Introduction
Stroke is the third leading cause of death in the United States with an annual incidence of 700,000, resulting in 150,000 deaths.¹ Extracranial atherosclerotic disease of the carotid arteries and aortic arch vessels account for more than 50% of all strokes.² Since an estimated two million people over the age of fifty have asymptomatic carotid stenosis of at least 50%, identifying these patients, modifying their risk factors, and monitoring disease progression prior to a stroke remains a paramount concern for clinicians.³

The events involved in progression of a benign carotid plaque to the point of rupture, and ultimately symptomatic disease, are an area of intense research. While the exact process remains a matter of debate, in addition to an atherosclerotic component, compelling evidence suggests a significant role for inflammation in the development and progression of carotid artery stenosis.^4–6 A recent review article summarizes the role of inflammation in the development of atherosclerotic vascular disease.⁵ Secondary serum markers of inflammation, such as C-reactive protein (CRP) and serum amyloid A (SAA), are elevated in patients with significant carotid artery stenosis.⁶ Clinically, signs of inflammation, such as increased carotid intima-medial thickness (IMT) are visualized on duplex ultrasonography. Previous authors have shown an association between increased IMT with elevated levels of CRP, suggesting a strong correlation between inflammation and carotid artery stenosis.⁷ Considering these findings, the development of screening tools and medications that interact with the inflammatory component of atherosclerotic plaques is an area of intense research. We report the case of a 55-year-old male with documented bilateral carotid artery stenosis, who following a course of high dose steroids for a separate medical condition, had incidental and almost complete regression of his carotid disease.

Case Report
A 55-year-old male presented to the vascular clinic following a suspected transient ischemic attack (TIA). He had two prior strokes, each over 15 years ago. At that time, work-up demonstrated an absence of carotid artery disease (CAD). On presentation, the patient’s neurological exam was normal and the remaining part of his physical exam was unremarkable. Carotid duplex examination revealed a right carotid bulb with 50–59% stenosis and left carotid bulb with 60–69% stenosis and a correlating systolic velocity of 287 cm/sec and diastolic velocity of 120cm/sec (Figure 1). A brain CT and an MRI demonstrated no acute abnormalities. A subsequent arteriogram (Figure 2) confirmed the duplex results, and he was scheduled to undergo a left carotid endarterectomy.

Subsequently, he had two additional follow-up visits and duplex scans that revealed gradually progressive carotid stenosis on the left, though he remains clinically asymptomatic. At nine months, his left common carotid had a maximal velocity of 138 cm/s consistent with a 50–59% stenosis. CRP drawn at that time was 0.40 mg/dl. At twelve months, the left carotid bulb velocity increased to 203 cm/s consistent with 50–79% stenosis and a CRP of 18.8 mg/dl.

Discussion
Recent reports have indicated an inflammatory component in the development and progression of carotid artery stenosis.^8,9 While markers such as CRP, SAA, interleukin 6 and soluble CD40 ligand appear to be associated with asymptomatic carotid lesions, the degree to which these markers play a role in symptomatic disease remain unclear.¹⁰ As in the present case, different markers of inflammation, including high-sensitivity CRP and ESR, have been shown to be elevated in patients with narrowing of the carotid vessels.^7,11 Similarly, intima-medial thickness as seen on ultrasound correlates with not only the degree of stenosis, but also with elevated CRP levels.^5,7,8 In the present case, duplex ultrasonography demonstrated increased IMT with elevated CRP and ESR, only to have both the serum inflammatory markers and IMT both return to normal levels following the course of steroids. One study suggested that underlying inflammation, as demonstrated by elevations in CRP, may promote atherogenesis via its effect on other conventional risk factors, especially obesity.¹¹ However, there remains no consensus on the definitive role of inflammation, or the value of monitoring inflammatory markers such as CRP in the evaluation of CAD.

In the present case, some carotid disease remained despite the course of steroids. However, the large percentage of disease regression suggests a significant inflammatory component to our patient’s carotid disease. Steroids work to decrease inflammation by several mechanisms: decreased delayed hypersensitivity, decreased cytotoxic T cells, inhibition of antibody-dependent cytotoxcity, and decreased pro-inflammatory interleukins such as IL-1, IFN gamma, and IL-2. Steroids also decrease the migration of neutrophils and inhibit the release of lysosomal enzymes.¹² Steroids are often used in the setting of inflammation to attenuate the physiologic response. Markers of inflammation, such as CRP and ESR, often normalize in response to a decreased inflammatory response. Both of these markers decreased following the steroid treatment in our patient, lending further support to an underlying inflammatory component to the carotid stenosis.

The question remains as to whether or not tracking changes in inflammatory markers, such as CRP and ESR, could help identify acute progression of disease before other clinical manifestations. The results of the ICARAS study indicate that there may be a role for monitoring CRP and SAA as indicators of active atherosclerotic disease.¹³ CRP has been linked to increased carotid atherosclerotic activity during its early stages.¹⁴ Elevations in these markers and evidence of increased inflammatory cells have also been associated with rupture into the plaque, leading to clinical symptoms of TIA and stroke.¹⁵ Other theories contend that CRP elevation is a marker of thrombotic risk rather than the degree of underlying atherosclerosis.¹⁶ CRP in our patient’s case increased with the severity of stenosis and subsequently decreased with the resolution of the inflammatory condition and a correlating decrease in carotid stenosis. Although the exact mechanism remains unknown, inflammation appears to play a significant role in the disease process. CRP is a marker of that inflammation.

Our patient had a systemic inflammatory process. He was treated with steroids, and subsequently had regression of his carotid disease. It is possible that his disease may have improved with other anti-inflammatory medications, such as aspirin. Aspirin, a platelet inhibitor and non-steroidal anti-inflammatory drug (NSAID), has long been a therapy for prevention of stroke. Aspirin therapy alone for primary and secondary prevention of strokes results in a 25% relative reduction in the incidence of ischemic stroke versus placebo.¹⁷ While its anti-platelet effect is felt to be the primary mechanism in stroke prevention, its anti-inflammatory component, like that of steroids, might also be at work. Currently, there is strong interest and ongoing research concerning the role of statin therapy to decrease inflammation. The authors do not suggest that patients with carotid artery stenosis should be placed on steroids. Further research is needed on the role of inflammation and carotid disease. As the exact role of inflammation in carotid disease is elucidated, anti-inflammatory agents might then become a first-line or second-line agent in the treatment of CAD, and surgery might be delayed or avoided. In addition, further studies need to be performed on the role of inflammatory markers such as ESR, CRP, and SAA, in CAD in following disease progression, and possibly even the timing of intervention.