Transient perivascular inflammation of the carotid artery (TIPIC) syndrome
An updated multinational analysis of 72 patients
Abstract
Summary:Background: The Transient Perivascular Inflammation of the Carotid artery (TIPIC) syndrome is presumably a very rare disease characterized by a local transient inflammation of the tissue around the carotid artery. Its pathophysiology remains unknown. We performed an updated study of TIPIC syndrome cases in the setting of a multinational collaborative study. Methods: This study was conducted as an observational multinational retrospective individual patient level cohort study. Information from all known cases diagnosed with TIPIC syndrome in the literature (2005–2020) was collected after a semi-structured literature search of PubMed and Web of Science. We also collected unpublished information of patients from French, Swiss, and Italian vascular medicine or radiology departments. Results: A total of 72 patients were included and served for data analysis: 42 (58.3%) were women; the mean age was 47.9 (SD=11.4) years. Symptoms were unilateral in 92% of patients and 81.4% required pain killers. At baseline, irrespective of the imaging method used, the median thickness of the carotid lesions was 5 (Q1–Q3: 4–7; range: 2–11) mm and the median length of the lesion was 20 (Q1–Q3: 10–30; range: 3–50) mm. We found a positive linear correlation between thickness and length. At follow-up, the thickness of the carotid lesions decreased to a median of 2 (Q1–Q3: 1–3; range: 0–6) mm; the length decreased to a median 10 (Q1–Q3: 5–15; range: 0–41) mm. A linear correlation between baseline and follow-up values was observed for both thickness and length measurements. Symptoms disappeared after a median of 14 (Q1–Q3: 10–15) days. Thirteen patients experienced a recurrence after a median follow-up of 6 (Q1–Q3: 2–12) months. Conclusions: The present analysis elucidates clinical and sonographic characteristics of TIPIC syndrome, indicating the benign nature of this condition. A future international registry will study the long-term course of the disease.
Introduction
The Transient Perivascular Inflammation of the Carotid artery (TIPIC) syndrome, historically denominated “carotidynia” or named after Dr. Fay (“Fay syndrome”), is characterized by a local transient inflammation of the tissue around a small portion of the carotid artery. It usually manifests itself as a tenderness and self-limiting neck pain, which often radiates to other contiguous regions. Being a rare vascular disorder with an estimated prevalence of 2.8% [1] among subjects presenting with acute neck pain, it is only recently that it has been nosologically defined, although its first descriptions dates back in the 1960s [2]. The pathophysiology of TIPIC remains unknown.
Current knowledge on the disease primarily derives from a cohort study of 47 patients, which contributed to first establish the diagnostic criteria for the syndrome, permitting its classification, and investigate the general characteristics [1]. It is still unclear, for instance, whether structural abnormalities of the carotid wall are as a diagnostic criterion for TIPIC syndrome beyond the typical inflammatory changes of the perivascular soft tissue in the carotid.
The aim of this multicenter multinational retrospective cohort study is to provide an updated individual patient level analysis of a larger cohort of patients with TIPIC syndrome, including novel and all previously published cases, to better describe its clinical and imaging characteristics.
Patients and methods
This study was conducted as an observational multinational retrospective individual patient level cohort study. The aim was to collect information on all known cases diagnosed with TIPIC syndrome who have been either already described in the literature or newly diagnosed at selected tertiary European centers and still unpublished. We screened the literature for the period elapsing from 2005 to 2020 and collected patient data from multicenter cohorts, series of cases, or case reports [1, 3–24]. The potentially eligible full-text studies were screened with a semi-structured literature search of PubMed and Web of Science combining (i) keywords (“TIPIC” or “Transient Perivascular Inflammation of the Carotid” or “Fay* syndrome” or “Carotidynia” or [“Carotid” and {“Vasculitis” or “Inflammation” or “Pain”}]), (ii) a cross search of bibliography lists of potentially eligible studies, (iii) key reviews of the literature. In addition, we collected unpublished information of patients from French, Swiss, and Italian departments (n=5) where data from additional patients were collected after the publication of the prior cohort of 47 patients, the largest to date [1]. The remaining patients were described in isolated case reports of small series of cases: for those, additional information was obtained after contact with the corresponding authors, if required. A total of 72 patients were included in the study and used for data analysis.
The diagnosis of TIPIC was accepted in the presence of typical acute cervical pain and after confirmation by at least one diagnostic imaging test (magnetic resonance imaging, computed tomography, or ultrasonography), as previously defined [1].
The following clinical data was collected for the present analysis: demographic characteristics of the patients, the recent or past medical history, as well as the major cardiovascular risk factors (arterial hypertension, smoking, diabetes, hypercholesterolemia and atherothrombotic artery disease). Data about the clinical presentation were also collected, particularly the pain intensity, localization of the pain, the pain resolution time and the presence of local swelling or tenderness or adenomegalies at palpation, as well information on clinical follow-up. The main diagnostic imaging data used at baseline and during the follow-up period was collected. Follow-up visits were performed at the discretion of the treating physicians at each center and the clinical or radiological information was collected, as reported in the original medical charts.
This analysis was approved by the institutional research ethical committees at individual institutions, where required. All patients gave their consent for the use of clinical data for research purposes.
Descriptive analyses of the baseline and follow-up characteristics used counts and percentages for categorical data, whereas continuous data were expressed as mean (SD) or as medians and quartiles 1–3 (Q1–Q3). In this purely descriptive, exploratory non-prespecified analysis, we abstained from doing any inferential analysis due to the nature of the study, the anticipated high frequency of missing data, and the recommendations from statistical society against such an approach in this setting. SPSS version 26.0 (IBM Corp., Armonk, NY, USA) was used for statistical analysis.
Results
Characteristics of the study population
Data from a total of 72 patients was collected and served for analysis. The baseline and demographic characteristics of the study population are described in Table I. Of 72 patients, 42 (58.3%) were women and the mean age was 47.9 (SD=11.4) years. The prevalence of concomitant diseases was overall low. The most frequent risk factor for cardiovascular diseases was active smoking, which was reported for 19/69 (27.5%) patients of the population. In total, 4/70 (5.7%) patients reported a recent viral infection. No patient underwent recent neck manipulation or experienced recent trauma in the neck region.
Table II summarizes the main clinical features at the time of initial clinical presentation of the TIPIC syndrome. More than 90% of the study population had pain on palpation in the affected area, which was described as “moderate” in two thirds of them. Symptoms were unilateral in 92% of patients with local pain. Ten of 60 (17%) patients had lymphadenopathy on palpation. Other signs or symptoms included local swelling (29%), fever (6%), and headache (11%). A total of 57/70 patients (81.4%) required supportive therapy with aspirin, nonsteroidal anti-inflammatory drugs or low-dose glucocorticoids.
Characteristics of imaging
Irrespective of the imaging method used, the median thickness of the carotid lesions was 5 (Q1–Q3: 4–7; range: 2–11) mm and the median length of the lesion was 20 (Q1–Q3: 10–30; range: 3–50) mm. Figure 1 indicates a positive linear correlation between these two parameters and provides information on the distribution of the observed values.
Sonographically, the median maximum wall (or perivascular) thickness of the carotid artery was 5 (Q1–Q3: 4–6) mm and the median length of the lesion was 15 (Q1–Q3: 8–22) mm. The carotid bulb or carotid bifurcation was the most frequently affected area. Sonographic lesions were eccentric in 88% of patients and localized in the posterior or lateral part of the artery in three quarter of patients. The lesion did not cause a stenosis in 66% of patients: a slight or mild visual narrowing was described in all cases with stenosis. No severe hemodynamic changes, as quantified by using the North American Symptomatic Carotid Endarterectomy Trial criteria, were found in patients examinated with ultrasound colorDoppler. The overall sonographic characteristics of the study population are described in Table III. In one case a contrast-enhanced ultrasound (CEUS) was performed, which showed a massive number of microbubbles in the surrounding medial–adventitial lesion. At 3 months follow-up, the lesion disappeared.
The detailed measures and imaging characteristics by computer tomography (CT) and magnetic resonance (MRI) are presented in Tables IV and V, respectively. In agreement with the sonographic findings, most of the lesions were eccentric, with a localization mainly at the level of the carotid bulb/carotid bifurcation. The lesion thickness and length were comparable to that measured on sonography: however, the fact that only one of the three methods was often used prevents us from a direct comparison of these techniques.
Follow-up results
Follow-up data were available for 70/72 (97.2%) patients. Median follow-up time was 105 (Q1–Q3: 50–180) days; Table II. Symptoms disappeared after a median of 14 (Q1–Q3: 10–15) days. Thirteen (18.6% of patients with available data) patients experienced a recurrence after a median follow-up of 6 (Q1–Q3: 2–12) months. The general clinical and radiological characteristics of patients with and without recurrence are presented in Electronic Supplementary Material (ESM) 1.
Irrespective of the imaging method used to assess the lesions, the thickness of the carotid lesions at follow-up decreased to a median of 2 (Q1–Q3: 1–3; range: 0–6) mm, whereas the length of the lesion at follow-up decreased to a median 10 (Q1–Q3: 5–15; range: 0–41) mm; Figures 2A and 2B. We found a linear correlation between baseline and follow-up values concerning the thickness and length of the carotid lesions: Figures 3A and 3B depict this correlation for patient with available baseline and follow-up values.
With sonography, the median maximum wall or perivascular thickness at follow-up of the carotid artery was 1.5 (Q1–Q3: 0.9–2.8) mm and the median length of the lesion was 7.0 (Q1–Q3: 4.3–10.0) mm. With MRI, the median maximum wall or perivascular thickness at follow-up of the carotid artery was 2.7 (Q1–Q3: 1.9–3.8) mm and the median length of the lesion was 13.5 (Q1–Q3: 9.8–18.0) mm; Table IV.
Discussion
This observational multicenter multinational retrospective cohort study is an updated analysis of patients with the TIPIC syndrome. In this study, a total of 72 subjects were selected based on homogeneous diagnostic criteria and included with the aim of assessing the clinical and radiological characteristics of this rare vascular condition. To our knowledge, this represents the most comprehensive analysis of patients with the TIPIC syndrome. Furthermore, it paves the way for future collaboration aiming at improve the evidence on this syndrome, namely fostering the creation of a collaborative international registry with pre-specified outcomes and follow-up.
This syndrome is still largely unknown for what concerns its triggers, pathophysiological mechanisms, and long-term relevance. Indeed, the initial symptomatology is often mild and self-limiting. The changes in diagnostic imaging are rapidly reversible. This suggests that a substantial underdiagnosis is likely among patients with acute onset pain in the neck for whom no sonographic investigation is planned. According to previously published studies, also in our study, most patients present with unilateral pain (93%) and more rarely the pain is localized to both sides. The characteristics of clinical manifestations at onset and localization of the TIPIC lesions appear to be rather typical, ideally leading to a swift confirmatory diagnosis. A throughout personal history and general assessment of patient status should routinely be performed in order to exclude the presence of signs or manifestations of a systemic autoimmune disease at baseline as well as during follow-up (Table VI).
Sonographic, computed tomographic and magnetic resonance imaging findings of vascular or perivascular involvement, with a subsequent thickening of the wall often described as soft plaque, have also been found in several other case reports and may probably be caused by the inflammatory process itself. This hypothesis is also supported by laboratory and clinical findings, with increased levels of inflammatory parameters (C-reactive protein, Erythrocyte Sedimentation Rate and white blood cells) and the presence of lymphadenopathy, as demonstrated in our cohort of patients. What our analysis suggests is that there was a positive correlation between the length and the thickness of the lesions, indicating that the disease burden may manifest also in a quantitative manner. Whether the size of the lesions correlates with the type of symptoms should be object of future analyses.
Patients with TIPIC syndrome experienced an improvement and in most cases a complete resolution of the vascular involvement on imaging, with a reduction of the vascular thickening and the length of the lesion. However, in some cases, there is a slower resolution or sometimes persistence of vascular abnormalities. This may be explained by the persistence of a mild chronic inflammatory process and simultaneous deposition of fibrotic material in situ. Both a spontaneous resolution of symptoms and a normalization of the sonographic parameters without the need of immunosuppressive treatment appear to be the most typical aspects of this benign syndrome, permitting a distinction between TIPIC and systemic vasculitides provided that the treating physicians are aware of the TIPIC syndrome. Indeed, one cannot exclude that the major criteria of the syndrome listed in [1] and adapted in Table VI may refer to overt manifestations of disease only, therefore leaving out a milder spectrum of the syndrome, which may remain unnoticed and ultimate underdiagnosed. Although in the past definitions one of the criteria for the diagnosis of carotidynia was the disappearance of symptoms spontaneously within 14 days, in the new definition proposed by Lecler and colleagues in 2017, the resolution of symptoms by anti-inflammatory treatment has been introduced. In our cohort of patients, the majority (81%) benefited from anti-inflammatory therapy using nonsteroidal anti-inflammatory agents and aspirin. However, the resolution of symptoms was longer than described in the literature, with an average of 17 days, compared to 13 days proposed by Lecler [1]. In agreement with prior literature, recurrence also occurred in approximately 20% of patients in our cohort. To better follow the course of symptoms, it appears reasonable to schedule a short-term visit in all patients with an initial diagnosis of TIPIC, for instance within 2 weeks of onset. Similarly, a mid-term visit may follow to exclude the presence of pathological conditions that did not emerge during the initial assessment. With this respect, it must be highlighted that no data is available on the long-term complications and course of TIPIC: therefore, it is reasonable to follow these patients and monitor the onset of signs or symptoms indicating any systemic disorder. An overview of the adapted diagnostic criteria, based on [1], and a brief overview of an ideal follow-up scheme and differential diagnoses is presented in Table VI.
Limitations
One of the limitations is the small size of this cohort and the fact that data were collected in a retrospective fashion at different centers with heterogeneous approaches in terms of diagnosis, management, and follow-up. Moreover, a proportion of the current sample size was taken from a prior study from the literature: therefore, it does not come as a surprise that some observations represent a valuable confirmation of prior findings. Finally, this study focuses necessarily on patients who received a diagnosis of TIPIC syndrome: these may represent a minority of a hypothetical whole TIPIC population and we cannot exclude that the less severe cases (not referred for advance diagnostics) may have been underdiagnosed.
This data illustrates that a correct diagnosis of TIPIC syndrome is important to reduce the number of useless additional examinations and therapies that the individual patient may undergo. In particular, ultrasonography may represent an easy and reproducible method for initial assessment and confirmation of the regression of the lesions. Moreover, data about the use of CEUS for the diagnosis of TIPIC syndrome are emerging, suggesting that CEUS could be used as a diagnostic tool in the future and also for the follow-up of the patients in order to assess the enhancement of lesions [25].
The favourable short- or mid-term prognosis of this syndrome should be anticipated when it comes to informing the patients about the course of the diseases. Future multinational registries will help to elucidate pathophysiological elements and the long-term course of the syndrome.
Electronic supplementary material
The electronic supplementary material (ESM) is available with the online version of the article at https://doi.org/10.1024/0301-1526/a000989
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