiotensin-converting enzyme (ACE) inhibitor in combination with a diuretic: Perindopril and Indapamide], the patient’s clinical evolution was good and the neurological symptoms completely resolved in the next three days. No surgical interventions were considered necessary in order to resolve the vascular abnormalities.
Discussions
Internal carotid artery (ICA) hypoplasia
ICA is a terminal branch of CCA. It arises at the level of the hyoid bone, (between the C4 and C6 vertebral bodies) where CCA divides into ICA and external carotid artery (ECA) [191].
Morphological variations of ICA are exceptionally rare, while carotid anomalies related to developmental defects are an infrequent occurrence [155,160]. They have been categorized by Lie into three groups: agenesis (absence of the entire artery and its bony canal), aplasia (a vestige of ICA is present, as well as the carotid canal) and hypoplasia (both the artery and the carotid canal are small but with a normal structure) [160,161]. The left ICA dysgenesis cases are three times more frequent that those concerning the right one (as in our case) [154].
ICA hypoplasia – the carotid anomaly identified in our case – is a very rare anomaly occurring in 0.079% of individuals [154,160,162].
The formation of the ICA occurs in the 3- to 5-mm embryonic stage, and it is completed by the 6th week of gestation [192]; the formation of the skull base is first seen in the 5th or 6th embryonal week [193,194]. Therefore, the development of ICA is mandatory for the formation of the carotid canal in the skull base [164,193]. The structures that give rise to ICA are the dorsal aorta, the ventral aorta, and the third aortic arch [183,192]. The embryological developmental defect that causes ICA hypoplasia is still unclear: it has been suggested as possible mechanisms a secondary involution of the ICA ensuing a phase of proper development or an arrest of the artery development at a given moment in time [154,155].
The lack of blood flow caused by unilateral ICA hypoplasia is mostly compensated by the intact collateral circulation developed from the contralateral ICA and vertebrobasilar system [157,162,164]. Thus, the condition is usually asymptomatic and incidentally discovered. Also, even when the vascular anatomy is markedly altered, MRI or single-photon emission computed tomography (SPECT) rarely found evidence of brain lesions or perfusion defects [155,178,189]. Although most of the cases of ICA hypoplasia remain asymptomatic, some patients present ischemic or hemorrhagic cerebral events secondary to cerebral hypo- perfusion or bleeding from aneurysms or dilated collaterals. The clinical presentations of this condition may include seizure, transient ischemic attack (TIA), ischemic or hemorrhagic stroke, migraine-like headache and spasmodic torticollis [154]. In our case, the ICA hypoplasia was an incidental diagnosis – none of the symptoms accused, as neither the imaging lesion found being consistent with the vascular territory of this artery.
The diameter of the ICA ranges between 4 mm and 5 mm [184]. The diagnosis of ICA hypoplasia is based on neuroimaging and includes: color-coded carotid duplex sonography followed by angiography – CT/MRA or DSA [154,164]. The CT of the skull base will help to differentiate the congenital from the acquired narrowing of the ICA [155]. The presence of a small bony carotid canal on CT imaging at the level of the left petrous ICA, demonstrated, in our patient case, the diagnosis of ICA hypoplasia, excluding the hypothesis of ICA acquired stenosis and respectively of ICA agenesis.
CCDS is usually the first study performed by physicians to rule out carotid disease. It is non-invasive and accurate in analyzing both parietal anomalies (hypoechoic plaques, clotting and parietal hematoma) and the external diameter of the artery; it can rule out both stenosis and occlusion in the carotid bulb. Also, the use of a color-coded Doppler flow imaging technique improves the accuracy of flow measurement and provides information on smaller arteries with low flow. Among the limitations of CCDS, the most important one is represented by the fact that, using this technique, it is impossible to exam the ICA in its high cervical, intrapetrous and intracranial segments and also, it is especially difficult to describe a deep cervical variant of this artery [154,155]. There have been several reports concerning the CCDS findings in ICA hypoplasia, but, until now, there is no consistent evidence on the reliability of CCDS as an assessment tool of the diameter and flow volume in hypoplastic ICA [186].
According to Chen et al., there are direct and indirect CCDS signs suggesting ICA hypoplasia [154]. Direct findings are a long segmental small-caliber (about 50% smaller than the size of the unaffected contralateral artery) lumen accompanied by a significant reduced flow volume (13% of the normal side) in the affected vessel, but without important atherosclerosis, a false lumen, or notable wall thickening (as in our case). Indirect signs encompass a significantly augmented total flow volume in the bilateral VAs (augmented by over 130% of the normal value), anterograde ipsilateral ophthalmic arterial flow, a diminishing artery diameter, and higher flow resistance in the ipsilateral CCA (as in our case) [154,155].
However, MR/CTA is the best noninvasive method to assess narrowed ICA, collateral circulation and possible associated intracranial aneurysms. As we stated above, congenital ICA hypoplasia is always accompanied by a small carotid canal given that the carotid canal formation is a direct consequence of its respective embryonic artery presence. Thus, demonstration of a small carotid canal (on CT of the skull base) (as in our case), along with a well-developed collateral circulation (on CT/MRA) are essential arguments in favor of the congenital nature of the condition [154,155,164].
ICA hypoplasia should be differentiated from a variety of other vasculopathies including atherosclerosis, arteritis, tubular fibromuscular dysplasia, intimal dissection, transient perivascular inflammation of the carotid artery (TIPIC) syndrome and Moya-Moya syndrome. Also, a hypoplastic ICA may be confused with a “functional narrowing” of the arterial lumen (e.g., vasospasm, increased intracranial pressure) or with a dilated ascending pharyngeal artery [154,155,101]. The ICA hypoplasia prognosis depends on the eventual concomitant presence of intracranial aneurysms given that this anatomic anomaly induces a hemodynamic pressure increase in collateral arteries [155,164]. Lhermitte et al. described three vascular conditions associated with ICA hypoplasia; anomalies and variants of the circle of Willis, aneurysms, and intense collateralization [154,185]. It is important to emphasize that the reported prevalence of intracranial aneurysms in affected patients is 24–34% about 10 times higher compared to the normal population (2–4%) [164,188]. No aneurysms have been found in our case. Also, discovering an ICA hypoplasia has important implications in the assessment of cerebral embolic events considering that emboli in one cerebral hemisphere may originate from an atherosclerotic contralateral ICA [164,190]. Also, this condition, alongside other carotid dysgenesis, should be taken into account, when interventions including carotid endarterectomy or trans-sphenoidal pituitary surgery are considered [159,164].
Due to the rarity of this condition, no optimal treatment has been yet established for the symptomatic stenosed hypoplastic ICA [157].
Common carotid artery (CCA) hypoplasia
The ICA hypoplasia is often associated with a smaller diameter of the ipsilateral CCA (also found in our patient). The presence of concomitant CCA hypoplasia suggests the congenital character of the process [154].
It is important to know that patients with distal ICA dissection may show a similar CCDS pattern, but the reductions in the ICA and CCA calibers and augmentation in collateral flow from the VA are usually less pronounced than those found in the cases of congenital hypoplasia [154].
Vertebral artery (VA) anomalies
The VA is a part of the vertebrobasilar cerebral circulation being the largest and most constant stem of the ipsilateral subclavian artery (SCA) [165-167]. However, the VA origin can be variable in a minority of cases – VA can arise from the aortic arch (in 6% of the population, mostly on the left) (as in our case), brachio-cephalic artery (on the right) or from the ECA [71,168,174]. From its origin, VA takes a postero-vertical course to enter into the sixth cervical transverse foramen (90–95% of the cases), then bends medially, behind atlas, and goes into the cranium through the foramen magnum [169,171,179,195,196]. After giving rise to the posterior inferior cerebellar artery, the VAs joins at the lower pontine border to form the basilar artery (BA) [169,174]. We have to mention that when the origin of the VA is from the aortic arch, then the artery usually enters the foramen transversarium at a higher level than normal (C5 instead of C6) [168]. This artery is typically divided into four sections: the first segment (V1 – preforaminal) starts from its origin (V0 – ostium) on the SCA to the C6 transverse process; the second (V2 – foraminal) from C6 to C2 transverse process; the third (V3 – atlantic): from C2 to the foramen magnum; and the fourth (V4 – intracranial) from the foramen magnum to the vertebrobasilar junction [167-169].
The VA has a normal diameter of 3–5 mm. It has important anatomical relationships with the ipsilateral ICA and hypoglossal nerve (CN XII) and represents the primary blood supply for the infratentorial brain structures [168,170].
Aortic arch origin of VA
The VA is subject to numerous anatomical variations, most of them incidentally discovered during angiographic or anatomic postmortem studies [172,179,181]. Among these variants, the most frequently reported form is represented by a VA arising from the aortic arch, situation that occurs in about 6% of the population. In other rare cases, left VA arises from the left CCA or the root of the left SCA [166,179,180]. The abnormal arising of VA from the aortic arch (also described in our patient) is the consequence of an error that occurs during the human embryonic development [181].
It was reported that the left VAs originating from the aortic arch are frequently hypoplastic and go into the foramen transversarium at a different level (C5 instead of C6) [168,173,181]. However, in our case, the left VA had a normal caliber, while the right VA is hypoplastic; also, the CTA revealed that, in our patient, the left VA entered into the C6 transverse foramen.
In most cases, these anomalies are asymptomatic or incidental, however, we should be able to recognize them for several reasons [166,172,180]:
-the aortic arch and VA anomalies may interfere with endovascular, neurosurgical or ear-nose-throat (ENT) interventions [172,180,197];
-variants of the aortic arch can be taken as occluded vessels, when the artery is not found at its conventional site during angiography or surgical interventions [180];
-it has been suggested that, possibly due to the resulting altered hemodynamics, these variants can be associated with the presence of intracerebral aneurysms [180,198].
VA hypoplasia
The normal diameter of VAs varies from 1.5 to 5 mm. Congenital anatomical variations of both VAs are common among healthy individuals without symptoms of vertebrobasilar insufficiency; left VA dominance presents in 65% of the population, identical width of VAs occurs with a 25% prevalence, whereas in only 10%, the right VA is larger than the left one [167,170,187,199,200].
There is a lack of consensus on the definition of VA hypoplasia because the majority of studies were not conducted on healthy subjects or the sample size was small [182]. Thus, operational definitions of VA hypoplasia varies between diameters of less than 2 mm to less than 3 mm (measured in the entire course of the artery), associated with an asymmetry ratio threshold >1:1.7 (also, observed in up to 10% of normal individuals) [167,170,201]. Additional suggestive sonographic criteria include reduced blood flow velocity and volume, increased resistance index (RI) values, and a compensatory increase in the vessel diameter of the contralateral VA. According to recent data, a cut-off point of 2.2 mm was fixed as a defining criterion for VA hypoplasia [167,175,182].
VA hypoplasia is a common vascular variant; however, its reported frequency is dependent on the definition used for this abnormality [162,182]. Thus, the VA hypoplasia prevalence found in the literature is highly inconsistent ranging from 1.9 to 26.5% [170]. In terms of side difference, the right hypoplastic VA occurring more frequent than the left one, may be explained by the fact that the left SCA (the VA’s origin), being a direct branch of the aortic arch, is exposed to an increased shear stress during development. Thus, the blood supply, usually, end-up being dominated by the left VA [167,170].
Visualization of VA and its eventual pathological modifications is possible by using Doppler ultrasonography or some sort of angiography techniques, such as DSA, CT/MRA [171,172].
Nowadays, CCDS is the first test used in the assessment of extracranial segment of VA, being non-invasive, cost-effective and reproducible [171,173]. With CCDS, it can be obtained significant information especially about the proximal brachiocephalic vessels, while the inter- vertebral segment of the artery is usually more difficult to assess. The Doppler waveform, which corresponds to VAs, is monophasic with prominent diastolic flow and spectral broadening [174]. The CCDS assessment of the VA includes the measurement of the arterial diameter (4.6 mm in average), the peak systolic velocity (PSV) (56 cm/s in average) and end diastolic velocity (EDV) (17 cm/s in average), the RI (0.69 in average) and the net vertebral flow volume (200 mL/min in average) [174-176].
The hemodynamic consequences of VA hypoplasia revealed by CCDS include:
-a narrower vessel lumen [diameter of ≤2.5 mm (5), ≤2.2 mm (9), or ≤2 mm (7), according to different definitions of VA hypoplasia] [167,170].
-an increase of ipsilateral RI (>0.75) [175];
-a PSV usually <40 cm/s [167];
-a decreased ispilateral net vertebral flow volume<100 mL/min [164] and a slightly increased one in the contralateral VA [175,178];
-a significantly lower mean net flow volume (the sum of the net flow volume of bilateral VA) [187].
We have to mention that this method is not useful in the assessment of the exact trajectory of this artery and it may not be enough in order to differentiate VA hypoplasia from aplasia, occlusion or dissection. CT/MRA usually confirms the diagnosis [173,187].
In our case, the CCDS assessment of the VAs revealed a right VA hypoplasia, diagnosis which was then confirmed by CTA.
The clinical relevance of VA hypoplasia is still debatable; however, it was reported that VA hypoplasia is more common in patients with migraine with aura or those suffering from vestibular neuronitis rather than in those without these diseases, suggesting that this anomaly may be an additional factor involved in the pathogenesis of these conditions [170,175,201,202].
In the past years, it was suggested that an ipsilateral hypoplastic VA represents a risk factor for ischemic stroke in the vertebrobasilar territory – particularly for ischemic events in the posterior inferior cerebellar artery (PICA) and lateral medullary territories [162,170]. Recent evidence has revealed that the diminished blood flow detected on the same side with the hypoplastic VA might augment the risk for thrombosis and deficient clearance of thrombi leading to stenosis of the distal artery [170,171,187]. Supporting these statements, we mention a study that showed that the VA hypoplasia leads to regional hypo- perfusion in the respective PICA territory in 42% of individuals tested [175].
According to Palmer, the presence of this anomaly may increase the hemodynamic significance of the atheromatous disease affecting the proximal CCA, possibly by limiting the potentialities of compensatory blood circulation [202-204]. Related to this, it is also the fact that the patients with both carotid and VA diseases seems to have a higher incidence of vertebrobasilar TIAs (71%) in comparison with those diagnosed with isolated carotid artery disease (8%) [187].
At the moment, the hypoplastic VA is not seen as an independent risk factor for stroke, however it is important to know that, if associated with other risk factors, it may induce ischemic stroke in the posterior circulation territories [172,187]. Therefore, we can assume that the presence of the right hypoplastic VA (associated to other vascular anomalies in a hypertensive patient) may have played an important role in the cerebral ischemic event presented in our case.
VA hypoplasia can be associated with other coexisting pathologies, such as aneurysms, BA hypoplasia, arachnoid cyst and hereditary connective tissue disorder (e.g., Ehlers–Danlos syndrome) [172,202].
The structural anomalies of VA are important to be identified in those cases when spinal, laryngeal or thyroid gland surgery is needed and also, if the patient has to undergo an endovascular intervention or an endarterectomy of extracranial arteries [173].
Accurate assessment of anatomic variations of Vas is mandatory when planning surgical treatment in order to avoid an eventual injury of the artery during surgery [173,179].
Ischemic stroke in the vertebrobasilar territory
Penetrating arteries (thalamo-perforators) from the BA supply the pons. Frequently, infarcts in the pons are unilateral, and paramedian (as in our case). The differential diagnosis of a unilateral pontine lesion always should include multiple sclerosis – which, in our patient, was excluded based on clinical and imagistic findings [205,206].
Conclusions
Our diagnosis – multiple congenital anomalies of carotid and vertebral arteries – was based on CCDS and CTA, knowing that the combined use of these methods allows a non-invasive and precise assessment of the neck vessels and their pathology. It was shown that the ICA and VA dysgenesis, in coexistence with other risk factors for stroke may be involved in cerebral ischemic events and respectively in the vertebrobasilar ischemic stroke pathogenesis.
1.3.3.1.9. Large Giant Cell Arteritis with Eye Involvement. Data from the literature. Personal contributions
1. Introduction – Giant cell arteritis
Giant cell arteritis (GCA), also called Horton, temporal, or granulomatous arteritis, is a primary vasculitis that affects extracranial medium (especially branches of the external carotid artery (ECA)) and large-sized arteries (aorta and its major branches) [207]. The diagnosis of GCA requires age more than 50 years at disease onset, new headache in the temporal area, temporal artery tenderness, and/or reduced pulse, jaw claudication, systemic symptoms, erythrocyte sedimentation rate (ESR) exceeding 50 mm/hr, and typical histologic findings (granulomatous involvement) in temporal artery biopsy (TAB) [208]. Approximately 40-50% of these patients have ophthalmologic complications, consisting of visual loss secondary to arteritic anterior ischemic optic neuropathy (AION), or central retinal artery occlusion (CRAO), homonymous hemianopsia or cortical blindness (unilateral or bilateral occipital infarction). [209-215]
2. Pathogenesis – Giant cell arteritis
GCA is an autoimmune vasculitis. It involves predominantly medium-sized arteries, especially the superficial temporal, ophthalmic, posterior ciliary, and other peripheral arteries. The typically predominant extracranial vascular involvement is explained by the affinity of inflammation to the elastic fibers. As intracranial arteries have less elastic fibers in the media, they are seldomly involved. The severity and extent of the involvement are associated with the quantity of elastic tissue in the media of the artery. [209-215]
According to Weyand, two different types of inflammatory reactions are found in the temporal arteries (TAs) in patients with GCA. One is related to foreign-body giant-cell reaction, directed at small calcifications of the internal elastic membrana. The foreign-body type of inflamation is focal, affecting only part of the arterial circumference. The other type of lesion is characterized by diffuse inflammation in which mononuclear inflammatory cells invade the layers of the arterial wall in the whole circumference of the vessel. [210-216]
Weyand noted that GCA is an antigen-driven disease with local T cell and macrophage activation in the vessel wall, and with an important role of proinflammatory cytokines. Inflammation of the arterial wall and vessel occlusion through fast and concentric intimal hyperplasia leads to the severe ischemic complications observed in patients with GCA. Dendritic cells localized at the adventitia–media border of normal medium-sized arteries produce chemokines and recruit and locally activate T cells. Moreover, dendritic cells express a singular surface receptor profile, including a series of Toll-like receptors (TLRs). Ligands of TLR-4 promote activation and differentiation of adventitial dendritic cells into chemokine-producing effector cells with high-level expression of both CD83 and CD86, and mediate T cell recruitment through the release of interleukin-18 (IL-18). Activated T cells experience clonal expansion and are stimulated to produce interferon-gamma (IFN-gamma). This leads to the differentiation and migration of macrophages and the formation of giant cells. In the adventitia, macrophages produce proinflammatory cytokines such as IL-1 and IL-6, whereas in the media and intima they contribute to arterial injury by producing metalloproteinases and nitric oxide. [210,216]
Weyand asserted that this destructive mechanism of the arterial wall is associated with a repair mechanism that includes the secretion of growth and angiogenic factors (platelet-derived growth factor and vascular endothelial growth factor) through the infiltration of mononuclear cells and multinucleated giant cells. These changes ultimately lead to the degradation of the internal elastic lamina and to occlusive luminal hyperplasia. In addition to IL-1 and IL-6, IFN-gamma specifically seems to play a pivotal role in the pathogenesis and in the clinical expression of GCA. In this regard, IFN-gamma is expressed in nearly 70% of the TAB samples from patients with GCA. High transcription of IFN-gamma messenger RNA (mRNA) is associated with the formation of giant cells and with the evidence of cranial ischemic symptoms in GCA patients. The absence of IFN-gamma expression in TAB samples from patients with isolated PMR suggests that its production may be crucial to the development of GCA. TAB specimens from GCA patients with ocular ischemia expressed high amounts of IFN- gamma mRNA, whereas those from GCA patients with fever had less IFN-gamma mRNA. Therefore, clinical correlates suggest a role of IFN- gamma in the process of luminal obstruction. By regulating giant cell formation, IFN- gamma could indirectly control intimal hyperplasia. IFN-gamma may dictate the functional properties of other cell populations in the vascular infiltrates and, by means of this mechanism, guide the response-to-injury reaction of the artery. [210-216]
3. Diagnosis – Giant cell arteritis
According to Hunder, a definitive diagnosis is made following the criteria of the American College of Rheumatology which include: age, temporal headache, swollen TAs, jaw claudication, eye involvement, the TAB, and its histologic evaluation. The disease affects elderly patients, with a mean age of 70 years. [210-215]
Diagnostic criteria of temporal arteritis:
Three of the five diagnostic criteria for GCA have to be met [208]:
1) Age 50 years or more. 2) New developed headache. 3) Tenderness of the superficial TAs. 4) Elevated ESR, at least 50 mm/h. 5) GCA in a biopsy specimen from the TAs.
Large vessel giant cell arteritis is a subgroup of GCA described in at least 17% of cases. In these patients, inflammation occurs also at the level of the aorta and its branches (especially of the subclavian, the axillary arteries, etc., ), although symptoms of aortic involvement (aortic aneurysm rupture) may appear years after the initial diagnosis of this vasculitis [217].
Personal contributions
Interestingly, in some cases, the common carotid arteries (CCA) and the internal carotid arteries (ICA) are also involved. [210-215,218]
4.1. Clinical features – Giant cell arteritis
The typical neurological symptoms and classic clinical features of GCA are presented by new moderate bitemporal headache, especially common at night, jaw claudication, scalp tenderness (which is first noticed when combing the hair), or abnormal superficial TAs (tender, nodular, swollen, and thickened arteries) on palpation. [209-215]
Gonzalez-Gay asserted that, initially, temporal pulsation is present, although the thickened arteries cann’t be flattened against the skull. The best location to feel for pulsation is directly in front of the upper pole of the pinna of the ear. Later, the TAs present a decreased pulsatility. Lack of pulsation is very suggestive of GCA because it is most unusual for the superficial TAS to be non-pulsatile in normal elderly individuals. The jaw claudication is the result of ischemia of the masseter muscles, which causes pain on speaking and chewing. [209,210]
A study aiming to establish the best set of clinical features that may predict a positive TAB in a community hospital disclosed that headache, jaw claudication, and abnormal TA on palpation were the best positive predictors of positive TAB in patients on whom a biopsy was performed to diagnose GCA. These authors established clinical differences between biopsy proven GCA and biopsy-negative GCA patients. Moreover, they observed a non–significantly increased frequency of abnormal palpation of the TAs on physical examination in biopsy-proven GCA patients (73.3%) compared with biopsy-negative GCA patients (54.2%). [209,215]
Less common neurologic complications (approximately 4% of patients) include transient ischemic attacks, or stroke, more frequently in the posterior circulation, than in the carotid territory, manifested by homonymous hemianopsia or cortical blindness (unilateral or bilateral occipital infarction), and audio-vestibular dysfunction. They occur more commonly at the time of GCA diagnosis or within the first 4 weeks after the onset of corticosteroid therapy. Almost all patients with GCA-associated strokes have a significant acute phase response with elevated ESR and C-reactive protein (CRP). The mortality has been reported to be as high as 75%. The impact of cardiovascular risk factors on the occurrence of cerebral ischemic events has been evaluated in the Reggio Emilia region of Italy in patients with biopsy-proven TA. Both a history of hypertension or ischemic heart disease were associated with a higher risk of stroke. [219]
Systemic symptoms includ fever, fatigue, malaise, weight loss, and/or polymyalgia rheumatica. Polymyalgia rheumatica (PMR) is a disease characterized by severe bilateral pain and aching involving the neck, shoulder, and pelvic girdles associated with morning stiffness. PMR is more common than GCA, and it may present as an isolated entity, or may be the presenting feature in patients who later develop typical cranial manifestations of GCA. Population-based studies have shown the presence of “silent” biopsy-proven GCA in 9–21% of the patients presenting with PMR features. Also, PMR manifestations are observed in up to 40–50% of patients with biopsy-proven GCA. The nephritic syndrome has been reported in patients with GCA in the setting of focal segmental glomerulonephritis, membranous glomerulonephritis, amyloidosis, and necrotizing glomerulonephritis. [210-215,220]
Ocular ischemic complications are the major source of chronic disability among GCA patients. In some cases, the development of blindness may be preceded by episodes of amaurosis fugax. They are generally early manifestations due to the vasculitic involvement of retrobulbar (orbital) vessels deriving from the ophthalmic artery (OA). In unselected patients with biopsy-proven GCA, visual ischemic complications occur in 25% and irreversible visual loss occurs in 10–15% of the patients. There is a significantly increased frequency of severe visual ischemic complications (transient or permanent visual loss) in the group of biopsy-proven GCA patients compared with GCA patients with a negative TAB. These interesting observations are in agreement with previous population-based studies that disclosed that biopsy-negative patients have less frequency of severe ischemic complications than those with biopsy-proven GCA. Ocular ischemic complications are generally due to arteritic anterior ischemic optic neuropathy (AAION). More rarely, visual loss is caused by central retinal artery occlusion (CRAO), or ischemic retrobulbar neuritis. [210-215,221]
Arteritic anterior ischemic optic neuropathy (AAION) results from short posterior ciliary arteries (PCAs) vasculitis and the consecutive optic nerve head (ONH) infarction. Human autopsy studies of acute AAION demonstrate optic disc edema with ischemic necrosis of the prelaminar, laminar, and retrolaminar portions of the optic nerve and infiltration of the PCAs by chronic inflammatory cells. In some cases segments of these vessels have been occluded by inflammatory thickening and thrombus. [210-215,222]
According to Arnold, patients with an unilateral AAION present the following key features:
a) abrupt, painless, severe loss of vision of the affected eye. b) anterior segment examination of both eyes is normal. c) the ophthalmoscopy of the affected eye reveales diffuse pale optic disc edema, but within 1-2 months, the swelling gradualy resolves and the entire optic disc will become atrophic. [210-215,218]
Typically, in AAION the severe visual loss is preceeded by transient visual loss similar to that of carotid artery disease. This symptom is unusual in the nonarteritic form of AION. The ophthalmoscopy indicates that pallor is associated with the edema of the optic disc more frequently in the arteritic than in the non arteritic form of AION. Although simultaneous bilateral involvement is rare in the arteritic form of AION, about 65% of untreated patients become blind in both eyes within a few weeks. The optic disc of the fellow eye is of normal diameter, with a normal physiological cup (absence of „disk at risk”, with postulated structural crowding of the axons at the level of the cribriform plate, associating mild disc elevation, and disc margin blurring without overt edema). [210-215,222]
Central Retinal Artery Occlusion (CRAO) is the result of an abrupt diminuation of blood flow in CRA, severe enough to cause ischemia of the inner retina. Due to the fact that there are no functional anastomoses between choroidal (posterior ciliary arteries) and retinal circulation (CRA), CRAO determines severe and permanent loss of vision. Therefore, it is very important to identify the cause of CRAO, in order to protect the contralateral eye. Frequently, the site of the blockage is within the optic nerve substance and for this reason, it is generally not visible on the ophthalmoscopy. [210-215,223]
Patients with an unilateral CRAO present the following key features:
a) abrupt, painless, severe loss of vision of the affected eye. b) anterior segment examination is normal in both eyes. c) the fundus of the affected eye presents: ischemic whitening of the retina; cherry-red spot in the center of the retina; the site of obstruction of CRA is not visible on ophthalmoscopy (no embolus is found). [210-215,218]
In only 20-25% of cases are emboli visible in the CRA or one of its branches, suggesting that an embolic cause is not frequent in CRAO (embolic material from either the heart, the ascending aorta or the ipsilateral ICA). It is currently believed that the majority of CRAO are caused by thrombus formation due to systemic diseases: haematological disorders, and last but not least, systemic vasculitis (including GCA). For this reason, all patients with CRAO should undergo a systemic evaluation. [210-215,224]
In CRAO the retina appears white as a result of cloudy swelling. The „cherry-red spot” appearence in the center of the retina is due to the relatively intact choroidal circulation, in contrast to the ischemic retina. [224]
4.2. Laboratory findings – Giant cell arteritis
Laboratory findings reveal a raised Erythrocyte sedimentation rate (ESR) and increased values of C-reactive protein (CRP). ESR is often very high in GCA, with levels more than 60 mm/hr. In interpreting the ESR it should be emphasized that the levels of 40 mm/hr may be normal in the elderly and cases of biopsy- proven GCA have been reported in patients with ESR levels lower than 30 mm/hr. Approximately 20% of patients with GCA have a normal ESR. CRP is invariably raised in GCA and may be helpful when the ESR is equivocal. [225] This acute phase response is induced by pro-inflammatory cytokines, mainly interleukins (IL) 1, 6 and tumor necrosis factor (TNF) alpha. These are produced by activated macrophages in the vessel wall. The target antigen of the CD4+ T cell immune response in GCA is probably located in the internal elastic layer of the vessel wall which explains that arteries of the anterior intracerebral circulation are infrequently affected because these lacks an internal elastic layer. [226]
Several imaging modalities may be useful to make a diagnosis of GCA. In this regard, Pipitone et al., 2008 performed an interesting review of the role of imaging studies in the diagnosis and follow-up of large vessel vasculitis (Pipitone et al., 2008). [210]
4.3. Extracranial Duplex sonography – Giant cell arteritis
A high –frequency probe provides both an axial and a lateral resolution of 0.1 mm (100um) [227]. The smaller the vessel diameter, the more difficult is the assessment of vessel wall alterations, so that in this case the most informative ultrasound data are based on Doppler spectral evaluation. This is also valid for evaluation of medium to small vessel inflammation such as intracranial vasculitis. Small vessel vasculitides such as the ANCA-associated or the immune complex vasculitis are not a domain of ultrasound [228,229]
a). Ultrasonography (US) of the of the large cervical and cervico-brachial vessels
The Chapel Hill Consensus Conference 2012 [228] defined large vascular vasculitis (LVV) as vasculitis affecting the aorta and its major branches more often than other vasculitides; however, any size of artery may be affected. This definition does not state that LVV predominantly affects large vessels because in many patients, the number of medium and small arteries affected is greater than the number of large arteries affected. For example, in GCA, only few branches of the carotid arteries may be affected when there is involvement of numerous small branches extending into the head and neck (e.g., small ocular and periocular arteries). [229]
Sturzenegger noted that angiography cannot depict the vessel wall. In consequence, US has a role in the diagnosis of inflammation of the large cervical and cervico-brachial vessels (aorta and its supra-aortic branches) since it can delineate alterations of the vessel wall with the use of B-mode imaging, whereas Doppler spectral flow velocity evaluation can help diagnose the stenosis of occlusion on the vessel. [229]
Color Doppler Duplex sonography (CDDS) is an excellent tool to screen for large vessels involvement. According to different authors, including Sturzenegger, the two ultrasonographic hallmarks of GCA are: 1) Vessel wall thickening, that typically is homogeneous, circumferential and over long segments; 2). Stenosis, typically displaying smoothly tapered luminal narrowing (hour glass like) [229]
b). Ultrasonography (US) of the temporal arteries (TAs) has raised great interest in the diagnosis of GCA. Extracranial Duplex sonography investigates almost completely the whole length of the common superficial TAs, including the frontal and parietal branches, and founds that inflammation is segmental (discontinous arterial involvement). The common superficial TA derives from the ECA. It divides into the frontal and parietal ramus in front of the ear. The distal common superficial TA and the rami are localized between the two layers of the temporal fascia, which is like a bright band at ultrasound examination. [210-215,230]
Technical requirements
High-resolution color Doppler US can show the vessel wall and the lumen of the temporal arteries. One should use linear probes with a minimum gray scale frequency of 8 Mhz. Color frequency should be about 10 Mhz. [210-215,230]
Machine adjustments
The pulse repetition frequency (PRF) should be about 2.5khz as maximum systolic velocities are rather high (20-100 cm/s). Steering of the color box and the Doppler beam should be maximal as the rami are paralel to the probe. It is important that the color covers the artery lumen exactly. [210-215,230]
Sonographer training.The sonographer should perform at least 50 Duplex ultrasound of the TAs of subjects without GCA to be sure about the appearance of normal temporal arteries before starting to evaluate patients with GCA. [210-215,230]
Sequence of the Ultrasound examination
The investigation should start at the common superficial TA using a longitudinal scan. The probe should then be moved along the course of the TA to the parietal ramus. On the way back one should deliniate the TA in transverse scans. Using the transverse scan, one can find the frontal ramus, which should then be delineated in both scans (longitudinal and transverse). If the color signals indicates localized aliasing and diastolic flow, one should use the pw-Doppler mode to confirm the presence of stenoses. [210-215,230]
Schmidt et al., 1997 demonstrated that the most specific (almost 100% specificity) and sensitive (73% sensitivity) sign for GCA was a concentric hypoechogenic mural thickening, dubbed “halo”, which the authors interpreted as vessel wall edema. Other positive findings for GCA are the presence of occlusion and stenoses. [210-215,231]
In conclusion, three findings are important for the ultrasound diagnosis of temporal arteritis:
a) „dark halo” sign – a typically homogeneous, hypoechoic, circumferential wall thickening around the lumen of an inflamed TA – which represents vessel wall edema and a characteristic finding in temporal arteritis (TA)/GCA. It is well delineated toward the luminal. [210-215,232]
b) stenoses are documented by blood-flow velocities, which are more than twice the rate recorded in the area of stenosis compared with the area before the stenosis, with wave forms demonstrating turbulence and reduced velocities behind the area of stenosis.
c) acute occlusions, in which the ultrasound image is similar to that of acute embolism in other vessels, showing hypoechoic material in the former artery lumen with absence of color signals. [210-215,231]
Similar ultrasound patterns can be found in other arteries: the facial, the internal maxilary, the lingual, the distal subclavian, and axilary arteries.
Interestingly in some cases [218], the common carotid and the internal carotid arteries are also involved (large-vessel GCA).
Ultrasound investigation has to be performed before corticosteroid treatement, or within the first 7 days of treatment, because with corticosteroid therapy the ”halo” revealed by TAs ultrasound disappeares within 2-3 weeks. The wall swelling, stenoses, or occlusions of the larger arteries (CCA, ICA) remaines for months, despite the corticosteroid therapy. Nevertheless, diagnostic assessment should not delay the start of therapy. Ultrasound may also detect inflamed TAs in patients with clinically normal TAs. Some patients with the clinical image of polymyalgia rheumatica, but with occult TAs may be diagnosed by ultrasonography.
Arida et al., 2010 looked for studies that examined the sensitivity and specificity of the halo sign demonstrated by TA ultrasound (US) for GCA diagnosis versus the American College of Rheumatology (ACR) 1990 criteria for the classification of this vasculitis (used as a reference standard). Only 8 studies involving 575 patients, 204 of whom received the final diagnosis of GCA, fulfilled the technical quality criteria for US. This meta-analysis disclosed a sensitivity of 68% and a specificity of 91% for the unilateral “halo” sign, as well as 43% and 100%, respectively, for the bilateral “halo” sign in TA US for GCA diagnosis when the 1990 ACR criteria are used as the reference standard. The authors confirmed that the halo sign in US is useful in diagnosing GCA. [210-215,232]
In the case of concordant clinical and sonographic results, temporal arteries biopsy (TAB) seems not justified [229]
Sturzenegger asserted that, since GCA with large vessels disease affects almost exclusively patients above the age of 50 years, differential diagnosis with arteriosclerosis is important. Arteriosclerotic wall changes/thickening usually appear less homogeneous, less circumferential, with calcified arteriosclerotic plaques ulcers; stenosis extends over shorter segments, they are not concentric, not tapering and location of lesions is different (e.g., mainly bifurcations). [229]
Furthermore, according to Sturzenegger, differential diagnosis with the other large vessels vasculitis (LVV), namely Takayasu arteritis, has to be considered: TA usually affects women below the age of 40 years, symptoms like tender scalp or polymyalgia syndrome are exceptional: involvement of temporal artery in TA is not known but involvement of CCA is more frequent; ultrasound image of wall thickening (halo) is brighter in TA than in GCA probably due to a larger mural edema in GCA which is a more acute disease than TA. [223,229,233,234]
4.4. Color Doppler Imaging (CDI) of retrobulbar vessels.
Schmidt, 2006 compared the results of TA US examinations with the occurrence of visual ischemic complications (AAION, CRAO, branch retinal artery occlusion, diplopia, or amaurosis fugax) in 222 consecutive patients with newly diagnosed, active. However, findings of TAs US did not correlate with eye complications. [210-215,230] For this reason , we have to exam the orbital vessels.
Intraorbital (retrobulbar) vessels.
The ophthalmic artery (OA) branches in several arteries, including central retinal artery (CRA), and aa. ciliares posteriors breves (PCRs)-and finishes in the a. supratrohlearis and a. dorsalis nasi. [233,235]
Probe selection
Standard neurovascular ultrasound machines equipped with linear-array transducers emitting 6-12 \MHz (up to 15MHz) are sufficient for detecting (by Color Doppler sonography), and measuring (by spectral analysis pulsed Doppler sonography) the blood flow in the orbital vessels: the OA; the CRA and central retinal vein (CRV), PCAs, and the superior ophthalmic vein (SOV). [210-215, 233,236]
a) the CRA, a distal branch of the OA, enters the ON approximately 1-1.5 cm distal from the bulbus coming from the dorsolateral direction. Parallel to this is the CRV.
b) the PCA is located near the ON. [233,237]
If the vessels are difficult to display, the power showed be elevated for a short time if the clinical question is important. [233]
Arterial blood supply of the anterior part of the optic nerve
The optic nerve head (ONH) consists of, from front to back: a). surface nerve fiber layer, b) prelaminar region c). lamina cribrosa region, and d). retrolaminar region.
a) The surface nerve fiber layer is mostly supplied by the retinal arterioles. The cilioretinal artery, when present, usually supplies the corresponding sector of the surface layer. [211,227,228]
b) The prelaminar region is situated in front of the lamina cribrosa. It is supplied by centripetal branches from the peripapillary choroid. [211,227,228].
c) The region of the lamina cribrosa is supplied by centripetal branches from the posterior ciliary arteries (PCAs), either directly or by the so-called arterial circle of Zinn and Haller, when that is present. [211,227,228]
d) The retrolaminar region is the part of the ONH that lies immediately behind the lamina cribrosa. It is supplied by two vascular systems: the peripheral centripetal and the axial centrifugal systems.
The former represents the major source of supply to this part. It is formed by recurrent pial branches arising from the peripapillary choroid and the circle of Zinn and Haller (when present, or the PCAs instead). In addition, pial branches from the central retinal artery (CRA) also supply this part. The latter is not present in all eyes. When present, it is formed by inconstant branches arising from the intraneural part of the CRA.
From the account of the arterial supply of the ONH given above, it is evident that the PCAs are the main source of blood supply to the ONH. [211,227,228]
Pathophysiology of factors controlling blood flow in the optic nerve head
The blood flow in the ONH depends upon: a). resistance to blood flow, b). arterial blood pressure (BP), and c) intraocular pressure (IOP). [211,227,228]. a). resistance to blood flow. It depends upon the state and caliber of the vessels supplying the ONH, which in turn are influenced by: the efficiency of auto-regulation of the ONH blood flow, the vascular changes in the arteries feeding the ONH circulation, and the rheological properties of the blood.
b). arterial blood pressure. Both arterial hypertension and hypotension can influence the ONH blood flow in a number of ways. In an ONH, a fall of blood pressure below a critical level of auto-regulation would decrease its blood flow. Fall of BP in the ONH may be due to systemic (nocturnal arterial hypotension during sleep, intensive antihypertensive medication, etc.) or local hypotension.
c). IOP. There is an inverse relationship between intra-ocular pressure and perfusion pressure in the ONH.
The blood flow in the ONH is calculated by using the following formula: [227]
Perfusion pressure = Mean BP minus intraocular pressure (IOP).
Mean BP = Diastolic BP + 1/3 (systolic – diastolic BP).
Anterior Ischemic optic neuropathies (AIONs)
AION represents an acute ischemic disorder (a segmental infarction) of the ONH supplied by the PCAs. [211,227] Blood supply blockage can occur with or without arterial inflammation. For this reason, AION is of two types: non-arteritic AION (NA-AION) and arteritic AION (A-AION). The former is far more common than the latter, and they are distinct entities etiologically, pathogenically, clinically and from the management point of view. [211,227,228]
A history of amaurosis fugax before an abrupt, painless, and severe loss of vision of the involved eye, with concomitant diffuse pale optic disc edema is extremely suggestive of A-AION. None of these symptoms are found in NA-AION patients. [211]
Personal contributions.
4.4.1. Spectral Doppler analysis of the retrobulbar vessels in A-AION.
In acute stage, blood flow cannot be detected in the PCAs in the clinically affected eye of any of the GCA patients with A-AION. Low end diastolic velocities (EDV) and high resistance index (RI) are identified in all other retrobulbar vessels (including the PCAs in the fellow eye) of all A-AION patients. [211]
At 1 week, color Doppler imaging (CDI) examination of retrobulbar vessels reveals blood flow alterations in all A-AION patients despite the treatment with high-dose corticosteroids. Severely diminished blood flow velocities (especially EDV) in the PCAs of the affected eye (both nasal and temporal), compared to the unaffected eye, are noted. An increased RI in the PCAs is noted (the RI is higher on the clinically affected eye as compared to the unaffected eye). [211]
Fewer abnormalities are observed in the CRAs: high RI are measured in both sides, with decreased peak systolic velocities (PSV) in the CRA of the clinically affected eye. [211]
Similar abnormalities are noted in the OAs: high RI are measured in both sides.
At 1 month, after treatment with high-dose corticosteroids, CDI examinations of orbital blood vessels reveals that blood flow normalization is slow in all A-AION patients. [211]
In conclusion, the Spectral Doppler Analysis of the orbital vessels in A-AION indicates (after a few days of treatment with corticosteroids) low blood velocities, especially EDV, and high RI in all retrobulbar vessels, in both orbits. These signs represent characteristic signs of the CDI of the orbital vessels in A-AION. [210-215]
4.4.2. Spectral Doppler analysis of the retrobulbar vessels in NA-AION.
In contrast, the patients with NA-AION present the following aspects in acute stage, and at 1 week of evolution: [210-215]
1). slight decrease of PSV in PCAs (nasal and temporal) in the affected eye, compared to the unaffected eye [211];
2). slight decrease of PSV in CRA of the affected eye, due to papillary edema.
3). in OAs, PSV are variable: normal to decreased, according to ipsilateral ICAs status. Severe ICA stenosis (70% of vessel diameter) combined with an insufficient Willis polygon led to decreased PSV in ipsilateral OA. [211];
At 1 month, CDI examinations of orbital blood vessels reveal that blood flow normalization is reached. The exceptions are the cases with severe ipsilateral ICA stenosis/oclusion.
In conclusion, in NA-AION, blood velocities and RI in PCAs are preserved. Similar results were obtained in other studies [208,211,238,239];
Fluorescein angiogram and CDI of retrobulbar vessels data support the histopatological evidence of involvement of the entire trunck of the SPCAs in the arteritic AION (impaired optic disc and choroidal perfusion in the patients with arteritic AION). In contrast, in the nonarteritic AION, the impaired flow to the optic nerve head (ONH) is distal to the PCAs themselves, possibly at the level of the paraoptic branches (only 1/3 of the flow of the PCAs). [235]
These branches supply the ONH directly (impaired optic disc perfusion, with relatively conservation of the choroidal perfusion). [210-215]
Extremely delayed or absent filling of the choroid has been depicted as a fluorescein angiogram characteristic of arteritic AION and has been suggested as one useful factor by which arteritic AION can be differentiated from nonarteritic AION.
The patients with an unilateral CRAO present at the Spectral Doppler analysis of the retrobulbar vessels the following aspects: [210-215,218,240]
a) an increased RI in the CRAs (the RI is higher on the affected side, than it is on the unaffected side); with severe diminished blood flow velocities (especially end-diastolic velocities) in the CRA.
b) less abnormalities are observed in the PCAs, and in the OAs.
4.5. Others imaging techniques
Recent studies using higher quality imaging techniques like MRI, MRA, CT, positron emission tomography (PET) and Duplex ultrasonography have shown that a greater number of GCA patients exhibit extracranial vasculitis involving the proximal epiaortic arteries of the upper extremities and, in particular, the axillary, subclavian and, less frequently, the carotid arteries. [229]
4.6.Temporal artery biopsy (TAB) and the histopathologic picture
A TAB is the gold standard test for the diagnosis of GCA.[241]
European League against Rheumatism recommendations emphasize that TAB should be performed whenever a diagnosis of GCA is suspected. Because corticosteroid therapy is required in most cases for more than 1 year in GCA, the pathologic confirmation of this vasculitis is advisable. However, GCA affects vessels focally and segmentally, yielding areas of inflammatory vasculitic lesions juxtaposed with areas of normal artery. Histologic signs of inflammation may be missed in TABs performed in arteritis-free segments. [242] Because of segmental (discontinous) involvement of TAs, a biopsy result may be negative in 9-44% of patients with clinical positive signs of temporal arteritis; for this reason the TAB has to be guided by Doppler Ultrasonography and typical clinical features (tender, swollen portions of temporal arteries). Prior treatment with steroids for more than 7 days may be associated with loss of the histological features of active arteritis. As a consequence, the ultrasound investigations and TAB have to be performed before corticosteroid treatment. Interestingly, 2 population-based studies have shown that patients with negative biopsy samples have less frequency of severe ischemic complications than those with biopsy-proven GCA. [210,243]
Taylor-Gjevre et al., 2005 noted that a threshold length of 1.0 cm of postformalin fixed arterial segment was associated with an increased diagnostic yield of GCA. [244]
They recommended collecting a minimum TAB length of 1.5 cm to allow for tissue shrinkage during fixation that was estimated to be about 10%. More recently, Mahr et al., 2006 reported that a postformalin fixed TAB length of at least 0.5 cm could be sufficient to make a histological diagnosis of [245]
TAB is generally performed on the most symptomatic side. Breuer et al., 2009 performed a study to establish the relationship between TAB length and the diagnostic sensitivity for GCA. [243]
In this study, the TAB in the subgroup of biopsy-positive GCA patients was significantly longer than in biopsy-negative GCA cases. The rate of positive biopsies was only 19% with TAB length of 5 mm or less but increased to 71–79% with TAB lengths of 6–20 mm, and to 89% when TAB length was longer than 20 mm. Only 3% of positive biopsies were 5 mm or shorter. These authors concluded that TABs with post-fixation length shorter than 5 mm yield an increased biopsy negative rate. As a result, the authors supported the claim that a TAB length longer than 5 mm is required for accurate diagnosis of GCA.
In the presence of unilateral ocular involvement, we took a biopsy from the ipsilateral side representing 2.5 cm of the tender, swollen segments of the affected artery („skip lesions”). [218]
Serial sections were examined, as there could be variations in the extent of involvement along the length of the artery. [210-215,246]
However, due to the segmental inflammatory involvement of the TA, a contralateral biopsy may be required in patients with high clinical suspicion of GCA. Breuer et al., 2009 found that performing bilateral TABs increases the diagnostic sensitivity of the procedure by up to 12.7% compared with unilateral biopsies. [243]
The definitive diagnosis of GCA requires the pathologic demonstration of a vasculitis with mononucleated cell infiltrates of all mural layers and occurrence of giant cells on a TAB. The degree of intimal hyperplasia on histology findings is associated with neuro-ophthalmic complications the presence of giant cells in particular is associated with permanent visual loss. [210-215]
5. Changes in Current Practice in our Departments
Color-coded Duplex sonography (CCDS) has a high sensitivity to detect vessel wall thickening with typical configuration in the case of large vessel vasculitis (LVV) such as GCA. [229]
According to Ching, given an experienced sonographer and optimal equipment, a rapid GCA diagnosis can be established in a fast track clinic setting, taking into consideration clinical assessment, scoring, and US findings. A huge advantage of US is that it provides immediate information that can be used to inform treatment decisions, including a potential reduction in loss of sight and avoidance of unnecessary long-term steroid treatment by early exclusion of mimics. [223]
In consequence, in our department, CCDS has emerged as a safe and reliable alternative to TAB as a point of care diagnostic tool in the management of GCA-temporal arteritis.
On the other hand, the eye involvement in Horton’s disease consists in AION or CRAO with abrupt, painless, and severe loss of vision of the involved eye. Because findings of TAs US do not correlate with eye complications, CDI of the retrobulbar vessels is of critical importance. It may be helpful to detect the blood flow in the orbital vessels, especially in cases of opacity of the medium, or when the clinical appearance of ophthalmologic complications in temporal arteritis is athypical. The Spectral Doppler Analysis of the orbital vessels in GCA reveales low blood velocities, especially end-diastolic velocities, and high resistance index in all retrobulbar vessels, in both orbits, for all patients (especially on the affected side). [210-215,218]
1.3.3.1.10. Vojnosanitetski Pregled (Military Medical and Pharmaceutical Journal of Serbia) 2016 April Vol.73 (No.4), 397-401.
Color Doppler imaging features in patients presenting central retinal artery occlusion with and without giant cell arteritis
Authors: Dragos Catalin Jianu, Silviana Nina Jianu, Mihnea Munteanu, Daliborca Vlad, Cosmin Rosca, Ligia Petrica.
Introduction
Central retinal artery obstruction (CRAO) is the result of an abrupt diminution of blood flow in the central retinal artery (CRA), severe enough to cause ischemia of the inner retina with permanent unilateral visual loss [223,224,247]. Frequently, the blockage is located within the optic nerve substance and for this reason, it is generally not visible on ophthalmoscopy [223,224,247]. We presented the role of color Doppler imaging (CDI) of orbital vessels and extracranial duplex sonography (EDS) in the etiological diagnosis of CRAO in two patients with clinical suspicion of acute unilateral right CRAO.
Case report
Two patients were examined at presentation in our ophthalmology and neurology departments in January 2012 with the following protocol: collection of detailed history of all previous or current systemic diseases, including arterial hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation (AF), valvular diseases, ischemic heart disease, stroke, carotid artery disease, systemic coagulopathies (including thrombophilia), and vasculitis, including giant cell arteritis (GCA); complete physical examination, including the temporal arteries (Tas), was performed by a neurologist and an internist in order to detect eventual temporal arteritis as part of GCA; comprehensive ophthalmic evaluation, conducted by an ophthalmologist by recording visual acuity with the Snellen visual acuity chart, visual fields with a Goldmann perimeter, relative afferent pupillary defect, intraocular pressure, slit-lamp examination of the anterior segment, lens and vitreous, direct ophthalmoscopy, and color fundus photography; laboratory workup, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), factor V Leiden mutation, etc.; cranial computed tomography (CT) scanning, in order to identify whether stroke was associated with CRAO; CT-angiography (CT-A), performed at presentation, which allowed analysis of the arterial wall and the endoluminal part of the aorta and its branches; ECG, and transthoracic echocardiography (TIE), to detect eventual cardiac source of emboli; CDI of retrobulbar (orbital) vessels, performed with an ultrasound (US) equipment (Logic 500, GE) with a 9 MHz linear probe for detecting and measuring orbital vessel blood flow in the ophthalmic arteries (OAs), the CRAs, the superior ophthalmic veins, and the posterior ciliary arteries nasal and temporal (PCAs) [248,249], EDS, performed with an US equipment (My Lab50 Esaote) with a 7.5-10 MHz linear array transducer to determine the carotid source of emboli and with a 10 MHz linear probe for the examination of the TAs. All CDI of retrobulbar vessels and EDS examinations were performed by the first two authors of the study. One investigator, who was unaware of the patients diagnoses, looked only for detecting and measuring orbital and extracranial vessels blood flow. If their results disagreed, then the investigators would have examined the results together and would have reached a consensus on the findings; temporal artery biopsy (TAB) was assessed at 1st day after presentation when GCA was suspected, for the second case.
Case 1 – Central retinal artery obstruction with embolic mechanism
A 73-year old hypertensive woman presented with sudden and painless visual loss in the right eye. She had visual acuity of 20/20 in her left eye, and saw only hand movements in the right eye. Anterior segment examination was normal in both eyes. The fundus of the affected right eye presented ischemic whitening of the retina, cherry-red spot in the center of the retina, and the site of obstruction of the right CRA was not visible on ophthalmoscopy (no embolus was found).
B-scan ultrasound evaluation found a small round, moderately reflective echo within the right optic nerve, 1.5 mm behind the optic disc. This image suggested a cholesterol structure of the embolus (Fig. 1.12.a). CDI of retrobulbar vessels revealed normal right OA hemodynamic parameters, but the patient had no blood flow signal on CDI on the surface of 1.5 mm behind the right optic disc (Fig. 1.12.b). The arterial flow signal stopped at the level of emboli, and could not be recorded in front of it (right CRAO). In contrast, the left eye had the normal aspect on CDI of retrobulbar vessels, including left CRAO.
Right internal carotid artery (ICA) EDS examination, and CT-A identified a severe stenosis at its origin. TTE, the sonography of the TAs, and laboratory data were all normal, the only exception being an increased ESR (40 mm/hr.). After eleven months, a diminished arterial flow signal could be detected at the level of the right CRA (Fig. 1.12.c).
Case 2 – Central retinal artery obstruction with vasculitis mechanism, due to occult giant cell arteritis
A 71-year old hypertensive man presented with CRAO of the right eye, with the abrupt painless severe loss of vision of the right eye (visual acuity 0.1), with normal anterior segment examination in both eyes, and a fundus of the right eye with ischemic whitening of the retina, and a cherry-red in its center. The site of obstruction of the right CRA was not visible on ophthalmoscopy.
The patient developed moderate right temporal headache, one week before presentation in our departments. The superficial TAs were normal at clinical examination, including TA's pulsation. He did not present associated systemic symptoms: fever, fatigue, and/or malaise.
A normal ESR (8 mm/hr.), and the elevated CRP (6.4 mg/L) were revealed in this patient the other laboratory data were all normal.
EDS investigated almost completely the whole length of the common superficial TAs, including the frontal and parietal branches [211,231], and found only dark hypoechoic circumferential wall thickening (halo) around the lumen of a segment of the frontal branch of the right TA. Normal US patterns were found in all the other branches of the two external carotid arteries and for the other extracranial vessels (facial arteries, etc.). TAB was guided by Doppler US of the TAs at the level of the affected segment of the frontal branch of the right TA. We observed characteristic lesions for GCA: intimal thickening, internal limiting lamina fragmentation, and chronic inflammatory infiltrate with giant cells [3].
Spectral Doppler analysis of retrobulbar vessels revealed in this case severely diminished blood flow velocities especially end-diastolic velocities (EDV) in both CRA (Fig. 1.13.a and 1.13.b), normal values: peak systolic velocity (PSV) 17.3 ± 2.6 cm/s; EDV 6.2 ± 2.7 cm/s [248,249], despite the fact that the left eye had the normal aspect at ophthalmoscopy. Less abnormalities were observed in the PCAs (Fig. 1.13.c and 1.13.d), (normal values for temporal PCA: PSY: 13.3 ± 3.5 cm/s; EDY: 6.4 ± 1.5 c1n/s ; normal values for the nasal PCA: PSY: 12.4 ± 3.4 cm/s; EDY: 5.8 ± 2.5 cm/s) [248,249], and in the OAs (normal values: PSV: 45.3 ± 10.5 cm/s; EDY: 11.8 ± 4.3 cm/s) [248,249]. CT-A, and TTE were normal in this case. CT-scanning excluded strokes in both presented patients.
Discussion
Since there are no functional anastomoses between choroidal (nasal, and temporal PCAs) and retinal circulation (CRA), CRAO determines severe and permanent loss of vi sio n, as mentioned in different studies [210,221,223,240,247,250-254] Therefore, it is very important to identify the cause of CRAO, in order to protect the contralateral eye [210,221,223,240,247,250-254]. According to Gonzales-Gay [3] and Gonzales-Gay et al. [221] the majority of GCA patients with CRAO develop the classic clinical symptoms of GCA: new moderate bitemporal headache, scalp tenderness, and abnormal TAs on palpation (tender, nodular, swollen, and thickened arteries). However, in the case at hand, the second patient presented developed only new moderate right temporal headache.
Gonzales-Gay [3] and Gonzales-Gay et al. [221] along with Duker et al. [224], Connolly et al. [240], and Foroozon et al. [254] continue to argue that most of the patients with GCA and CRAO present systemic symptoms: fever, fatigue, malaise, and weight loss. Contrary to what they found, the second patient with CRAO due to GCA did not show systemic symptoms. Nevertheless, a study of Gonzales-Gay et al. [221] show that 21% of the patients with positive TAB for GCA have no systemic symptoms or signs and the only presenting sign was visual loss. He named this type of GCA occult GCA [3,221] which matched the profile of our second patient.
Lopez-Diaz et al. [225] note that the ESR is often very high in GCA, with the levels more than 50 mm/hr. (fairly suggestive of this disease). In interpreting the ESR, he observes that the levels of 40 min/hr. may be normal in the elderly [225] (as we found in our first case with CRAO due to embolic mechanism) and cases of biopsy-proven GCA have been reported in patients with ESR levels lower than 30 mm/hr. [231,247] In his study, approximately 20% of the patients who have a positive TAB for GCA present a normal ESR [225] (like in our second case). Lopez-Diaz et al. [225] concluded that "normal" ESR does not rule out GCA. CRP is generally raised in GCA (the normal range is < 5 mg/L) [3,211,221]. It generally runs parallel with ESR and may be helpful when the ESR is equivocal [3,211,221]. However, in some cases, Gonzales-Gay [3] and Gonzales-Gay et al. [211] demonstrated ESR elevation but not CRP. In their opinion, the combination of ESR and CRP together gives the best specificity (97%) for detection of GCA [3,211].
Schmidt et al. [231] and Arida et al. [232] demonstrate that EDS examination of the TAs in temporal arteritis has garnered considerable interest as a GCA diagnosis tool, because it indicates segmental inflammation of TAs. A meta-analysis of Arida et al. [232] confirm that the halo sign in US is useful in diagnosing GCA. US may also detect inflamed TAs in patients with clinically normal TAs [211,231,232]as we observed in our second case. Schmidt et al. [231] compared the results of TAs EDS examinations with the occurrence of visual ischemic complications (CRAO, arteritic anterior ischemic optic neuropathies, etc.) in patients with newly diagnosed active GCA. However, findings of TAs EDS did not correlate with eye complications. For this reason, CDI of retrobulbar vessels is of critical importance. In Foroozon et al.'s [254] opinion, this technique is able to detect certain orbital vascular abnormalities in patients with CRAO, because it indicates the direction of blood flow, and allows calculation of the PSV, EDV, and the mean velocities of flow, and estimation of the resistance index (RI) of these vessels. These abnormalities are not detected by the standard diagnostic modalities now used to evaluate permanent monocular blindness [211,254], diagnostic imaging (including CT-A, neuro-sonological investigations, ECG, TTE, etc.) revealed a large-artery atherosclerosis etiology (ICA's severe stenosis) for CRAO [210,223,224,251,254,255].
According to Duker [226], less than one third of CRAO results from emboli. We did not perform prolonged cardiac monitoring in both cases for detection of paroxysmal AF, because, according to the Rabinstein study, there were no risk factors for paroxysmal AF detection (left dilatation on TTE, frequent premature atrial complexes on ECG, etc.) [256]
Platelets and fibrin are the materials found in cardiac emboli [224,255], which was not the case of our first patient (emboli of cholesterol). Duker [224] noted that cholesterol emboli typically emanate from atheromatous plaques of the ipsilateral ICA. In the first presented case (CRAO with artery to artery embolism), detecting by B-scan US evaluation the retrobulbar embolic material interrupting the pixels of color of the right CRA was helpful in eliminating the diagnosis of GCA with eye involvement [254]. When CDI localizes retrobulbar embolus, the patient does not have to be subjected to high-dose corticosteroids, even if the ESR is elevated, like in the first case. The patient received antiplatelet aggregating agents and statins before right carotid endarterectomy. In the second case (CRAO with vasculitic mechanism, due to GCA), the patient had the normal ESR without systemic/clinical symptoms, even a swollen TA (occult GCA) [3,211]. His spectral Doppler analysis of the orbital vessels revealed characteristic CDI findings for GCA (severe diminished blood flow velocities, especially EDV, in retrobulbar vessels, especially in CRAs) [211,251,254]. In patients with CRAO due to occult GCA prompt recognition and early cortico-therapy are crucial to prevent further visual loss in the contra-lateral eye [3,210,211,224,240,251-254].
Conclusion
In the presented cases, ultrasound investigation enabled prompt differentiation (when no emboli are visible on ophthalmoscopy in the retinal circulation) between central retinal artery occlusion of embolic mechanism due to severe stenosis of the ipsilateral internal carotid artery and central retinal artery occlusion caused by vasculitis from occult giant cell arteritis.
1.3.3.1.11. Vojnosanitetski Pregled (Military Medical and Pharmaceutical Journal of Serbia) 2018 August Vol.75 (No.8), 773-779.
Clinical and ultrasonographic features in anterior ischemic optic neuropathy
Authors: Dragos Catalin Jianu, Silviana Nina Jianu, Mihnea Munteanu, Ligia Petrica
Introduction
Anterior ischemic optic neuropathy (AION) represent an acute ischemic disorder involving the anterior part of the optic nerve, also called the optic nerve head (ONH), supplied by the posterior ciliary arteries (PCAs) – nasals and temporals [221,222,235,257-260]. Blood supply blockage of the PCAs can occur with or without arterial inflammation. There are two types of AIONs: arteritic (A-AION), caused by a vasculitic mechanism due to giant cell arteritis (GCA) and non-arteritic (NA-AION) [221,222,235,257-260].
GCA is a primary vasculitis that concerns predominantly extracranial medium-sized arteries especially branches of the external carotid artery (ECA). Including the superficial temporal arteries (TAs) [217,221,222,235,257-260]. The typically predominant extracranial vascular involvement (including the orbital vessels) is explained by the affinity of inflammation to the elastic fibers in the media; as intracranial arteries have fewer elastic fibers in the media, they are seldom involved [217,221,222,235,257-260]. The diagnosis of GCA requires, according to the criteria established by the American College of Rheumatology, age more than 50 years at clinical disease onset, new headache in the temporal area, temporal artery tenderness, and/or reduced pulse, jaw claudication, systemic symptoms, erythrocyte sedimentation rate (ESR) exceeding 50 mm/h, elevated C-reactive protein (CRP), and typical histologic findings (granulomatous involvement) in temporal artery biopsy (TAB) [217,221,222,235,257-260]. Approximately 20% of patients with GCA have ophthalmologic complications, including visual loss secondary to A-AION or central retinal artery occlusion [217,221,222,235,257-260]. These are generally early manifestations due to the vasculitic involvement of retrobulbar (orbital) vessels deriving from the ophthalmic artery (OA) more precisely the PCAs and the central retinal artery (CRA) [217,221,222,235,257-260].
NA-AION IS a multifactorial disease that results in hypoperfusion and ischemia of the ONH, with multiple risk factors that contribute to its development (nocturnal arterial hypotension, etc.) [221,222,235,257-260]. According to Biousse and Newman [257], the most important contributing factor to NA-AION is represented by congenital and physiologic small cups. They mentioned that the size of the ONH (optic disc) and the physiological cup depend on the size of the scleral canal, a small scleral canal will result in a small cup (with a crowded ONH and a small cup-to-disc ratio) [217,257,258]. The presence of a “disk at risk “, with structural crowding of nerve fibers (crowded disk) and reduction of the vascular supply will impair perfusion of the ONH to a clinical degree [222,235,257-261].
The main purpose of our study is to show the essential role of color Doppler Imaging (CDI) of orbital vessels in order to quickly differentiate the mechanism of AION (arteritic, versus non-arteritic); the former should be treated promptly with systemic corticosteroids to prevent further visual loss of the fellow eye.
Methods
In this prospective, comparative and observational study, we Included 62 consecutive patients who presented, m our ophthalmology and neurology departments from June 20l2 through February 20l5, with clinical suspicion of acute unilateral AION.
The study was approved by the “Victor Babes" University of Medicine and Pharmacy Local Research Ethics Committee. All patients gave informed consent and were examined following a complex protocol, including:
1.a complete history of all previous or current systemic diseases;
2.an ophthalmological examination, (conducted by an ophthalmologist at the presentation, at 2 weeks, at 1 month and at 2 months), including visual acuity with the Snellen visual acuity chart, visual fields with a Goldmann perimeter, relative afferent pupillary defect, intraocular pressure, slit-lamp examination of the anterior segment, lens and vitreous, direct ophthalmoscopy and color fundus photography (both methods were used at the presentation and repeated at 2 weeks after the onset of visual loss) and fluorescein fundus angiography which was performed during the first 2 days after the presentation (acute stage of AION);
3.a physical examination (including possible contralateral neurologic signs such as hemiparesis, the inspection and palpation of the TAs) was performed at the presentation by a neurologist and an internist in order to detect an eventual stroke or a temporal arteritis (as part of GCA);
4.a CDI of orbital vessels was realized with a 10 MHz linear probe for detecting (by color Doppler sonography) and measuring (by spectral analysis pulsed Doppler sonography) the blood flow in the orbital vessels: the OAs, the CRAs, the PCAs (nasal and temporal), and the superior ophthalmic veins. Blood flow towards the transducer was depicted as red and flow away from the transducer was colored blue: a) the CRA was identified just below the optic disc (< 1 cm) and had a forward red-coded blood flow; b) the nasal and temporal trunks of PCA were identified along both sides of the optic nerve. The arteries had a forward red-coded blood flow; c) the OA was identified deeper in the orbit usually before crossing the optic nerve. It had a forward red-coded blood flow. The Doppler sample gate placed on the detected vessel was 15 mm. When the orbital vessels were not parallel to the ultrasound beam, we performed an angle correction between 0-60°. Also, a spectral velocity analysis was performed. The peak systolic velocity (PSV) and end-diastolic velocity (EDV) were calculated for each vessel. The resistance index (RI) was automatically calculated according to the following equation: RI=(PSV-EDV)/PSV. Absent signals not corresponding to ipsilateral internal carotid occlusive disease were classified as Doppler sonographic findings typical of GCA of the orbital arteries (occlusion of an orbital artery). Serial CDI examinations of the orbital blood vessels were performed at the presentation, at 1 week, and at 1 month on all AIONs patients.
5.Extracranial arteries were examined with a 7.5-10 MHz linear array transducer, combining B mode and color-coded Doppler/pulsed wave Doppler ultrasound duplex sonography (EDS), looking for an internal carotid arteries (ICA) source of emboli and with a 10 MHz linear probe for the examination of ECA branches, especially temporal arteries (TAs). Color box steering and beam steering were maximal and the color covered the artery lumen exactly because using these machine adjustments, sensitivities and specificities of the temporal arteritis diagnosis are higher. We examined both common superficial TAs mid their frontal and parietal rami in longitudinal mid transverse planes. Concentric hypoechogenic mural thickening (also called halo) was considered as an ultrasonographic finding typical of GCA.
Arterial segment was considered stenosed when PSV was more than twice than in the pre-stenotic segment with wave forms demonstrating turbulence and reduced velocity beyond the stenosis. Acute occlusion was considered if the ultrasound (US) showed hypoechoic material in the artery lumen with absence of color signals.
The first two authors of the study performed both CDI of orbital vessels and EDS. The first investigator, who was blinded to the patient’s ophthalmological status, looked only for detecting and measuring orbital and extracranial vessels blood flow. Discrepancies were resolved by consensus.
EDS was performed at the presentation, 2 weeks and at 1 month on all A-AIONs patients, and at the presentation on all NA-AION patients.
6.Electrocardiogram (ECG) in all patients, and transthoracic echocardiography (TTE) in selected cases were performed in the first 2 days after the presentation to detect an eventual cardiac source of emboli in selected cases (atrial fibrillation, etc.) were done during the first 2 days after the presentation.
7.Cranial computed tomography (CT) scanning was performed at the presentation in all AION patients in order to identify a concomitant stroke.
8.CT-angiography (CT-A) was done at the presentation and after EDS, only in selected cases (it allowed the assessment of the arterial wall and the endoluminal part of the aorta and its branches in selected cases of ipsilateral severe ICA stenosis/occlusion).
9.A laboratory work-up, including ESR, CRP, factor V Leiden, glycemia. etc. was done during the first 2 days after the presentation.
10.A temporal artery biopsy (TAB) was selectively done when GCA was suspected following the criteria of the American College of Rheumatology. Because of unilateral clinical ocular involvement in all cases, we took a biopsy from the ipsilateral TA representing 2.5 cm of the tender, swollen segment of the affected artery or from the TA's site targeted by the color coded Doppler (TAB was guided by EDS because of segmental/discontinuous TA' s involvement in GCA: skip lesions). All TABs were performed on the second day after the presentation.
Data analvsis
The evaluation of the duplex color-coded Doppler of the orbital vessels quality in order to foresee the A-AION diagnostic was completed by the SPSS v. 17 program by using the calculated RI for the clinically affected eye for all orbital arteries. Starting from the receiver operating characteristics (ROC) curve coordinates for each investigated artery, the best threshold value was identified in order to achieve the minimum cost of the test (maximum of the sensitivity – Se + specificity – Sp.). Using Microsoft Excel, the classification quality assessment was performed for the following parameters: sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV).
Results
We found 12 patients with unilateral acute A-AION, all of them with biopsy-confirmed disease (TAB positive), and 50 patients with unilateral acute NA-AION (no TAB).
We obtained the two groups of AION patients, using both clinical features, laboratory data, and results of ultrasound exams.
The comparison of major features of unilateral acute AAION and NA-AION patients are presented in Table 1.5.
All 12 A-AION patients presented with GCA. The NAAION patients presented with: a) systemic associations: 20 (40%) patients with arterial hypertension, 13 (26%) patients with diabetes mellitus, 10 (20%) patients with normal arterial hypertension, 4 (8%) patients with ipsilateral ICA’s disease, and 3 (6%) patients with neoplasms, and/or: b). ocular and ONH risk factors: 38 (76%) patients with small cup in the optic disc and 2 (4%) patients’ optic disc drusen. On the other hand, all 12 A-AION patients presented large cups. Anterior segment examination of both eyes was normal in all 62 patients. Amaurosis fugax was an important early visual symptom in 4 (33.3%) A-AION patients and preceded permanent visual loss. The 8 other A-AION cases developed permanent visual loss without any warning. However, amaurosis fugax was never found in NA-AION patients.
Visual fields
The most common visual field defect in NA-AIONs cases was an inferior nasal sectorial defect found in 32 (64%) patients which was relative or absolute. The next most common visual field defect was relative or absolute inferior altitudinal in 12 (24%) patients.
Color coded duplex Doppler of the retrobulbar (orbital) vessels features
1). Spectral Doppler analysis of the retrobulbar vessels in 12 A-AION patients: in the first week of evolution found an undetectable or severe diminished of blood flow velocities in the PCAs on the affected side (orbit), with an increased RI in all other retrobulbar vessels in both orbits (including the PCAs in the contralateral orbit) (Fig. 1.14.A and 1.14.B), despite the treatment with high-dose corticosteroids was found. In month one, CDI examinations of orbital blood vessels revealed practically the same aspects.
2). Spectral Doppler analysis of the retrobulbar vessels in 50 NA-AION patients: by contrast, in all NA-AIONs cases, blood flow velocities and RI in PCAs were generally preserved. In the first week of evolution. this analysis revealed only a slight decrease of PSV in PCAs (nasal and temporal) in the affected eye, compared to the unaffected eye and a very slight decrease of PSV in CRA of the affected eye due to papillary edema. In OAs, PSV were variable – normal to decreased, according to ipsilateral ICA’s status. In 4 patients severe ICA stenosis (> 70% of vessel diameter) combined with an insufficient Willis polygon led to decreased PSVs in the ipsilateral OAs.
In month I, CDI examinations of orbital vessels revealed that blood flow normalization was reached. The only exceptions were the 4 cases with ipsilateral severe ICAs stenosis.
Analysis of the data (Table 1.6) revealed that a threshold value of 0.71 for the IR of the temporal PCAs in the clinically affected eye, provided the best combination of Se (86%), Sp (96%), PPV (88%) and NPV (96%), respectively, for the detection of A-AION. A threshold value of 0.68 for the IR of the nasal PCAs in the clinically affected eye, provided the best combination of Se (86%), Sp (93%), PPV (76%), and NPV (96%), respectively, for the detection of A-AION.
Extracranial Duplex Sonography (EDS)
1). EDS in all 12 A-AION patients: EDS demonstrated segmental inflammation of TAs in 12 patients with A-AION. At the presentation, we identified: a) “dark halo" sign in 11 patients (Fig. 1.15): b) stenoses in 5 cases, and c) acute occlusions in 2 patients. Similar ultrasound patterns were discovered in other branches of the ECAs, including the facial, internal maxillary and lingual arteries. In week 2 and in month, the "halo" revealed by TAs ultrasound disappeared, because of the treatment with corticosteroids.
2) EDS in 50 NA-AION patients: at the presentation we identified 4 cases with ipsilateral severe ICA stenosis and consecutive NA-AION:
CT and CT-A
CT – scanning excluded strokes in all 62 patients. CT-A done in 4 patients confirmed severe ICA stenosis and consecutive ipsilateral NA-AION in their cases.
ECG and TTE
The examinations excluded an eventual cardiac embolic source of NA-AION.
Treatment and evolution of A-AION patients
In all 12 GCA patients with A-AION the treatment was initiated before TAB with intravenous methyl-prednisolone, 1 g/day for 3 consecutive days after the presentation, followed by oral prednisone 60 mg daily for one month. The daily dose was then reduced by 5 mg weekly in the next month of follow-up. All 12 patients with A-AION presented stationary ophthalmologic evolution in 2 months (unilateral visual loss) without classic clinical symptoms of GCA (temporal headache. etc.) and any systemic manifestations (fever, malaise, etc.).
Discussion
In the patients with A-AION due to GCA, transient visual loss caused by optic nerve or choroidal ischemia (amaurosis fugax) often precedes permanent visual loss by days to weeks (like in 4 of our 12 cases with A-AION). This symptom is unusual in NA-AIONs cases [210,211,218,221,222,235,252,257,259,260,262], and we did not come across them in our NA-AION patients.
Biousse and Newman [257] mentioned that the degree of visual loss is often more severe in A-AION than in NA-AION. In one study, 54% of the patients with A-AION had an initial visual loss degree ranging from counting fingers to no light perception, as compared to 26% in the NA-AION group [260]. This result shows that acute, painless, severe permanent loss of vision is extremely suggestive of A-AION, as in 10 out of 12 our cases with AAION. Different authors noted that once an untreated patient with GCA lost vision in one eye, the risk of GCA – related visual loss in the second eye is highest in the following hours to weeks (in at least 50% of cases) [257,263-266], we did not come across with the situation in our A-AION patients because they were treated with high doses of corticosteroids.
We noted that inferior nasal field defect was the most common diagnostic visual field defect in our NA-AION patients, such as it was found reported in literature [217,221,259,261,262]
According to Biousse and Newman [257], NA-AION is manifested as isolated, sudden, painless, monocular vision loss with edema of the optic disc. Ophthalmoscopy indicated that optic disc edema was associated more frequently with hyperemia in our NA-AION patients and with pallor (a chalky white color) in our A – AION patients, like in others studies [210,211,218,221,222,235,252,259,260,262]
We found a small, crowded ONH with a small physiological cup in 38 of our 50 patients with NA-AION. The small cup-to-disc ratio defines a "disc at risk" [257]. Although this is difficult to observe during the acute phase of NA AION, when the optic disc is swollen, examination of the clinically normal fellow eye should show a “disc at risk” [257]. According to different authors, the absence of a crowded optic disc in the second eye of a patient with AION should increase the probability of A-AION [257,261]: we found only large cups in our 12 A – AION patients.
A – ION results from entire PCAs trunk vasculitis and the consecutive ONH infarction. Human autopsy studies of acute A-AION demonstrated ischemic necrosis of the ONH and infiltration of the PCAs by chronic inflammatory cells. In some of the cases reported in the studies, segments of PCAs were occluded by inflammatory thickening and thrombi [217,221,222,235,259,260]. Severe diminished blood flow velocities in the PCAs, especially on the affected side, and high RI in all retrobulbar vessels in both orbits, represented characteristic signs of the CDI of the orbital vessels in A-AION in our study [210,211,236,248,249,252,262]. In NA -AION, blood velocities and RI in PCAs were preserved. Similar results were obtained in others studies [210,211,236,248,249,252,262]. The small number of A-AION cases could influence the calculated values (both the threshold values and the classifier quality). In spite of this, high PPV and NPV values in cases of temporal and nasal PCAs of the clinically affected eye, suggest that color coded duplex Doppler of orbital vessels may be a valid tool in the diagnosis of A-AION [262].
Extremely delayed or absent filling of the choroid, which was identified in all our 12 A-AION fluorescein angiograms, was suggested in other studies as a fluorescein-angiograms characteristic of A-AION [210,211,218,221,222,235,252,259,260,262].
In our study, Duplex Doppler of retrobulbar vessels and fluorescein angiogram data supported the histopathological evidence from other studies [217,221,222,235,259,260] of the involvement of the entire PCA trunk in A-AION (impaired both ONH and choroidal perfusion in these patients) [210,211,236,248,249,252,262]. In contrast, in NA-AION cases, impaired flow to the ONH is distal to the PCA trunk, usually at the level of the para optic branches [210,211,236,248,249,252,262].
While color coded Doppler sonography of orbital blood vessels does not eliminate the need for intravenous fluorescein angiography, it does, however, enhance the precision and reliability of the diagnostic evaluation for these patients, because it accurately, reproducibly and safely assesses the vascular supply of the optic nerve and retina [262].
There were certain cases in our study where the differential diagnosis between A-AION and NA-ION was difficult: a) three patients with NA-AION had high ESR levels due to an associated neoplasm: b) two patients with GCA had a normal ESR; c) one case with GCA without systemic/clinical symptoms, even without a swollen TA (occult GCA) [221].
Biousse and Newman [257] asserted that systemic symptoms of GCA (malaise, fever, temporal headache) may precede visual loss by months; however, about 25% of patients with positive TAB for GCA presented isolated A-AION without any systemic symptoms (so-called occult GCA) [221,4,264-268].
We believe that when duplex Doppler does not show evidence for A-AION, the patient should not receive high dose of corticosteroids until a TAB is performed, even if the ESR is elevated. On the other hand, patients with clinical evidence of A-AION, who have typical signs on Doppler of retrobulbar vessels, should be treated with corticosteroids before TAB in order to protect the fellow eye from going blind [236,247,4,262,264-269].
Ultrasonography of the TAs in temporal arteritis is ve1y important for the GCA diagnosis [263,264] Schmidt et al. [231] and Schmidt [230] asserted that the most specific (almost 100 % Sp) and sensitive (73% Se) sign for GCA was a concentric hypoechogenic mural thickening “halo” which was interpreted as vessel wall edema. Other positive findings for GCA are the presence of occlusion and stenoses. We detected these signs in 11 out of 12 our patients in our A – AION group with GCA. The 12th patient presented an occult GCA. Ultrasound investigation of the TAs needs to be perfomed before corticosteroid treatment or within the first 7 days of treatment because the "halo" revealed by TAs ultrasound disappears within 2 weeks of corticotherapy like in our 11 cases with temporal arteritis [221,230,231,250].
Schmidt et al. [231] and Schmidt [230] compared the results of TAs ultrasound examinations with the occurrence of visual ischemic complications in 222 consecutive patients with newly diagnosed, active GCA. However, findings of the TAs ultrasound examinations did not corelate with eye complications. For this reason, color coded duplex sonography of the retrobulbar vessels is of critical importance to identify A-AION [210,211,218,252,262].
Conclusion
A history of transient visual loss (amaurosis fugax) associated with an acute, painless, and severe visual loss of the involved eye, with concomitant diffuse pale optic disc edema were characteristics of A-AION. On the other hand, none of these symptoms and signs were found in the NA-AION patients. The resence of a disc at risk in the fellow eye in a patient with unilateral AION increased the probability of NAAION. Color coded duplex sonography of the orbital vessels identified the alterations in orbital blood flow, especially in the PCAs, which corresponded with the clinical features of AAION, and enabled prompt differentiation between NA-AION and A-AION.
1.3.3.2. The role of the transcranial Doppler ultrasonography in the diagnosis of cerebrovascular and associated diseases.
1.3.3.2.1. Transcranian Doppler (TCD) and Transcranian Color – Coded Sonography (TCCS)-Background
Intracranial circulation can be examined by Transcranial Doppler ultrasonography (TCD) or Transcranial Color-Coded Duplex Sonography (TCCS) through different bone windows (transtemporal, transforaminal, transorbital). The signal can be enhanced by using ultrasound contrast agents. [270-276] TCD combines in real-time intracranial blood flow patterns and velocities modifications with arterial diameter in the stenotic vessels. The most important data are: depth, blood flow direction, different velocities (peak systolic-PSV, end diastolic-EDV, mean blood flow velocity-MFV), pulsatility index-PI, and resistance index-RI. The physiological data assessed from TCD are complementary to the anatomical data analyzed from other neuroimaging techniques (DSA, CTA, MRA). [270-276]
ATCD has some advantages: inexpensive, noninvasive, portable test than can be performed bedside, serial examination, emboli detection, vasomotor reactivity testing. TCD has high specificity, sensitivity and negative predictive value (NPV). [270-276] In the same time, TCD has some disadvantages: low reliability, technical limits (inadequate or absent windows, the tortuous course of the basilar artery, etc.), operator-dependent results. TCD presents a modest positive predictive value (PPV) (36–75%). Therefore, it is useful to exclude significant ICAS with high certainty but requires confirmation by other imaging methods when stenosis is suggested. [270-279] The circle of Willis is complete in only 20% of cases, in other cases one or several vascular segments may be hypoplastic or aplastic. Visualization of the intracranial vessels and assessment of cerebral hemodynamics is only possible with TCCS, but this technique still requires further certification in larger studies. [270-279]
Prabhakaran, and co-workers suggested that TCD can specify mechanisms of stroke in symptomatic ICAS by using surrogate imaging markers of stroke risk: for the mechanism of decreased antegrade flow: the surrogate imaging marker of flow velocity, for the progression of stenosis: the flow velocity, for the poor collateral flow: the circle of Willis collaterals, for the artery-to-artery embolism: the micro-embolic signal, for the impaired vasomotor reactivity: the cerebrovascular reactivity. [270-279] Serial monitoring of flow velocities by TCD can detect evolution of ICAS and therapeutic effects. [279,280]
Transcranial ultrasound is used for multiple aims: TCD/TCCS can detect, localize, and grade the severity of ICAS, can detect and localize the intracranial arterial occlusion, can realize real time monitoring of recanalization in patients treated with systemic thrombolysis and of rescue reperfusion techniques: thrombectomy (identification of reocclusion, hyper-perfusion syndrome, etc.), can detect clinically silent emboli: micro embolic signals (MES), which recognizes patients at higher risk of embolic stroke, can recognize patients with extracranial internal carotid artery (ICA) stenosis at a higher stroke risk, and can assess both collateral pathways, and the vasomotor reactivity (VMR), which detects risk stratification of hemodynamic stroke [270,274-276,279,280], TCD/TCCS can identify intracranial arterial blood flow steals.
1. TCD/TCCS can detect, localize, and grade the severity of ICAS
In clinical practice, interpretation of TCD data should be individualized, with various parameters (velocities values, spectrum, waveform patterns, flow pulsatility, collateral flows, status of extracranial arteries, systemic conditions: anemia, etc.). TCD presents higher precision for identification of ICAS in the MCA and BA than in other intracranial arteries, due to the tortuosity in the latter. [270,272]
ICAS criteria are direct and indirect. (table 1.7, table 1.8)
A. Direct criteria (modifications observed at the stenosis level) include:
a). a color aliasing phenomenon (only in TCCS exam), which may indicate augmented flow velocities, caused by a stenosis or other etiologies (tortuosity, etc.). [272]
b). a progressive focal increase of blood flow velocities in ≥50% stenosis or paradoxical velocity decrease with very severe stenosis, near-occlusion or diffuse intracranial disease
c). Baracchini noted that, as a rule for a vessel with straight walls, a 50% diameter reduction double the velocity, and a 70% stenosis may triple the velocity at the end of the stenosis compared with a pre-stenotic segment or with the contralateral no affected side. The velocity values detected by TCCS are higher than those by TCD (due to angle correction). [272]
d). a significant (>30%) side-to-side difference of velocity (for symmetrical vessel segments after angle correction). [272]
B. Indirect criteria (changes observed in other arteries)
a). only observed in very severe stenosis (>80%);
b). are the same as for occlusion: proximal or distal flow alterations: a diastolic velocity dropp, and high RI in the feeding vessel or in the proximal segment of the stenotic vessel, a delayed systolic flow augmentation and velocity drop downstream, flow diversion and signs of collateralization. [272,279,281,282]
TCD criteria for ICAS in anterior as well as posterior circulation have been validated against DSA, MRA, CTA, and serve as reliable tools for their diagnosis (table 1.7.). [270]
The velocity criteria for ≥50% ICAS were detected by Feldmann, and co-workers in (SONIA) trial [277], that standardized the data of TCD, MRA, and DSA. The cut points were measures of continuous variables such as percentage of stenosis on MRA or velocity on TCD for each intra-cranial arterial vessel:
a). MRA ≥50% stenosis, without occlusion, or the presence of a flow gap, defined a positive test. Stenosis ≥50% on TCD was identified using a MFV) >100 cm/ s in MCA, >90 cm/s in the intracranial ICA, or >80 cm/s in the BA or VAs. [277]
b). For 80% stenosis on MRA, the SONIA TCD-MFV (cm/s)- cut points for 70 to 99% DSA stenosis of different arteries were: MCA 240, ICA 130, BA 130, VA 130. [277]
SONIA trial established that both TCD and MRA could reliably exclude the presence of ICAS, rather than identifying them; abnormal findings on TCD or MRA requiring a confirmatory test such as DSA to diagnose ICAS. [277]
The correlation between TCD and DSA for identification of ≥50% ICAS at laboratories with (SONIA) TCD scanning protocol were established by Limin Zhao, and co-workers. [278] Stenosis ≥50% on TCD was detected using a MFV >100 cm/s in the MCA, >90 cm/s in the intracranial ICA, or >80 cm/s in the VAs/BA. For ≥70% ICAS, they used expanded criteria (MFV-MCA>120 cm/s, MFV-VAs/BA >110 cm/s, stenotic/prestenotic velocity/ratio-SPR ≥3, and low velocity). These criteria demonstrated excellent-to-good sensitivity of TCD and indicated good agreement with DSA. [279,280]
Baumgartner, and co-workers conducted a TCCS study that evaluated PSV cutoff values for the assessment of>50% and<50% stenosis of the intracranial arteries (table 1.8.). [281]
2. TCD/TCCS can detect and localize the intracranial arterial occlusion.
Intracranial occlusion can be directly or indirectly detected by ultrasound examination.
a). direct criteria for intracranial arterial proximal occlusion are diagnosed using the Thrombolysis in Brain Ischemia (TIBI) flow-grading system. They include: no flow signal (TIBI 0) and minimal flow signal (TIBI 1), while blunted flow signal (TIBI 2) and dampened flow signal (TIBI 3) are criteria for distal occlusion. A missing flow signal could be occlusion or hypoplasia/ aplasia (it is essential to use ultrasound contrast agents, and to verify for indirect criteria of intracranial arterial occlusion). [272,273,276,282,283]
b). indirect criteria for intracranial arterial occlusion comprise proximal or distal flow alterations: a diastolic velocity drop, and high RI in the feeding vessel or in the proximal segment of the stenotic vessel, a delayed systolic flow augmentation and velocity drop down stream, flow diversion and signs of collateralization. [270-276]
3. TCD/TCCS can realize real-time monitoring of recanalization in acute ischemic stroke patients treated with systemic thrombolysis, and of rescue reperfusion techniques (identification of reocclusion, hyperperfusion syndrome, etc.)
TCD/TCCS can detect the residual flow at thrombus-blood interface.
The TIBI flow grading system: TIBI: 0-5, was elaborated to identify residual flow and to monitor thrombus dissolution in real time). [275,276,282,283]
Absent flow (TIBI 0): no flow signals, or lack of regular pulsatile flow signals (using lowest pulse repetition frequency-PRF and increased color-gain settings).
Minimal (TIBI I): systolic spikes of variable velocity and duration; absent diastolic flow during all cardiac cycles.
Blunted (TIBI II): flattened or delayed systolic flow acceleration compared with control side: positive end-diastolic velocity (EDV): pulsatility index (PI) <1.2.
Dampened (TIBI III): normal systolic flow acceleration; positive EDV; >30% decrease in mean flow volume (MFV) compared with control side.
Stenotic (TIBI IV): MFV> 80 cm/s and velocity difference >30% compared with control side: if velocity difference is < 30%, look for additional signs of stenosis; affected and comparison sides have MFV<80cm/s.
Normal (TIBI V): <30% MFV difference compared with control side; similar wave form shapes compared with control side. [275,276,282,283]
TIBI flow grades I-III correspond to acute proximal intracranial artery occlusion, while a TIBI flow grade of IV is indicative of proximal artery hemodynamically significant (>50%) stenosis.
The assessment of the diagnostic value of Transcranial power motion-mode Doppler (PMD-TCD) against computed tomography angiography (CTA) in patients with acute ischemic stroke was evaluated by Tsivgoulis, and co-workers. They asserted that PMD-TCD detected a substantial proportion of ICAS or occlusions, in concordance with CTA in patients with acute ischemic stroke. PMD-TCD identified data supplementary to the CTA: collateralization of flow with extra-cranial ICA stenosis/occlusion, real-time embolization-MES, and arterial blood flow steal. [284]
The evaluation of the diagnostic value of PMD-TCD against DSA in detection of acute posterior circulation steno-occlusive disease was realized by Tsivgoulis, and co-workers. They showed that the higher value of PMD-TCD compared with single-gate TCD may be associated to its ability to observe flow on the PMD display along tortuous and long arterial segments that may not be readily identified by sonographers during a single-gate TCD exam. In conclusion, PMD-TCD can exclude vertebro-basilar artery occlusion and can select patients for DSA and endovascular interventions if the sonographers are confirmed by DSA. [285]
An acute arterial occlusion differs from chronic as it is often partial, incomplete and exhibits dynamic processes (partial obstruction to flow, thrombus propagation, reocclusion, and sometimes spontaneous recanalization). TCD can rapidly identify patients with these lesions, and detect not only the flow-limiting lesion, but also the ongoing embolization, the collateralization, and the failure of the vasomotor reserve. [285,286]
4. TCD can identify clinically silent emboli: micro embolic signals (MES), which recognizes patients at higher risk of embolic stroke
MES detection in different interventional procedures (cerebral and coronary angiography, angioplasty, carotid endarterectomy, etc.) and in patients with extra and intracranial large artery atherosclerotic stenosis is useful in risk stratification, thus enabling to select those patients who could benefit from a more aggressive treatment. [270,276,279,280] MES detection requires continuous monitoring (at least one hour) of the major intracranial arteries. Most MES can be detected several days after the embolic event. The origin of emboli is important: detection of an embolic signal in the distal MCA might represent an atherosclerotic plaque in the ipsilateral MCA or ICA. On the other hand, identification of MES in multiple bilateral arteries, indicates a cardiac origin. [270,275,276,279,286]
5. TCD can identify intracranial arterial blood flow steals (reversed Robin Hood syndrome).
Intracranial arterial blood flow steals can be detected in chronic disease (e.g. subclavian artery stenoses, arterio-venous malformations, fistulas), but also in patients with acute ischemic stroke. Flow diversion is the hallmark of a steal and can appear at any level of the intracranial arteries (large proximal vessels, small distal vessels). [270-272,275,276]
6. TCD can recognize patients with extra-cranial ICA stenosis at a higher stroke risk, and can assess both collateral pathways, and the vasomotor reactivity (VMR), which detects patients at higher risk of hemodynamic stroke
Severe extra-cranial ICA stenosis may produce embolic or hemodynamic hemispheric infarct. [275,276,287] While the risk of an embolic ischemic stroke increases with the severity of ICA’s stenosis, the hemodynamic risk correlates less well with the degree of stenosis because of the functional capacity of the collateral pathways. [275,276,287] A complete circle of Willis and the possibility to activate primary collaterals (anterior communicating artery-ACoA, posterior communicating artery-PCoA) or secondary collaterals (ophthalmic artery-OA, lepto-meningeal arteries) reduces the risk of hemodynamic infarct ipsilateral to the extra-cranial ICA disease. [270,274-276] In patients with collateral flow signals (reversed OA, anterior cross-filling, PCoA flow) identified by TCD, proximal ICA occlusion is confirmed by subsequent neck CTA, MRA, or DSA. [270,274-276]
Vasomotor reactivity (VMR)
When cranial perfusion pressure is reduced, the cerebral resistance vessels compensatory presents vasodilatation (cerebrovascular auto-regulation). In the condition of compensatory maximal dilated cerebral arterioles, an additional vasodilator stimulus will not increase cerebral blood flow (CBF) further. [288]
VMR defines the auto-regulatory vasodilation of cerebral vessels in response to a vasodilator challenge, such as hypercapnia or acetazolamide (apnea test, – the breath-holding test, Diamox test). [289]
The breath-holding maneuver (TCD breath-holding test)
According to Fulesdi, the concept behind this test is that elevation of tidal volume and/or breathing frequency results in a decreased PaCO2 whereas a decreased minute volume leads to an increased PaCO2. [290]
It is performed according to the procedure of Markus and Harrison [289]: after normal breathing of room air for approximately 4 minutes, the patients are instructed to hold their breath after a normal inspiration. During the maneuver the middle cerebral artery-mean flow velocity (MCA-MFV) is recorded continuously. The mean blood velocity-MFV at the TCD display immediately after the end of the breath-holding period is registered as the maximal increase of the MCA-MFV (while breath-holding). The time of breath-holding is also registered. This procedure is repeated after a rest of 2 to 3 minutes to allow the MFVs to return to their initial values. For the maximal MCA-MFV increase and for the time of breath-holding, the mean values of both trials are taken. The breath-holding index (BHI) is calculated from these data as percent increase in MCA- MFV recorded by breath-holding divided by seconds of breath-holding ([Vbh−Vr/Vr] · 100 · s−1), where Vbh is MCA-MFV at the end of breath-holding, Vr the MCA-MFV at rest, and s-1 per second of breath-holding. The breath-holding maneuver is without side effects, but the procedure had to be explained repeatedly to some patients to achieve the desired level of cooperation. [289,291,293]
The TCD acetazolamide test
Another pharmacological method for cerebral vasoreactivity testing is intravenous injection of 15mg/kg body weight acetazolamide. This is a reversible inhibitor of the enzyme carbonic anhydrase that causes a slight and temporary metabolic acidosis. [290] It is a potent vasodilator of cerebral resistance vessels, leading to a smooth increase of blood velocity with plateauing of blood velocity after 10 to 15 minutes. [292] 15 minutes after the injection of acetazolamide, the MFVs are measured again with the ultrasound sample volume in the same depth of the MCA compared with the resting examination, again measuring the highest MFV that could be recorded constantly during a period of 10 seconds. The percent VMR after acetazolamide stimulation (%VMRacet) is calculated as percent change in MCA-MFV after stimulus application compared with MFV at rest ([Vacet−Vr/Vr] · 100), where Vacet is the maximal increase of the MCA-MFV after acetazolamide application and Vr the MFV at rest. [292]
This test does not depend on the patients’ cooperation but involves some slight and completely reversible side effects such as dizziness, slight headache, and dysesthesia (perioral or at the fingertips, usually persisting for not more than 30 minutes). [292]
Muller, and co-workers mentioned in their study [292] that the assessment of VMR by TCD correlated with cerebral blood flow changes even when different vasodilator stimuli were used. Both breath-holding and acetazolamide stimulation techniques similarly indicated significantly reduced VMR with increasing degree of ICA lesions (P < or = .01). However, the acetazolamide challenge differentiated more accurately between the various groups of ICA findings. On the other hand, in cooperative patients the breath-holding maneuver as vasodilator stimulus seemed clinically useful for a first estimation of cerebral VMR. [292]
VMR represents a measure of dynamic cerebrovascular reserve capacity. Its study recognizes patients at higher risk of hemodynamic stroke, in both intra-, and extra-cranial large vessel disease, thus allowing to select those patients who could benefit from a more aggressive treatment. [275,276,287,293]
In another study, Muller, and co-workers [288] noted that the compromise of cerebrovascular auto-regulation in severe stenosis/occlusion of ICA depends on the functional capacity of collateral pathways. They used TCD to determine both collateral pathways and VMR.
In patients with occlusion or stenosis of more than 90% of the ICA, diminished VMR as a close correlate of cerebral auto-regulatory capacity was reported to be significantly associated with low-flow infarctions [294] and with a higher rate of future ipsilateral stroke compared with patients with a normal or only slightly disturbed VMR distal to such ICA lesions. The collateral pathways were classified into the willisian type (filling of the relevant MCA via the ACoA and/or the PCoA), in which the cerebral auto-regulatory response was usually well preserved, and the ophthalmic (collateral blood flow mostly through the OA) and leptomeningeal types, in which auto-regulatory capacity was severely decreased or diminished. [294] TCD has been proven to accurately determine intracranial collateral pathways compared with cerebral angiography, [295] and its measurement of blood velocity changes stimulated by acetazolamide or carbon dioxide (CO2) correlates well with rCBF changes, indicating that VMR evaluated by blood velocity changes adequately reflects cerebral auto-regulatory response. [295]
According to Prabhakaran, presence of MES, poor collateral flow, and impaired VMR predict high risk of recurrence in intracranial atherosclerosis. [275,276,279]
In the following pages, I will present the three papers, published in ISI journals, to which I was first author (1 paper), principal author (1 paper), and coauthor (1 paper), respectively.
1.3.3.2.2. Vascular aphasias – Data from the literature.
Aphasia is a central disorder of language that impairs a person's ability to understand and produce spoken language. Impairments in reading (alexia) and writing (agraphia) are often associated with aphasia. It is caused by brain damage (localized/diffuse?). It cannot be attributed to a peripheral sensory motor disorder. It is an acquired phenomenon that appears after the language has been already learned. In a more general sense, aphasia may disrupt the ability to generate and use symbol systems, because aphasia affects not only spoken, and written language, but also musical notation, telling time, mathematical operations, and even discerning meaning from rudimentary as traffic signals, emergency vehicle warning sirens, or dealing with money, etc. (such as weakness of the muscles of articulation) that may mimic aphasia. [296-299]
Aphasia has a prevalence of 25-30% in acute ischemic stroke (vascular aphasia); it is a marker of stroke severity and is associated with a higher risk of mortality, poor functional prognosis (can have a dramatic impact on person's ability to communicate), and increased risk of post-stroke dementia. [296,297]
Vascular aphasic syndromes (vascular aphasias) have not typically corresponded to linguistic domains because lesions typically involve vascular territories, rather than being restricted to the dorsal fronto-parietal language network or the ventral temporal language network, for example. [300-303]
The vascular syndromes refer to a collection of frequently co-occurring symptoms (aphasia, hemiparesis, hemianopia, etc.,) that are observed together because they represent functions that depend on tissue supplied by the same cerebral vessel (which can be occluded and cause a stroke) [304-306]
The assessment of aphasias in clinical practice is based on classical analysis of oral production and comprehension. The language disturbances observed are usually combined into aphasic syndromes (non-fluent/ fluent aphasias, etc.) that may evolve rapidly at the acute stage of ischemic stroke. The global aphasia and anomic plus aphasia are more frequent in acute ischemic stroke; Broca, Wernicke, and transcortical motor aphasia present an intermediate frequency, and other aphasias are rare. [296,297]
Types of aphasias [307-309]
1. Broca’s aphasia (motor aphasia)
2. Wernicke’s aphasia (sensory aphasia)
3. Conduction aphasia
4. Transcortical aphasias: a) transcortical motor aphasia, b) transcortical sensory aphasia, c) mixed transcortical aphasia)
5. Global aphasias
6. Anomic aphasias.
The determinants of the type of aphasia are: a). the site of the lesion, b) age, with a higher frequency of non-fluent aphasias in young patients, and c) sex, with a higher frequency of non-fluent aphasias in men. [310]
The main determinant of the type of vascular aphasia is the infarct location (especially left anterior, posterior or complete middle cerebral artery ischemic stroke). [296,297] Different recent studies have noted characteristics of aphasia at the hyperacute stage of ischemic stroke, re-examined its anatomy using imaging of white matter tracts, indicated prognosis in the era of stroke units, thrombolysis and thrombectomy (aphasias have a parallel course to that of cortical hypoperfusion, and the reversal of cortical hypoperfusion, following recanalization, is associated with resolution of aphasia). [296,297] Although vascular aphasic syndromes have been defined in stroke patients, at least 10% remains unclassifiable, and this is more frequent in patients with a previous stroke: atypical aphasias: mixed aphasias, thalamic aphasias, capsulo-striat aphasias. [297,311-313].
Language therapy is needed as soon as permitted by clinical condition. Unfortunately, pharmacotherapy remains to be evaluated. Other studies examined the potential interest of new treatment, such as transcranial magnetic stimulation. [296,297]
1.Broca’s aphasia [314-320]
The main features of Broca’s aphasia include:
A. Assessment of oral production:
1). Fluency:
Non-fluent verbal output, characterized by difficulty to initiate speech, effortful with hesitations and slow output (10-15 words/min). Disprosody: oral expression is monotonously, melodic modulation being absent. [296-298,314,315]
2). Presence of deviations at various levels:
a). sound/arthric level (incorrect articulation of a sound)-disartria
b). phonemic level (omission, substitution, addition, or inversion of a phoneme)-fonematic and semantic paraphasias.
c). verbal level (word-finding difficulty-anomia), especially in spontaneous speech/deficits in action naming are more severe than deficits in object naming.
d). syntactic level: agrammatism, usually more apparent after the acute phase: omission of functional words (articles, prepositions, conjunctions, pronouns, auxiliary verbs/e.g. the, an), while conceptual words (nouns, verbs and adverbs) are used in a greater proportion–”telegraphic speech”, [299-301,316,317]
The patient with Broca’s aphasia is aware of his oral expression disorders and he can develop depression. [296]
B. Assessment of repetition:
Poor repetition – the patient will find difficult to repeat operational words and flexional endings, resulting fonematic and semantic paraphasias (eg.: “The boy eats an apple”/ “Boy – eat – apple”).
Repetition and naming are impaired, although this is less marked than spontaneous speech.
Automatic speech – enumerating the days of the week, the months of the year, numbering from 1 to 10, repeating a poem, a.s.o., can ameliorate the verbal out-put. [302,303,316,317]
C. Assessment of oral comprehension
Good oral comprehension.
In some cases, syntactic comprehension can be affected-as requested to understand complex sentences and multiple instructions
a). the patient is unable to distinguish between different operational words like “on” or “in
b). comprehension of passive reversible sentences can be affected. [304,305,318-320]
D. Assessment of reading and writing:
Reading (frontal alexia-literal alexia), and writing (frontal agrafia) are also impaired [302]
E. Associated signs and symptoms:
Contralateral hemiparesis – lesions that cause Broca’s aphasia also interrupt adjacent cortical motor fibers and deep fiber tracts; facial weakness; facio-buco-lingual apraxia (effortful, trial and error, groping articulatory movements and attempts at self-correction). Dysprosody unrelieved by extended periods of normal rhythm, stress and intonation. Articulatory inconsistency on repeated attempts of the same utterance. Obviously, difficulty initiating utterances. [296-298]
Anatomo-clinical correlations
Lesions usually involves on the left side in right-handed individuals: Broca’s area: the posterior part of the third frontal gyrus-F3-(Brodmann areas 44 and 45) – a milder form of aphasia with anomia, rolandic operculum (lower part of motor area: Fa), – prominent arthric deformation, insular cortice, and subjacent white matter, centrum semiovale (sometimes isolated large lesions), capsulo-striatum (caudate nucleus head and putamen), periventricular areas.
Broca’s aphasia is produced by infarcts of the superior division of the left MCA. [296,297,300,321-323]
2. Wernicke’s aphasia
The main features of Wernicke’s aphasia include:
A. Assessment of oral production
1). Fluency:
Fluent verbal output = easy initialization of speech, plentiful output (100-200 words/minute), normal phrase length (~5-8 words/phrase) with normal prosody/ hiperprosody. There is no quantitative reduction of output. Even more, the oral production may be augmented (logorrhea), concerning patients with jargonophasia and anosognosia. [296,297,300,324-329]
2). Presence of deviations at various levels:
a). sound/arthric level: good articulation of sounds.
b). phonemic level: semantic paraphasias (semantically related word substitutions), phonemic paraphasias (phonologically related word or non-word substitutions) and jargon-aphasia.
c). verbal level: word-finding difficulty – anomia, frequently associated circumlocutions, perseveration, and neologisms);
d). syntactic level: paragrammatism: nouns replaced by pronouns (“that”, those”) or by unspecific words (“thing”). [296,297,300,324-329]
B. Assessment of repetition:
Repetition is severe impaired. [296,297,300,324-329]
C. Assessment of oral comprehension
Oral comprehension – is severe impaired, due to: disturbances in language sounds perception (repetition is impossible); incapacity of accessing the meaning of the word (repetition is normal); decrease of verbal memory (repetition may be disturbed depending on the length of the verbal output of the speaker); perturbation in comprehension of the lexico-semantic relations of the phrase or utterance. [296,297,300,324-329]
Sometimes, comprehension is more difficult for isolated words; on the other hand, verbal reception of some lexico-semantic categories may be partially or totally preserved. Sintactic comprehension is significant impaired. [296,297,300,324-329]
D. Assessment of reading and writing
Reading – is frequently impaired (alexia).
Writing (agraphia): spontaneous and dictated graphia are fully of paragraphias and paragrammatism; copying a text is easier than writing after hearing one. [296,297,300,324-329]
E. Other signs:
Homonymous hemianopia – frequent associated; complete/dissociated Gerstmann syndrome (agraphia, acalculia, finger agnosia, and inability to distinguish between the right and left sides of one's body); limbs apraxia; anosognosia – it can be observed at the beginning, and decreases gradually; high excitation: logorrhea, hyperprosody, exaggeration of mimico-gestual language. The patient with Wernicke’s aphasia is unaware of his oral expression disorders. [296,297,300,324-329]
Anatomo-clinical correlations:
Wernicke area: posterior part of the first two temporal gyri-T1/T2 (BA 22); inferior parietal lobes: angular gyrus (BA 39), and supra-marginal gyrus (BA 40); lesions can extend to the insular-external capsule region, and anterior part of temporal gyri (BA22). Besides the cortical destructions from these areas, subjacent white matter can be also affected. Wernicke’s aphasia is the result of an infarct of the inferior division of the left MCA (supplies the posterior part of the temporal lobe and inferior parietal lobule); usually an embolic occlusion/ atherothrombotic. It is more current in elderly people. [296,297,300, 321-323]
3. Conduction aphasia
Is rarely observed at the acute stage of stroke and more frequently affects younger patients.
A. Assessment of oral production:
1). Fluency: Verbal Output is fluent, although some hesitations, and self-correction attempts to interrupt the flow. [296,297,300,330-333]
2). Presence of deviations at various levels:
a). sound/arthric level: normal articulation;
b). phonemic level:
-phonemic paraphasias are typically for conduction aphasia. The production of phonemic paraphasias across verbal tasks represents the cardinal feature of conduction aphasia.
-the conduit d’approche (i.e. attempts to correct phonemic deformations by successive approximations) is characteristic of conduction aphasia.
-semantic paraphasias or neologisms are less frequent in conduction aphasia than in other fluent types of aphasia.
c). verbal level: anomia – naming may be mildly impaired
d). syntactic level: the grammar is preserved. [296,297,300,330-333]
B. Assessment of repetition: repetition is impaired. [296,297,300,330-333]
C.Assessment of oral comprehension: sparing of oral comprehension. [296,297,300,330-333]
D. Assessment of reading and writing:
Good reading comprehension, but paraphasic oral reading.
In conclusion: conduction aphasia presents three major characteristics: a relatively fluent, though phonologically paraphasic speech; poor repetition; relatively spared comprehension. [296,297,300,330-333]
E.Associated signs: oral and limb apraxia; ideomotor apraxia; right sensory impairment. [296,297,300]
Anatomo-clinical correlations
The responsible stroke usually concerns the external capsule, insular cortex, or the inferior parietal lobes, particularly the supra-marginal gyrus (Brodman area 40). These locations classically disrupt the arcuate fasciculus, although its role remains debated: disconnection between the posterior superior temporal cortex (and angular gyrus) and the inferior frontal gyri. Alternative explanations have been proposed, such as short-term memory syndrome (impairment to limited working memory-associated lesions to be in areas critical for working memory.
Conduction aphasia is the result of an embolic infarct of the inferior division (posterior temporal or parietal) of the left MCA. [296,297,300,321-323]
4. Transcortical aphasias
Transcortical aphasia is the most less common type of aphasia. It is characterized by preservation of word repetition, even of those words without meaning. Repetition of words is mediated by the perisylvian cerebral region (fronto-temporo-parietal region). Generally, in this type of aphasia, Broca’s area, Wernicke’s area and the arcuate fasciculus are intact. In transcortical aphasia exist a disconnection between motor and/or sensory areas of language from hemispheric cortex, a process that occurs from lesions of border areas: a). from ACA and MCA (transcortical motor aphasia), b).from MCA and PCA (transcortical sensory aphasia). [296,297,300,321-323]
a).transcortical motor aphasia
Clinical aspects:
Non-fluent, reduced oral output (poor spontaneous speech), with possible initial mutism, loss initiation, hypophonia, perseveration, reduced phrase length, naming is frequently preserved, simplification of grammatical form, repetition and oral comprehension are typically spared. [296,297,300,334-337]
Anatomo-clinical correlations:
a). cortical frontal lesions of border areas (watershed area) from ACA and MCA; less frequently: left premotor and prefrontal regions, situated anterior and superior of Broca’s area (dorso-lateral region-sparing Broca area), supplementary motor area (supero-mesial area of the frontal lobe)
b). subcortical frontal lesions: thalamus, centrum semiovale with variable extension into the striatum. [296,297,300,321-323]
b). transcortical sensory aphasia
Clinical aspects:
Oral output is fluent, with verbal paraphasias, word-finding difficulty, circumlocutory speech (use of generic words such as “bird” for a duck and “furniture” for a table), semantic jargon, comprehension is severely impaired at the word level. This contrasts with repetition sparing (this is the key feature that distinguishes it from Wernicke aphasia). The patient is unable to define accurately a name that is correctly repeated. [296,297,300,334-337]
Anatomo-clinical correlations:
Lesions of border areas from MCA and PCA territories (temporo-parieto-occipital junction), infero-temporal region (second and third temporal gyri), anterolateral thalamus. Semantic variant of PPA, Alzheimer’s disease, and Creutzfeldt-Jacob disease can cause a similar syndrome. [296,297,300,321-323]
c). mixed transcortical aphasia
Clinical aspects:
Non-fluent (reduced spontaneous speech), impaired comprehension, reading (alexia), and writing (agraphia), relatively spared repetition. It presents like a global aphasia with relative sparing of repetition. [296,297,300,334-337]
Anatomo-clinical correlations:
Lesions isolating the perysylvian language areas (watershed territory between the left ACA and MCA in addition to the watershed territory between the left MCA and PCA). [296,297,300,321-323]
5. Global aphasia
Clinical aspects:
It is the most severe form of aphasia, that associates: major disorders of oral production-speech output/fluency (mutism, stereotyped utterances), and major disorders of the oral and written comprehension. [296,297,300,338]
It can associate: right hemiparesis/hemiplegia, right hemi-hipoestesia, right homonym hemianopia, limbs apraxia, and facio-buco-lingual apraxia. [296,297,300,338]
Anatomo-clinical correlations:
Large peri-Sylvian lesions are noted. Broca and Wernicke areas may be hypoperfused in the acute period. Extended lesions (total MCA/C1 occlusion) including anterior and posterior language areas (global aphasia with hemiplegia); frontal and temporo-parietal lesions – two lesions (global aphasia without hemiplegia); frontal lobe, basal ganglia and insula – spearing temporo-parietal region. (global aphasia with hemiplegia and improvement of comprehension); subcortical infarct extended into basal ganglia. [296,297,300,321-323,338]
6. Anomic aphasia
Clinical aspects
Fluent aphasia with word-finding difficulty (observed in spontaneous speech and naming); frequently associated with circumlocutions; comprehension and repetition are preserved. [296,297,300,339]
Anatomo-clinical correlations:
Acute anomic aphasia may be observed in many locations. It also represents an evolutive stage of all aphasic syndromes when they improve. [296,297,300,321-323]
Personal contributions
Since 1996, I have systematically used the Western Aphasia Battery-WAB- test (Kertesz, A 1980) (the Romanian version-Kory Calomfirescu, Stefania-1996) in the examination of Romanian aphasic patients. In this way, the evolution of aphasia in patients with Romanian mother tongue can be quantified judiciously. My main contributions in the field of vascular aphasias refer to the conduction aphasia, the transcortical aphasias, the supplementary motor area aphasia, the subcortical aphasias, as well as to the identification of the particularities of agrammatism, according to the structural typology of the Romanian language. At the same time, I contributed to establish clinical-imagistic correlations (CT, MRI) of the aphasias, which allowed the formulation of relevant pathophysiological mechanisms. [300,301,318,319,329,333,335,336]
The study entitled Cerebrolysin adjuvant treatment in Broca’s aphasics following first acute ischemic stroke of the left middle cerebral artery (J. Med. Life 2010; Authors: Jianu DC, Muresanu DF, Bajenaru O, et al.,) demonstrates that i.v. adjuvant treatment with Cerebrolysin results in statistically significant and clinically important improvements of language function in patients with Broca’s aphasia with a first acute ischemic stroke. [320]
A cerebro-vascular diagnostic examination is considered part of the standard work-up after cerebral ischemia. However, only scarce data exist on the distribution and prognosis of steno-occlusive disease in patients with aphasia. Transcranial Doppler (TCD) is a useful noninvasive method of intracranial circulation assessment.
In our study (Extra and transcranial color-coded sonography data in aphasics with left internal carotid artery, and/or left middle cerebral artery stenosis or occlusion”, European Journal of Neurology (The official journal of the European Academy of Neurology, Authors: D C Jianu,et al 2018), we wanted to investigate the role of TCCCS in determination of abnormalities affecting intracranial, and/or extracranial parts of vessels supplying the brain in aphasics with acute ischemic stroke and large artery disease.
We concluded that Broca's aphasia was the most frequent aphasic syndrome in the acute stage of ischemic stroke in the territory of the left middle cerebral artery (MCA). The cerebral lesions of most aphasics were meted with classical language functional areas; but others sites damaged also could produce aphasia. TCSS was a reliable method for the evaluation of the intracranial ICA and MCA stenosis/occlusion and helped identify the intracranial hemodynamic impairment in the extracranial ICA diseases causing post-stroke aphasia.
1.3.3.2.3. European Journal of Neurology (The official journal of the European Academy of Neurology-EAN), Volume 25, Supplement 1 (pg 35-36), April 2018, 23rd Meeting of the ESNCH: Book of Abstracts, Prague, Czech Republic, April 13–16, 2018
Extra and transcranial color-coded sonography findings in aphasics with internal carotid artey, and/or left middle cerebral artery stenosis or occlusion
Authors: Dragos Catalin Jianu, Silviana Nina Jianu, Flavius Traian Dan, Georgiana Munteanu.
ABSTRACT
Introduction Large artery disease (LAD) is presumed in aphasics with ischemic stroke and significant stenosis (>50%) or occlusion of the ipsilateral ICA/MCA. However, only scarce data exist on the distribution of the steno-occlusive diseases in aphasics.
Aims To investigate the role of Transcranial Color Coded Sonography (TCCS) in determination of abnormalities affecting intracranial, and/or extracranial arteries in aphasics with acute ischemic stroke.
Patients and methods A total of 180 patients with a first acute ischemic stroke (LAD) and aphasia were selected between January 2012 and October 2017. Their language function was evaluated by means of the Romanian modified version of the Western Aphasia Battery. They received MRI, MR-A, TTE, extracranial color Doppler sonography (ECDS) and TCCS examinations in the first 12 hours of stroke onset. There were no brain DWI/MRI findings of an earlier stroke.
Results The main aphasic syndrome at admission was Broca’s aphasia (60%). In 130 cases (72.2%) the lesions were located at classical language centers. Ultrasonographic results were: 75 patients (41.7%) with no changes in the intracranial hemodynamics, and 105 cases (58.3%) with the following changes: a) 31 patients (17.2%) with MCA, siphon or terminal ICA (C1) stenosis/ occlusions; b) 74 patients (41.1%) with hypo perfusion of the left MCA; 39 of them had a severe stenosis/or occlusion of the extracranial ipsilateral ICA, with collateral circulation.
Conclusions TCSS was a reliable method for the evaluation of the intracranial ICA and MCA stenosis/occlusion and helped identify the intracranial hemodynamic impairment in the extracranial ICA diseases causing post-stroke aphasia.
1.3.3.2.4. Cerebral vessels endothelial dysfunction. Diabetic microangiopathy. The inter-relation between chronic kidney disease and cerebrovascular disease in diabetic patients. Data from the literature. Personal contributions
Pulsatility. Background
According to Kirklin, pulsatility represents an intrinsic property of the cardiovascular system, governed by the resistance differential across the arteriolar bed, which allows the potential energy stored in the elastic, proximal arteries to propagate throughout the microcirculation at a mean pressure consistent with adequate perfusion. [340] At the capillary/cellular level, pulsatility is characterized by sheer stress (the stress or forces are parallel to the surface of the material, in this case the vascular wall) and pulse pressure, which induce specific cellular signaling pathways. In the microcirculation, these pathways are largely regulated through the vascular endothelium. [340] The cyclical changes in sheer stress associated with pulsatile flow induce endothelial responses, which directly affects systemic vascular resistance. [340] Kirklin noted that non-pulsatile (or reduced pulsatile) flow impairs endothelial-dependent vascular relaxation and constriction, related in part to reduced nitric oxide production. [340] Impaired cyclical vasoconstriction has been correlated with increased smooth muscle proliferation, increased apoptosis, and reduced vascular smooth muscle cell contractile protein expression. The non-pulsatile flow is associated with elevated oxidated stress, a pro-inflammatory state, and arterial remodeling. [340] These chronic changes in systemic vascular resistance induce decreased vascular reactivity after 6 weeks of non-pulsatile circulatory support in an experimental model. [340]
Pulsatility Index (PI) and other hemodynamic parameters. Background
Pulsatility Index and other hemodynamic parameters are used to assess the effectiveness of continuous flow pumps in providing “physiologic” perfusion of the microcirculation. [340]
The Gosling’s pulsatility index (PI)
PI is calculated automatically using this formula:
PI = (PSV−EDV)/MV, where
PSV: peak systolic velocity, EDV: end-diastolic volume, and MV: mean flow velocity. (normal value PI<1).
The Pourcellot’s resistance index (RI):
RI=(PSV−EDV)/PSV
(normal value RI<0.7)
PI and RI measure the resistance of blood flow and are used in the evaluation of physiologically low resistance vessels, e.g., the internal carotid artery (ICA) or middle cerebral artery (MCA). Clinical scenarios in which PI or RI are calculated include: cervical ICA evaluation for stenosis, and transcranial Doppler (TCD). The increased PI and RI in the ICAs and MCAs reflect increased resistance in the examined vessels. [341]
Transcranial Doppler sonography (TCD), the pulsatility index (PI), and the cerebrovascular reactivity (CVR). Background
TCD (vide supra) provides three essential vascular biomarkers: mean cerebral blood flow velocity, PI, and cerebrovascular reactivity (CVR). [9,342]
The mean cerebral blood flow velocity offers information regarding the integrity in arterial perfusion, while the PI assess the cerebrovascular resistance and intracranial compliance. [9,34,343] The changes in the cerebral arteriolar tone are most sensitively reflected by the PI that decreases during vasodilatation and increases after vasoconstriction of the cerebral arterioles. Thus, increased PI can indicate an increased vasculature resistance distal to the examined artery, which shows that there is hypoperfusion in that area. [9]
The cerebrovascular reactivity (CVR) (vide supra) is a haemodynamic parameter which represents normal cerebral artery blood flow velocity increase in response to a vasodilatory stimulus, such as hypercapnia. A decreased CVR is indicative of pre-existing vasodilation, which reflects a reduced reserve capacity of cerebral auto-regulation. The CVR provides information with regard to the intra-cerebral arterioles which may be already maximally dilated, thus being unable to react to drops in blood pressure or to vasodilator stimuli with further dilation. [9,344]
In consequence, according to Lee, TCD may provide indirect assessment of the cerebral microvasculature by increased PIs and reduced CVR of the MCAs, changes consistent with microangiopathic remodelling of the cerebral vessels. Therefore, diseases or dysfunctions of distal small intracranial perforating arteries (old age, DM, hypertension, intracranial atherosclerosis, vascular dementia) may increase the PI of the proximal larger intracranial arteries, such as the MCAs. [345]
Endothelial dysfunction (ED). Data from the literature.
According to Csiba, endothelial dysfunction (ED) consists in the abnormal activity of the endothelium. It represents the reduced nitric oxide (NO) bioavaibilty due either to low production of NO by endothelial nitric oxide synthase (eNOS), or accelerated NO breakdown by oxygen species, or both. [346] NO diffuses to the vascular smooth cells producing cyclic guanosine monophosphate-mediated vasodilatation under physiological circumstances. Under normal conditions, shear stress is an essential activator of eNOS. eNOS can be activated by other molecules (adenosine, vascular endothelial growth factor and serotonin). In the early stages of atherosclerosis, endothelial function may be compensated by the upregulation of the vasodilating prostacyclin and or endothelium-derived hyperpolarizing factor(s) (EDHF). [346] Csiba noted that ED has been detected in atherosclerosis and has also been asociated to the presence of dyslipidemia, hypertension, DM, smoking and other factors. Many of these diseases present overproduction of reactive oxygen species (ROS) and in turn augmented oxidative stress. [346] In consequence, oxidative stress represents probably one of the main mechanisms in the evolution of ED. On the other hand, other factors also contribute to it, for example, local shear stress, pressure and pulsatility, and genetic factors. As a consequence of ED, a range of proatherosclerotic molecular events occur that for prothrombotic events. [346]
Techniques for measurement of ED
We can use direct measurements of circulating endothelium markers involved in vasoconstriction and vasorelaxation (e.g., endothelin, endothelial-derived NO compounds or prostacyclin metabolites). Serum levels of C-reactive protein, interleukins and other cytokines, phospholipases, markers of oxidative stress or proangiogenic factors and endothelial progenitor cells may provide further insights into early E.D. [346]
Flow-mediated dilatation (FMD) is measured by ultrasound of the brachial artery (BA). This noninvasive test has become the most important method of measuring ED. The endothelial cells release NO and other endothelium-derived relaxing factors in response to reactive hyperemia (after a short occlusion of the BA with a blood pressure cuff). FMD is NO mediated and altered in patients with atherosclerosis and CV risk factors and correlates well with coronary vascular endothelial vasodilatator function and serolological markers of ED. [346]
Intima–media thickness (IMT) (vide supra) may provide further insighs into ED. [346]
Csiba asserted that the measurement of endothelial function can distinguish responders from nonresponders to therapy. Those patients whose endothelial function doesn’t improve after therapeutic interventions are at a high risk for further events. Thus, the therapy can be guided by repeated endothelial function measurements, but we need more studies to answer the question of whether endothelial function-guided therapies help to decrease the risk of future events. [346]
Diabetes mellitus (DM)-Risk factor for ischemic stroke. Background
DM represents an important risk factor for ischemic stroke, with a relative risk for ischemic stroke of 2.5 in males and 3.6 in females. [347] In addition, DM patients have a worse prognosis and an augmented mortality after stroke. [345,348,349]
This occurs through pathophysiologic changes to the macrocirculation (which implies internal carotid, vertebral and basilar arteries, middle, anterior, and posterior cerebral arteries,) as large artery atherosclerosis (cerebral macroangiopathy), and the microcirculation (which consists in small cerebral vessels) as arteriolosclerosis (cerebral microangiopathy). Both vascular complications in the course of DM (atherosclerosis and arteriosclerosis) imply impaired cerebral haemodynamics, which result in increased prevalence of stroke in type 2 DM patients. Cerebral microangiopathy is associated with similar morphological abnormalities in other microvascular territories, such as the kidney, the retina and the peripheral nervous system. [345,350-352]
According to Lee et al., cerebral macroangiopathy in DM can be assessed by methods such as extracranial ultrasonography, MR angiography (MR-A), CT angiography (CT-A), and digital substraction angiography (DSA). [345] Carotid intima-media thickness (cIMT) (vide supra) as measured by B-mode carotid ultrasonography is associated with an increased risk of coronary artery disease and stroke. [76,353] In ischemic stroke, increased cIMT is more related to non-lacunar infarction than to lacunar infarction. [354], cIMT being a useful marker for diabetic cerebral macroangiopathy. [345,355]
Bal and Demchuk asserted that newer techniques focused on advanced parenchymal imaging (including CT perfusion, quantitative MRI, and diffusion tensor imaging) identified brain lesion burden due to DM. These imaging approaches have provided insights into the DM brain and cerebral circulation patho-physiology. Imaging has taught us that diabetics develop cerebral atrophy, silent infarcts, and white matter disease more rapidly than other patient populations. Longitudinal studies are needed to quantify the rate and extent of such structural brain and blood vessel changes. [356]
Lee asserted that, in contrast to diabetic cerebral macroangiopathy, assessed with many invasive and non-invasive investigations, diabetic cerebral microangiopathy, which may contribute to the development of lacunar infarction involving the small perforating artery, has no specific diagnostic tool. [345]
Several attempts have been made to detect minor modifications in their structure and function by utilising various imaging techniques. Of these, TCD ultrasonography seems to be the simplest, non-invasive and accurate method; the marked increase in the PIs of MCAs and reduced CVR measurements using TCD may be indirectly a useful predictor of cerebral microangiopathy in type 2 DM patients.The presence of cerebral microangiopathy may be of positive predictive value for the diagnosis of microangiopathic lesions in other vascular territories, such as the kidney and the retina. [345]
Cerebral vessels endothelial dysfunction (ED) in normoalbuminuric patients with type 2 diabetes mellitus. The inter-relation between chronic kidney disease (CKD) and cerebrovascular disease. Data from the literature.
The role of ED in the pathogenesis of diabetic microangiopathy is well established. Two types of modifications have been described:
a). reversible alterations in microcirculation, which are detected at an early stage in the course of DM and which consist of increased capillary pressure, blood flow and endothelial permeability,
b). irreversible structural modifications of the vessel wall, which are found in the later stages of DM and comprise the thickening of the basement membranes due to extracellular accumulation of proteins [357]and proliferation of the endothelium. [358]
ED may precede the onset of microangiopathic vascular remodelling in DM. Several factors are central in the development of these vascular lesions: hyperglycaemia, abnormalities of lipoprotein metabolism, accumulation of advanced glycation end-products, increased oxidative stress, and hyperinsulinism with associated insulin resistance. [357-360] Increased insulin responses and elevated glucose levels after oral glucose stimulation or increased fasting insulin levels have been found in patients with cerebrovascular diseases. In addition, there is a high susceptibility of the cerebral microvascular endothelium to the mitogenic and metabolic effects of insulin as compared with the endothelium from other vascular territories, and elevated insulin and C-peptide levels are associated with cerebral small-vessel disease [358,360].
The temporal relation between ED (increase in markers of ED) and albuminuria is difficult to establish in the course of type 2 DM due to the fact that in certain patients albuminuria may occur in the absence of markers of ED, while in other patients these markers have a predictive value for the occurrence of albuminuria [360,361].
These aspects point to the fact that, according to the current pathogenic hypothesis, albuminuria in the course of early diabetic nephropathy (DN) is caused by the impairment of the retrieval pathway of albumin at the level of the proximal tubule (PT), a phenomenon which precedes the glomerular lesion [360-362].
On the one hand, microalbuminuria in DM may reflect the renal manifestation of systemic ED [363], and thus glomerular ED and microalbuminuria may be considered a risk marker for cardiovascular and cerebrovascular diseases in both type 1 and type 2 DM patients [364-366].
On the other hand, multiple markers of ED (vasculopathy) have also been documented in normoalbuminuric subjects with type 2 DM, suggesting that the vasculopathy occurs before the development of microalbuminuria [367].
Intact albuminuria in DM is preceded by peptiduria which consists of albumin-derived peptides, the excretion of which may achieve nephrotic levels, according to the fact that there is an increased glomerular sieving coefficient for albumin in a normal glomerulus [362]. Thus, albuminuria in DM does not associate with modifications of the glomerular permeability, but with alterations of the capacity of albumin processing by the PT under hyperglycaemic conditions. It is considered that peptiduria may be a marker of early DN [363].
Personal contributions.
ED may be different in various vascular territories, in patients with type 2 diabetes mellitus (DM) and as such, there are different patterns of vascular damage according to the vascular bed affected at a certain point in the course of DM. [360,368-373]. In order to evaluate the pattern of ED and its potential variability in different vascular territories, we assessed in our studies (Petrica, Vlad, Jianu, et al.,) [360,368-373] the ED in two vascular beds, the kidney and the brain, both affected by diabetic vasculopathic complications. The cerebral microvascularization presents similarities to the glomerular one in terms of structure and function. ED in the cerebral vessels occurs before the endothelial impairment at the glomerular level, thus explaining why patients with type 2 DM may develop cerebral vessels structural and functional modifications while remaining normoalbuminuric. In our studies, at brain level, the plasma levels of asymmetric dimethyl-arginine (ADMA) correlated with the cerebral haemodynamic indices, evaluated by neurosonological methods (PIs, RIs, CVR, evaluated through extra- and TCD ultrasonography). [360,368-373] In studies conducted by our group (Petrica, Vlad, Jianu, et al.,) in normoalbuminuric patients with type 2 DM we have shown that PT dysfunction may precede the stage of microalbuminuria. Thus, it is possible that in early DN, sequentially, PT dysfunction precedes glomerular ED. [360-362]. Several biomarkers were utilized in our studies (Petrica, Vlad, Jianu, et al.,) [360,368-373], in order to assess PT dysfunction, and ED.
On the one hand, the increase in biomarkers for PT dysfunction in incipient DN and diabetic cerebral microangiopathy: (urinary beta2-microglobulin, and urinary alpha1-microglobulin) preceded the increase in the urine albumin: creatinine ratio (UACR), thus showing that PT dysfunction may develop before the stage of microalbuminuria. On the other hand, the levels of ADMA (a biomarker of ED) did not correlate with the UACR and the markers of PT dysfunction (urinary alpha1-microglobulin and urinary beta2-microglobulin), respectively.
The peptides which derive from advanced glycation end-products (AGES), such as glycated albumin, might have a potential nephrotoxic effect on the PT, thus contributing to the occurrence of PT dysfunction in the normoalbuminuric patients (early DN) [368,370-373]. In our studies (Petrica, Vlad, Jianu, et al.,) [360,368-373], we observed that, in patients with Type 2 DM, cerebral ED is strongly related to AGEs. Furthermore, the ED in the cerebral vessels occurs before the endothelial impairment at the glomerular level, thus explaining why patients with Type 2 DM may develop cerebral vessels structural and functional modifications while remaining normoalbuminuric.
In conclusion, it may be assumed that in the course of type 2 DM there are distinct endothelial territories, the kidney and the brain, in which ED occurs within different time frames [360,373].
Cerebral microangiopathy has a high prevalence in normotensive Type 2 DM patients. These cerebral vascular changes correlate with the duration of DM, ED, parameters of inflammation, AGEs, UACR, cystatin C, and glomerular filtration rate. [368,369]. In our studies (Petrica, Vlad, Jianu, et al.,) [368,369], the presence of cerebral microangiopathy is of predictive value for the concomitant development of diabetic nephropathy (DN) [368]. The reverse is also valid, because it may also occur in normoalbuminuric patients with type 2 DM [371].
We observed that Doppler ultrasound is a sensitive and a reliable tool in the detection of cerebral microangiopathy in diabetic patients. According to our studies (Petrica, Vlad, Jianu, et al.,) [368,369], Transcranial Doppler ultrasound (TCD) may be of positive predictive value for the strong association between DN and cerebral microangiopathy. In addition, it provides prognostic data on the potential evolution of a major cerebrovascular events. Therefore, TCD should be considered as a non-invasive, simple routine examination in diabetic patients. [368,369]
In our studies (Petrica, Vlad, Jianu, et al.,) [368,369], cerebral vascular reactivity (CVR) was impaired in normoalbuminuric patients with Type 2 DM patients. The cerebral vasodilatory capacity was diminished during hypercapnia induced by the breath-holding test. These cerebral haemodynamic changes correlated significantly with the duration of DM, glomerular filtration rate (GFR), cystatin C, plasma asymmetric dymethylarginine, plasma glycated peptides, and with parameters of inflammation [360,368-373].
1.3.3.2.5. Wien. Klin. Wochenschr. (The Middle European Journal of Medicine) 2007; 119(11-12): 365-371, Ed. Springer Wien New York.
Cerebrovascular reactivity is impaired in patients with non-insulin-dependent diabetes mellitus and microangiopathy
Authors: Ligia Petrica, Maxim Petrica, Adrian Vlad, Flaviu Bob, Cristina Gluhovschi, Gheorghe Gluhovschi, Catalin D. Jianu, Sorin Ursoniu, Adalbert Schiller, Silvia Velciov, Virginia Trandafirescu, and Gheorghe Bozdog
Introduction
The highest rates of morbidity and mortality in patients with diabetes mellitus (DM) type 1 or type 2 may be attributed to cardiovascular complications. Epidemiological studies have reported that in patients with type 2 DM, the risk of having an incident myocardial infarction or stroke is increased 2-to-3-fold and the risk of death is increased 2-fold, independent of other known risk factors for cardiovascular disease (Copenhagen City Heart Study of 13,105 subjects followed up prospectively for 20 years) [374].
DM is considered a very strong risk factor for acute stroke [375]; it is assumed that the risk of stroke is increased by 1.5–3-fold for patients with diabetes. Furthermore, DM doubles the risk of stroke recurrence, and stroke outcomes and prognosis are very poor in the long term in these patients [376]. In the Framingham Study the incidence of cerebrovascular disease in diabetic men was reported to be twice as that of non-diabetic persons and the incidence in diabetic women almost three times greater [377].
Cerebrovascular reactivity (CVR) is a hemodynamic parameter representing the increase in normal cerebral artery blood flow velocity in response to a vasodilatory stimulus such as hypercapnia. Decreased CVR is indicative of preexisting vasodilatation, reflecting reduced reserve capacity for cerebral autoregulation. Measurement of CVR provides information on the intracerebral arterioles, which may be already maximally dilated and thus unable to react to drops in blood pressure or to vasodilatory stimuli with further dilation [344].
Cerebral hemodynamics and CVR may be assessed through several methods for measuring the changes in cerebral blood flow, such as positron emission tomography (PET), single-photon emission tomography (SPECT), Xenon-computed tomography, functional magnetic resonance imaging, and transcranial Doppler (TCD) ultrasonography [292,344,378]. Various vasodilatory stimuli may be used in order to evaluate CVR; for example, the increase in arterial PCO2 (CO2 test by inhaling 5% CO2 in 95% O2) or the intravenous administration of acetazolamide (Diamox test) [33].
TCD ultrasonography is a noninvasive and nonradioactive method that enables measurement of blood flow velocities in the main intracranial arteries and changes in flow velocity after a vasodilatory stimulus such as hypercapnia. The cerebral vasodilatory capacity is impaired in patients with DM, both type 1 [379-381] and type 2 [381-383].
In patients with diabetes, CVR may be easily assessed using TCD ultrasound to evaluate the increase in mean flow velocity (MFV) in the cerebral arteries as a result of their dilatation in response to the CO2 test [344], i.v. acetazolamide [379-381], or to hypercapnia, which may be induced by the breath-holding test (BHT) [289,291,292,344].
The aim of our study was to assess CVR using TCD ultrasound and the BHT in normotensive type 2 DM patients. In addition, the cerebrovascular response to hypercapnia was evaluated in relation to risk factors for cerebral microangiopathy. Special attention was paid to diabetes specific cerebrovascular risk factors, such as glycemic control and inflammation, and the relation of the cerebral modifications to other microangiopathic complications, mainly diabetic nephropathy.
Patients and methods
Patients and controls
The study was carried out in a group of 34 normotensive non-insulin-dependent diabetes mellitus (NIDDM) patients and a group of 31 sex- and age-matched normal controls. The NIDDM group was subdivided into 21 patients (Group A: 12 men, 9 women; mean age 58.77 ± 8.91 years) who presented with microangiopathic complications (diabetic nephropathy, diabetic retinopathy and diabetic peripheral nerve disease) and 13 patients with no such complications (Group B: 8 men, 5 women; mean age 56.34 ± 9.83 years). The normal control group (Group C) consisted of 17 men and 14 women, mean age 58.43 ± 6.31 years. Exclusion criteria were hypertension and past or present symptomatic cerebrovascular disease. Metabolic control was achieved through diet, oral medication and insulin. None of the patients was on lipid-lowering drugs.
Doppler ultrasonography
All patients and normal controls were evaluated using TCD ultrasound by means of a Doppler velocimeter (Explorer CVC-DMS-Montpellier, France) with fast-Fourier transformation spectral analysis, utilizing a 2-MHz PW probe, through the transtemporal window, at a depth of 50 mm. Each middle cerebral artery (MCA) was examined separately by evaluating the MFV and the systolic and diastolic flow velocities at rest (normal respiration). CVR was assessed during the BHT as follows: the patient breathed normally by inhaling the air in the examination room and then held the breath for 20 seconds at the end of a normal inspiration. The MFV and the systolic and diastolic flow velocities were monitored for each patient and normal control in both MCAs at rest (normal respiration – normocapnia), during breath holding, and at the end of the BHT when the flow velocities reached their maximal values (hypercapnia). CVR was estimated in relation to the increase in the MFV in both MCAs during hypercapnia compared with the basal velocity in cm/sec and in % increase: normal CVR % increase > 15%; diminished CVR % increase 5–15%; exhausted CVR % increase < 5% [344].
The % increase in the MFV was correlated with both classic and diabetes – specific cerebrovascular risk factors.
Clinical and biological data
All patients and controls underwent screening for factors favoring cerebrovascular remodeling, such as: systolic blood pressure, diastolic blood pressure, serum cholesterol, triglycerides, fibrinogen, C-reactive protein, hematocrit, proteinuria, serum creatinine, daily mean glycemia (average of glycemia levels/day) and smoking (pack-years).
Statistical analysis
Data were expressed as means ± SD. One-way analysis of variance (ANOVA) was used to assess the significance of difference among the three study groups. The Bonferroni t-test was used in the post-hoc analysis.
The Bonferroni-Dunn test requires a researcher to initially stipulate the highest family-wise type I error rate that can be tolerated [384,385]. Since three simple comparisons are made for each set of data, to ensure that the family-wise type I error rate does not exceed 0.05, we decided to divide this value by three. The resulting value 0.0167 represents, for each of the comparisons that are conducted, the likelihood of committing a type I error. Thus, even if a type I error is made for all of the comparisons, the overall family-wise type I error will not exceed 0.05 (3 x 0.0167).
Univariate regression analysis was used to assess the significance of the relation between CVR and both classic and diabetes-related cerebrovascular risk factors. Multivariate regression analysis was used to exclude the possible confounding effect of other variables on the results of the correlation analysis. Epi Info v.3.2.2 and SPSS v.10 software were used for the statistical analysis. Significance was considered as P < 0.05.
The clinical and biological characteristics of the patients and control group are presented in Table 1.9. Among the patients, the duration of DM was 16.77 ± 11.23 years in the complications group vs. 7.12 ± 1.08 years in the no-complication group (P < 0.0043).
No major differences in clinical and biological parameters were found between Groups A, B and C, except for fibrinogen (P< 0.0001), C-reactive protein (P < 0.0001), glycosylated hemoglobin (P < 0.0001), fasting glycemia (P < 0.0001), proteinuria (P < 0.0001) and serum creatinine (P <0.0001).
Assessment of CVR
The increase in the MFV in both MCAs was significant in normal controls (Group C), mild in patients with non-complicated DM (Group B) and very slight in patients with complicated DM (Group A). In Group A the CVR was significantly decreased in 15 patients (71.42%), in Group B four patients (30.76%) presented with mildly to moderately impaired CVR, and the CVR was normal in Group C.
Among the patients with microangiopathic complications (Group A), 19 (90.46%) had diabetic nephropathy and 12 of the 19 (63.15%) had impaired CVR, thus highlighting the abnormal response to hypercapnia in patients who associate microangiopathic modifications in two vascular territories, the brain and the kidney.
Table 1.10. shows the differences in CVR between the three groups. Comparison of CVR assessed using the % increase in MFV during the BHT showed significant differences between Groups A and B (P < 0.0001), A and C (P < 0.0001), B and C (P < 0.0001) and A, B and C (P < 0.0001). The same differences were revealed by assessment of CVR through the increase in MFV in cm/sec: between Groups A and B (P < 0.0001), A and C (P < 0.0001), B and C (P < 0.0001) and A, B and C (P < 0.0001).
Relation of CVR and diabetes-specific cerebrovascular risk factors
Predictors for impaired % increase in the MFV during the BHT demonstrated by univariate regression analysis were: duration of DM (r = 0.802; P < 0.0001), fibrinogen (r = 0.574; P < 0.0001), C-reactive protein (r = 0.525; P < 0.001), proteinuria (r = 0.924; P < 0.0001) and serum creatinine (r = 0.969; P < 0.0001) (Table 1.11.). In the multivariate regression analysis, the % increase in MFV was the dependent variable and duration of DM, fibrinogen, C-reactive protein, proteinuria and serum creatinine were included as independent variables. Only duration of DM (P < 0.0001), proteinuria (P < 0.0001) and serum creatinine (P < 0.0001) were significantly included in the model.
Discussion
Vascular remodeling which involves cerebral vessels in DM consists of two main processes: atherosclerosis or large-artery disease (which implies carotid and middle cerebral arteries) and arteriosclerosis or small-vessel disease (which implies small cerebral vessels) [350]. The latter, known as cerebral microangiopathy, is associated with similar morphological modifications in other microvascular territories such as the kidney, the retina and the peripheral nervous system. Of special interest is the involvement of downstream cerebral small vessels, which is consistent with underlying microangiopathic modifications. This particular vascular remodeling, as demonstrated by Doppler ultrasound, has increased prevalence in patients with diabetes.
As a result of these structural and functional modifications in the cerebral small vessels, autoregulation of the cerebral blood flow is impaired, as demonstrated by the inappropriate response of the cerebral vessels to various stimuli. Impairment of cerebral artery myogenic behavior in diabetes might have significant effects on cerebrovascular hemodynamics [386]. Long-term diabetes is associated with endothelial dysfunction, with the predominance of vasoconstrictive factors and impaired endothelium-dependent vasorelaxation related to decreased nitric oxide synthesis [386,387].
One of the major triggers of inadequate endothelium-dependent vasodilation is the long-standing exposure to high levels of glucose in the course of DM, which might affect basal tone and myogenic reactivity in the cerebral small vessels. Elevated glucose levels produce vasodilation and loss of intrinsic basal tone, thus rendering arteries incapable of responding adequately to various stimuli (transmural pressure, changes in the metabolic milieu). Under these circumstances the impaired autoregulation of cerebral blood flow and the subsequent decreased vascular resistance in the downstream arterioles and capillaries may explain the reduced CVR in patients with DM [383,386,388].
CVR and reserve capacity are reduced in patients with long-term DM, both type 1 [379,380,389] and type 2 [381,382]. These modifications have been demonstrated through several methods, of which TCD ultrasound is of major importance [292,380-383,389-391].
Our study reveals decreased levels of the basal flow velocity in both MCAs and an inappropriate increase in the MFV during hypercapnia induced by the BHT in normotensive NIDDM patients with long-standing DM and microangiopathic complications. Previous studies using TCD ultrasound in diabetic patients demonstrated changes consistent with microangiopathic remodeling of the cerebral vessels [392,393]; however, hypertension, a major cerebrovascular risk factor, was present in the studied patients and might have modified the interpretation of the data. In order to exclude the interference of hypertension, other studies have been performed in normotensive patients with long-standing DM type 1 [379] and type 2 [394,395]. These studies showed that impaired hemodynamic indices may be found even in normotensive patients with DM in association with other microvascular complications of DM. The modifications were ascribed to cerebral microangiopathy, which proved to be closely related to the duration of DM [379,394,395].
Our study was therefore performed in normotensive patients, in order to avoid the possible interference of hypertension with the interpretation of data relating to diabetic cerebral microangiopathy and the vasodilatory response to hypercapnia.
It has been suggested that duration of diabetes is an important factor in determining cerebrovascular reserve capacity, as demonstrated in diabetic patients with over 10 years’ disease duration, which was also the case in our patients with complications [380,381,383].
Furthermore, impairment of CVR may be associated with increased markers of inflammation, such as fibrinogen [379] and C-reactive protein [396]. In our study, patients with severely impaired CVR presented with increased levels of both these parameters of inflammation, both correlating significantly with an inappropriate response to hypercapnia during the BHT. These modifications are an argument for the structural and functional changes of cerebral small vessels.
Hyperglycemia leads to impaired vascular function through endothelial cell dysfunction. The pathway that appears most affected in diabetic patients is that of nitric oxide; loss of this pathway is accompanied by loss of response to PaCO2 and lack of flow and pressure-related cerebral autoregulation [388,397]. Of note, HbA1c and retinopathy are related to impairment of the vasodilatory response to CO2, thus demonstrating that HbA1c is an indicator of the severity of diabetic cerebral microangiopathy [383]. In our patients with complicated DM the levels of HbA1c were significantly higher than levels in patients without complications. On correlation analysis, however, the levels of HbA1c did not correlate with cerebral hemodynamic indices.
Age is considered an important factor in the cerebrovascular response to hypercapnia, as CVR is markedly lower in elderly patients than in younger ones [383]. Our patients were of near similar ages and therefore this parameter did not interfere with interpretation of the data.
The presence of cerebral microangiopathy has predictive value for concomitant development of diabetic nephropathy, but the reverse is also true. Albuminuria is significantly related to intracranial cerebrovascular disease and may be accepted as an independent predictor of increasing levels of vascular risk factors and microvascular and macrovascular disease in patients with type 2 diabetes [398]. Moreover, microalbuminuria may identify cerebrovascular diabetic involvement and modifications of brain vasomotor reactivity, as it predicts both macroangiopathic and microangiopathic brain impairment [355,399].
Our results are in keeping with these observations, as a high percentage of the patients with diabetic nephropathy in the group with complications of DM presented with modified response to the BHT, consistent with abnormalities of the cerebral vascular tonus and alterations in brain vasomotor reserve. Also, proteinuria and serum creatinine correlated independently with the modified hemodynamic parameters. Serum creatinine seems to be particularly relevant for our study addressing cerebral small vessel involvement, since this parameter has been proved instrumental in the occurrence of atherosclerotic disease of large cerebral vessels such as the internal carotid artery [400].
Other studies highlight the possible association between retinopathy and abnormal cerebrovascular CO2 response [383]. Impaired CVR may be associated with retinopathy and nephropathy [379,392], which was the case with our patients too. However, impaired cerebrovascular reserve capacity may not be associated with peripheral neuropathy in the setting of microangiopathic complications, as the CVR might be predominantly due to structural changes of resistant arteries or to metabolic rather than neurogenic factors [402].
From the practical standpoint, CVR may be assessed using several methods, among which TCD ultrasound is a noninvasive method that may accurately indicate the severity of microangiopathy. The accuracy of TCD ultrasound is comparable to that of other noninvasive methods such as CT scan, MRI, PET and SPECT, and when performed during hypercapnia may demonstrate reduced vasomotor reactivity in diabetic patients [383,390]. TCD ultrasound is a reliable tool in the detection of diabetic cerebral microangiopathy and its consequences on the vascular tonus at a very early stage of endothelial dysfunction, and may indicate impaired vasodilatory response caused by a lack of dilative agents under regulative conditions, thus increasing rigidity of the vessel wall [383,389].
The BHT is a useful method in the assessment of CVR by TCD ultrasound, and is easier to perform than the CO2 test or the acetazolamide test [378]. It has an excellent clinical tolerance, a fact observed in our patients too; the only adverse effect was a compelling urge to breathe by the end of the apneic phase, recorded in five patients. Nevertheless, several sources of error may occur, of which the most notable seems to be that during the BHT PaCO2 may rise at different rates in different subjects [378].
A highly impaired CVR, which occurs in patients with long-standing DM and microangiopathic complications, is of predictive value in identifying patients at increased risk of developing stroke in the long term [402].
In conclusion, CVR is impaired in normotensive NIDDM patients. Cerebral vasodilatory capacity is diminished during hypercapnia induced by the BHT, and these cerebral hemodynamic changes correlate significantly with the duration of DM and with proteinuria, serum creatinine and parameters of inflammation. TCD ultrasound and the BHT proved to be a reliable tool in the assessment of CVR in these patients and we therefore suggest it should be performed on a routine basis in diabetic patients in order to detect those with cerebral microvascular modifications.
1.3.3.2.6. J Diabetes Complications, March 2015, Volume 29, Issue 2, pg 230-237
Glycated peptides are associated with the variability of endotelial dysfunction in the cerebral vessels and the kidney in type 2 diabetes mellitus patients: a cross-sectional study
Authors: Ligia Petrica, Adrian Vlad, Gheorghe Gluhovschi, Florica Gadalean, Victor Dumitrascu, Daliborca Vlad, Roxana Popescu, Silvia Velciov, Cristina Gluhovschi, Flaviu Bob, Sorin Ursoniu, Maxim Petrica, Dragos Catalin Jianu
1.Introduction
Diabetes mellitus (DM) is now the leading cause of end-stage renal disease worldwide and may be attributed up to 20-40% of cases referred to renal replacement therapies, both in developed and emerging countries [403].
The epidemiology of microalbuminuria shows a close association with systemic endothelial dysfunction, thus involving glomerular endothelial dysfunction and microalbuminuria in cardiovascular and cerebrovascular disease [364-366]. Due to the fact that microalbuminuria is related to endothelial dysfunction, diabetic atherosclerosis and microangiopathy parallel diabetic nephropathy (DN), thus albuminuria may be considered a very powerful risk marker for cardiovascular and cerebrovascular disease in both type 1 and type 2 DM patients.
It is assumed that the course and the degree of albuminuria do not represent a sufficiently significant and robust marker for the development of chronic kidney disease (CKD) in the course of DM. The onset of albuminuria is not conditional on the development of diabetic CKD in both type 1 DM [404], and type 2 DM [405]. Albuminuria should be regarded as a dynamic process and a continuous variable, with a high potential to transform into normo-albuminuria or proteinuria. The changes in albuminuria are dynamic, under active control and subject to change, while changes in the glomerular filtration rate (GFR) are progressive, a process that is advancing and continuously increasing in severity [406]. Also, it is worth underlining that in patients with glomerular hyperfiltration, as compared to patients with normal eGFR, this glomerular phenomenon is a trigger for proximal tubule (PT) dysfunction in early DN [407].
The explanations concerning the mechanisms of albuminuria in the course of diabetic CKD have raised a heated debate which attempts at establishing a consensus between the glomerular theory and the tubular theory in the occurrence of albuminuria. These two theories have been proposed starting from the observation according to which the progressive decline in renal function may develop in normoalbuminuric patients with type 1 DM [404,406] and type 2 DM [405]. Multiple markers of endothelial dysfunction have been documented in normoalbuminuric subjects with type 2 DM, suggesting that the vasculopathy occurs before the development of microalbuminuria [367]. These observations point to the fact that endothelial dysfunction may be different in various vascular territories. We forward the hypothesis that there are different patterns of vascular damage according to the vascular bed affected at a certain point in the course of DM. In our previous studies we showed that in normo-albuminuric patients with type 2 DM, glomerular endothelial dysfunction is dissociated from endothelial dysfunction in the brain, another organ of which the vasculature shares similarities in terms of structure and function with the glomerular microvascularization [360,372].
Higher levels of advanced glycation end-products (AGE) are associated with incident fatal and non-fatal cardio- and cerebrovascular disease, as well as all-cause mortality in individuals with type 1 DM [408]. Glycated albumin has a proven role in the occurrence of microvascular complications in patients with type 1 DM [409] and type 2 DM [410], even prior to onset of DN. Moreover, AGE are strong contributors to impaired vasodilatory responses [411].
Based on these research hypotheses, we aimed at evaluating the pattern of endothelial dysfunction in two vascular territories, the kidney and the brain, both affected by diabetic vasculopathic complications. The endothelial variability was evaluated in relation to plasma and urinary AGE-modified peptides.
2.Materials and methods
2.1.Subjects
A total of 70 patients with type 2 DM attending the Outpatient Department of Diabetes and Metabolic Diseases (from January 2013 through March 2013) [48 patients with normo-albuminuria (group 1) and 22 patients with microalbuminuria (group2)] and 11 healthy control subjects (group3) were enrolled in a cross-sectional study. The inclusion criteria were DM duration higher than 5 years, normo-albuminuria [urine albumin: creatinine ratio (UACR) b 30 mg/g)] or microalbuminuria (UACR N 30 mg/g), therapy with oral antidiabetic drugs, angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers, and statins. Exclusion criteria were symptoms and/or history of cerebrovascular disease (transient ischemic attack, stroke), as well as stenoses or occlusions in the vessels examined.
The County Emergency Hospital Ethics Committee (Board of Human Studies) approved the protocol (approval number 4/ 11.01.2013), and every patient provided written informed consent before enrolment.
2.2.Laboratory assessments
All patients were assessed concerning UACR; plasma and urinary AGE; plasma asymmetric dimethyl-arginine (ADMA) was utilized as a biomarker of endothelial dysfunction due to its close relationship with nitric oxide (NO) release and the intervention in vascular response to flow-mediated stimuli; and serum cystatin C. Serum and urinary biomarkers were determined in specimens frozen at −80 °C and thawed before assay. Chronic kidney disease was defined according to the KDIGO Guideline for the Evaluation and Management of chronic kidney disease (2009 CKD-EPI cystatin C-creatinine equation) [412,413].
2.2.1.Plasma ADMA was evaluated by the ELISA method with K7828 ADMA ELISA Kit (Immunodiagnostik AG, Bensheim, Germany). The reference interval was 0.45 ± 0.19 μmol/l. The intra-assay precision was 6.2–10.5% (0.27 ± 0.021 μmol/l; 0.78 ± 0.041 μmol/l), while the inter-assay precision was 6.2–7.9% (0.33 ± 0.029 μmol/l; 0.79 ± 0.045 μmol/l).
2.2.2.Cystatin C was assessed in serum with N Latex Cystatin C Kit (Siemens Healthcare Diagnostics, Marburg, Germany) through particle-enhanced immunonephelometry using the BNProSpec System. The reference interval was calculated nonparametrically and was determined to be 0.53–0.95 mg/l. The intra-assay precision was 2.5% coefficient of variation (CV) and inter-assay precision was 2.0% CV with a total of 2.8% CV. Analytical sensitivity was calculated as two standard deviations above the mean signal of 20 replicates of N diluent and was determined to be 0.005 mg/l. A typical detection for N Latex Cystatin C is 0.05 mg/l.
2.2.3.Albuminuria was measured in the second morning urine specimen through immunonephelometry on the BNProSpec System, with N Antiserum to Human Albumin (Siemens Healthcare Diagnostics, Marburg, Germany). Microalbuminuria was defined by UACR between 30 and 300 mg/g, and normoalbuminuria by UACR b 30 mg/g. The N Antiserum to Human Albumin was evaluated for the assay of urine on a BN System and yielded a Within-Run CV of 2.2% and a total CV of 2.6% with a mean of 79 mg/l. The results (ten runs, four determinations per run) were evaluated by analysis of variance. Urine cultures were negative for bacteriuria in all patients.
2.2.4.Plasma and urinary AGE peptides were assessed by the ELISA method with Human Advanced Glycosylation End-Products ELISA Kit (E01A0002), Shanghai Blue Gene Biotech Co., Shanghai, China. The sensitivity in this assay measured in two 24-hour urine samples was 1.0 pg/ml. This assay has high sensitivity and excellent specificity of AGE. This assay contains polyclonal antibodies that assess protein-bound AGE. The system utilized allows the assessment of both high and low molecular AGE species. No significant cross-reactivity or interference between AGE and analogues was observed.
2.3.Cerebrovascular ultrasound measurements
2.3.1.Measurement of intima-media thickness (IMT) was performed in the commoncarotid arteries (CCA), bilaterally, with a high- resolution carotid artery ultrasound equipment (MYLAB 50-ESAOTE, Italy), provided with PW and CW Doppler, colour and power Doppler and a linear transducer of 5–7.5 MHz.
All scanning throughout the study was performed by two experienced neurologists at the same location using the same equipment. The mean inter-observer difference was 0.002 ± 0.049 mm. The ultrasound beam was adjusted to obtain longitudinal scans of the right and the left CCA to assess two parallel echogenic lines corresponding to the blood–intima and media–adventitia interface on the posterior wall of the artery. The localized thickness of more than 2 mm was excluded as plaque lesion. IMT values were averaged on three determinations for both CCA, and the greater value of averaged IMT was considered significant for each measurement (normal range values—up to 1 mm). The CV of the repeated IMT measurement was 1% [414].
2.3.2.The pulsatility indices (PI) and resistance indices (RI) in the internal carotid arteries (ICA) were assessed by extracranial Doppler ultrasound with fast-Fourier spectral transformation analysis (Explorer CVC-Montpellier, France); a continuous wave (4 MHz-CW) probe was utilized for extracranial Doppler ultrasound exploration of the ICA, bilaterally, with regard to their patency, the Gosling's PI [(systolic flow velocity − diastolic flow velocity)/mean flow velocity; normal range values PI b 1], and the Pourcelot's RI in the ICA, which evaluates the distensibility and compliance of the sonorized arteries [(systolic flow velocity − diastolic flow velocity)/systolic flow velocity) (normal range values RI <0.7); a pulsed-wave (2 MHz-PW) probe was utilized for transcranial Doppler ultrasound of the middle cerebral arteries (MCA), bilaterally, through the transtemporal window at a depth of 50 mm. The patency of the vessels, the PI and the RI were estimated for each artery as described above [414].
2.3.3.The cerebrovascular reactivity (CVR) was evaluated in the MCA (with the same transcranial Doppler ultrasound equipment as described above) by the breath-holding test (BHT). Both MCA were examined separately by evaluating the mean flow velocity (MFV), systolic flow velocity and diastolic flow velocity at rest (normal respiration). The patient breathes normally by inhaling the air from the examination room, holding breath thereafter for 30 seconds by the end of a normal inspiration. The MFV, systolic flow velocity and diastolic flow velocity were monitored for each patient in both MCA at rest (normal respiration—normocapnia), during the maneuver of breath-holding and by the end of the BHT, when the flow velocities reached their maximal values (hypercapnia). The CVR was estimated in relationship with the increase in the MFV in both MCA during hypercapnia as compared to the resting velocity. BHI is obtained by dividing the percentage increase in the MFV occurring during the BHT by the length of time (seconds) that patients held their breath after a normal inspiration [(MFV at the end of BHT − MFV at rest)/MFV at rest] × 100/seconds of breath-holding [291,289].
2.4.Statistical analysis
Clinical, biological and cerebral hemodynamic indices are present- ed as medians and IQR, as for variables with skewed distribution. Mann–Whitney U test was used to compare two groups (group 1 vs. 2, group 1 vs. 3, group 2 vs. 3) and the Kruskal–Wallis test was used to compare the three groups of sample data.
Univariable regression analyses were carried out to evaluate the significance of the relation between continuous variables. Only significant variables yielded by univariable regression analysis were introduced in the models for multivariable regression analysis. The p values for all hypothesis tests were two-sided, and statistical significance was set at p <0.05. All analyses were conducted with Stata 9.2 (Statacorp, Texas, USA).
3.Results
Characteristics of the study subjects are presented in Table 1.12. as medians and IQR. There were no significant differences between the right and left CCA, ICA, and MCA with regard to the neurosonological parameters studied. Therefore, the correlations in the regression analyses were carried out with the parameters yielded by the right CCA, ICA, and MCA measurements, respectively. None of the groups studied displayed glomerular hyperfiltration as assessed by the eGFR. The results of the univariable regression analysis concerning ADMA are presented in Table 1.13. Potential confounders for ADMA, such as age, hypertension, and the lipid profile have been included in the analysis. Plasma ADMA, a marker of endothelial dysfunction, showed no correlation with UACR, but only with high sensitivity C reactive protein (hsCRP), plasma AGE, serum cystatin C, estimated glomerular filtration rate (eGFR), and DM duration. Also, there was a significant correlation of UACR with urinary AGE (R2 = 0.257; p <0.001).
Univariable regression analysis showed significant correlations of IMT-CCA, RI-ICA, PI-ICA, RI-MCA, PI-MCA, and BHI with plasma ADMA, plasma AGE, hsCRP, duration of DM, glycated hemoglobin (HbA1c), cystatin C, and eGFR (Table 1.14.). Multivariable models for the cerebral hemodynamic indices were adjusted for age, sex, BMI, DM duration, blood pressure, HbA1c, eGFR, lipid profiles, hsCRP, plasma AGE, plasma ADMA, and cystatin C, as independent variables. The results showed significant correlations of the cerebral hemodynamic indices (PI-MCA, PI-ICA, RI-MCA, RI-ICA, IMT-CCA, BHI) with cystatin C, hsCRP, and DM duration (R2 = 0.745; R2 = 0.692; R2 = 0.692; R2 = 0.627; R2 = 0.649; R2 = 0.554; p <0.001), while the correla- tion of ADMA with AGE, hsCRP, and cystatin C also remained significant (R2 = 0.394; p <0.001) (Table 1.15.).
4.Discussion
In our study we found that in normoalbuminuric patients with type 2 DM, endothelial dysfunction in the cerebral vessels did not parallel glomerular endothelial dysfunction. Cerebral ultrasound measurements revealed cerebral vessels involvement and a significant association with endothelial dysfunction as assessed by ADMA, with plasma AGE, inflammation, duration of DM, metabolic control, serum cystatin C, and eGFR, even in the normoalbuminuria stage. The results provided by our study emphasize the importance for the clinical practice of an early approach to cerebral vessels impairment in normoalbuminuric patients with type 2 DM, a group often considered at low risk of developing major cerebrovascular events.
4.1.Endothelial dysfunction in early DN
Endothelial dysfunction may occur in patients with type 2 DM even when the patients are still normoalbuminuric, a fact demonstrated by markers of endothelial dysfunction which may be elevated years before any evidence of microangiopathic complications in both types of DM [415].
NO is synthesized by the vascular endothelium from the aminoacid L-arginine by constitutive and inducible NO-synthase and plays an important role in the maintenance of vascular homeostasis. The endogenous L-arginine metabolite, ADMA, inhibits cellular L-arginine uptake and NO-synthase activity. Circulating ADMA is elevated in patients with overt DN, even when the GFR is still within normal range [416].
It has been stated that in both normo- and microalbuminuric diabetic patients, plasma ADMA levels have prognostic implications for the transition to a more advanced stage of albuminuria [417].
In our study, ADMA levels were increased in a small number of the normoalbuminuric patients and did not correlate with UACR. Plasma ADMA correlated with inflammation, plasma AGE, serum cystatin C, eGFR, and DM duration. These results revealed in our normoalbuminuric patients are close to the data found in microalbuminuric patients with type 2 DM [418], thus giving rise to the speculation that an inflammatory state at the glomerular level may be found in normoalbuminuric patients with type 2 DM. This inflammatory state could represent a stage of endothelial impairment preceding the expression of glomerular endothelial dysfunction.
In previous studies we demonstrated that in early DN, PT dysfunction precedes glomerular endothelial dysfunction, and could explain the steady decline in renal function (as assessed by cystatin C and eGFR) in type 2 DM patients while remaining normoalbuminuric. Moreover, there was no association between endothelial dysfunction demonstrated within the brain vasculature and PT dysfunction, as shown by the lack of correlation between the cerebral hemodynamic parameters and the biomarkers of PT dysfunction studied (urinary alpha1-microglobulin and urinary beta2-microglobulin) [360].
In another study performed by us in type 2 DM patients we found that urinary AGE did not correlate with ADMA, a biomarker of endothelial dysfunction, but only with biomarkers of PT dysfunction (urinary alpha1-microglobulin and urinary kidney injury molecule-1), thus showing that the expression of glomerular endothelial dysfunction is not conditional on the onset of albuminuria in early DN [419].
4.2.AGE-mediated endothelial dysfunction in the cerebral vessels
Due to the fact that in our patients there was a lack of correlation between ADMA, a biomarker of endothelial dysfunction and UACR, we queried whether in the course of type 2 DM there may be different vascular territories. In order to clarify this assumption, we evaluated endothelial dysfunction in the brain vasculature, which shares structural and functional similarities with renal vascularization.
The genetic background linked to endothelial dysfunction is also important. Calcium/calmodulin-dependent kinases, of which CaMK4 and its genetic polymorphism could affect endothelial functions, such as the control of vascular resistance, and changes in its level of expression or activity in endothelial cells might alter the fine regulation of vascular responses and its interactions with eNOS [420]. G-protein coupled receptor kinases (GRKs) and functional genetic polymorphisms in the genes coding for GRK2 (ADRBK1) and GRK5 (GRK5) might intervene in endothelial dysfunction and its variability in different vascular territories [421,422]. These genetic polymorphism data, although instrumental in endothelial dysfunction, were beyond the scope of our study in which we assessed endothelial behavior in relation to AGE.
4.3.Atherosclerotic remodelling of cerebral vessels
Carotid artery IMT is a parameter that evaluates atherosclerotic remodelling of cerebral vessels and its increased values are consid- ered a surrogate marker for cardiovascular and cerebrovascular risk [423], even in high-to-normal albuminuric diabetic patients [424].
In our study, IMT-CCA correlated with plasma ADMA, plasma AGE, hsCRP, DM duration, HbA1c, cystatin C, and eGFR, similarly to the results provided by other studies performed by us in normoalbuminuric patients with type 2 DM [360,370,372]. ADMA has a very narrow range of normal concentrations. Even when these concentrations are only slightly increased, ADMA is associated with high cardiovascular and cerebro-vascular risks in type 1 and type 2 DM [425].
AGE promote atherosclerosis through binding to their receptor, RAGE. Soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE) are associated with atherosclerotic risk factors in early- stage atherosclerosis, suggesting that their levels evolve in correlation with those of metabolic components and inflammation. Low-sRAGE and esRAGE levels are associated with high IMT-CCA [426,427].
A negative correlation between the carotid IMT and GFR has been demonstrated [428], an observation also valid in normoalbuminuric patients with type 2 DM [429], as was the case with our patients too. It should be underlined that this correlation was valid in our patients when the analysis included eGFR based on cystatin C and serum creatinine. Cystatin C was significantly and gradually associated with future cardiovascular events in patients with carotid atherosclerosis. In contrast, neither serum creatinine, nor estimated GFR based on serum creatinine was a significant predictor of adverse cardiovascular and cerebrovascular outcomes [430].
4.4.Diabetic cerebral microangiopathy
The underlying pathological condition of diabetic cerebral microan- giopathy is arteriosclerosis, which increases the resistance of cerebral vessels. ADMA may increase vascular stiffness and decrease cerebral perfusion in diabetic patients [431]. Plasma ADMA levels are directly involved in the microangiopathy-related cerebral damage in normoalbuminuric diabetic patients [360,372,432].
The PI and RI reflect vascular resistance distal to the artery examined. Impairment in the small intracerebral perforating arteries mainly involved in diabetic cerebral microangiopathy may be evaluated by assessment of the PI and RI in the carotid and vertebrobasilar arteries, and MCA [360,372,394,425].
In our study, the PI and RI in the ICA and MCA correlated with plasma ADMA, plasma AGE, hsCRP, DM duration, HbA1c, cystatin C, and eGFR, data consistent with previous studies [360,368,369,372,425]. Soluble RAGE can neutralize the adverse effects of RAGE signaling by acting as a decoy. RAGE signaling contributes to the development of diabetic microangiopathy and of severe acute stroke. Kidneys play a role in the removal of sRAGE. RAGE signaling can contribute to the deterioration of neuronal damage under severe leukoaraiosis, resultng in severe acute stroke patients and poor prognosis of these patients [433].
4.5.AGE-induced impaired cerebral auto-regulation
CVR is a hemodynamic parameter that represents normal flow velocity increase in the cerebral artery blood flow in response to a vasodilatory stimulus. A decreased CVR is indicative of pre-existing vasodilatation, which reflects reduced reserve capacity of cerebral auto-regulation [414]. The cerebral vasodilatory capacity is impaired in patients with type 2 DM [360,369,372,381,383,425].
It has been demonstrated that NO is a critical regulator of brain perfusion, a fact supported by the presence of NO-synthase in the brain and cerebral arteries [432]. Long-term DM is associated with endothelial dysfunction, which results in a decreased release of endothelial NO and consequently affects the ability of cerebral vessels to relax efficiently [388,431,434]. CO2 vasoreactivity of the cerebral vasculature is impaired in patients with endothelial dysfunction and may serve as a surrogate of cerebrovascular endothelial function [434]. Because ADMA is produced in relatively high amounts in the brain, it may be an important endogenous modulator of cerebral vasculature tone under resting conditions and in response to vasoreactive stimuli, including hypercapnia [431].
Our present study reveals decreased levels of basal flow velocity in both MCA and an inappropriate increase in MFV during hypercapnia induced by the BHT in normoalbuminuric patients with type 2 DM, as described previously [360,370,372].
The BHI in the MCA correlated with ADMA, thus confirming the involvement of ADMA in impaired endothelial-dependent vasodilatation of cerebral vessels during hypercapnia. In addition, the BHI correlated with DM duration, HbA1c, plasma ADMA, plasma AGE, hsCRP, cystatin C, and eGFR, which is in agreement with previous results in patients with type 2 DM [360,369,370,372,381].
Although impaired CVR has been described in patients with DN and type 1 DM [435] and type 2 DM [369], in our study impaired CVR occurred even in normoalbuminuric patients with type 2 DM, thus showing that endothelial response in cerebral vessels changes early in the course of DM, as compared to the response of the glomerular endothelium [360,372].
In our study, plasma AGE were increased in patients with CVR impairment, even in the normoalbuminuria stage. It is very likely that glycated peptides modulate NO-synthase activity in the cerebral vessels’ endothelial cells [436].
The binding of AGE albumin complexes to the brain vasculature suggests the presence of receptors for AGE on the surface of the brain microvascular endothelium [437]. The excessive accumulation of AGE-modified proteins in the cerebral vasculature alters the local environment and microcirculation, and thereby contributes to the development of impaired vasodilatory capacity and to cognitive dysfunction in diabetic patients [438].
As shown by our results, we believe that plasma glycated peptides are an important causative factor of vascular dysfunction linked to the induction of NO resistance. AGE-modified rat serum albumin had a significant influence on the impaired vasodilatory response to acetylcholine [439], similar to that one seen in our present and previous studies utilizing hypercapnia during the BHT [360,369,370,372].
Our study has several limitations. First, the small study cohort affects the statistical power of the study. Second, despite significant correlations in multivariable analysis between the variables studied, residual confounding factors could have interfered interpretation of data, such as the extent and intervention of tubulointerstitial injury, as well as of genetic polymorphisms related to endothelial dysfunction. Third, blood CO2 levels were not assessed during the BHT in order to increase the accuracy of the measurements. Finally, this is a single-center cross-sectional study that requires validation by a follow-up protocol in a longitudinal study in order to prove causality between glycated peptides and cerebral vessels endothelial dysfunction.
In conclusion, in type 2 DM patients, AGE could impact both the cerebral vessels and the glomerular endothelium. Presumably, AGE- induced endothelial dysfunction may occur initially in the brain vasculature, even in the normoalbuminuria stage. Thus, endothelial dysfunction in the cerebral vessels appears to be dissociated from glomerular endothelial dysfunction in early DN. It may be assumed that in the course of type 2 DM there are distinct endothelial territories, in which endothelial dysfunction occurs within different time frames. This observation points to the clinical implication of an early approach to cerebral vessels impairment in normoalbuminuric patients with type 2 DM, often perceived as a group of patients at low risk of developing cerebrovascular complications. Further prospective studies on larger cohorts are warranted in order to support these data.
1.3.3.3. Concluding remarks
1. TransIent Perivascular Inflammation of the Carotid artery (TIPIC) syndrome should be consider in the differential diagnosis of neck pain.
We propose four major criteria as follows: a).presence of acute pain overlying the carotid artery, which may or may not radiate to the head, b).eccentric perivascular infiltration (PVI) on imaging, c).exclusion of another vascular or nonvascular diagnosis with imaging, d).improvement within 14 days either spontaneously or with anti-inflammatory treatment.
Ultrasonography is a suitable examination for screening because it can detect PVI with high accuracy, similar to other imaging methods, but without any exposure to radiation, high magnetic fields, or the administration of intravenous contrast agents.
2. Carotid body paragangliomas (CBPGLs), which are hypervascularized tumors of the carotid body are represented by a painless cervical mass, usually with no functional or bilateral neck tumors.
We propose that the imaging techniques for diagnosis of CBPGLs be performed in the following sequence: (a) duplex ultrasound, (b) MRI, and (c) MR-A. Duplex ultrasound helps define vascularity of the tumor (data regarding blood flow in the mass itself), and precise tumor location at carotid bifurcation.
Relatively early evaluation of CBPGL can be possible using multidisciplinary teams. Tumors early diagnosis, and complete surgical excision are imperative (only Shamblin group II tumors), minimizing the known risk of complications associated with large CBPGLs (Shamblin group III)
3. The congenital anomalies of the supra-aortic arteries and their branches as potential risk factors for ischemic stroke are not yet fully investigated and understood. In the situation of multiple congenital anomalies of carotid and vertebral arteries, their diagnosis is based on combined use of duplex ultrasound and CTA.
In our opinion, internal carotid artery (ICA) and vertebral artery (VA) dysgenesis, in coexistence with other risk factors for stroke, may be involved in ischemic stroke pathogenesis.
4. Large Giant Cell Arteritis (GCA).
Duplex ultrasonography has a high sensitivity to detect the“dark halo”sign in the case of large vessel vasculitis such as GCA. In a few cases of our studies, the common carotid arteries and the ICAs are also involved. In our opinion, in the case of concordant clinical and sonographic results, temporal arteries biopsy (TAB) is not justified.
5. Giant Cell Arteritis (GCA) with Eye Involvement.
The eye involvement in Horton’s disease consists in arteritic anterior ischemic optic neuropathy or central retinal artery occlusion, with abrupt, painless, and severe loss of vision of the involved eye.
Because Duplex ultrasonographic data of temporal arteries do not correlate with eye complications, Color Doppler imaging of the orbital (retrobulbar) vessels is of critical importance, in order to quickly differentiate the mechanism of eye involvement (arteritic, versus non-arteritic); the former should be treated promptly with systemic corticosteroids to prevent further visual loss of the fellow eye.
The Spectral Doppler Analysis of the orbital vessels in GCA with eye involvement reveales low blood velocities, especially end-diastolic velocities, and high resistance index (RI) in all retrobulbar vessels, in both orbits, for all patients (especially on the affected side).
6. Vascular aphasias and duplex ultrasound
Aphasia represents a central disorder of language that impairs a person's ability to understand and produce spoken and written language. Vascular aphasias (aphasias in ischemic stroke) have not typically corresponded to linguistic domains because lesions involve vascular territories, rather than being restricted to the dorsal fronto-parietal language network or the ventral temporal language network, for example.
Duplex ultrasound is a reliable method for the evaluation of the intracranial ICAs and middle cerebral arteries stenosis/occlusions and helps identify the intracranial hemodynamic impairment in the extra-cranial (cervical) ICAs diseases causing vascular aphasias.
7. In type 2 diabetes mellitus (DM) there are distinct endothelial territories in two vascular beds, the kidney and the brain, in which endothhelial dysfunction (ED) occurs within different time frames.
Endothelial dysfunction in the cerebral vessels occurs before the endothelial impairment at the glomerular level, thus explaining why patients with type 2 DM may develop cerebral vessels structural and functional modifications while remaining normoalbuminuric. At brain level, the plasma levels of a biomarker of ED, asymmetric dimethyl-arginine (ADMA) correlated with the cerebral hemodynamic indices, evaluated by neurosonological methods (pulsatile index-PIs, RIs, cerebral vascular reactivity-CVR, evaluated through extra- and transcranial Doppler-TCD ultrasonography).
8. In normoalbuminuric patients with type 2 DM, proximal tubule dysfunction may precede the stage of microalbuminuria.
It is possible that in early diabetic nephropathy, sequentially, proximal tubule dysfunction precedes glomerular endothelial dysfunction.
On one hand, the increase in biomarkers for proximal tubule dysfunction in incipient diabetic nephropathy and diabetic cerebral microangiopathy: (urinary beta2-microglobulin, and urinary alpha1-microglobulin) preceded the increase in the urine albumin: creatinine ratio (UACR), thus showing that PT dysfunction may develop before the stage of microalbuminuria.
On the other hand, the levels of asymmetric dimethyl-arginine (ADMA) (a biomarker of ED) did not correlate with the UACR and the markers of PT dysfunction (urinary alpha1-microglobulin and urinary beta2-microglobulin), respectively.
9. In our studies we found that plasma glycated peptides (AGEs) are directly involved in the endothelial dysfunction in the brain vasculature, and are associated with the proximal tubule dysfunction in normoalbuminuric patients with Type 2 DM. Proximal tubule dysfunction induced by AGEs is the key factor which could make the difference between normo-and microalbuminuric patients.
10. Cerebrovascular microangiopathy has a high prevalence in normotensive type 2 DM patients. The presence of cerebral microangiopathy is of predictive value for the concomitant development of diabetic neuropathy. The reverse is also valid, because it may also occur in normoalbuminuric patients with type 2 DM.
11. Doppler ultrasound is a sensitive and a reliable tool in the detection of cerebral microangiopathy in diabetic patients. TCD may be of positive predictive value for the strong association between diabetic neuropathy and cerebral microangiopathy. In addition, it provides prognostic data on the potential evolution of a major cerebrovascular event. Therefore, TCD should be considered as a non-invasive, simple routine examination in diabetic patients.
12. Cerebrovascular reactivity (CVR) is impaired in normoalbuminuric type 2 DM patients. The cerebral vasodilator capacity is diminished during hypercapnia induced by the breath-holding test (BHT). These cerebral haemodynamic changes correlate significantly with duration of DM, endothelial dysfunction, parameters of inflammation, AGEs, UACR, cystatin C, and glomerular filtration rate. TCD and the BHT proved to be a reliable tool in the assessment of CVR in these patients.
First Appendix – Tables
Table 1.1.: Characteristics of patients
Table 1.2: Diagnostic imaging data
Table 1.3: Follow-up imaging data
Table 1.4.: Clinical presentation of unilateral carotid body paragangliomas (CBPGLs)
Table 1.5: Comparison of major features of arteritic anterior optic neuropathies (A-AION) and non-arteritic anterior ischemic optic neuropathies (NA-AION) patients
TAs – temporal arteries; ESR – erithrocyte sedimentation rate; CRP – C-reactive protein; PCAs – posterior ciliary arteries; RI – resistance index.
Table 1.6. – The threshold values of resistance index (RI) in the orbital vessels and the corresponding values of sensitivity (Se), specificity (Sn), positive predictive value (PPV) and negative predictive value (NPV)
CRA – central retinal artery; PCA t – temporal posterior ciliary artery; PCA n – nasal posterior ciliary artery; OA – ophthalmic artery.
Table 1.7.: TCD criteria for intracranial stenosis (ICAS) [273]
MCA: middle cerebral artery, ACA: anterior cerebral artery, PCA: posterior cerebral artery, BA: basilar artery, VA: vertebral artery, MFV: mean flow velocity, n.a.: not available, SPR: stenotic/prestenotic MFV ratio.
Table 1.8: TCCS criteria for intracranial stenosis (ICAS) [281]
MCA: middle cerebral artery, ACA: anterior cerebral artery, PCA: posterior cerebral artery, BA: basilar artery, VA: vertebral artery, PSV: peak systolic velocity.
Table 1.9: Comparison of clinical and biological data in diabetes mellitus patients with or without complications and in normal controls
Comparison between groups AB, BC, AC: Student’s t-test; comparison between groups ABC: one-way ANOVA, statistical significance P < 0.05; post-hoc Bonferroni t-test, statistical significance *P < 0.0167; SBP systolic blood pressure, DBP diastolic blood pressure
Table 1.10.: Comparison of cerebrovascular reactivity in diabetes mellitus patients with or without complications and in normal controls
CVR cerebrovascular reactivity, RMCA right middle cerebral artery; one-way ANOVA; significance P < 0.05.
Table 1.11: Predictors for impaired mean flow velocity (MFV) % increase; univariate regression analysis; significance P < 0.05
Table 1.12
Clinical and biological data of the patients studied.
DM—diabetes mellitus, SBP—systolic blood pressure, DBP—diastolic blood pressure, Hb—hemoglobin, eGFR—estimated glomerular filtration rate (cyst C-creat), HbA1c—glycated hemoglobin, ADMA—asymmetric dymethyl-arginine, RI—resistance index, PI—pulsatility index, IMT—intima–media thickness, CCA—common carotid artery, ICA—internal carotid artery, MCA—middle cerebral artery, BHI—breath-holding index; clinical, biological and cerebral hemodynamic indices are presented as medians and IQR, as for variables with skewed distribution. Mann–Whitney U test was used to compare two groups (group 1 vs. 2—p*, group 1 vs. 3—p**, group 2 vs. 3—p***) and the Kruskal–Wallis test was used to compare the three groups of sample data (p)
Table 1.13.
Univariable regression analysis for ADMA.
ADMA—asymmetric dimethyl-arginine, hsCRP—high-sensitive C-reactive protein, DM—diabetes mellitus, eGFR (cyst C-creat)—glomerular filtration rate, HbA1c —glycated hemoglobin, AGE-advanced glycation end-products, UACR—urine albumin:creatinine ratio; SBP—systolic blood pressure; DBP—diastolic blood pressure.
Table 1.14. Unvariable regression and analysis for the cerebral hemodynamic indices.
BHI—breath-holding index, IMT—intima-media thickness, CCA—common carotid artery, RI—resistance index, ICA—internal carotid artery, PI—pulsatility index, MCA—middle cerebral artery, ADMA—asymmetric dimethyl-arginine, AGE—advanced glycated end-products, hsCRP—high sensitivity C reactive protein, eGFR (cyst C-creat)—glomerular filtration rate, DM—diabetes mellitus.
Table 1.15. Multivariable regression analysis for the cerebral hemodynamic indices and ADMA.
CI—confidence interval, PI—pulsatility index, MCA—middle cerebral artery, ICA—internal carotid artery, RI—resistance index, IMT—intima-media thickness, CCA—common carotid artery, BHI—breath holding index, ADMA—asymmetric dimethyl-arginine, hsCRP—high sensitive C reactive protein, DM—diabetes mellitus, AGE—advanced glycation end-products.
Second Appendix-Figures
Fig. 1.1. Diagnostic ultrasonography (A–D) shows an eccentric perivascular infiltration (arrowhead) at the level of bifurcation, with a soft intimal plaque (arrow) and a mild lumen narrowing without a hemodynamic change in Doppler mode. Follow-up ultrasonography (E) shows a marked decrease in the perivascular infiltration (arrowhead) and complete disappearance of the soft intimal plaque.
Fig. 1.2. CTA shows a left posterolateral eccentric perivascular infiltration (arrowhead) surrounding the carotid artery, with a distinct low-density soft intimal plaque (arrow)
Fig. 1.3. Initial diagnostic ultrasonography (A) and follow-up ultrasonography at 14 days (B) and 6 months (C) show a perivascular infiltration (arrowheads) at the level of the internal carotid artery just at the level of bifurcation, with a quick decrease at 14 days and the persistence of a thin abnormality at 6 months.
Fig. 1.4. Pre (A) and post (B) contrast fat-suppressed 3D T1 and 3D T2-weighted (C)MR imaging in an axial plane shows T1 hypointense and T2 hyperintense perivascular infiltration (arrowhead) at the level of the carotid artery bifurcation, enhanced after gadolinium injection. A distinct soft intimal plaque (arrow) is visible at the posterior part of the carotid artery. A sagittal curvilinear reconstruction of the right internal carotid artery on the postcontrast T1-weighted imaging (D) shows the PVI (arrowhead) centered at the level of the right carotid artery bifurcation and extended to both the distal common carotid artery and proximal internal carotid artery. Note that there is no vascular or perivascular abnormality involving other parts of the common or the internal carotid arteries.
Fig. 1.5. – Duplex ultrasound – longitudinal view: carotid body tumor at right carotid bifurcation. Hypervascular cervical mass widening the right carotid bifurcation (the internal and external carotid arteries are separated by the tumor; accelerated and turbulent flow in the vessels of the tumor). CCA: Common carotid artery; ICA: Internal carotid artery; ECA: External carotid artery; CBPG: Carotid body paraganglioma.
Fig. 1.6. – MRI of neck – axial T2-weighted images after Gadolinium: carotid body tumor at left carotid bifurcation. Hypervascular carotid space mass (arrow) splaying the internal and external carotid arteries. Typical “salt and pepper” aspect with prominent vascular flow voids.
Fig. 1.7. – Angio-MRI (MR-A) of neck – coronal view: carotid body tumor at left carotid bifurcation. Typical pattern of a CBPGL with splaying of the carotid bifurcation.
Fig. 1.8.: Histology of carotid body tumor at left carotid bifurcation: well-defined nests of cuboidal cells (zellballen) are separated by highly vascularized fibrous septa (Hematoxylin–Eosin staining, ×400).
Fig. 1.9 – Brain magnetic resonance imaging (MRI). The FSE T2-weighted axial (A) and sagittal (B) scans show high signal intensity, representing vasogenic edema – unilateral paramedian acute (over 12 hours after onset of symptoms) pontine infarct. FSE: Fast spine echo.
Fig. 1.10 – Computed tomography angiography (CTA) of the neck (i.v. contrast) [Reconstructions: (A) VRT of the carotids; (B, C and E) MPRs; (D) MIP] revealing the anatomic abnormalities described: left ICA hypoplasia, left CCA hypoplasia (A and C), right VA hypoplasia (D), and the emergence of the left VA from the aortic arch (E). VRT: Volume- rendering technique; MPRs: Multi- planar reconstructions; MIP: Maximum intensity projection; ICA: Internal carotid artery; CCA: Common carotid artery; VA: Vertebral artery.
Fig. 1.11 – Extracranial color-coded duplex sonography (CCDS) indicating the anatomic abnormalities described: (A) B-mode imaging (left ICA hypoplasia); (B) Color Doppler flow imaging (left ICA hypoplasia). ICA: Internal carotid artery; CCA: Common carotid artery.
Fig. 1.12 -First patient: a) B-scan ultrasound evaluation of the right eye; b) Color Doppler imaging (CDI) of the right central retinal artery; c) CDI of the right central retinal artery after 11 months.
Fig. 1.13. -Second patient: a-d) Spectral Doppler analysis of retrobulbar vessels.
Fig. 1.14: – Color Doppler imaging (CDI) of the posterior cilliary arteries (PCAs) in arteritic, anterior ischemic optic neuropathies (A-AION): decreased blood flow velocities (especially euddiastolic velocity – EDV) in the nasal PCAs: A) of the clinically affected right eye, and B) of the clinically unaffected left eye.
Fig. 1.15: – Extracranial duplex sonography (EDS) of the temporal ramus of the right temporal artery (TA) – "dark halo" sign.
2. PLANS FOR CAREER DEVELOPMENT
The second part of the thesis is dedicated to career development plans.
2.1. Development of academic (didactic, teaching) career
The major short-term objective in terms of academic career development is getting my habilitation in order to be able to supervise PhD students in the field of Neurology. I will encourage doctoral students to apply for doctoral grants to provide some of the funding needed to carry out a successful research project.
In the near future as an already Professor at the 8th Department of Neurosciences “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania, I will develop the existing collaboration with other medical universities from Romania (“Iuliu Hateganu” University of Medicine and Pharmacy, Cluj-Napoca, and “Carol Davila” University of Medicine and Pharmacy, Bucharest) and other countries (France-Paris, Serbia-Belgrad).
Moreover, I will organize conferences and work-shops comprising up-to-date information in neurology, as well as data deriving from my personal research, concerning especially cerebrovascular and associated diseases.
I will increase the standards of didactic excellence, centered on student education, because the teaching activity implies the continuous improvement of the didactic methodology, with the support and involvement of the colleagues and students in the educational process.
On one hand, a special place will have the collaboration on interdisciplinary common courses and work-shops with other colleagues (nephrology, diabetes and metabolic diseases, ophthalmology, anatomy, etc.,), neurologists, resident neurologists, and, in the future, doctoral students.
On the other hand, in order to develop the didactic skills, I will diversify my teaching methods by expanding the use of informatics and technology (newer techniques focused on advanced parenchymal imaging: including CT perfusion, quantitative MRI, and diffusion tensor imaging, and methods to assess cerebral macroangiopathy, such as Doppler ultrasonography, MR angiography, CT angiography, and digital substraction angiography).
I will contribute to the improvement of the feedback of students during each lecture, as well as at the end of the semester, to find out and try to respond to their expectations and requirements.
I will update periodically the lectures and the curriculum, presented in a clear, concise and logical manner, in order to adapt them to the changes that have occurred, facilitating the access of the students to the newest and the most complete data in the field of Neurology.
I will include into the lectures the information required for the residency exam (cerebrovascular diseases) in order to facilitate the future preparation of the students for this very important competition of their career.
Thus, in April 2020, I will edit (first author) two new printed courses of Neurology (in Romanian and French, respectively) for the students of the Faculty of Medicine, University of Medicine and Pharmacy Timisoara.
In May 2020, I will edit (single author) an electronic course of Neurosonology (in English) for neurologists.
Because the students of the Faculty of Medicine come to my classes in the 5th year, they already have important knowledge that they must develop and apply in practice. In my opinion, they have to decide for a future physician career. For this reason, I will improve the teaching activity by expanding the clinical application of the theoretical knowledge which they acquire at the neurology courses. I will encourage them to deepen the individual theoretical study and I will mediate their interaction with my patients, in order to understand what their needs are and what expectations they have from the physician who treats them.
I will develop the educational infrastructure, by creating lectures and clinical internships in the virtual environment, which could help solve the problems related to the limited space of our Clinic of Neurology and the privacy of our patients, which have special needs (paresis, troubles of sensibility or vision, cognitive impairment, including troubles of speech and language, etc.,).
I will promote the mobility of students and teachers through the Erasmus program. This will contribute to the development of the collaboration with other European universities of medicine, to the improvement of language skills and to the acquirement of teaching techniques used in Neurology in other European Union countries.
The objectives formulated in this plan for the development of the academic career can be achieved only through a sustained collaboration with the colleagues from our discipline of Neurology.
I will continue to supervise diploma theses in the field of Neurology, and to organize postgraduate courses in Neurology entitled “Actualities in ischemic stroke” at "Victor Babeș" University of Medicine and Pharmacy-Discipline of Neurology.
I will participate as a lecturer in different national postgraduate courses and, as a member of different committees for rendering academic degrees.
I will continue my activity as a member of the Medical Committee of the “Victor Babeș” University of Medicine and Pharmacy Timișoara.
Since 2020, I will be a member of the Professional Council of the Faculty of Medicine of the “Victor Babeș” University of Medicine and Pharmacy Timișoara.
2.2. Development of professional (medical) career
In the near future, I would like to widen the field of knowledge regarding the inter-disciplinary of neurology, and to deeply integrate my didactic with scientific and professional activities.
I will continue to participate and to sustain lectures at national and international conferences and congresses of Neurology or Cerebrovascular diseases.
I will also continue to attend courses and workshops organized by European Stroke Organization, World Stroke Organization, European Society of Neurosonology and Cerebral Hemodynamics, European Academy of Neurology, and Society for the Study of Neuroprotection and Neuropasticity. My professional development through participation in these events is necessary for the acquisition of the latest scientific data in neurology.
I will continue the collaboration with the Stroke-Unit and the Department of Radiology from: Fondation Ophtalmologique “Adolphe de Rothschild”, Paris, France, and with the Department of Clinical Neurophsiology from the Medical Faculty Military Medical Academy, Belgrade, Serbia.
I will try to maintain the current relationships we have with the “Vlad Voiculescu” National Institute of Neurology and Cerebrovascular Diseases in Bucharest, with the university departments of neurology in Bucharest and Cluj-Napoca, as well as with the Nephrology, Diabetes and Metabolic Diseases , Ophthalmology, and Anatomy departments from Timisoara, with which we have many common topics of research and scientific debate. I established excellent group relationships with my colleagues and friends from the nephrology, diabetes and metabolic diseases, ophthalmology, and anatomy departments. The complex team I am part of, has supported me constantly in my professional activity.
I will also try to establish new collaborations in professional, teaching and in terms of research activity. I will enrich my Clinical Study Experience: ongoing studies: Thales, C-Regs 2, Post Code. I will continue my activity as leader of the research group in Neurosonology, and of the research group in Disorders of speech and language/aphasias, respectively, at the Department of Neurology, University of Medicine and Pharmacy “Victor Babeș”, Timișoara. As Secretary of the National Commission of Neurology of the Romanian Health Ministry, I will try to fulfil the multiple tasks that I have.
I will continue to be a member or chair of the commissions for the degree of specialist physician in neurology, senior physician in neurology, or for the position of neurologist, senior neurologist.
My main professional activity will be Head of the First Department of Neurology of the Clinical Emergency County Hospital, Timisoara with complex managerial and medical/ neurological responsibilities.
2.3. Plans for further scientific achievements (Fields of research, Research projects)
In addition to the current didactic and medical responsibilities, a university teacher must also carry out a sustained scientific activity. This is necessary both for maintaining and expanding the level of scientific knowledge, which are subsequently passed on to students, as well as for developing the professional horizon.
As a habilitated Professor at “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania, I will continue to be actively involved in the development of research programs, specifically focusing on cerebrovascular and associated diseases, by creating and participating in multi- and trans-disciplinary research teams.
To ensure the quality of scientific research, interdisciplinary collaboration is absolutely necessary.
I will continue and develop my collaboration with:
a). the disciplines of Nephrology, Diabetes and Metabolic Diseases, and Cellular and Molecular Biology of the “Victor Babes” University of Medicine and Pharmacy Timisoara, in order to decipher the early mechanisms of cerebral and renal impairment in patients with DM;
I will expand my research scopes by further developing studies on cerebral vessels endothelial dysfunction in diabetes mellitus, and on the inter-relation between kidney disease and cerebrovascular disease in diabetic patients.
b). the disciplines of Ophthalmology and Anatomy and Embryology, and the Department of Radiology from the Fondation Ophtalmologique “Adolphe de Rothschild”, Paris, France, regarding the field of Neuro-ophthalmology: anterior ischemic optic neuropathies, central retinal artery occlusion, giant cell arteritis or other diseases with eye involvement, evaluated by Color Doppler ultrasound of orbital vessels.
c). the disciplines of Neurology from other medical universities from Romania (“Iuliu Hateganu” University of Medicine and Pharmacy, Cluj-Napoca, and “Carol Davila” University of Medicine and Pharmacy, Bucharest), and the Department of Clinical Neurophsiology from the Medical Faculty Military Medical Academy, Belgrade, Serbia, in order to assess Vascular cognitive impairment, and Mild Cognitive Impairment, and to manage vascular aphasias (assessment of aphasias-using Western Aphasia Battery-Romanian version; speech and language therapy; Transcranial magnetic stimulation and pharmacological treatments of aphasias).
d). the Stroke–Unit, and the Department of Radiology from the Fondation Ophtalmologique “Adolphe de Rothschild”, Paris, France, regarding the field of ischemic stroke, including cerebral venous thrombosis.
For a good research activity, it is necessary a financial support for the purchase of high-level medical equipment and reagents for laboratory tests. Consequently, it is essential to obtain funds through research grants. The experience gained in previous years in this regard (six research projects to which I took part, in two of them I was Director) will help me to successfully apply for various internal, national or international competitions, a process in which I will actively involve the future PhD students.
For the next period, I propose the following research directions:
1. Cerebral and renal impairment in patients with diabetes mellitus-DM. (Cerebral vessels endothelial dysfunction in DM, the early mechanisms of albuminuria in diabetic nephropathy, and the inter-relation between kidney disease, and cerebrovascular diseases in diabetic patients).
Chronic systemic inflammation and inflammatory response play an important role in the occurrence and progression of CKD. Activation of immune and inflammatory pathways would be key mediators in its pathogenesis. The inflammatory response involving the innate immune system, as well as a number of epigenetic mechanisms, also seem to play an important role in the occurrence of albuminuria in type 2 DM. Circulating levels of pro-inflammatory cytokines, such as IL-1α, IL-8 and IL-18, are of major importance, as they are elevated in patients with diabetes, where they act as pathogenetic mediators.
MiRNA are short, noncoding RNA, endogenous products, containing 21-25 nucleotides, which play important roles in modulating gene expression and promoting the initiation or progression of various diseases, including diabetic nephropathy (DN). Several types of miRNA (21, 124, 125a, 126, 146a, 192) are of interest for experimental and clinical research. They have been shown to have biological effects (beneficial or harmful) in the kidney, and the cerebral vessels but the results of different studies are not consistent. Abnormal expression of several miRNA has been linked to variations in levels of central inflammatory mediators, such as IL, given their role as positive or negative regulators of pro-inflammatory mediators.
We already published numerous scientific papers (full-text or abstract) and two research projects on this subject (the evaluation of endothelial dysfunction at glomerular and cerebral level through specific pro-inflammatory cytokines);
In order to investigate the early mechanisms of albuminuria in diabetic nephropathy, we propose to extend the research in the direction of the podocytes and to the increased permeability of the glomerular capillary endothelium. For this purpose, it is essential to collaborate with colleagues from the Departments of Cellular and Molecular Biology (for the podocyte cultures), and from the Department of Nephrology, and Diabetes and Metabolic Diseases (in order to establish correlations between glomerular and cerebral endothelial dysfunction).
2. Neuro-ophthalmology: anterior ischemic optic neuropathies, central retinal artery occlusion, giant cell arteritis and other diseases with eye involvement, evaluated by Color Doppler ultrasound of retrobulbar (orbital) vessels.
Giant cell arteritis (GCA) is a primary vasculitis that affects extracranial medium (especially branches of the external carotid artery (ECA)) and large-sized arteries (aorta and its major branches). Clasically, it’s diagnosis consists in: age more than 50 years at disease onset, new headache in the temporal area, temporal artery tenderness, and/or reduced pulse, jaw claudication, systemic symptoms, erythrocyte sedimentation rate exceeding 50 mm/hr, and typical histologic findings (granulomatous involvement) in temporal artery biopsy (TAB).
Over the last 30 years, GCA has been found to be the most common type of vasculitis in Europe and North America. Incidence of GCA is higher in white individuals than those of other ethnicities. The incidence of GCA is lower than 12/100,000 people per population age 50 years in Southern European and Mediterranean countries. It increases with age and peaks in the 70–79 years age group: 100,000 people per population age 50 years. Women are affected more frequently than men. As the population throughout the world (including Romania) continues to age, an increased prevalence of disease should be expected.
Half of patients with GCA have ophthalmologic complications, consisting of arteritic anterior ischemic optic neuropathy (A-AION), or central retinal artery occlusion (CRAO), with abrupt, painless, and severe loss of vision of the involved eye.
Clasically, accurate diagnosis of GCA requires TAB, but:
a). on one hand, TAB is an invasive investigation, which is very rarely performed in our department, because of the patient’s refusal, and because of the need for a specialized medical team, b). on the other hand, findings of TAs ultrasound do not correlate with eye complications.
Therefore, we use in our department a simple, non-invasive method that allows early diagnosis of eye involvement in GCA or other diseases.
This is Color Doppler Imaging (CDI) of the (orbital) retrobulbar vessels. Our team has started a collaboration program with the Ophthalmology, and Anatomy and Embryology Departments of our university, and with the Department of Radiology from the Fondation Ophtalmologique “Adolphe de Rothschild”, Paris, France, regarding the field of Neuro-ophthalmology: anterior ischemic optic neuropathies, central retinal artery occlusion, giant cell arteritis with eye involvement, evaluated by CDI of orbital vessels. We already published a monograph in Romania and two chapters in international treaties. Some preliminary results have already been published (full-text or abstract); they are encouraging and indicate the usefulness of (CDI) of the orbital vessels for the diagnosis of eye involvement in patients with GCA or other diseases.
3. Vascular cognitive impairment, Mild Cognitive Impairment, and vascular aphasias (assessment of aphasias using Western Aphasia Battery-Romanian version, speech and language therapy, transcranial magnetic stimulation and pharmacological treatments of aphasias).
Vascular cognitive impairment (VCI)
VCI is a heterogeneous group of cognitive disorders (from mild cognitive impairment-MCI to dementia) that share a presumed vascular cause (determined by stroke). It includes the whole spectrum of cognitive alterations greater than expected for normal aging, attributed to ischemic of hemorrhagic cerebral insults. VCI cases that do not meet the criteria for dementia can be labeled as vascular mild cognitive impairment (vascular MCI). It is important to mention that, unlike Alzheimer’s disease, VCI is not itself a disease, but rather the form of expression of the complex interactions between vascular risk factors cerebrovascular disease (CVD) etiologies (e.g. cardio-embolic, atherosclerotic, ischemic, hemorrhagic or genetic) and morphological changes within the brain regarding cognition.
Mild cognitive impairment (MCI)
MCI is a syndrome characterized by a cognitive decline greater than expected for an individual’s age and education level, but with no significant daily functional disability. Within the MCI concept we distinguish amnestic MCI (a-MCI) from multiple-domain MCI (md-MCI). a-MCI is defined only by a memory deficit, while md-MCI is characterized by impairment in several cognitive domains (e.g., language, executive function, visuospatial skills). Individuals with md-MCI may also have memory impairment. A third subtype of MCI is characterized by a single cognitive domain impairment without memory involvement. Currently, MCI is regarded as a transitional, reversible stage between normal aging and dementia.
We already finished on this subject an international Scientific project, titled “Improved health care in neurology and psychiatry-longer life” (acronym IHC)-RORS-9 INTERREG-IPA CBC Romania-Serbia Program (Project Director: Professor Dragos Catalin Jianu). The overall objective of the project (vide supra) was an improvement of the diagnosis, treatment and quality of life in border region (Banat) in patients with VCI. This fundamental research was the basis of the publication of a monograph. Some preliminary results have already been published; they are encouraging and indicate the usefulness of early detecting of vascular MCI.
Until now, there has been a collaboration with the Department of Neurology from “Carol Davila” University of Medicine and Pharmacy, Bucharest, concerning: “Effectiveness and Safety Profile of Ginkgo Biloba Standardized Extract (EGb761®) in Subjects with Amnestic Mild Cognitive Impairment (aMCI)” (in press).
Given the actuality of the subject, I believe that this collaboration should continue and that it should be amplified, the topic proposed above being just an example in this regard. Vascular aphasias
Aphasia is a central disorder of language that impairs a person's ability to understand and produce spoken and written language. It has a prevalence of 25-30% in acute ischemic stroke (vascular aphasias). Aphasia is a marker of stroke severity and is associated with a higher risk of mortality, poor functional prognosis (can have a dramatic impact on person's ability to communicate), and increased risk of post-stroke dementia. The assessment of aphasias in clinical practice is based on classical analysis of oral production and comprehension. The language disturbances observed are usually combined into aphasic syndromes (non-fluent/ fluent aphasias, etc.) that may evolve rapidly at the acute stage of ischemic stroke.
The main determinant of the type of vascular aphasia is the infarct location (especially left anterior, posterior or complete middle cerebral artery ischemic stroke). Different recent studies have noted characteristics of aphasia at the hyperacute stage of ischemic stroke, re-examined its anatomy using imaging of white matter tracts, indicated prognosis in the era of stroke units, thrombolysis and thrombectomy (aphasias have a parallel course to that of cortical hypoperfusion, and the reversal of cortical hypoperfusion, following recanalization, is associated with resolution of aphasia).
Language therapy is needed as soon as permitted by clinical condition. Unfortunately, pharmacotherapy remains to be evaluated. Other studies examined the potential interest of new treatment, such as transcranial magnetic stimulation.
I started my research activity with the PhD thesis entitled “Contributions to the semiology of expressive disturbances in aphasias” (2001). This was the first doctoral thesis in Romanian concerning the domain of aphasias. This fundamental research allowed the drawing of conclusions with practical applicability on diagnosis and treatment of vascular aphasias and was the basis of the publication of two monographs, as well as of numerous scientific papers (full-text or abstract).
We already finished on this subject an international scientific project, titled: “Diagnosis and rehabilitation of aphasics with mother tongue Romanian after ischemic stroke”. (Project Director: Associate Professor Dragos Catalin Jianu).
In order to investigate the management of vascular aphasias in Romanian patients (in different departments of Romania), we recently started a collaboration program with the discipline of Neurology from “Iuliu Hateganu” University of Medicine and Pharmacy, Cluj-Napoca. Vascular aphasias and transcranial magnetic stimulation.
Functional imaging studies of language in patients with non-fluent aphasia frequently reveal a possible over-activation in right hemisphere language homologues. Evidence exists that left hemisphere functional recovery is clinically more relevant than right hemisphere activation as a compensatory mechanism after stroke. In that sense, right hemisphere activation might be a negative factor for aphasia recovery after stroke. Use of transcranial magnetic stimulation (TMS) could provide right hemisphere inhibition and, therefore, increase recovery of language deficits. Preliminary reports showed that TMS can improve naming in stroke patient with non-fluent aphasias.
We propose to extend the vascular aphasias research in the direction of new treatments, such as TMS. For this purpose, it is essential to collaborate with colleagues from the Department of Clinical Neurophsiology from the Medical Faculty Military Medical Academy, Belgrade, Serbia and from the discipline of Neurology from “Iuliu Hateganu” University of Medicine and Pharmacy, Cluj-Napoca.
4. The field of ischemic stroke, including cerebral venous thrombosis.
Cerebral venous thrombosis (CVT)
Rare (0.5-1% of all strokes), but alarming disease, CVT has a higher frequency among young adults (< 40 years of age), patients with thrombophilia, and women who are pregnant or using oral contraceptives.
The most frequent symptoms are headache, papilledema, seizures, motor, sensory or language deficits, altered mental status and decreased consciousness. CVT can be caused by multiple predisposing conditions and precipitants. At least one risk factor can be identified in more than 85% cases, multiple risk factors, in about ½ of patients, while in less than 15% no underlying cause can be found. Different brain imaging techniques (computed tomography, magnetic resonance imaging, and magnetic resonance angiography) allow the diagnosis of benign forms of CVT with minimal, nonspecific symptoms and spontaneous recovery. The CVT treatment is based on a combination of etiologic and symptomatic medications. Currently, the main treatment of choice for CVT is heparin (intravenous heparin or subcutaneous low-molecular-weight heparin) in therapeutic dosages.
The CVT prognosis depends on the early detection, but it should be mentioned that mortality trends have diminished over the last decades. Because of its frequently misleading presentation, its wide spectrum of causes, its unpredictable course, and its occasional treatment problems, CVT remains a challenge for the clinician. We also want to emphasize that, due to its features, CVT should remain a disease of interest not only for neurologists, but also for other specialists – neurosurgeons, ear, nose and throat specialists, ophthalmologists, hematologists, obstetricians, internists, and oncologists.
We already published one chapter in an international monograph, as well as numerous scientific papers (full-text or abstract), concerning the field of CVT.
In the months to come, our team will start a collaboration program with the Department of Radiology from the Fondation Ophtalmologique “Adolphe de Rothschild”, Paris, France, concerning the diagnosis of CVT which is based on neuroimaging.
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