ISCHEMIC STROKE / VASCULITIS

Takayasu arteritis

Created 24/05/2023, last revision 07/11/2023

Etiology

Takayasu arteritis is an inflammatory disease affecting the aorta and its branches
predominantly occurs in young oriental women (with a female-to-male ratio of 8:1)
etiology is unknown
cell-mediated immune mechanisms are involved; histology shows similar findings to those of temporal (giant cell) arteritis
- inflammation starts with adventitial mononuclear infiltration
- later, mononuclear inflammation of the media may occur, accompanied by granulomatous changes
onset typically in the first 3 decades of life

inflammation leads to irregular thickening of the affected artery, potentially resulting in:
- concentric stenosis or occlusion (initially with granulomatous changes of the media and adventitia, later involving intimal hyperplasia)
- thrombosis
- aneurysm formation (∼ 30% of patients)

Clinical presentation

Systemic symptoms

most commonly in the initial phase
fatigue, fever, weight loss, night sweats, myalgia, and/or arthralgia
many patients may present only with focal symptoms resulting from hypoperfusion of the affected organ or limb

CNS involvement

symptoms of decreased cerebral perfusion
dizziness and syncopes (> 50%), subclavian steal syndrome
ischemic stroke
visual disturbances (visual field defects, amaurosis, retinal hemorrhages)
intracerebral hemorrhage (most commonly due to aneurysm rupture)

Involvement of the heart and other arteries

secondary renovascular hypertension
limb arteries involvement
- the diagnostic hallmark is weakened pulse (“pulseless disease“); most patients exhibit an absent pulse in at least one limb
- reduced blood pressure in one or both arms
  - blood pressure difference > 20mm Hg between the left and right arm or between the arm and leg on the same side
- bruits are often audible over the subclavian arteries (in the supraclavicular fossa), brachial arteries, carotid arteries, abdominal aorta, or femoral arteries
- limb claudication
- Takayasu arteritis is a chronic disease where collateral circulation usually develops; ischemic ulcerations or gangrenes are uncommon
signs of aortic coarctation (e.g., hypertension, headache, leg claudication)
cardiac symptoms
- angina pectoris / myocardial infarction (due to the narrowing of the coronary artery orifice)
- heart failure due to aortic regurgitation
pulmonary hypertension, pulmonary infarcts

Diagnostic evaluation

The diagnosis of Takayasu arteritis is based on:

typical symptoms and signs (see above)
typical imaging findings
evidence of inflammation detected by blood tests

Imaging methods

characteristic findings in the aorta and its branches (always examine the descending aorta and renal arteries):
- segmental concentric stenoses/occlusions
- poststenotic dilation
- collateral arteries
- aneurysms
carotid ultrasound – a direct visualization of wall thickening, may assess the flow in distal segments and collaterals
magnetic resonance imaging
- MRA
- T1C+ dark(black) blood sequence helps to detect inflammatory changes in the vessel wall
CTA
DSA
FDG PET/CT
- demonstration of inflammatory arterial involvement [Chrapko, 2015]
- hypometabolism in some brain regions [Berlit, 2010]

Takayasu arteritis may progress silently even if clinical status and laboratory studies suggest remission ⇒ periodic vascular imaging is required

Takayasu arteritis - enlarged wall on ultrasound

Blood tests

tests are nonspecific
↑CRP (C-reactive protein), ESR (erythrocyte sedimentation rate) > 40mm (however, normal values do not exclude active disease)
anemia of chronic disease (usually mild)
leukocytosis
elevated platelet counts
↑ metalloproteinases MMP-2, MMP-3 and MMP-9

Blood pressure measurement

BP should be measured in all extremities
accurate measurement can be difficult
- if both subclavian arteries are affected, systemic BP can be measured only in the unaffected legs
- if both subclavian arteries are affected, and the patient has coarctation of the descending aorta, and/or involvement of both iliac/femoral arteries, accurate noninvasive BP measurement is not possible ⇒ central arterial pressure may be measured via angiography to detect occult hypertension
additional indicators of occult hypertension are:
- hypertensive retinopathy
- echocardiographic evidence of concentric left ventricular hypertrophy
severe hypertension may cause complications that could be mistaken for symptoms of vasculitis

Diagnostic criteria and classification

American College of Rheumatology 2022

Diagnostic criteria of Takayasu arteritis ( American College of Rheumatology, 2022)
Absolute requirements age ≤ 60 years evidence of vasculitis in the aorta or its branches (by MR, CTA, DSA, ultrasound, PET)
*Additional clinical* criteria** female sex +1 angina or ischemic cardiac pain +2 arm or leg claudication +2 vascular bruit +2 detected by auscultation of large arteries reduced or absent pulse in upper extremity +2 physical examination of the axillary, brachial, or radial arteries carotid artery abnormity +2 reduced or absent pulse, tenderness of the carotid artery SBP difference in arms ≥ 20 mmHg +1
*Additional imaging* criteria** number of territories involved (thoracic, abdominal aorta, mesenteric, left or right carotid, subclavian or renal artery) one +1 two +2 three or more +3 symmetric involvement (stenosis, occlusion aneurysm) of paired arteries +1 subclavian, carotid, or renal arteries abdominal aorta involvement with renal or mesenteric involvement +3
A score of ≥ 5 points is needed to classify as Takayasu arteritis

(Grayson, 2022)

American College of Rheumatology 1990

Diagnostic crieteria of Takayasu arteritis ( American College of Rheumatology, 1990)
Typical clinical complaints lasting > 1 month arm or leg claudication decrease brachial artery pulse BP difference > 10mmHg in both arms amaurosis syncope, palpitations	major
increased ESR	minor
hypertension aortic regurgitation carotid artery tenderness	minor minor minor
Proof of arterial involvement left subclavian artery left subclavian artery pulmonary artery left CCA brachiocephalic trunk descending thoracic aorta abdominal aorta coronary arteries annuloaortic ectasia (dilatation of the ascending aorta, the aortic annulus)	major major minor minor minor minor minor minor minor
High probability of Takayasu arteritis ≥ 2 major criteria 1 major criterion + 2 minor criteria 4 minor criteria

Angiografic classification

DSA classification of Takayasu arteritis

Differential diagnosis

atherosclerosis
- age > 40 years
- more common in men
- lesions in typical locations
fibromuscular dysplasia (FMD)
- rarely affects the subclavian artery; almost never the aorta
temporal arteritis (does not affect CCA and subclavian artery)
vascular infections
- syphilitic aortitis (with typical aortic calcifications)
- tuberculous, fungal aortitis
neurofibromatosis type I
idiopathic inflammatory conditions (e.g., ankylosing spondylitis with aortitis, Behçet syndrome, sarcoidosis)

Management

→ Systematic Review of TA Management in Rheumatology 2014

Stroke prevention

antiplatelet therapy [Souza, 2010]
treatment of hypertension (problem with BP assessment in cases of subclavian artery stenosis/occlusion)
low sodium diet
stenting or bypass surgery in cervical artery lesions
- procedures performed during remission yield more favorable outcomes

Corticosteroids

start with PREDNISONE 1 mg/kg, then gradually taper over several weeks; the target maintenance dose should be individualized (based on inflammatory markers and clinical status)
after achieving remission (decrease in ESR and CRP, correction of anemia), maintain a dose of 5-10 mg/day for 1-2 years
rapid tapering may lead to relapse
prevention of osteoporosis is necessary during long-term corticosteroid treatment – e.g., by administering Caltrate PLUS twice daily or Kombi-Kalz 1000/880 once daily
whenever possible, combine corticosteroids with immunosuppressants or immunomodulators to enhance treatment efficacy

Immunosuppressive drugs

Immunosuppressants – cytostatics

approximately 50-70% of patients require adjunctive treatment with immunosuppressive drugs
for less aggressive forms, consider the following:
- azathioprine (IMURAN) 1-2 mg/kg/day
- mycophenolate (CELLCEPT)
for more aggressive or refractory forms:
- methotrexate is administered once weekly (due to its potential for toxicity)
  - starting dose 7.5-15 mg once per week
  - the dose may be increased gradually as needed and tolerated, with a usual maximum of about 20-25 mg per week
  - may help to improve disease control and facilitate cumulative CS dose-sparing
  - monitor patients for potential side effects, including hepatotoxicity, bone marrow suppression, and lung toxicity, among others
  - supplementation with folic acid is standard to mitigate some of the side effects
- cyclophosphamide
  - typical dose of 1-2 mg/kg per day
  - Intravenous pulse dosing given as 500-1000 mg/m² body surface area, administered once every month

New immunosuppressive agents [Mekinian, 2015]

biological-targeted treatments
monoclonal antibody against the IL-6 receptor – tocilizumab (ROACTEMRA)
TNF-alpha blockers – reserved for conditions resistant to standard therapies

Reconstructive procedures

vascular procedures for organ-threatening ischemia, such as stenting or bypass surgery (indicated not only for cervical artery involvement but also for limb, mesenteric, and renal artery disease)

Follow up

Laboratory tests

CRP unreliable
ESR – decline during remission present in ∼ 60% of cases ⇒ unreliable marker [Matsuyama,2003]
metalloproteinases [Matsuyama,2003]
- MMP-2 diagnostic > 800 ng/mL
- relapse – MMP-3 > 100 ng/mL and MMP-9 > 75 ng/mL

Imaging methods

vascular lesions may progress even when clinical and laboratory findings suggest remission
periodic vascular imaging to assess stenosis grade and wall width/enhancement is essential
- MRI of the neck (incl. black blood sequences) + MRA
- neurosonology
- CT angiography

Takayasu arteritis - ultrasound monitoring

Prognosis

the clinical course is usually relapsing and remitting or chronic/progressive
despite therapy, the prognosis is uncertain, and the disease often progresses
restenosis of the intervened arterial segments often occurs, despite combined immunosuppressive therapy