TIPIC Syndrome: Beyond the Myth of Carotidynia, a New Distinct Unclassified Entity

Clinical and Imaging Characteristics

This entity was relatively rare in our study, with an estimated prevalence of 2.8% (18/654) among patients with acute neck pain in the first center. However, we can presume that this particular cluster of symptoms is underestimated because of the relatively mild clinical symptoms and the quick relief of pain and decrease of imaging abnormalities within 13 days. This entity has been previously reported on in a few small series as carotidynia, but we present the largest series published so far with 3 distinct imaging modalities and follow-up data.

Clinically, all our patients presented with acute pain directly around the level of the carotid bifurcation. Eight patients presented with previously undescribed, transient neurologic symptoms, which lacked explanation despite a brain parenchyma MR imaging. After imaging, the presence of a unilateral eccentric PVI at the level of bifurcation was the most striking feature described.^6,7,10 Two patients presented with bilateral carotid involvement,⁹ though most were unilateral.^6,7 PVI imaging characteristics were similar to those found in the literature, with a median diameter of 5 mm and a median span of 20 mm.^7,15

Some patients had a mild associated narrowing of the lumen,^6,16 though most patients had no luminal change^7,10 or any hemodynamic abnormality.

We report the presence of a self-limited, intimal soft plaque in half of our patients, which has been described in previous reports.^6,17 These intimal changes might be induced by the healing phase of the carotid inflammatory process.

Nonsteroidal anti-inflammatory agents and high doses of aspirin were the most frequent treatment in our population and in the literature, with a complete median delay of pain relief in 13 days.^5⇓–7 Some authors reported full recovery with clopidogrel⁸ or without any treatment at all.⁷ All patients had complete clinical resolution during follow-up. Nine patients presented with ≥1 relapse with intervals ranging from 1 to 6 months, similar to what is found in the literature.¹⁸

Although early case reports described the complete disappearance of clinical and imaging abnormalities,⁷ more recent case reports showed a persistence of imaging abnormalities, similar to our findings.^6,17,19 It could be explained by the development of early fibrosis associated with low-grade chronic active inflammation, as described in the only histologic study found during the literature review.²⁰

Possible Pathophysiologic Mechanisms

Most case reports and small studies hypothesized that observed vascular and perivascular changes were consistent with inflammation.^9,19 Clinical findings support this hypothesis, with ipsilateral lymph node enlargement and/or contiguous pharyngolaryngeal inflammation,²¹ as well as biologic findings, with a mild increase of the erythrocyte sedimentation rate or C-reactive protein.^8,9,22,23 In our series, only 3 patients had a mild increase of the erythrocyte sedimentation rate or C-reactive protein levels. Eight patients had an autoimmune disease such as rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylarthritis, Graves disease, Sjögren syndrome, or Hashimoto thyroiditis. Most interesting, 7 over these 8 patients presented with several simultaneous clinical relapses of the perivascular inflammation of the carotid artery and of their autoimmune disease, suggesting a link between the diseases. One study reported a case of fluoxetine-induced carotidynia, presumably explained by the inflammatory modulation induced by the antidepressants.²⁴ Some studies reported an increased activity corresponding to the region of soft-tissue thickening within the carotid sheath with FDG-PET-CT,^8,9,25 though these findings were not specific for inflammation. Other hypotheses were discussed, such as vasculitis.²⁶ However, PET-CT with abnormally increased activity in neither the remainder of the body nor the vessels was described.^8,9 In our center, none of the patients with biopsy-proved giant cell arteritis presenting with acute neck pain or tenderness had abnormalities of the carotid bulb on imaging, and no relationship between the 2 entities was reported in literature. Spontaneous resolution excludes neoplastic processes. Finally, 1 study reported histologically proved findings of chronic inflammation in 1 patient with pathologic changes consisting of vascular and fibroblast proliferation and predominantly lymphocytic low-grade chronic active inflammation.²⁰ Therefore, given that the pathogenesis remains unknown, this entity may be an inflammatory process of unknown origin or part of an autoimmune process.

Proposition for a New Entity

In 2004, carotidynia was removed from the International Classification of Headache Disorders.³ Causes of acute neck pain are numerous,²⁷ and we agree that the term “carotidynia” is confusing and should not be used anymore.⁴ However, our study strongly suggests the existence of a clinical entity that was formerly poorly described (often under the “carotidynia” label) with very consistent clinical and imaging characteristics. In our study, the attempt to label this entity was shown to be dysfunctional and confusing among the different centers with at least 4 distinct labels used to describe the same entity (“carotidynia,” “carotidodynia,” “carotidobulbia,” or “carotiditis”). In the past, some authors proposed terms such as “idiopathic carotiditis”¹⁹ or “carotid periarteritis,”⁹ but these terms were not accurate because vascular and perivascular abnormalities occur simultaneously.

Consequently, we strongly support the need for a new label, and we suggest an acronym most apt for this entity: TransIent Perivascular Inflammation of the Carotid artery (TIPIC) syndrome. This acronym was chosen by consensus of the neurologists, radiologists, internists, and vascular physicians working at the different centers that collaborated on this project.

We believe that this entity should be added to the International Classification of Headache Disorders-III.²⁸ We propose 4 major criteria as follows:

1. Presence of acute pain overlying the carotid artery, which may or may not radiate to the head

2. Eccentric PVI on imaging

3. Exclusion of another vascular or nonvascular diagnosis with imaging

4. Improvement within 14 days either spontaneously or with anti-inflammatory treatment.

Additionally, a minor criterion could be the presence of a self-limited intimal soft plaque.

Limitations of the Study

Our study has some limitations. First, it was a retrospective, descriptive study with a small number of patients, thus limiting its scope mostly in the descriptive and exploratory fields. Second, a non-negligible number of patients were probably not selected during the screening process because of a lack of diagnostic imaging or a delayed order for diagnostic imaging. Third, our median follow-up duration was short, and we could not say whether follow-up imaging would eventually show the complete disappearance of the PVI, relapses, or development of atherosclerosis. Fourth, because of the benign course of the disease, adding details from pathology is difficult and not feasible; thus, better comprehension of the physiopathology has been stalled for the moment.

Changes in Current Practice

We believe that clinicians should think about the TIPIC syndrome in the differential diagnosis of neck pain. They could set a precise diagnosis with adequate imaging modalities, to exclude other entities in the differential diagnosis and propose adequate treatment. Recognition of this syndrome would be cost-effective and avoid unnecessary, additional diagnostic examinations. US appears to be a suitable examination for screening because it can detect PVI with high accuracy, similar to other imaging methods, but without any exposure to radiation, high magnetic fields, or the administration of intravenous contrast agents. It is affordable and easily accessible, and it has excellent interreader concordance. Imaging diagnosis should be performed without delay because these abnormalities decrease very quickly. Follow-up could be made with US to assess PVI decrease and control lumen narrowing or soft intimal plaque.⁵

Our study raised concerns about 2 major issues. First, the neurologic risk may not be as low as previously reported in the literature because 8 of our patients had neurologic events. We do not have a convincing explanation regarding the possible relationship between this entity and the neurologic events encountered. The lumen caliber narrowing was mild, and there were no local or distal hemodynamic changes with cervical or transcranial US. Brain MR imaging performed at the time of the neurologic events did not show any acute brain abnormality with diffusion or FLAIR-weighted imaging. Therefore, the hypothesis of a brain ischemia linked to the carotid artery narrowing, either due to distal embolism or low-flow, is unlikely. An inflammatory hypothesis involving both the carotid artery and intracranial arteries at the same time might be considered, but our imaging protocol was not designed to detect intracranial vessel wall inflammation.

Second, the persistence of vascular wall abnormalities, including an intimal soft plaque with imaging, suggest the hypothesis of a secondary development of atherosclerosis in these patients, therefore justifying a longer follow-up.

Recognition of this entity favors further, large prospective studies to answer these major questions and to elucidate the prevalence, pathophysiologic mechanisms, risk factors, etiologic processes, and potential therapies for this condition.