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A Takayasu tale that tells it all: Diagnostic and therapeutic discussions on an interesting case
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.253645
Sir, Stroke, when it affects the very young, is a challenge both for the treating physician as well as the concerned families who go through a huge ordeal. Takayasu arteritis (TA) is a relatively rare cause of stroke in the young subjects. It is an inflammatory arteritis of unknown cause which primarily affects the aorta and its major branches but has a propensity to affect any vessel in the body. Pathologically, there is panarteritis with involvement of all layers of affected medium and large arteries with secondary fibrosis, thrombus formation, and embolization. Although the geographical distribution of the disease is wide, Asian and Latin American populations have the highest incidence. Young adults, especially females, are the usual victims. The clinical manifestations are usually the result of cerebral hypoperfusion, subcalvian steal phenomenon, or microembolization. Syncope, dizziness, and visual disturbances are common but the disease largely remains undiagnosed for a long time before a systematic clinical examination reveals absent pulses or asymmetry of blood pressure recordings between the upper limbs. A 14-year-old girl with no remarkable past or family history was first brought to medical attention 1 year earlier for evaluation of frequent headaches, which were described as hemicranial, throbbing, always affecting the right half of her head associated with vomiting, photophonophobia, and worsening with any form of movement or activity. Precipitating factors were not distinctly identified. She was managed with symptomatic use of nonsteroidal anti-inflammatory drugs. The attacks became infrequent over time until 3 months back when there was an apparent increase in their frequency and severity. Moreover, the episodes were intermittently associated with blurring of vision lasting for seconds to a few minutes. It was after a bout of diarrhoea and vomiting that she was finally hospitalized. On examination, she had absence of right radial and brachial pulses and rest of the examination was unremarkable. Blood pressure in the left upper limb was 126/74 mmHg. Investigations revealed a Hb of 13.1 g/dl and hs CRP − 0.2(Normal−<0.5); WBC 13200 cells/mm 3, 83% neutrophils; platelet count 300,000 cells/mm 3, ESR19. Vasculitic profile, angiotensin converting enzyme level, antiphospholipid antibodies, serological tests for syphilis, chest X-ray, and ultrasound abdomen were normal. Magnetic resonance imaging (MRI) of the brain also did not reveal any abnormalities. Computed tomography (CT) angiography of the thoracic aorta revealed mural thickening of the arch of aorta and its branches with significant stenosis of the brachiocephalic trunk and complete stenosis of the right internal carotid artery. Transcranial Doppler (TCD) revealed an audible bruit in the middle cerebral artery M1 segment at all depths with normal flow velocities and pulsatility index (probably transmitted from the carotid). Digital subtraction angiography of the arch, abdominal aorta and cerebral vessels showed occlusion of the right common carotid artery from its origin with distal reformation retrogradely through the right thyrocervical artery. The first part of subclavian artery showed severe stenosis along with mild stenosis of the right vertebral artery at its origin. A good collateralization of the right middle cerebral artery (MCA) territory through the anterior communicating artery (ACOM), posterior communicating artery (PCOM), and right thyrocervical artery was noted [Figure 1]. She was started on antiplatelets and oral steroids 1 mg/kg. A week later, she presented with severe headache of 2–3 hours duration followed by sudden-onset weakness of left upper and lower limbs along with slurring of speech. On examination, she had moderate facial palsy, left upper limb 2/5 power and left lower limb 1/5 power. MRI brain revealed acute right basal ganglia infarct [Figure 2]. She was attended by the treating neurologist (SS) who recorded a National Institutes of Health Stroke Scale (NIHSS) of 14 when intravenous thrombolysis with 0.9 mg/kgr-tPA was initiated (3.5 hours after the symptom onset). TCD was used to monitor the thrombolytic treatment as well as for the potential therapeutic benefit for the next 2 hours [Figure 3]. This was followed by administration of 10 mg of cerebrolysin and 1g pulse methylprednisolone. Clinical improvement was noted after 30 minutes and was complete after 2 hours (NIHSS, 0). She was discharged a week later on oral prednisolone 1 mg/kg and mycophenolate 500 mg/day.
TA owes its name to the Japanese Ophthalmologist Mikito Takayasu who along with Katsutomo Onishi was responsible for the discovery of this entity in 1908.[1] The infective etiological hypothesis for this vasculopathy has pointed to agents such as Spirochetes, Mycobacteria, and Streptococcus. However, the putative role of Mycobacterium tuberculosis has recently been conclusively negated by the conspicuous absence of mycobacterial DNA in the blood and arterial specimens of TA patients.[2] Genetic susceptibility has been attributed to HLA-B52 which also influences the severity of disease and response to steroids in Japanese patients, where as other related loci are implicated for other populations such as the Chinese.[3],[4] Autoantibodies directed against endothelial cells and antiaorta antibodies as well as cell-mediated immune mechanisms are the most likely final common pathway of injury to the large elastic arteries.[5] The American College of Rheumatology Criteria requires the presence of ≥3 of the following 6 criteria for a clinical diagnosis of TA: onset age <40 years, claudication of an extremity, decreased brachial artery pulse, >10 mmHg difference in systolic blood pressure between arms, a bruit over the subclavian arteries or the aorta, and arteriographic evidence of narrowing or occlusion of the entire aorta, its primary branches, or large arteries in the proximal upper and lower extremities. Three out of 6 criteria are required for diagnosis and demonstrate a sensitivity of 90.5% and a specificity of 97.8%.[6] The new angiographic classification of TA describes four subtypes:[7] Type I: Branches from the aortic arch Type IIa: Ascending aorta, aortic arch and its branches Type IIb: Ascending aorta, aortic arch and its branches, thoracic descending aorta Type III: Thoracic descending aorta, abdominal aorta, and/or renal arteries Type IV: Abdominal aorta and/or renal arteries Type V: Combined features of types IIb and IV Aortoarteritis can occur in a host of other diseases such as syphilis, tuberculosis, sarcoidosis, giant cell arteritis, Bechet's disease, ankylosing spondylitis, Kawasaki disease, rheumatoid arthritis, IgG4 related disease, and Erdheim–Chester disease, most of which were excluded by relevant clinical and laboratory evaluation.[8] In our patient, two cardinal manifestations were present namely migraine headaches and ischemic stroke. The understanding of the pathogenesis of these events is pivotal in developing a strategy to prevent them. In a recent meta-analysis of case-control and cohort studies, the estimated prevalence of transient ischemic attack (TIA) in TA was 15.8% (95% confidence interval (CI): 10.7–22.6%); and, of stroke, 11.7% (95% CI: 10.1–13.5%). Vascular inflammation and thrombosis are unequivocally responsible for stroke, as per the literature. In an interesting study of transcranial examination of cerebral vessels to detect microembolic signals among 18 patients with TCD, 30% of the patients with a raised erythrocytic sedimentation rate (ESR) and 13% with a normal ESR had a positive examination. The anterior circulation was always affected, whereas the subtypes associated with cerebral embolism were exclusively types I and III. Treatment, both immunosuppressive and anti-platelet/anticoagulant, did result in a reduction in microembolic signals [MES], but there was no statistically significant difference between different modes of treatment.[9] We addressed this important concern by performing a 45 minute emboli monitoring which did not show any MES. Focal cortical ischemia can present with typical attacks of migraine with aura, which in fact is the best explanation for these symptoms in a 14-year-old patient.[10] Headache and visual disturbances were noted in 22 and 16% of cases in a large series of 50 cases from south India.[11] However, because migraine is common in this age group, a high index of suspicion is required to expose a secondary cause of migraine. Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS), cerebral autosomal dominant arteriopathy with subcortical ischemic strokes and leucoencephalopathy (CADASIL), essential thrombocythemia, and vasculitis are other disorders, which can cause both migraine and stroke. A patent foramen ovale and dissection are less established causes linking the two entities. Therapeutic issues and dilemmas in TA can be summarized under the following heads: (1) Medical vs surgical management, (2) monitoring of therapy, (3) Management of acute vascular occlusions. Medical treatment should always be chosen as the first line mode of management. There are two goals of medical management (a) Suppression of disease activity, for which steroids are the preferred option along with other agents such as mycophenolate, azathioprine, cyclophosphamide, tacrolimus, toclizumab, and methotrexate; and (b) thromboprophylaxis, in which aspirin should be used in all patients who have active disease. Other antiplatelets and oral anticoagulants have also been tried in documented microembolism.[12] Monitoring of therapy is done by assessing the clinical response along with laboratory markers such as C-reactive proteins (CRP) and ESR. Vascular imaging can also be used whenever indicated. Risk factors such as diabetes, hypertension, dyslipidemia, sleep apnoea, and smoking should be addressed as they add to the risk of vascular events.[13] Regarding acute vascular occlusions, especially ischemic stroke, there is no consensus on the line of management. However, not many cases of TA presenting as stroke are treated with intravenous thrombolysis using tissue plasminogen activator (tPA). Here, we highlight the necessity of using thrombolysis if the patient presents with an acute ischemic stroke during the window period as the disabling symptoms are reversible with effective therapy.[14],[15],[16] However, TPA has its limitations as ischemia may not be restricted to cerebral vasculature. Moreover, diffuse, multifocal, and ostial vessel involvement in TA can hamper the efficacy of the drug. Rapid progression of the disease can occasionally result in an aneurysm formation as a consequence of inadequate fibrosis of the affected arteries, and thrombolysis would be contraindicated in such cases.[16] Mechanical thrombectomy can also be performed provided there is a good access to the site of thrombus. Surgical treatment of hemodynamically significant stenosis by bypass grafting/balloon angioplasty and stenting can be offered, especially if medical management fails to stabilize the disease course and radiological progression is documented.[17],[18],[19] The few previous reports of acute interventions attempted in the management of acute stroke in TA are summarized in [Table 1].
TA is an important cause of stroke in the young, especially in Asian countries. A clear guideline for the management of stroke among the young is necessary to ensure that patients receive the best possible treatment. Acknowledgements We acknowledge the Director of St Stephen's Hospital and the Hospital management for allowing us to publish this case report. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3]
[Table 1]
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