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by Norman Neaderhiser
Abstract: Takayasu’s arteritis is a chronic inflammatory disease characterized by the progressive inflammation of the media portion of the arterial wall. Chronic inflammation leads to decreased flow and pulselessness distally and can culminate in peripheral ischemia. Originally documented in medical literature in 1830, modern medicine attributes the discovery of the disease to Dr. Mikito Takayasu, a Japanese ophthalmologist, in 1908. Angiography and ultrasonography are two of the primary modalities used to image the disease. Ongoing research is optimistic on the discovery of biomarkers to assist in the early diagnosis of this inflammatory disease.
Takayasu’s Arteritis is a chronic inflammatory disease characterized by the progressive inflammation of the media portion of the arterial wall. The disease typically affects the great vessels and their immediate branches and results in hemodynamically significant stenosis of these vessels. Originally documented over 170 years ago, research continues to this day on this rare and debilitating vascular disorder.
Research into the first known cases of Takayasu’s disease dates back to 1830 and was recorded in a book published by Rokushu Yamamoto. The book, entitled Kitsuo-Idan and meaning “medical records of my private hospital under the big orange tree”, contains the oldest description of Takayasu’s Arteritis found in literature. In it, Yamamoto, who practiced Japanese style medicine, described a 45-year old man who initially visited him for high fever. One year later the patient presented with pulselessness in the right radial artery and a very weak pulse in the left radial artery. Moreover, Yamamoto described the clear presence of the pulse in both lower extremities. Later, both carotid artery pulses became progressively weaker and finally non-palpable. The patient gradually became emaciated and complained of dyspnea, (difficulty breathing). He suddenly died in the 11th year of follow-up. When Yamamoto mentioned this patient’s case to Tokaku Wada, a physician in Kyoto, Wada stated that he also had examined two patients with the same symptoms. These records may be the oldest descriptions of Takayasu’s Arteritis found in modern literature.(1)
Although this morbid condition is a vascular disease, it was first reported to the modern medical community by Mikito Takayasu, a Japanese ophthalmologist, who lived between 1859 and 1938. His report was presented at the 12th Annual meeting of the Japan Ophthalmology Society held in 1908 in Fukuoka, Japan. Dr. Takayasu reported a case of a 21-year old woman who had a peculiar “wreathlike” appearance of blood vessels in the back of the eye around the retina. Two other Japanese colleagues reported similar eye findings along with the absence of wrist pulses. It is now known that the blood vessel malformations that occur in the retina are a response to arterial narrowings in the neck. The body compensates through the creation of collateral pathways. While it has been argued that Mikito Takayasu should not receive credit for the discovery since he failed to mention the absence of pulses in his patient, the condition was officially named Takayasu’s Arteritis in 1975.(1)(2)
There are many synonyms for Takayasu’s Arteritis, including aortic arch arteritis, arteritis brachiocephalica, pulseless arteritis, etc.(2) Takayasu’s Arteritis is a chronic vasculitis mainly involving the aorta and its main branches, such as the brachiocephalic, carotid, subclavian, vertebral, and renal arteries, as well as the coronary and pulmonary arteries. Due to stenotic lesions or thrombus formation, it induces clinically varied ischemic symptoms such as blindness, cataract and/or retinal hemorrhage, pulselessness, aortic regurgitation and/or congestive heart failure due to dilatation of the ascending aorta. Progression that is more acute causes destruction of the tunica media of the arterial wall, leading to the formation of aneurysms, dissections, and/or rupture of the arteries. Takayasu’s Arteritis is characterized histologically as “panarteritis”, which involves all layers of the arterial wall. This will therefore include intimal fibrous thickening, destruction of the medial smooth muscles and elastic layers, and a thickened tunica adventitia.(1)
There is a 9:1 worldwide female predominance in this disease, however it appears to occur more often in Asian women. In fact, the typical patient with Takayasu’s Arteritis is a woman of Asian descent under the age of 40.(3) Epidemiologists are noting an increase in the number of Hispanic’s who present with Takayasu’s Arteritis.(4) Regardless of genetic predisposition, Takayasu’s Arteritis remains a rare disease.
Clinicians divide Takayasu’s Arteritis into two phases. The first phase is the systemic phase and the second is the occlusive phase. In the systemic phase, patients have symptoms and signs of an active inflammatory illness.(5) These symptoms may include fever, fatigue, weight loss, arthritis, and non-specific aches and pains. There may be tenderness overlying the affected arteries.(6) Most patients have some sort of polycythemia(7) which is an elevated red blood cell count and erythrocyte sedimentation rate due to inflammation,(3)(4) During the following occlusive phase, patients begin to develop symptoms caused by the narrowing of affected arteries. Symptoms may include pain in the limbs that occurs during repetitive activities as well as dizziness upon standing, headaches, and visual problems.(3) During the occlusive phase affected blood vessels may be narrowed to such an extent that the normal arterial pulsations (pulses) in the neck, antecubital fossa, wrist, and a lower extremity cannot be felt. Using a stethoscope, one may also hear bruits. Hypertension is common but blood pressures taken in the arms may be read as falsely low if there is a narrowing of an artery high up in the arm. With some patients it is impossible to get accurate blood pressure readings in the arms. Using an ophthalmoscope, malformations of the blood vessels in the eye may be observed. Although the lung involvement in Takayasu’s Arteritis is often overlooked because of other large vessel involvement, the pulmonary arteries may also be affected by this disorder.(3)
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What causes Takayasu’s Arteritis? The actual cause of the disease is unknown at this time. It has been theorized that the infection might have bacterial or viral causes.(3) Further theories suggest a genetic predisposition(3) since there are documented cases of identical twins suffering from the same affliction.(6)(1) However, with the worldwide rate-of-incidence being so low, there is no concrete evidence to make any one theory more worthy than the other. What the history of the disease does show is that it has had its highest occurrence in Asian women although it has been documented in all ethnic groups.
Methods for detecting and diagnosing Takayasu’s Arteritis are varied. The symptoms of pulselessness are easily picked up with indirect physiologic testing, but these tests by themselves are inconclusive. Muted or absent pulses, muted waveforms of a pulse volume recording (PVR), or diminished waveforms of a photo plethysmographic (PPG) exam would simply present the case for the presence of claudication. More definitive types of tests are required to arrive at a diagnosis of Takayasu’s disease.(7)(8)9)
Ultrasound is ideal if the vessels are accessible to the transducer beam. Duplex Doppler may be used to evaluate and monitor disease in the common carotids and subclavian arteries. However, sonography is not useful in evaluating the aortic arch and its branch vessels.(3) Carotid evaluation reveals a homogenous circumferential thickening of the vessel wall that is distinguishable from atherosclerotic thickening. Echocardiography can be used to establish a baseline in evaluating the aortic valve with subsequent follow-ups performed as indicated to monitor aortic valve insufficiency.(3)
Angiography is a useful imaging modality in the detection of Takayasu’s Arteritis. Because of its invasiveness, angiography is not the first-line study in most patients, especially pediatric patients. With angiography, focal, smooth, symmetric narrowing of the aorta as well as multiple branch vessel stenoses are revealed. Stenosis is the most common finding, although arterial dilatation and aneurysms are also often found. With subclavian involvement, the lesion begins within a few centimeters of the arch and extends to the origin of the vertebral artery. These lesions are often multiple and symmetric, thereby increasing the degree of stenosis through their increased resistive effect.(5)
Gadolinium-enhanced magnetic resonance imaging (MRA) can demonstrate thickening of the arterial wall with crescents and indistinct outlines. This examination method is quite useful with pediatric patients in whom the complications of angiography are greater than in adults. Soft tissue differentiation obtained with MRA techniques can help distinguish the acute phase from the chronic phase of the disease. The one disadvantage of MRA is that it is incapable of measuring the hemodynamic significance of the lesions involved.(5)
Sonography and angiography are complementary methods in the diagnosis of Takayasu’s Arteritis. Angiography shows changes in the lumen in many arteries, whereas sonography shows changes of the arterial wall in a small number of important arteries. Sonography is superior to angiography in the detection of smaller carotid lesions. In one study, inflammatory wall thickening of the carotid arteries could be documented in 19 of 23 patients by sonography, whereas angiography detected pathologies in only 13 of these patients. In another study, sonography found pathological wall thickening in 28 of 44 carotid arteries of 22 patients with Takayasu’s Arteritis. Angiography detected a stenosis in only 21 of these 44 arteries. In six instances, sonography detected marginal but definite blood flow in severe stenosis, i.e. trickle flow, that angiography had failed to reveal.(8)
Medical evaluation and treatment can be performed on an outpatient basis unless the patient is acutely ill. The goal of medical treatment is to control active inflammation and to normalize clinical and laboratory parameters while preventing further vascular damage. Initially, daily high-dose corticosteroids are administered. This regimen is maintained until all evidence of active inflammation has subsided. Steroid dosages are then tapered in an effort to control side effects. Unfortunately, 40% of patients on this therapy relapse. A variety of other immunosuppressants can be used for patients who cannot tolerate corticosteroid therapy; however, each of these regimens comes with its own cornucopia of side effects. Surgical efforts include percutaneous balloon angioplasty and endovascular stenting. Both of these methods have proved effective in patients with Takayasu’s Arteritis with improvement being sustained for as long as 3-5 years.(3)
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In April 2006, the Johns Hopkins Vasculitis Center, Boston University of Medicine, Mayo Clinic College of Medicine, and the Cleveland Clinic Foundation jointly launched a new study with the purpose of establishing new biological markers (biomarkers) in an effort to assess the severity of disease in people with Takayasu’s Arteritis. Total expected enrollment for the study is expected to be 160 individuals and this study will last for 5 years. Study visits will occur monthly for the first year and then at three (3) month intervals for the remaining four (4) years. Diagnostic testing will include radiographs, echocardiograms, magnetic resonance imaging, and angiography.
Males or females wishing to participate in the study must exhibit evidence of abnormalities compatible with Takayasu’s Arteritis. In addition, one of the following criteria must also be demonstrated:
1. Age at disease onset 50 years or less
2. Claudication of the arms or legs
3. Decreased brachial artery pulse (one or both arteries)
4. Blood pressure differences between the arms of at least 10 mm/Hg
5. Bruit over the subclavian arteries or aorta
Exclusion criteria include:
1. Arteriographic lesions that could be entirely due to atherosclerosis
2. Fibromuscular dysplasia
3. Cogan’s syndrome
4. Behcet’s disease
5. Sarcoidosis
6. Kawasaki’s disease
7. Giant cell arteritis (large vessel vasculitis and a minimum age of 50 years old)
8. Syphilis or other infectious forms of large vessel vasculitis
Children under the age of 18 may participate in the study with parental consent.
This study will use scientific methods to establish new biomarkers to be used in monitoring disease activity in individuals with Takayasu’s Arteritis. Current tests used to measure vessel inflammation are considered unreliable and inconsistent. These new biomarkers may be used to help direct clinical care and assist in future drug development.(10)
In conclusion, it is evident that Takayasu’s Arteritis is a severely debilitating disease if left untreated. While moderate progress has been made in the diagnosis and treatment of the disease process over the last 100 years, significant strides remain to be made in regards to Takayasu’s Arteritis. While the rarity of the disease is a limiting factor, ongoing research should yield pertinent findings resulting in improved diagnostic and treatment efficacy.
References:
1. The Story of Takayasu’s Arteritis, F. Numano, Oxford textbook of medicine, 4th edn.Oxford: Oxford University Press 2001. http://rheumatology.oxfordjournals.org/cgi/content/full/41/1/103
2. Takayasu’s Arteritis, Synonyms, http://www.whonamedit.com/synd.cfm/2722.html
3. The John Hopkins Vasculitis Center, Division of Rheumatology, 1998-2006. http://vasculitis.med.jhu.edu/typesof/takayasu.html
4. UVMFLOWNET Archives – June 1998 (#22) http://list.uvm.edu/cgi-bin/wa?A2=ind9806&L=UVMFLOWNET&P=R1388&I=-3
5. Arteritis, Takayasu; by Robert L Cirillo, Jr., M.D., MBA, Assistant Professor of Radiology, Mercer University School of Medicine, Assistant Professor, Department of Radiology, division of Interventional Radiology, Memorial Health University Medical Center., http://www.emedicine.com/radio/topic51.htm
6. Takayasu Arteritis, by Christine Hom, M.D., Assistant Professor, Department of Pediatrics, Division of Pediatric Rheumatology, New York Medical College. http://www.emedicine.com/ped/topic1956.htm
7. Taber’s Cyclopedic Medical Dictionary, 19th Edition, F. A. Davis Co., Philadelphia, 1997, ISBN 0-8036-0655-9
8. Diagnosis of Early Takayasu’s Arteritis with Sonography, by W.A. Schmidt, A. Nerenheim, E. Seipelt, C. Poehls, and E, Gromnica-Ihle., Rheumatology 2002;41: 496-502 @ 2002 British Society for Rheumatology http://rheumatology.oxfordjournals.org/cgi/content/full/41/5/496
9. Introduction to Vascular Ultrasonography, Zwiebel, Pellerito, 5th Edition, Chapter 15, published by Elsevier Saunders, 2005. ISBN 0-7216-0631-8.
10. Clinical Trial: Determining Disease Activity Biomarkers in Individuals With Takayasu’s Arteritis, Office of Rare Diseases (ORD), Clinical Trials.gov Identifier: NCT00315471, http://clinicaltrials.gov/ct/show/NCT00315471
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