Cerebrovascular manifestations of Takayasu arteritis in Europe

P. A. Ringleb*, E. I. Strittmatter*, M. Loewer, M. Hartmann, J. B. Fiebach, C. Lichy, R. Weber, C. Jacobi, K. Amendt1 and M. Schwaninger

Department of Neurology, University of Heidelberg and 1 Diakonie Krankenhaus, Mannheim, Germany.

Correspondence to: M. Schwaninger, Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany. E-mail: markus.schwaninger{at}med.uni-heidelberg.de


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objectives. Takayasu arteritis is well known as a cause of stroke in Asia but has rarely been described in the Western world. Here we report the clinical and neuroimaging follow-up of a series of patients with Takayasu arteritis from Europe.

Methods. Seventeen consecutive patients who fulfilled the diagnostic criteria for Takayasu arteritis of the American College of Rheumatology were evaluated on follow-up by standardized neurological examination, sonography and MRI.

Results. At follow-up almost 20 yr after onset of symptoms, the subclavian artery and the common carotid artery were often affected. In addition, evidence of intracranial pathology was found in seven patients. In contrast to the severe vessel involvement, the neurological state was stable. Two patients had suffered from stroke before the diagnosis was made and therapy was initiated, and one patient had recurrent transient ischaemic attacks. Intermittent dizziness was associated with pathology of the vertebral and basilar arteries. However, clinical symptoms of subclavian steal syndrome were rare.

Conclusion. This case series shows that the clinical neurological course of Takayasu arteritis on treatment is benign in most cases despite the severe vascular involvement.

KEY WORDS: Takayasu arteritis, Vasculitis, Stroke, Cerebral ischaemia, Sonography, MRI


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Takayasu arteritis (TA) is a chronic inflammatory disease of the aorta and its main branches. It is common in Asia and Mexico but rare in Europe and North America. The annual incidence of TA in North America was estimated to be 2.6 per million [1]. The rarity of the disease results in low clinical awareness in the Western world and a longer delay in diagnosis compared with Asia [2]. TA commonly presents first with non-specific symptoms, such as fever, night sweats, malaise and arthralgia. After a time lag of months and sometimes years, symptoms of organ ischaemia may develop (e.g. renovascular hypertension, coronary artery disease). Cerebral ischaemia can give rise to devastating neurological symptoms. Approximately 10–20% of patients with TA will have ischaemic stroke or transient ischaemic attacks [3]. However, the incidence of specific organ involvement differs in the various reported series, which may relate to differences in ethnic background [4]. According to Moriwaki et al. [4], in Japanese patients, mainly the aortic arch and its branches are affected, whereas in Indians the abdominal aorta and renal arteries are mainly involved. Little is known about neurological manifestations of TA and the natural course of the disease in a European population with supraaortic blood vessel involvement. Therefore, we have performed a clinical, sonographic, and magnetic resonance imaging (MRI) follow-up investigation in a series of 17 patients who fulfilled the diagnostic criteria of TA according to the American College of Rheumatology [5].


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
Seventeen consecutive patients seen at the Department of Neurology, University of Heidelberg, a tertiary referral centre for cerebrovascular disorders, were followed up. Twelve patients were referred from rheumatological out-patient clinics, four patients were referred by their family doctor, and one patient was referred from the department of vascular surgery. Long-term care for all patients was provided by a rheumatologist. Informed consent was obtained from all subjects. In 15 cases, the diagnosis had been supported by panaorto-arteriography previously. In one patient, CT angiography provided unequivocal evidence for stenoses of both subclavian arteries. In two patients, CT or magnetic resonance (MR) angiography had provided unequivocal evidence for occlusion or stenosis of the subclavian arteries. A standardized neurological examination was performed.

Ultrasonographic studies
A complete conventional Doppler examination (Medasonics CDS; Medilab, Germany; 4 MHz Continuous Wave (CW) probe, 2 MHz Pulsed Wave (PW) probe), and an extracranial duplex examination (HP 4500 or HP 5500; 7–11 MHz linear scanner) was performed in all patients following a standardized protocol. Nine patients were also examined by transcranial duplex sonography (2–4 MHz sector scanner).

All extracranial brain-supplying vessels and the subclavian arteries were examined to get information about stenoses and occlusions. In the duplex sonography, the thickness of the intima media layer of the common carotid artery and the perivascular tissue was of special interest [6, 7]. Transcranial sonography was performed to examine collateral pathways and possible additional pathologies. An intracranial stenosis was diagnosed if an increased flow velocity could not be explained by a collateral pathway or systemic conditions such as anaemia. Because of the complex vessel status in TA patients with multifocal pathology, we did not use any fixed definition for intracranial stenoses. The diagnosis of an intracranial stenosis was based on the judgement of an experienced neurosonologist (P.A.R., C.L., R.W.).

MR studies
Patients were imaged with a 1.5-tesla scanner with high gradient performance (Siemens Symphony®, Erlangen, Germany). The MRI protocol consisted of conventional T2-weighted and T1-weighted axial images [field of view (FOV) 21 cm, voxel size 0.9 x 0.8 x 6 mm]. Diffusion-weighted imaging was performed at b-values of 0 and 1000 s/mm2 with a voxel size of 1.8 x 1.8 x 6 mm [repetition time (TR) 3200 ms, echo time (TE) 94 ms, FOV 230 mm]. In 15 patients contrast-enhanced MR angiography from the aortic arch to the base of the skull was performed during administration of 10 ml gadolinium-DTPA (Magnevist®; Schering, Berlin, Germany). The voxel size was 1.4 x 0.7 x 1.4 mm (TR 3.7 ms, TE 1.43 ms, flip angle 25°, FOV 360 mm). Three-dimensional reconstructions were postprocessed from subtracted images. Intracranial vessels were investigated by time-of-flight MR angiography in eight patients with a voxel size of 0.8 x 0.4 x 0.8 mm (TR 37 ms, TE 7.15 ms, flip angle 25°, FOV 200 mm). In another two patients, informative images of the intracranial vessels were obtained by contrast-enhanced MR angiography. The MR images were evaluated by two experienced neuroradiologists (M.H., J.B.F.).


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
All 17 patients fulfilled the diagnostic criteria for TA of the American College of Rheumatology (Table 1) [5]. As in other populations [4], most patients were female (Table 1). Notably, the diagnosis was delayed by 9 yr on average. Patients came to the follow-up investigation 20 yr on average after first onset of symptoms. At this time 14 patients were still on low doses of prednisolone, while all patients had received steroids at an earlier stage of the disease. Other vascular risk factors are listed in Table 1.


View this table:
[in this window]
[in a new window]
 
TABLE 1. Demographic and clinical features of patients

 
At follow-up investigation by sonography and MR angiography, there was still prominent vascular changes of the subclavian and common carotid arteries in most patients (Table 2). Several vessels showed a characteristic concentric thickening of the wall on duplex sonography [8, 9]. The internal carotid artery, the vertebral artery and the intracranial vessels were less often affected (P = 0.001, ANOVA, Bonferroni post hoc test). Still, 7 out of 17 patients had definitely abnormal blood flow in intracranial vessels on sonographic or MR investigation that could not be attributed to extracranial stenoses (patients 3, 6, 8–10, 15 and 16 in Table 2). In the ten patients in whom both sonography and intracranial MR angiography was available, the latter technique verified three intracranial stenoses in three out of 10 cases. However, sonography indicated more frequent intracranial affection than MR angiography. According to sonography, five out of 10 patients had 10 intracranial stenoses.


View this table:
[in this window]
[in a new window]
 
TABLE 2. Cerebrovascular affection of patients with Takayasu arteritis

 
In six patients, sonography provided evidence for a subclavian steal, although there was no clinical history of subclavian steal syndrome. Non-specific intermittent dizziness was reported by 6 out of 17 patients and was associated with a pathological finding of the vertebral and the basilar arteries (Table 2). Five out of eight patients with definite or likely involvement of posterior vessels suffered from dizziness (P<0.05, Fisher's exact test). Other common problems were headaches in nine patients, intermittent visual disturbances in eight patients that seemed to be related to migraine in several cases (Table 2), and symptoms of a depressive mood disorder in five patients. Fortunately, only two patients had suffered a clinical stroke before the diagnosis was made and therapy initiated. One patient suffered from transient ischaemic attacks in the territory of a high-grade stenosis of the middle cerebral artery. In this patient (patient 3) and in another two asymptomatic patients (patients 13 and 14), MRI of the brain showed small lesions of the white matter that were presumably of vascular origin.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
TA is rare in Europe and North America. Therefore, many clinicians are not aware of this disease and the diagnosis is often delayed by many years or maybe even missed [10]. Our series of patients confirms that TA is also encountered in a European population [9]. The vascular territories affected by TA differ markedly between Indian and Japanese reports. While in Japan an involvement of the thoracic aorta and its branches has been described, in India the abdominal aorta is more often affected [4]. Although our follow-up did not include a formal investigation of the abdominal aorta, the prior history of our patients suggested an abdominal involvement only in a single male patient with an Indian ethnic background (patient 4). However, in all patients either the subclavian or common carotid arteries were affected. Thus, the distribution of the vasculitis was very much as has been described for Japanese patients. The inflammatory disease primarily involves the media and adventitia of vessel walls and thus results in luminal abnormalities (stenosis, occlusion, aneurysm formation). Often the arteries are affected over long segments and on both sides.

MR angiography and sonography provide two non-invasive techniques to investigate the vasculature that may supersede digital subtraction angiography in the future. Notably, the intracranial arteries showed clearly pathological findings in 7 out of 17 patients on Doppler sonography and MR angiography, which could not be explained by haemodynamic constraints of the extracranial vessels. However, there are several limitations of the neurosonological methods in detection of intracranial stenoses in complex vessel situations. Since the 1980s, transcranial Doppler sonography (TCD) has been widely used to assess cerebral artery flow velocities [11]. In the 1990s, transcranial colour-coded duplex sonography, which adds frequency-based colour Doppler imaging to TCD and B-mode imaging, became available [12]. Criteria to assess collateral flow through the circle of Willis and to detect intracranial stenoses have been reported [13, 14]. These criteria were evaluated in patients with isolated intracranial stenoses or intracranial pathology in addition to a single extracranial lesion. However, the complex bilateral vascular involvement in TA allowed only a tentative application of the reported criteria. MR angiography verified intracranial stenoses in some cases but clearly less often than suggested by sonography. All intracranial stenoses reported by MR angiography were detected by sonography, suggesting that the sensitivity of the latter technique is high. However, the specificity of sonographic detection of intracranial stenoses is unclear without conventional angiography. Future studies will clarify this point [15].

Intracranial stenoses in TA could be due to either vasculitic involvement or a prior embolization into the vessel. Evidence for vasculitic affection of intracranial arteries has been found in rare cases on conventional angiography [16]. At least one case report has described intracranial arteritis in a patient with TA discovered at autopsy [17]. Using transcranial Doppler sonography, Kumral et al. have detected microembolic signals in the middle cerebral arteries of 4 out of 18 patients with TA [18]. Involvement of cardiac valves and proximal arteries may provide a source of embolism in TA [2, 19].

In contrast to the severe vascular involvement, clinical findings were rather rare. The two strokes in our group of patients occurred before the diagnosis was made and therapy started. Upon immunosuppression, the disease took a stable course in all patients over an average of almost 20 yr. Several patients suffered from transient dizziness, which was associated with impairment of the posterior circulation, and headache. However, it is unclear whether these symptoms are of ischaemic origin.

In summary, our case series suggests that TA presents with similar cerebrovascular signs in Europe and Japan. In a young patient, affection of the aorta or the subclavian or common carotid artery is suggestive of TA, especially if it is associated or preceded by malaise. Despite involvement of multiple arteries, only transient neurological symptoms occurred during a follow-up of almost 20 years, while most patients were still on immunosuppression. The relatively high number of patients with additional intracranial pathological findings in our series suggests that examination of intracranial vessels in patients with TA may be helpful for primary or secondary prevention strategies.

The authors have declared no conflict of interest.


    Notes
 
* These authors contributed equally to this work. Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

  1. Hall S, Barr W, Lie JT, Stanson AW, Kazmier FJ, Hunder GG. Takayasu arteritis. A study of 32 North American patients. Medicine (Baltimore) 1985;64:89–99.[ISI][Medline]
  2. Johnston SL, Lock RJ, Gompels MM. Takayasu arteritis: a review. J Clin Pathol 2002;55:481–6.[Abstract/Free Full Text]
  3. Kerr GS, Hallahan CW, Giordano J et al. Takayasu arteritis. Ann Intern Med 1994;120:919–29.[Abstract/Free Full Text]
  4. Moriwaki R, Noda M, Yajima M, Sharma BK, Numano F. Clinical manifestations of takayasu arteritis in India and Japan—new classification of angiographic findings. Angiology 1997;48:369–79.[ISI][Medline]
  5. Arend WP, Michel BA, Bloch DA et al. The American College of Rheumatology 1990 criteria for the classification of takayasu arteritis. Arthritis Rheum 1990;33:1129–34.[ISI][Medline]
  6. Schwaninger M, Ringleb P, Annecke A et al. Elevated plasma concentrations of lipoprotein(a) in medicated epileptic patients. J Neurol 2000;247:687–90.[CrossRef][ISI][Medline]
  7. Poli A, Tremoli E, Colombo A, Sirtori M, Pignoli P, Paoletti R. Ultrasonographic measurement of the common carotid artery wall thickness in hypercholesterolemic patients. A new model for the quantitation and follow-up of preclinical atherosclerosis in living human subjects. Atherosclerosis 1988;70:253–61.[ISI][Medline]
  8. Kissin EY, Merkel PA. Diagnostic imaging in takayasu arteritis. Curr Opin Rheumatol 2004;16:31–7.[CrossRef][Medline]
  9. Schmidt WA, Nerenheim A, Seipelt E, Poehls C, Gromnica-Ihle E. Diagnosis of early Takayasu arteritis with sonography. Rheumatology 2002;41:496–502.[Abstract/Free Full Text]
  10. Sharma BK, Siveski-Iliskovic N, Singal PK. Takayasu arteritis may be underdiagnosed in North America. Can J Cardiol 1995;11:311–6.[ISI][Medline]
  11. Aaslid R, Markwalder TM, Nornes H. Noninvasive transcranial doppler ultrasound recording of flow velocity in basal cerebral arteries. J Neurosurg 1982;57:769–74.[ISI][Medline]
  12. Bogdahn U, Becker G, Winkler J, Greiner K, Perez J, Meurers B. Transcranial color-coded real-time sonography in adults. Stroke 1990;21:1680–8.[Abstract]
  13. Baumgartner RW, Baumgartner I, Schroth G. Diagnostic criteria for transcranial colour-coded duplex sonography evaluation of cross-flow through the circle of Willis in unilateral obstructive carotid artery disease. J Neurol 1996;243:516–21.[CrossRef][ISI][Medline]
  14. Baumgartner RW, Mattle HP, Schroth G. Assessment of ≥50% and <50% intracranial stenoses by transcranial color-coded duplex sonography. Stroke 1999;30:87–92.[Abstract/Free Full Text]
  15. Stroke Outcome and Neuroimaging of Intracranial Atherosclerosis (SONIA): design of a prospective, multicenter trial of diagnostic tests. Neuroepidemiology 2004;23:23–32.[CrossRef][ISI][Medline]
  16. Klos K, Flemming KD, Petty GW, Luthra HS. Takayasu's arteritis with arteriographic evidence of intracranial vessel involvement. Neurology 2003;60:1550–1.[Free Full Text]
  17. Molnar P, Hegedus K. Direct involvement of intracerebral arteries in Takayasu's arteritis. Acta Neuropathol (Berl) 1984;63:83–6.[CrossRef][ISI][Medline]
  18. Kumral E, Evyapan D, Aksu K, Keser G, Kabasakal Y, Balkir K. Microembolus detection in patients with Takayasu's arteritis. Stroke 2002;33:712–6.[Abstract/Free Full Text]
  19. Matteucci ML, Iascone M, Gamba A et al. Left main stem patch plasty and aortic root homograft in Takayasu's disease. Ann Thorac Surg 2004;77:314–7.[Abstract/Free Full Text]
Submitted 16 December 2004; revised version accepted 29 March 2005.



This Article
Abstract
Full Text (PDF)
All Versions of this Article:
44/8/1012    most recent
keh664v1
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Disclaimer
Request Permissions
Google Scholar
Articles by Ringleb, P. A.
Articles by Schwaninger, M.
PubMed
PubMed Citation
Articles by Ringleb, P. A.
Articles by Schwaninger, M.
Related Collections
Other Rheumatology