Abstract
Background
The present study aimed to describe the clinical and ultrasound (US) long-term follow-up of patients with transient perivascular inflammation of the carotid artery (TIPIC) syndrome and the risk of recurrence.
Methods
We enrolled patients with a definitive diagnosis of TIPIC syndrome who were included in a retrospective multicenter study. These patients were recontacted at least six months after the first TIPIC episode for a clinical and imaging follow-up. Each patient underwent a clinical evaluation through a tailored questionnaire as well as US imaging.
Results
Twenty-eight patients were enrolled with a median follow-up of 58.7 months (interquartile range = 8–121). Nineteen out of the 28 patients (67.8%) had residual pain, eight (28.6%) had experienced a clinical recurrence and 12 (42.9%) had a thickening of the carotid wall on US. No patients had neurological complication or other associated diseases.
Conclusions
Patients with TIPIC syndrome have often residual pain and recurrence in about one quarter of cases but the long-term follow-up is in favor a benign self-limited pathology.
Introduction
Transient perivascular inflammation of the carotid artery (TIPIC) syndrome is a recently recognized condition (1,2) that characterizes a specific clinical and radiologic entity previously identified as carotidynia (3,4). It involves a temporary inflammation surrounding the carotid bifurcation. The prognosis of TIPIC is generally favorable, with rapid and complete recovery either spontaneously or through anti-inflammatory medication. However, there is limited knowledge regarding the long-term clinical and imaging follow-up, especially in terms of the risk of recurrence. The present study aimed to describe the long-term clinical and ultrasound (US) follow-up of patients with TIPIC, with a particular focus on evaluating the risk of recurrence, residual pain, associated conditions and the long-term evolution of imaging abnormalities.
Methods
Ethics
Our analysis was conducted according to the Strengthening the Reporting of Observational Studies in Epidemiology criteria for observational studies (5). The clinical trial protocol has been approved by an institutional review board (IRB 2018-A00327-48). Written informed consent was obtained from all patients who participated in the study. This study has been registered on ClinicalTrials.gov (identifier NCT03804112). All data will be accessible upon request to the authors.
Study design and patients
Between December 2018 and January 2020, we conducted a multicenter study that involved the enrollment of patients with a confirmed diagnosis of TIPIC syndrome. The enrolled patients were those previously included through their medical records in an earlier retrospective study (1). These individuals were recontacted at least six months after their initial TIPIC episode for a follow-up clinical and imaging evaluation. To be eligible for inclusion in this subsequent study, patients had to meet specific criteria: (i) a definite diagnosis of TIPIC syndrome and (ii) clinical and imaging follow up of at least six months. A confirmed diagnosis of TIPIC syndrome was established based on published criteria, which include: (i) the presence of acute pain around the carotid artery that may or may not radiate to the head; (ii) evidence of eccentric perivascular infiltration on imaging that suggests TIPIC syndrome; (iii) exclusion of other vascular or non-vascular diagnoses through imaging; and (iv) improvement either spontaneously or with anti-inflammatory treatment.
Clinical evaluation
A senior neurologist centrally interviewed all patients, either in person or over the phone, utilizing a standardized questionnaire (see supplementary Material 1). The questionnaire was specifically designed to gather information on the recurrence of symptoms (including date, location, associated symptoms, events preceding the pain and treatment), as well as to provide a detailed description of the initial symptoms related to the first episode of TIPIC syndrome and any residual symptoms (such as residual pain or the development of other medical conditions). Demographic data, atherosclerotic risk factors, medical history (with a particular focus on hematologic, infectious, autoimmune disease or cancer), medications and treatments were also collected. Recurrence of TIPIC syndrome was defined as the appearance of new acute cervical pain that mimics the initial episode of TIPIC.
Radiological evaluation
Diagnostic was performed in all patients to examine the cervical and intracranial vessels using B-mode and color-coded duplex with spectrum analysis. For each imaging modality, readers evaluated various abnormalities, including the presence, location, dimensions (including largest axial diameter and span), eccentricity or concentricity, and percentage of vessel circumference involvement of perivascular infiltration (PVI). They also assessed the presence of other vascular abnormalities such as pseudo plaque (defined as a well-delineated, hypoechogenic plaque without posterior acoustic shadowing) or calcified plaque (defined as a hyperechogenic plaque with posterior acoustic shadowing), intraplaque hemorrhage, lumen caliber narrowing (quantified using the North American Symptomatic Carotid Endarterectomy Trial criteria)6, and vascularization of the PVI in Doppler or power-Doppler mode. Additionally, readers noted cervical carotid or intracranial vessel hemodynamic changes and the presence of adenomegalies, defined as lymph nodes with a small axis above 1 cm.
Statistical analysis
The study's descriptive design focused on describing the sociodemographic, clinical and imaging characteristics of the patients. Continuous (quantitative) variables are described as median (interquartile range (IQR)) and categorical (qualitative) variables as number and percentage. Univariable relationships between recurrences and baseline characteristics were assessed using a Mann–Whitney U-test for continuous variables and Fisher’s exact test for categorical variables, as appropriate. All tests were bilateral. p < 0.05 was considered statistically signiifcant. All statistical analysis were realized by a senior medical biostatistician using the R statistical software, version 4.0.3 (R Foundation, Vienna, Austria).
Results
Study population
At 10 centers, 47 patients with TIPIC syndrome were screened. Nineteen were not included in the final analysis as a result of being lost to follow-up (n = 10), missing clinical questionnaires (n = 5) or missing US (n = 4). Therefore, 28 patients were included in the final analysis. Table 1 presents their demographic, clinical characteristics and long-term clinical follow-up. The median time between the first TIPIC episode and inclusion was 58.7 months (IQR = 8–121) and the median patient age was 54.5 years (IQR = 48.8–61.3).
Baseline clinical characteristics in patients with TIPIC syndrome.
DVT, deep vein thrombosis; ENT, ear nose throat; NSAIDs, non-steroidal anti-inflammatory drugs; PE, pulmonary embolism; TIPIC, transient perivascular inflammation of the carotid artery.
Autoimmune disease: Five patients had a history of autoimmune diseases: two with Hashimoto's thyroiditis, one with systemic lupus erythematosus accompanied by antiphospholipid syndrome, one with ankylosing spondylitis and one with psoriasis. **Cancer: Three patients had a history of cancer: one with breast cancer, one with a brain tumor and one with multiple myeloma. ***ENT signs: five sore throats, one vertigo, one otalgia and one jaw pain. Categorical variables are expressed as numbers (%) and continuous variables as median (interquantile range).
Long-term clinical follow-up, risk of recurrence and residual pain
Follow-up characteristics are detailed in Table 1. Among 28 included patients 19 (67.8%) reported persistent pain, which was mostly spontaneous (39.2%) or on palpation (39.2%). Based on questionnaires and medical records, we identified eight of 28 (28.6%) who experienced at least one episode of cervical pain recurrence mimicking their initial TIPIC episode. Among these patients, three had imaging abnormalities consistent with TIPIC syndrome. The confirmed recurrences occurred between 4.5 and 15.5 months after the first episode (median 8.5 months) and no new general diseases were reported, except for one patient who was diagnosed with esophageal cancer.
Long-term US follow-up
All 28 patients underwent US examination, with 12 US scans (42.9%) showing thickening of the carotid wall (Table 2). Three patients (10.7%) had a calcified plaque and three others (10.7%) had a pseudo plaque (among those three patients, two also had a thickening of the carotid wall). At the end, 12 patients (42.9%) had normal ultrasonographic examination. None of the patients had perivascular infiltration, stenosis, or adenomegaly. Transcranial Doppler examination was normal in all cases.
Initial imaging and long-term ultrasonographic follow-up.
Categorical variables are expressed as numbers (%) and continuous variables as median (interquantile range). *Localization of thickening was only specified in four patients. **Three patients did not undergo transcranial doppler.
Discussion
Our multicenter cohort study of long-term follow-up of patients with TIPIC syndrome showed that: (i) a clinical recurrence occurred in one in four patient; (ii) most patients (70%) experience residual pain; (iii) residual thickening of the carotid wall was observed in 42.9% of patients and persistence of a pseudo plaque were present in 10.7% of our patients; and (iv) the TIPIC syndrome remains a local pathology without other specific neurological signs or associated diseases.
We advocate for the exclusive use of the term “TIPIC syndrome” for patients with such clinical presentations to avoid confusion and misclassification. The term “carotidynia” should be discontinued because of its ambiguity and lack of precision in describing the syndrome under discussion, as discussed in previous studies (1). Other differential diagnoses of acute cervical pain, such as cervical artery dissection, must be ruled out before diagnosing TIPIC syndrome, given its severity and potential for serious complications.
To the best of our knowledge, this is the first multicenter study reporting long-term clinical and imaging follow-up in patients with TIPIC syndrome. Compared to large retrospective multicenter studies or cohorts (1,6,7), we found a higher rate of recurrence (28% vs. 19%). This higher rate may be partly a result of the design of the present study, using a specifically dedicated questionnaire and longer follow-up (58.7 months) compared to previous retrospective studies with follow-up limited to three months (1,7,8). The mechanisms underlying clinical recurrence are unknown. Pathological findings in TIPIC report leukocytes and neovascularization detected in the external part of the adventitia (9). This points toward local inflammatory residual mechanisms in the perivascular wall that could potentially participate in increasing the risk of recurrence, with neovascularization increasing the potential influx of leukocytes toward the perivascular tissue.
We found a residual pain affecting more than two-third of patients. A potential mechanism behind this finding may be the initial injury to the terminal non-myelinated nerves in the carotid wall. The potential sensitive deafferentation of the carotid wall resulting from the initial perivascular inflammation may be the cause of the residual neurogenic pain in a large number of patients (10).
We also reported thickening of the carotid wall, as well as pseudo plaques in a significant proportion of patients. A complementary assessment using contrast-enhanced US or high-resolution vessel wall magnetic resonance imaging (MRI), not performed in the present study, could have potentially helped to identify residual changes in terms of neovascularization in the carotid wall (11,12). The presence of a calcified plaque in 10.7% of patients indicates the presence of carotid atherosclerosis. Atherosclerosis has been described in association with TIPIC syndrome (13). One could hypothesize that local inflammation may have increased the likelihood of local development of atherosclerosis. Additionally, a majority of our patients (57.1%) were smokers, which increases the likelihood of changes because of atherosclerosis not necessarily related to TIPIC.
We believe that this entity should be added to the International Classification of Headache Disorders. We propose four major criteria as follows: (i) Presence of acute pain overlying the carotid artery, which may or may not radiate to the head without other neurologic signs; (ii) eccentric perivascular inflammation on imaging (US is the first-choice imaging technique due to its simplicity, accessibility, affordability and global availability. MRI and computed tomography should be employed as secondary imaging techniques); (iii) exclusion of another vascular or non-vascular diagnosis with imaging; and (iv) improvement either spontaneously or with anti-inflammatory treatment. Additionally, two comments concern the follow-up: clinical recurrence, residual pain and residual thickening of carotid wall are possible (see illustrations in supplementary Material 2).
Our study has some limitations. First, the overall number of patients is too low to conduct any statistical analysis with sufficient power. The exclusion of 19 patients introduces potential selection bias, warranting caution in interpreting our results. However, TIPIC is a rare entity, and patients recover quickly. This disease is considered benign and systematic follow-up is unfrequently performed. Thus, the number of patients we enrolled in this study is substantial. Second, US was performed by local operators in each center. US is known to be operator-dependent; thus, it might have had an impact on the US findings collected. We did not have imaging data from before the first episode of TIPIC syndrome, so we cannot determine whether the abnormal findings were already present. Additionally, Doppler follow-ups were not conducted within the same time frame for all patients, meaning that the differences observed in Doppler findings could be dependent on the timing of the Doppler evaluations relative to the onset of the TIPIC syndrome. Third, since we did not evaluate the effectiveness of pain treatments, we are unable to provide recommendations regarding this. Finally, some patients were assessed five years after their initial TIPIC syndrome episode; therefore, there is a possibility of memory bias affecting the patients’ responses.
Conclusions
Overall, our study highlights the potential risk of recurrence and remaining pain in patients with TIPIC syndrome, as well as the importance of long-term follow-up and imaging surveillance of carotid artery abnormalities. However, it is reassuring for patients to know that TIPIC syndrome is a self-limited benign pathology.
Clinical implications
Our multicenter cohort study of long-term follow-up of patients with TIPIC syndrome showed that:
A clinical recurrence occurred in one in four patient. Most patients (70%) experience residual pain. Residual thickening of the carotid wall was observed in 42.9% of patients. TIPIC syndrome remains a local pathology without other specific neurological signs or associated diseases.
Supplemental Material
sj-pdf-1-cep-10.1177_03331024241230247 - Supplemental material for Long-term clinical and ultrasound follow-up after transient perivascular inflammation of the carotid artery (TIPIC) syndrome: a multicenter study
Supplemental material, sj-pdf-1-cep-10.1177_03331024241230247 for Long-term clinical and ultrasound follow-up after transient perivascular inflammation of the carotid artery (TIPIC) syndrome: a multicenter study by Michael Obadia, Nathalie Nasr, Geoffroy Volle, Frédérique Charbonneau, Jessica Guillaume, Olivier Naggara, Jean Claude Sadik and Augustin Lecler in Cephalalgia
Supplemental Material
sj-pdf-2-cep-10.1177_03331024241230247 - Supplemental material for Long-term clinical and ultrasound follow-up after transient perivascular inflammation of the carotid artery (TIPIC) syndrome: a multicenter study
Supplemental material, sj-pdf-2-cep-10.1177_03331024241230247 for Long-term clinical and ultrasound follow-up after transient perivascular inflammation of the carotid artery (TIPIC) syndrome: a multicenter study by Michael Obadia, Nathalie Nasr, Geoffroy Volle, Frédérique Charbonneau, Jessica Guillaume, Olivier Naggara, Jean Claude Sadik and Augustin Lecler in Cephalalgia
Supplemental Material
sj-pdf-3-cep-10.1177_03331024241230247 - Supplemental material for Long-term clinical and ultrasound follow-up after transient perivascular inflammation of the carotid artery (TIPIC) syndrome: a multicenter study
Supplemental material, sj-pdf-3-cep-10.1177_03331024241230247 for Long-term clinical and ultrasound follow-up after transient perivascular inflammation of the carotid artery (TIPIC) syndrome: a multicenter study by Michael Obadia, Nathalie Nasr, Geoffroy Volle, Frédérique Charbonneau, Jessica Guillaume, Olivier Naggara, Jean Claude Sadik and Augustin Lecler in Cephalalgia
Supplemental Material
sj-pdf-4-cep-10.1177_03331024241230247 - Supplemental material for Long-term clinical and ultrasound follow-up after transient perivascular inflammation of the carotid artery (TIPIC) syndrome: a multicenter study
Supplemental material, sj-pdf-4-cep-10.1177_03331024241230247 for Long-term clinical and ultrasound follow-up after transient perivascular inflammation of the carotid artery (TIPIC) syndrome: a multicenter study by Michael Obadia, Nathalie Nasr, Geoffroy Volle, Frédérique Charbonneau, Jessica Guillaume, Olivier Naggara, Jean Claude Sadik and Augustin Lecler in Cephalalgia
Footnotes
Acknowledgements
We extend our gratitude to Jeanne Pergeline for providing statistical support.
Declaration of conflicting interests
The authors declare that there are no potential conflicts of interest with respect to the research, authorship and/or publication of this article.
Ethical statement
The clinical trial protocol has been approved by an institutional review board (IRB 2018-A00327-48). Written informed consent was obtained from all patients who participated in the study.
Funding
Not funding was received.
Supplemental material
Supplemental material for this article is available online.
References
Supplementary Material
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