General Child Neurology
Cerebral venous thrombosis in infants and children
Nov. 21, 2022
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Cerebral artery dissection is the most common cause of stroke in young adults. Recent studies provide insights into the pathophysiology, risk factors, management, and outcome of this condition. In this article, the authors provide a comprehensive review of spontaneous (nontraumatic) carotid and vertebral artery dissections.
The first description of spontaneous dissection of the cervical arteries dates back to 1915 (143). In 1959, Anderson and Schechter were the first to clearly document a case of spontaneous dissecting aneurysm of the internal carotid artery (02; 32). The term "dissection," from the Latin verb disseco, implied the separation of anatomic structures along the natural lines by tearing of the connective tissue framework. As it is applied to vascular pathology, it relates to the separation of the different layers that constitute the arterial wall. This process can occur either spontaneously or following blunt trauma to the vessel. Sub-intimal dissections can cause lumen stenosis, and sub-adventitial dissections can cause aneurysmal dilatation. Strictly speaking, the lesion of dissection is a “dissecting aneurysm” and includes layers of the normal vessel wall (61). The term “pseudoaneurysm” is often used incorrectly for this same purpose, but this term refers to lesions that do not include components of the normal vessel wall. An example of pseudoaneurysm is a posttraumatic event where the vessel wall is severed and adjacent connective tissue maintains a lumen.
The most common clinical features of extracranial carotid dissection include ipsilateral headache or neck pain, Horner syndrome, and cerebral or retinal ischemia (52). An estimated 50% of cases develop stroke and 30% present with transient ischemic attack from hemodynamic compromise of the distal vasculature due to luminal narrowing, or by distal embolism due to thrombotic fragments that communicate with the lumen of the dissected vessel. Occlusive lesions tend to result in larger infarcts, and most infarcts occur within the first 3 to 5 days after dissection (101). The pain and headache of cervical artery dissection is typically located above the ipsilateral eyebrow and may be mild or severe, sometimes resembling that of migraine (including migrainous aura) or even thunderclap headache (127), but frequently it is dull and nonthrobbing. Scalp tenderness has been reported in a minority of patients. The pain may precede the development of symptoms of cerebral ischemia by as much as 2 days. A small percentage of patients (1% to 8%) develop isolated pulsatile tinnitus (121; 70) or an asymptomatic bruit. In addition to the symptoms noted, other findings include Horner syndrome (40% of cases) (86) or cranial neuropathies (83; 96; 124; 27), and both may occur in isolation. Cranial neuropathies may result from either direct compression of the evolving hematoma on the lower cranial nerves (nerves IX, X, XI, XII) in the region of the jugular foramen, or local ischemia to the vasa nervorum of the oculomotor nerves (nerves III, IV, VI) or facial nerve (nerve VII), which are supplied by the internal carotid artery (97; 27). The Horner syndrome of dissection consists of ptosis and miosis, but usually not anhidrosis because the facial sweat gland is innervated by the sympathetic plexus surrounding the external carotid artery (122). The presence of Horner syndrome is associated with a more benign clinical course after carotid artery dissection (86). Dysautonomia can develop after carotid dissection (25).
Intracranial carotid artery dissection represents a separate clinical entity with its own set of characteristics (33). Most published reports are from Asia or concern children, suggesting either a higher prevalence in these groups, or a publication bias, or both. The incidence is unknown, and unlike extracranial dissection, there is little knowledge of risk factors. The posterior circulation is more commonly affected in adults, and the anterior circulation more common in children. The mean age of intracranial dissection across published series is 50.4 years. Complications such as subarachnoid hemorrhage usually occur in older patients. Intracranial dissections carry a high risk for subarachnoid hemorrhage because the intradural arteries have little adventitial tissue and lack an external elastic lamina. The onset is characterized by severe headache ipsilateral to the carotid artery affected; the severity of the headache underscores the association of this condition with the development of subarachnoid hemorrhage (90; 75). Approximately 80% develop headache, over half present with subarachnoid hemorrhage, and one third to half develop ischemic complications. The mortality from intracranial carotid dissection is higher than that of extracranial dissection; the risk of death is 20% to 50% with subarachnoid hemorrhage but significantly lower in patients without subarachnoid hemorrhage. Up to 15% can develop recurrent ischemic complications.
Patients with vertebral artery dissection typically develop posterior head or neck pain followed by ischemia in the vertebrobasilar territory due to occlusion of the anterior spinal artery (99). Horner syndrome occurs in less than 15% of patients with vertebral artery dissection (86). Spontaneous vertebral artery dissections more commonly present with ischemic stroke (89%), and male gender, increasing age, and smoking appear to increase the risk for ischemic events (07). Intracranial vertebral artery dissection frequently results in subarachnoid hemorrhage and carries a poor prognosis (73; 117). In a study of 457 patients, nearly 80% presented with subarachnoid hemorrhage and over a third developed recurrent subarachnoid hemorrhage, suggesting a need for early treatment and intervention in this group of patients (73).
The clinical profile of carotid and vertebral artery dissection was compared in the ongoing CADISP study (35). As compared to patients with vertebral artery dissection, those with carotid artery dissection were older, more often men, had a higher frequency of recent infection, a lower frequency of neck trauma, more often had onset headache, and had more severe strokes and worse outcome although their frequency of stroke was lower than that of patients with vertebral artery dissection. As compared to patients with spontaneous vertebral artery dissection, patients with carotid dissection appear to have a shorter time to diagnosis, a shorter length of inpatient stay, but a higher incidence of persistent neurologic deficits (26). Similar differences have been reported in other studies (147). The CADISP study has also shown that delayed stroke (stroke preceded by nonstroke symptoms) is more likely in patients with occlusive dissections, multiple dissections, and vertebral dissections (82).
The outcome of stroke from spontaneous carotid and vertebral artery dissection depends on the extent of the ischemic lesion and the adequacy of the collateral circulation (132). As anticipated for stroke due to other etiologies, the development of large areas of infarction is associated with poorer prognosis. The outcome after extracranial cervical artery dissection is generally good to excellent: the mortality rate is less than 10%, another 5% to 6% have major residual neurologic deficits, 15% have minor residual deficits, leaving approximately 70% of patients with normal neurologic examinations. However, quality of life remains impaired in the majority of patients, including those without significant neurologic deficits (51).
In the prospective Cervical Artery Dissection in Stroke Study (23), recurrent stroke occurred in only 4 out of 250 randomized subjects within 3 months and the risk of recurrence was 2.4% at 1 year (87). This risk is much lower than reported in observational studies. In a study of 130 patients with cervical artery dissection followed for 6 months, recurrent ischemic stroke occurred in 4.8% of patients within 2 weeks after diagnosis (03). A collaborative German study found a recurrent stroke rate of 11% during the first year and 14% over 3 years (149). As with all major ischemic strokes, the prognosis is better in patients with robust intracranial collateral vessels (132). Patients with multiple and early recurrent dissections (within 6 months) are more likely to have recurrent cerebral ischemia within 3 to 6 months than patients with single dissections (28). Patients with occlusion of the dissected artery have a higher risk for stroke and unfavorable outcome (142). However, pulsatile tinnitus (70) and Horner syndrome (86) are associated with benign outcome.
In a long-term follow-up evaluation of 58 consecutive patients with carotid dissection, the course of a subgroup (16 patients; 20 vessels) that developed aneurysmal dilatation was documented (61). In this group of patients, spontaneous radiologic resolution was rare (5% of patients), 65% of aneurysmal lesions were unchanged, and 30% of the lesions decreased in size. More importantly, no clinical symptoms of rupture or embolization occurred in patients with dissecting aneurysms, and no patients required surgical intervention.
Of the 264 patients with imaging-confirmed cervical artery dissection in the CADISS study, there were 24 patients (9%) with dissecting aneurysm at baseline. After 3 months, 248 patients had follow-up imaging; 12 of the 24 baseline dissecting aneurysms persisted and an additional 24 patients developed new dissecting aneurysms (14%). There was no difference in the appearance of a dissecting aneurysm or resolution among treatment groups (antiplatelet agents vs. anticoagulants). There was also no difference in the rate of ischemic strokes after 12 months in patients with or without dissecting aneurysms. These findings indicate a benign prognosis in patients with dissecting aneurysms (78).
The prognosis of intracranial carotid artery dissection is, on the other hand, considered to be poor. The mortality from intracranial carotid dissection is higher than that of extracranial dissection: the risk of death is 20% to 50% with subarachnoid hemorrhage, although significantly lower in patients without subarachnoid hemorrhage. Up to 15% can develop recurrent ischemic complications.
The risk of recurrence of cervical artery dissection is estimated to be approximately 1% per year. Younger patients and those with a family history of spontaneous dissections have a greater risk of recurrence (125). An extracellular matrix protein signature has been found in patients with recurrent cervical artery dissection (91).
Case 1. A 40-year-old man presented with severe facial pain and a partial Horner syndrome on first diagnosis. MRA showed a small region of focal stenosis in the right internal carotid artery, and an earlier study showed flow into a false lumen; the right internal carotid artery thus has a bifid appearance.
Case 2. A 48-year-old receptionist developed severe left neck pain on awakening the morning after lugging heavy grocery bags over her head to close a car trunk. Neurologic exam revealed only a left Horner syndrome. MRA showed a wide region of carotid stenosis, and conventional angiography showed delayed emptying of contrast, due to distal narrowing of the internal carotid artery. The lesion resolved on follow-up MRA at 3 months after initial presentation.
Spontaneous carotid or vertebral artery dissection has traditionally been thought to occur in otherwise healthy individuals. There is a significant temporal association between the occurrence of "minor" cervical trauma, or torsion of the neck, and the development of symptoms in many patients (49). A variety of everyday activities have been reported in association with the development of cervical artery dissection, including coughing, nose blowing, hiccups, sexual activity, yoga exercises, trumpet playing, SCUBA diving, Wii video game sports, golfing, and even prolonged neck tilting (11; 135; 62). Multiple case reports have documented dissection after rollercoaster rides (76; 103). In fact, trivial traumatic events may conceivably be overlooked in the search for the cause of the condition, a concept that supports the notion that "spontaneous" dissection does not truly exist.
Traumatic dissection of the cervical carotid artery reflects the fact that the pharyngeal (extracranial) portion of the vessel, like sections of the vertebral artery and aorta, is mobile; other vessels of similar size, such as the coronary and renal arteries, are fixed in place and less likely to dissect due to trauma (64). The prepetrous segment of the internal carotid, from its origin at the carotid bulb to entry into the petrous portion of the temporal bone, is commonly implicated. The internal carotid artery is compressed against the transverse processes of upper cervical vertebra, C1-C2 nerves, and a hematoma forms on the posterior internal carotid artery wall (137). Patients with neck trauma that present with neurologic signs or cervical vertebral fractures are at increased risk for vertebral artery dissection and should probably receive vascular injury screening with neck CTA or MRA (65).
The potential hazard of chiropractic manipulation in precipitating vertebral artery dissection has been recognized since the early 1980s (14; 119). Although the incidence of dissection after spinal manipulation is believed to be low (50; 24), it is recommended that practitioners inform patients of a statistical association prior to undergoing neck manipulations (18), particularly of the extracranial vertebral artery, which has been estimated to be 1 in 20,000 spine manipulations. However, this association is controversial because neck pain from a spontaneous dissection may motivate the initial visit to the chiropractor.
Carotid dissections have been associated with elongated styloid processes, suggesting that mechanical trauma from the styloid may play a role (116). Redundancy of the internal carotid artery may be an anatomic predisposition to dissection of this vessel (13). Imaging findings of carotid redundancy (kinking, coiling, or loops) were associated with spontaneous carotid artery dissection in 8 of 13 (62%) patients, and 13 of 20 vessels (65%) with dissection, but the same findings existed in only 20 of 108 (19%) age-matched stroke patients without dissection. However, the findings of a case-control study do not support this hypothesis (45).
On presentation, many patients have a concomitant history of cardiovascular risk factors, such as hypertension, atherosclerosis, migraine, contraceptive agents, or alcohol intake (37). Hypertension may be an important modifiable vascular risk factor for cervical artery dissection; however, hypercholesterolemia and obesity are associated with a lower risk (40). An association between migraine and cervical artery dissection (vs. other etiologic subtypes of ischemic stroke) was suggested by a case-control study, leading the authors to wonder whether an arteriopathy could predispose to both disorders (144). However, some newly diagnosed migraineurs, unless cervical artery imaging is obtained, may actually have extracranial carotid artery dissection as the cause of their headache. One study found that a personal history of migraine was significantly associated with spontaneous carotid artery dissection (OR 3.91, CI 1.71-8.90) (109). Similarly, case-control studies have shown that migraine, particularly with aura, was more common in patients with dissection (08; 94). Recent studies have identified shared genetic risks for both migraine and carotid artery dissection (30).
Less frequently, other conditions capable of altering the vascular walls have been present prior to the episode of dissection. These include fibromuscular dysplasia (found in approximately 15% of the patients), giant cell arteritis, polyarteritis nodosa, meningovascular syphilis, Ehlers-Danlos syndrome, Marfan syndrome, cystic medial necrosis, late-onset Pompe disease, osetogenesis imperfecta, polycystic kidney disease, and moyamoya disease (37). Carotid and vertebral artery dissections have also been associated with hypertensive reversible leukoencephalopathy and the reversible vasoconstriction syndrome, which are both syndromes linked to disordered cerebral autoregulation (133; 134; 92; 16). Infection may increase the risk for dissection, particularly multivessel simultaneous dissections, presumably due to a transient arteritis or mechanical changes related to coughing (59). Influenza-like illness has been associated with an increased risk of dissection, especially in the first 15 days after infection (67). There have been case reports of cervical artery dissection associated with Covid-19 infection, in isolation or concomitant with reversible cerebral vasoconstriction syndrome. Whether the infection precipitated the dissection is still a matter of debate (31; 107).
The international CADISP-genetics study has been convened to uncover genetic risk factors for carotid and vertebral artery dissections (41). Genetic imbalances affecting arterial development are more frequent in patients with cervical artery dissection, particularly those with a familial history (63). Polymorphisms in ICAM-1 and COL3A1, hyperhomocystinemia (54; 108), particularly due to the MTHFR 677TT genotype, have been associated with carotid and vertebral artery dissections (38).
The rs9349379[G] allele (PHACTR1) has been associated with a lower risk for cervical artery dissection as well as migraine (36). Carotid dissection has been associated with dolichoectasia (21), and familial dissections have been associated with fibromuscular dysplasia (95). A study of familial cervical artery dissection found evidence for COL3A1 mutations and ultrastructural connective tissue abnormalities similar to that of Ehlos-Danlos syndrome (89). Clinical signs suggesting connective tissue abnormalities such as craniofacial dysmorphisms and skeletal, ocular, and skin abnormalities are detected more frequently in patients with spontaneous cervical artery dissections than in patients with ischemic strokes not related to cervical artery dissections (mean number of pathologic findings, 4.5 ± 3.5 vs. 1.9 ± 2.3; p < 0.001) (57). Although these studies further support a role for connective tissue disorders, the association seems rare even with familial occurrence of dissections (44; 34).
Rubinstein and colleagues conducted a systematic review of the risk factors for cervical artery dissection (120). Thirty-one case-control studies were included for analysis. Aortic root diameter greater than 34 mm (OR 14.2), migraine (OR 3.6), relative diameter change greater than 11.8% during the cardiac cycle of the common carotid artery (OR 10.0), trivial neck trauma or manipulation (OR 3.8), homocysteine (OR 1.3), and recent infection (OR 1.60) proved to be significant risk factors for dissection, although the authors found major sources of bias in most of the studies they reviewed.
Shin and colleagues compared potential risk factors among patients with intracranial and extracranial vertebral artery dissections (130). They found that intracranial vertebral artery dissections were particularly frequent near the posterior inferior cerebellar artery and in nondominant vertebral arteries. Patients with intracranial dissection usually had absent trauma history, were older, and were more often hypertensive.
Dissection of the artery is accompanied by hemorrhage into the subintimal, medial, and less commonly, adventitial layers of the vascular wall (42). Studies suggest that the media and adventitia, rather than the intima, are primarily affected in cervical artery dissections (146). Subintimal hemorrhages due to intimal tears, often caused by trauma, most commonly give rise to luminal narrowing. Subadventitial hemorrhages, attributed to microscopic rents in the tunica media, are more likely to lead to aneurysm formation and chronic dilatation of the vessel. The plane of dissection probably bears a relationship to systolic pressure, vessel location, and the presence of an underlying vasculopathy. Extracranial dissections most commonly involve the media or subadventitial layers, whereas intracranial dissections are usually subintimal. The pathogenesis of spontaneous dissection is an enigma because the majority of patients have morphologically normal arteries prior to the development of symptoms of dissection. Several associated conditions have been reported as possible predisposing factors for the development of spontaneous dissection, but the relationship between any of these processes and spontaneous dissection is unclear.
Carotid and vertebral artery dissection can induce symptoms of cerebral ischemia by hemodynamic compromise of the distal vasculature due to luminal narrowing, or by distal embolism due to thrombotic fragments that communicate with the lumen of the dissected vessel. Lesions causing high-grade stenosis and occlusion are more likely to result in intracranial obstructions and cerebral or retinal ischemic events, whereas those without luminal narrowing more often cause local signs and symptoms (Horner syndrome, cranial neuropathies, pulsatile tinnitus) (15). One series of 65 strokes due to carotid dissections in 40 patients found that the vast majority were likely embolic (84), but embolism and hemodynamic impairment often coexist. Serial transcranial Doppler ultrasound monitoring observed microembolic signals in 13 of 28 patients (98). Unlike atherosclerotic vascular occlusion, luminal compromise from dissection is a dynamic process that most often resolves with complete recanalization of the vessel. A study using serial ultrasound showed that the rate of complete arterial recanalization was 16% at 1 month, 50% at 3 months, and 60% at 6 months; patients with initial occlusion were less likely to recanalize (102). Another serial neurovascular ultrasound study showed that complete or hemodynamically significant recanalization occurs in over 70%, typically within the first few months (12). Rarely, extracranial dissection may primarily involve the common carotid artery, producing syndromes similar to those associated with internal carotid artery dissection (58). Intracranial dissections, in addition to producing symptoms of brain ischemia, have also been associated with subarachnoid hemorrhage (104).
It is estimated that cervical artery dissection accounts for approximately 2% of all ischemic strokes and up to 25% of stroke in young adults. One third of children with ischemic strokes have arteriopathy, of which dissection is the most common (27%) (115). Population-based data from the Mayo Clinic reveal an annual incidence rate of approximately 2.6 per 100,000 individuals, with the average annual incidence rate for internal carotid artery and vertebral artery dissection being 1.72 and 0.97, respectively, per 100,000 population (81). Cervical artery dissection occurs predominantly in the middle adult years. A large study of 696 cervical artery dissection patients showed that males are more commonly affected (57%) (06). The CADISP study shows a similar male preponderance (93). Affected women are younger (mean 42.5 years) as compared to men (mean 47.5 years), and more often have multiple dissections (18% vs. 10%; p=0.001), migraine (47% vs. 20%; p< 0.0001), and tinnitus (16% vs. 8%; p=0.001). There may be a seasonal variation, with the peak incidence in winter, perhaps due to higher rates of infection and hypertension in the winter months (106). There seems to be an increase in hospitalizations for dissection-related stroke in older patients (09). In patients 60 years or older, dissections are more often painless and are associated with fewer mechanical triggers (141).
The incidence of intracranial dissections is unknown. The published literature suggests a higher frequency in Asians and in children. A literature review of more than 2000 cerebral arterial dissections in children (patients less than 18 years old) found that they are most commonly intracranial, in contrast to an extracranial predominance in adults (53). Simultaneous dissection of 2 cerebral arteries can occur in approximately 20% of cases; some patients, particularly women, can develop dissection in 3 or even 4 cerebral arteries (05). Outcome and mortality are similar in both sexes (06; 22). Arterial occlusion, multiple dissections, and vertebral dissections may carry a higher risk for delayed stroke (82).
There are no specific means of preventing spontaneous cervical artery dissection. Patients who may be considered at risk (ie, those with any of the conditions listed earlier) are generally instructed to avoid physical activities that can lead to dissection (eg, wrestling, chiropractic neck manipulations) and to discontinue taking estrogen-containing compounds as these are known to promote intimal proliferation.
The differential diagnosis of spontaneous carotid or vertebral dissection is that of any condition that produces or mimics cerebral ischemia, including migraine with neurologic manifestations and cluster headache (131). Several aspects of the clinical history and physical examination should prompt the clinician to consider the diagnosis of dissection, particularly the association of an acute focal neurologic deficit with pain in the neck, face, or head, pulsatile tinnitus, a new bruit, or Horner syndrome ipsilateral to the carotid artery affected. In addition, carotid artery dissection should be in the differential diagnosis of isolated cranial nerve pareses, particularly the lower cranial nerves (83; 96; 124; 139). Spontaneous subarachnoid hemorrhage in a young individual should raise the suspicion of intracranial arterial dissection. Carotid dissection should be part of the differential diagnosis of patients who present with isolated Horner syndrome or acute and severe headaches (29).
The diagnosis of carotid and vertebral artery dissection rests on neuroimaging findings. Transfemoral cerebral angiography is the gold standard for diagnosis; however, over the past decade, the preference has been to image with CT angiography (CTA) or MR angiography (MRA), which can be repeated over time with lower risk. CTA is proving to be highly reliable in the diagnosis and follow-up of cervical carotid artery dissections (79; 80). In 1 study, CTA identified more intimal flaps, pseudoaneurysms, and high-grade stenosis as compared to MRA, and was the preferred technique particularly for vertebral artery dissections (145). However, evidence-based reviews suggest that the sensitivity, specificity, and positive and negative predictive value of MRI and CT are similar for the diagnosis of cerebral artery dissection (113). MRI and MRA have the following advantages: (1) axial T1-weighted images can detect small hematomas in cervical vessels that can be missed with conventional angiography; (2) MRA is an excellent noninvasive way to follow the resolution of dissection over time (123); (3) high-resolution 3-T MRI is showing promise in its ability to detect intracranial dissections, and in distinguishing intramural hematoma from thrombus (10). Contrast-enhanced MRA improves the resolution (111). Standard diffusion-weighted imaging (01) and especially newer MRI sequences such as 3-dimensional black blood T1-weighted imaging and fat-saturated SPACE sequences offer potential advantages in detecting dissections (including intracranial dissections) and evaluating the intramural hematoma (140).
The classic angiographic findings of cervical artery dissection include the “string sign,” dissection “flaps,” tapering arterial occlusion (“beaking”), and aneurysmal dilatation of a segment of the artery. Miscellaneous findings include branch artery occlusion, contralateral luminal irregularity, and chronic dissection with multiple outpouchings of the vessel wall (64).
In addition, it may be possible to uncover angiographic evidence of fibromuscular dysplasia. Intracranial dissections can also be demonstrated angiographically as an irregular tight narrowing ("string sign"), irregular scalloping ("pearl and string sign"), or "wavy ribbon appearance." Characteristic double lumen or intimal flaps have been found more frequently in patients with carotid dissection than they have been in the general population (126).
Carotid duplex ultrasound may show a tapering luminal stenosis and a double lumen, including an intimal flap, but this is not common. More frequently, extracranial Doppler shows reduced or absent distal carotid artery flow at the level of the bifurcation (138). Transcranial Doppler may be useful in identifying patients at higher risk for stroke by detecting high-intensity transient signals in the middle cerebral artery downstream from the dissection. High-intensity transient signals are believed to be microemboli, and they were more prevalent in patients with dissection who suffered stroke than in those who did not (136).
On diffusion-weighted MRI, the most frequent imaging pattern is acute multiple brain infarcts in a single arterial distribution (territorial infarcts, seen in nearly two-thirds of patients with dissection) (20). Infarcts typically occur in a borderzone distribution, suggesting a combination of low-flow hemodynamic and thromboembolic mechanisms (17; 74; 77). As compared to patients with dissection who have occluded arteries, patients with stenotic arteries show a higher incidence of multiple, small, borderzone infarcts (19).
In high-resolution magnetic resonance imaging, patients with dissection show local or generalized vessel wall inflammation, defined as perivascular contrast enhancement. Pfefferkorn and colleagues showed that patients with multiple dissections had more generalized vessel wall inflammation in high-resolution MRI and PET-CT (110).
Evidence based guidelines for the management of carotid artery dissection have been published (39). An international randomized controlled trial compared the efficacy of antiplatelet agents versus anticoagulation in patients with dissection (23). Among the 250 subjects (118 carotid, 132 vertebral artery dissection), 126 were randomized to antiplatelets and 124 to anticoagulation at an average of 3.65 days after symptom onset. The choice of antiplatelet and anticoagulant medication was at the discretion of the attending physician. In the antiplatelet group 22% received aspirin alone, 33% received clopidogrel alone, 1% received dipyridamole alone, 28% received aspirin and clopidogrel, and 16% received aspirin and dipyridamole. Within the anticoagulant therapy group 90% received heparin and warfarin and 10% received warfarin alone. A total of 4 strokes occurred in the 3-month follow-up period, 3 in the antiplatelet arm and 1 in the anticoagulation arm. One patient in the anticoagulation arm developed subarachnoid hemorrhage. Although designed as a feasibility study, the low overall event rates suggested that a definitive trial would require an estimated 10,000 patients. On the basis of these data, most clinicians prefer antiplatelet agents as treatment for spontaneous extracranial cervical artery dissection. It should be noted that randomization occurred a few days after onset, so anticoagulation (eg, heparin) could still be useful to prevent hyperacute stroke in the first 3 to 4 days when stroke risk is highest in such patients. There is very little information concerning the safety and efficacy of direct oral anticoagulants in cervical artery dissection (100; 128).
The results of the CADISS trial were supported by prior analyses. A review of the Cochrane Library Database comprising 36 observational studies with 1285 patients showed no difference in patient outcome with the use of antiplatelet agents versus anticoagulants (85). An analysis of prospectively collected data from 298 consecutive patients with spontaneous cervical artery dissection showed that the risk for recurrent stroke was low and not significantly different between those treated with aspirin or warfarin (55). The results of the “non-randomized” patients in CADISS, along with a metaanalysis, concluded that antiplatelet and anticoagulant agents were equally effective in secondary stroke prevention (72).
However, a randomized, multicentric study published in May 2021 showed different results (47). The TREAT-CAD trial compared treatment with either aspirin 300 mg daily or vitamin K antagonist started within 2 weeks of dissection and given for 90 days. One hundred ninety four patients were enrolled, and the primary endpoint was a composite of clinical outcomes (stroke, major hemorrhage, or death) and MRI outcomes (new ischemic or hemorrhagic brain lesions). As a surprise to many vascular neurologists, the final results did not show that aspirin was noninferior to vitamin K antagonists. The composite outcome occurred in 23% of patients in the aspirin group and in 15% of patients in the vitamin K antagonist group. Ischemic strokes occurred in 8% of patients in the aspirin group and in no patients from the other group, whereas major hemorrhage only occurred in the vitamin K antagonist group (1 patient) (47).
Both CADISS and TREAT-CAD evaluated patients with a similar profile, yet results differ significantly. An important difference between trials was the choice of antiplatelet agents. Although in the CADISS trial the attending physician could decide whether to use dual antiplatelet therapy or monotherapy, in the TREAT-CAD all patients in the antiplatelet group received aspirin. It is possible that the high rate of dual antiplatelet therapy in the CADISS trial influenced the results. Adequately powered studies are unfeasible to determine whether patients should be anticoagulated or receive antiplatelet therapy; at this time, based on available evidence, clinicians have flexibility to initiate either anticoagulation or antiplatelet therapy in patients with carotid artery dissection.
The adequate duration of use for an antiplatelet agent is uncertain, but dissections do not appear to pose long-term risks for older patients with atherosclerosis (where antiplatelet agents are recommended indefinitely). Caution should be exercised when using anticoagulant agents in patients with intracranial dissections because there have been reports of subarachnoid hemorrhage, worsening of deficits, and even death following early anticoagulation.
In the hyperacute setting, intravenous tissue plasminogen activator therapy appears safe (43; 56; 129; 114). However, thrombolysis was not found to improve outcomes (48), and, at present, most authors believe that it should not be withheld in patients presenting with acute ischemic stroke. There is little if any published experience with intra-arterial therapy for acute cervical artery dissection, but a critical challenge in cases we have evaluated is to navigate the catheter into the true lumen of the vessel. Endovascular thrombectomy for tandem acute ischemic stroke associated with dissection and carotid artery stenting during the treatment of tandem occlusions appears to be safe (46; 88). At present, neither anticoagulation nor thrombolysis has been demonstrated convincingly to extend the mural hematoma of extracranial dissection.
There is little evidence to justify surgical and neurointerventional procedures to treat cervical artery dissection. Angioplasty and stenting may be a therapeutic option in patients who fail medical management; however, the long-term safety and durability remains to be determined (68; 69). Ruptured fusiform dissecting aneurysms may be occluded with flow diversion techniques (60); however, aneurysm rerupture may occur despite treatment (112).
Several case reports describe cervicocephalic arterial dissections in postpartum women (118; 148; 66; 71). Arnold and colleagues analyzed their prospective registry of cervicocephalic dissections and found that postpartum dissection was more often associated with coexisting conditions such as reversible cerebral vasoconstriction syndrome and posterior leukoencephalopathy syndrome, as compared to non-postpartum dissection (04). It is conceivable that the postpartum state confers a higher risk for arteriopathies, including dissection (105).
Steven R Levine MD
Dr. Levine of the SUNY Health Science Center at Brooklyn has no relevant financial relationships to disclose.See Profile
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