Cervical artery dissections (CeAD) include both internal carotid and vertebral artery dissections. They are rare but important causes of stroke, especially in younger patients. CeAD should be considered in patients with strokelike symptoms, a new-onset headache and/or neck pain, and/or other risk factors. Early imaging with computed tomography (CT) or magnetic resonance imaging (MRI) is key to making the diagnosis. Treatment may vary depending on the extent of the dissection, timing of the dissection, and other comorbidities. The overall prognosis is good, but does depend on the initial severity of symptoms.
Key points
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Cervical artery dissections (CeAD) are rare but important causes of stroke, especially in the younger population.
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Consider CeAD in patients with new-onset headache and neck pain with or without strokelike symptoms.
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Imaging is key to diagnosis, with several options available.
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Management involves treating acute stroke with thrombolysis or surgical therapy for eligible candidates. All others may be candidates for anticoagulation or antiplatelet therapy to reduce the risk of potential or worsening stroke symptoms. Either agent may be used.
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Prognosis remains good with low morbidity and mortality rates.
Introduction
The cervical arteries comprise bilateral internal carotid and vertebral arteries. These arteries are important structures of the neck, as they carry the main blood flow to the brain. Any thrombosis or damage to these vessels, including dissection, can lead to complications, such as cerebral ischemia, stroke, blindness, or death. Although cervical artery dissections (CeADs) are rare causes of stroke overall, they are important causes of stroke in the younger population. Unfortunately, given its rarity and nonspecific symptoms, CeAD is a difficult diagnosis to make. Affected patients can remain completely asymptomatic or asymptomatic for long periods of time. Patients may sustain delayed-onset stroke, which can contribute to difficulty in making the diagnosis. Long-term, severe morbidity, such as stroke with loss of independence, can occur, and, thus, it is important to avoid missing this diagnosis.
Although patients with CeAD may deny history of trauma, the reality is that most patients tend to have a history of trauma, albeit very mild. In addition, spontaneous extracranial CeAD and extracranial CeADs that develop due to minor trauma are more commonly discussed in the literature. This is opposed to pure intracranial CeADs and those due to major trauma and blunt aortic dissection. This article focuses on the epidemiology, pathophysiology, diagnosis, and management of spontaneous extracranial CeADs and extracranial CeADs due to negligible trauma.
Introduction
The cervical arteries comprise bilateral internal carotid and vertebral arteries. These arteries are important structures of the neck, as they carry the main blood flow to the brain. Any thrombosis or damage to these vessels, including dissection, can lead to complications, such as cerebral ischemia, stroke, blindness, or death. Although cervical artery dissections (CeADs) are rare causes of stroke overall, they are important causes of stroke in the younger population. Unfortunately, given its rarity and nonspecific symptoms, CeAD is a difficult diagnosis to make. Affected patients can remain completely asymptomatic or asymptomatic for long periods of time. Patients may sustain delayed-onset stroke, which can contribute to difficulty in making the diagnosis. Long-term, severe morbidity, such as stroke with loss of independence, can occur, and, thus, it is important to avoid missing this diagnosis.
Although patients with CeAD may deny history of trauma, the reality is that most patients tend to have a history of trauma, albeit very mild. In addition, spontaneous extracranial CeAD and extracranial CeADs that develop due to minor trauma are more commonly discussed in the literature. This is opposed to pure intracranial CeADs and those due to major trauma and blunt aortic dissection. This article focuses on the epidemiology, pathophysiology, diagnosis, and management of spontaneous extracranial CeADs and extracranial CeADs due to negligible trauma.
Epidemiology
The estimated incidence of CeAD is 2.6 to 5.0 per 100,000 per year, but recent epidemiologic studies are lacking. An epidemiologic study in 2014 demonstrated that of nearly 1400 patients with stroke, CeAD accounted for only 2% of cases. Most recently, a study in Vancouver found that of 438 patients with transient ischemic attack (TIA) or ischemic stroke, approximately 5.9% were due to CeAD. This percentage included both internal carotid artery dissection (ICAD) and vertebral artery dissection (VAD), but 1 patient did have an intracranial dissection.
Compared with thrombosis, ischemic strokes due to CeAD are rare, approximating a total of only 1% to 2% of all ischemic stroke cases. However, CeAD accounts for a much larger percentage of ischemic strokes in the younger population. CeAD is most common in the fifth decade of life, and is rare in patients older than 65. In the Vancouver study, the mean age of patients with stroke/TIA due to CeAD was 49.1 years. In the 2014 study by Bejot and colleagues, a mean age of 49.1 years also was observed. Overall, the incidence of ICAD is approximately twice that of VAD. VAD tends to occur more commonly in younger women, whereas ICAD is more prevalent in older men. Importantly, most epidemiologic studies on CeAD are observational and based on European and American populations, and, thus, the incidence of CeAD is estimated and patterns may differ in other populations.
Pathophysiology
The pathogenesis of CeAD is not well delineated. However, as will be mentioned in a subsequent section, CeAD is thought to be caused by minor trauma. It also may occur spontaneously in patients with predisposing arterial defects. CeAD is characterized as a hematoma within the wall of the internal carotid artery or vertebral artery. Initially, a tear occurs in the artery where blood enters the wall under pressure and causes separation of the layers. A false lumen develops, resulting in a hematoma. This narrows the arterial lumen, increasing risk of occlusion by the hematoma. The hematoma or thrombus can lead to cerebral thromboembolism, decreased blood flow, and subsequent ischemic stroke. The hematoma may also cause a mass effect on surrounding structures, leading to Horner syndrome (ptosis, anhidrosis, and miosis, though anhidrosis may not be present).
Thromboembolism, rather than hypoperfusion, has been found to cause most ischemic strokes in CeAD.
CeAD is likely a multifactorial process that is not well understood but may be related to underlying risk factors, such as genetics, connective tissue diseases, and prior trauma. It is estimated minor trauma plays a role in approximately 40% of cases of spontaneous extracranial CeAD. In 2013, Engelter and colleagues compared patients with CeAD who had sustained known neck trauma, patients with ischemic stroke with other etiologies, and healthy subjects. Overall, the investigators found that prior mechanical trauma was more common in patients with CeAD than in patients with ischemic stroke from other causes. In addition, neck pain was more common in patients with CeAD than in patients with other causes of stroke.
Despite the suspected role of minor trauma, it is not typical for minor traumas such as whiplash to cause CeAD in most individuals. Thus, it is hypothesized that patients who sustain CeAD with or without minor trauma likely have an underlying arteriopathy, inflammatory process, or structural instability of the arteries. In fact, a 2011 study by Volker and colleagues demonstrated biopsy-proven structural differences in the arterial walls of patients with spontaneous CeAD and those patients who sustained major trauma. There also seems to be a positive association with underlying kinking and coiling of the internal carotid artery and dissection, which suggests an underlying predisposition. Of note, the underlying arteriopathy may or may not be permanent, may or may not be genetic, and may be due to inflammation, infection, or other unknown causes.
Other reported underlying risk factors for CeAD include a history of migraine headaches, pregnancy and postpartum states, and a history of hypertension. Manual strangulation can lead to CeAD but is considered to be uncommon. The diagnosis should be pursued in strangulation victims only if they arrive unconscious, demonstrate physical evidence of neck trauma, have voice changes, or if they show any other unilateral neurologic signs. Finally, even if patients deny trauma, the injury can be minor and may be something as simple as whiplash or stretching. Therefore, it is important that CeAD be considered in patients who have risk factors for CeAD with concerning symptoms.
Presentation
Diagnosis of CeAD is challenging, as presentations vary, including asymptomatic, mild cranial nerve deficit, and medullary ischemia leading to respiratory depression. Patients may present with headache only, whereas others may demonstrate disorientation, seizures, back pain, or visual changes. Case reports demonstrate some interesting manifestations of CeAD, including tongue swelling, vocal cord paralysis, and cervical radicular nerve pain. However, the most common symptoms of CeAD include unilateral headache and/or neck pain, which occur in up to 80% of patients. The characteristic presentation of ICAD is a partial Horner syndrome without anhidrosis, unilateral head and/or neck pain, and cerebral or retinal ischemia. VAD should be considered in patients with CeAD risk factors and new-onset headache with vertigo or ataxia. Typically, ICAD manifests as a frontal headache, whereas occipital headaches are more common in VAD. Many other neurologic signs can be present.
The International Headache Society (IHS) has developed diagnostic criteria called the International Classification of Headache Disorders (ICHD) that clinicians can refer to when considering CeAD. According to the ICHD criteria, CeAD is commonly seen in patients who have sudden-onset headache with facial and/or neck pain that is ipsilateral to the dissected vessel. The pain can be isolated or as a warning sign of impending stroke. Unfortunately, CeAD can mimic benign causes of headache, such as migraines, and therefore, it is important for providers to differentiate patients’ “typical” headache symptoms from any new symptoms that could be concerning for CeAD.
Another challenge in making the diagnosis of CeAD is that some patients can remain completely asymptomatic or asymptomatic for long periods of time. When symptoms do occur, they typically occur within minutes to hours after the dissection, but may occur up to 1 month after the onset of the dissection. The average time from the event to onset of symptoms is 2 to 3 days ( Box 1 ).
- 1.
New unilateral headache or neck pain in patients with underlying risk factors, such as a personal history of connective tissue disease, hypertension, or neck trauma
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Neck pain or a unilateral headache in any patient, but especially young patients, with neurologic deficits on examination
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A patient with a history of neck trauma with focal neurologic deficits or visible evidence of neck trauma
Diagnosis
As previously mentioned, CeAD can have a wide variety of presentations, mimic benign headaches, and even be asymptomatic for up to 1 month after the actual dissection occurs. Thus, it is not uncommon for diagnostic delays to occur. Although appropriate imaging can help make the diagnosis, patients may require more than 1 study if high clinical suspicion remains and the initial imaging study is normal. There are several options to image CeAD. These include digital subtraction angiography, ultrasound with or without Doppler, computed tomography angiography (CT-A), and MRI with angiography (MRI/MRA).
Digital Subtraction Angiography
Digital subtraction angiography (DSA) is considered the gold standard for imaging CeAD due to its capability to determine luminal abnormalities. DSA has limitations, however, in that it is costly, invasive, and inferior in detecting vessel wall abnormalities such as hematomas. In addition, DSA does not tend to identify the classic features of an intimal flap, double lumen, or dissecting aneurysms. Thus, angiography may actually be read as normal in certain cases, especially if the hematoma does not cause any disruption of the arterial lumen. DSA also has an associated risk of iatrogenic damage, vascular injury, contrast-induced kidney injury, and radiation exposure.
DSA is quite accurate in finding an intraluminal thrombus and assessing collateral circulation. Thus, it can be considered as a diagnostic modality when other imaging studies are negative, but the diagnosis is still highly considered.
Ultrasound
Ultrasound is a useful screening test, especially because it lacks ionizing radiation, does not require contrast dye, and is noninvasive. It is also helpful for monitoring patients with known CeAD, as serial imaging helps detect possible recanalization or progression to occlusion.
Ultrasound has been reported to be quite sensitive, but may not be reliable for those with only local symptoms and those who have dissections above the angle of the mandible. Ultrasound may be initially interpreted as normal, especially if the mural hematoma results in only small lumen abnormalities or if the dissection is in a specific segment, such as above the angle of the mandible, which is not accessed well by ultrasound. Typically, confirmatory tests with CT-A or MRI/MRA are required, especially if clinical suspicion remains high or the dissection is suspected to be above the angle of the mandible.
Signs of dissection on ultrasound include direct visualization of an intimal flap or mural hematoma as a thickened hypoechoic wall or an increase in the external caliber of the artery. Occasionally, stenosis or occlusion can be seen when Doppler is used. It is recommended that Doppler be used if there is a concern for hemodynamic impairment as a cause for the ischemia, even though thromboembolism is the most common cause of stroke from dissection. The main limitation of ultrasound is that it cannot evaluate the entire length of the arteries due to some areas being impenetrable to the ultrasound beam. These areas include the sub and intrapetrous internal carotid artery and the vertebral artery within the bony foramen. If CeAD occurs in these areas, ultrasound may not detect abnormalities. Thus, unless there is a very low clinical suspicion for dissection, other tests, such as CT-A or MRI/MRA, should be obtained. In addition, any positive findings on ultrasound should be confirmed with additional imaging studies, as false positives do occur.
MRI/Magnetic Resonance Angiography
The American Heart Association (AHA)/American Stroke Association (ASA) recommends MRI/MRA as one of the first-line imaging studies for diagnosing CeAD. Common findings on MRI/MRA include vessel wall thickening, acute ischemic stroke, and direct visualization of intramural hematomas. This modality better evaluates for intramural hematomas with less reliance on luminal irregularities. Dissections can be evaluated with cross-sectional T1, T2, or protein-density weighted images with MRA methods. This will visualize the intramural hematoma as well as directly evaluate the blood vessels without invasive angiography. MRA also can be combined with MRI to demonstrate acute ischemic lesions. This is especially important with concern for posterior fossa stroke.
An acute intramural hematoma can be hypointense on T1-weighted and T2-weighted images and therefore may be hard to detect within the first 48 hours of onset. Thus, a false-negative reading may occur with MRI at early stages, and if there is a high suspicion for CeAD, a different modality or repeat imaging is needed.
Reported sensitivities of MRI/MRA for ICAD range from 78% to 100% and 20% to 94% for VAD. Specificities of MRA/MRI for ICAD range from 99% to 100% and 29% to 100% for VAD.
Computed Tomography Angiography
CT-A tends to rely on irregularities of the arterial lumen. Signs of dissection on CT-A include increased wall thickening and wall diameter. There are very few other direct findings of CeAD on CT-A. However, CT-A does seem to be superior in demonstrating spatial resolution for severely narrowed vessels and may show intimal flaps better than MRI/MRA. CT-A may also be better than MRI/MRA in diagnosing VAD because of the tortuous course of the VA, its close proximity to bone, and the typically smaller size of the mural hematoma. Another concern with MRI/MRA in the diagnosis of VAD is that sometimes the perivertebral venous plexus can mimic similar intensity of a mural hematoma and thus, can falsely diagnose VAD. CT-A may be less accurate if heavy calcifications are present. Sensitivities of CT-A range from 47% to 100% for ICAD and 40% to 100% for VAD. Specificities range from 88% to 99% for ICAD and 90% to 99% for VAD. CT-A is recommended by the AHA, the ASA, and the IHS as an initial test for CeAD. Based on several studies, CT-A is preferential in the diagnosis of VAD.
Drawbacks to the use of CT-A in the diagnosis of dissection include exposure to ionizing radiation and decreased ability to directly visualize a mural hematoma. Despite its superiority in detecting VAD, CT-A is unable to adequately detect posterior fossa ischemic lesions, so if concern for posterior circulation stroke is present, additional imaging with MRI should be obtained. CT-A also cannot be used in patients with renal impairment or in those who have allergies to CT contrast.
Treatment
Because CeAD can cause stroke and significant disability, the major goals of treatment are twofold : acutely save at-risk brain tissue and prevent further ischemia and strokes from occurring. Typically, antithrombotic treatment is recommended to reduce the risk of stroke within the first few days of dissection. However, there are other options for treatment, including intravenous and intra-arterial thrombolysis and surgical or endovascular repair.
Until recently, no randomized controlled trials (RCTs) had been conducted solely comparing anticoagulation versus antiplatelet agents. There have been no known RCTs on thrombolysis or surgical therapy, but based on available data, these do remain options for eligible patients. Treatments have been mostly based on case series, meta-analyses, case reports, and clinician discretion. Although the focus of this article is on extracranial CeAD, some of the treatment regimens discussed as follows do not differentiate between intracranial and extracranial CeAD.
Thrombolysis
Stroke in patients with CeAD is most commonly caused by thrombosis. Thrombolysis treats acute ischemic stroke through recanalization of an occluded artery. It may include intra-arterial or intravenous thrombolysis. So far, no RCT has exclusively evaluated thrombolysis as a treatment for CeAD. The original trials on the use of intravenous thrombolysis in acute stroke included those patients with CeAD, so it still remains an option for those patients with CeAD who meet thrombolysis criteria. Unfortunately, the AHA/ASA does not directly address the use of thrombolysis in CeAD, and there are no known specific guidelines available.
The major risk of thrombolysis in any patient is spontaneous intracranial hemorrhage. In theory, thrombolysis may promote worsening perfusion by leading to more intramural bleeding. In addition, thrombolytics may potentially lyse the thrombus within the wall of the artery, leading to increased wall forces and dissection expansion. However, it is thought that thrombolysis may improve flow by diminishing the size of the thrombus. In the past 10 years, several nonrandomized studies have evaluated the use of both intravenous and intra-arterial thrombolysis in CeAD. Some included both intravenous and intra-arterial, and others evaluated one. Based on these studies, both intra-arterial and intravenous thrombolysis have shown safety outcomes in patients with CeAD similar to those patients with nondissection stroke. On the other hand, the actual efficacy of thrombolysis remains in question. A 2012 multicenter study comparing patients with extracranial CeAD stroke who received intra-arterial and/or intravenous thrombolysis or no thrombolysis found essentially no difference in favorable 3-month outcomes, defined as a modified Rankin score (mRS) of 0 to 2. Similarly, in a retrospective database study by Qureshi and colleagues, no differences in in-hospital mortality and minimal disability were found between patients with CeAD stroke treated with thrombolysis and patients with CeAD not treated with thrombolysis. In a 2012 prospective observational study by Fuentes and colleagues, patients with extracranial ICAD treated with thrombolysis tended to have similar 3-month outcomes (mRS) as those patients with ICAD not treated with thrombolysis. A 2011 meta-analysis of both intra-arterial and intravenous thrombolysis in CeAD essentially demonstrated similar findings and concluded that both intra-arterial and intravenous thrombolysis in patients with CeAD show similar safety and overall outcomes compared with patients with stroke without CeAD.
Most recently, there have been more studies on the safety and efficacy of intravenous and intra-arterial thrombolysis in cervical artery dissection and continue to confirm prior studies’ results. A 2015 prospective multicenter study and meta-analysis evaluated the safety and efficacy of intravenous thrombolysis in CeAD. In the investigators’ prospective study of 39 patients with dissection-related stroke, the rate of spontaneous intracranial hemorrhage was 0% and in-hospital mortality was 10%, whereas full recanalization and favorable functional outcome (mRS of 0–1) were 55% and 61%, respectively. In their meta-analysis of 10 case series with a total of 234 patients, the investigators found pooled rates of spontaneous intracranial hemorrhage to be 2%, with a mortality rate of 4%. The pooled complete recanalization rate was 45%, whereas the favorable functional outcome rate was 41%. Based on this case series and meta-analysis, the investigators conclude that intravenous thrombolysis is just as safe in patients with CeAD stroke as in patients with nondissection ischemic stroke. In addition, the rates of favorable functional outcomes did not differ between patients with nondissection stroke and patients with stroke due to CeAD. Similar results have been found in other studies evaluating intra-arterial thrombolysis. Based on the current data, intravenous thrombolysis should not be withheld in those eligible patients with stroke due to CeAD.
Antiplatelet/Anticoagulant Medications
In most patients with CeAD, the arterial lumen will heal on its own with a mean healing time of 3 months. The main goal of treating these patients is preventing stroke in the acute phase of CeAD via anticoagulation or antiplatelet agents. The 2011 AHA/ASA guidelines recommend treatment with either an anticoagulant, such as heparin or warfarin, or a platelet inhibitor, such as aspirin or clopidogrel, for at least 3 to 6 months.
The AHA/ASA does not specify a preferred regimen. Several nonrandomized studies and meta-analyses showed no significant differences between the 2 agents, leaving the decision up to clinicians.
Until recently, no RCT had been conducted on comparing antiplatelet versus anticoagulation for CeAD. In 2007, a multicenter RCT, named the Cervical Artery Dissection in Stroke Study (CADISS), evaluated the efficacy of antiplatelet agents versus anticoagulation therapy in acute (within 7 days of onset) extracranial CeAD.
In CADISS, antiplatelet agents included aspirin, dipyridamole, and/or clopidogrel, and anticoagulation agents included heparin followed by warfarin for at least 3 months. The investigators excluded intracranial dissections, those with symptom onset of more than 7 days, those already on an antiplatelet or anticoagulation agents, pregnant patients, and those with contraindications to antiplatelet or anticoagulant agents. The primary endpoint was recurrent stroke and death at 3 months, but patients were followed for 12 months. Secondary endpoints were ipsilateral TIA, stroke, death of any cause, major bleeding, or residual stenosis. The investigators enrolled 250 patients with ICAD and VAD between 2006 and 2013. The included patients presented with variable symptoms, such as stroke or TIA, and local symptoms, such as headache, neck pain, and Horner syndrome.
The CADISS data were published in early 2015 and the investigators found no difference in the efficacy of antiplatelet versus anticoagulant medications at preventing stroke and death in CeAD. Overall, only 4 (2%) of 250 patients had stroke recurrence, 3 in the antiplatelet group and 1 in the anticoagulant group. One major bleed in the anticoagulant group occurred, with no deaths. The investigators note no major differences in the other secondary endpoints between the 2 treatment groups. Therefore, similar to prior nonrandomized studies, the investigators concluded no difference in the efficacy of antiplatelet and anticoagulant medications at preventing stroke and death in patients with symptomatic ICAD and VAD.
CADISS is a phase 2 feasibility study. The investigators planned a sample size of 250 to allow for an estimation of recurrent stroke and sample sizes for a phase 3 trial to be calculated. Essentially, CADISS is not powered enough to draw final conclusions between the use of antiplatelet and anticoagulant drugs. The investigators note that up to 10,000 patients would be needed to detect a 1% difference in the occurrence of stroke or death or major bleeding between the 2 agents. In addition, novel oral anticoagulants (NOACs) were not included in this trial, and given the popularity of these agents, it would be reasonable for future RCTs to include the NOACs. However, based on this clinical trial, either agent is reasonable to use in those patients with extracranial CeAD who do not require surgery or endovascular repair.
Surgical and Endovascular Repair
Although data on surgical therapy are limited, most investigators state that candidates for procedural therapy include those with recurrent ischemia despite medical treatment, patients with contraindications to anticoagulants or antiplatelet medications, patients with significantly compromised cerebral blood flow or with severe occlusion or luminal narrowing, and those with enlarging pseudoaneurysms.
Recently, Moon and colleagues followed 116 patients with extracranial CeAD treated with endovascular therapy for a mean of 41.6 months. Endovascular therapy included stent placement, coil occlusion of a parent artery, and stenting with contralateral vessel coil occlusion. Overall, the investigators found the patients with ICAD were more likely to have enlarging pseudoaneurysms, thromboembolic events, and failed medical therapy when compared with patients with VAD. Patients with ICAD were more likely to undergo stent placement. Importantly, the overall stroke rate was only 0.9% over 2825 patient years, and no patients worsened with regard to mRS after stent placement. The investigators conclude that endovascular intervention is effective and that it may be more relevant for those with failed medical therapy, pseudoaneurysms, and significant thrombotic events.
The AHA/ASA recommends that angioplasty and stenting be considered when ischemic neurologic symptoms have not responded to medical therapy. The AHA/ASA makes these recommendations only for ICAD and not VAD. They also do not mention exactly when medical therapy should be abandoned for surgical intervention. Nevertheless, several other studies have been conducted on endovascular repair of ICAD as well as VAD with successful results regarding safety and recurrent stroke ( Box 2 ).
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