Stroke as a consequence of a non-atherosclerotic disease process is most commonly described as being a disease of the young. Nevertheless, there are myriad potential causes of non-atherosclerotic stroke, including dissection, trauma, fibromuscular dysplasia, vasculitis, and moyamoya disease. The following review will discuss several non-atherosclerotic etiologies associated with stroke in patients of all ages.

Dissection

Cervical artery dissection is the most common nonatherosclerotic cause of stroke in young adults.¹ Dissections account for 20% of all ischemic strokes in the young, including a quarter of brainstem and cerebellar infarctions.² One community-based study estimated the annual incidence of spontaneous internal carotid artery dissection to be 2.6 per 100,000 for all ages (95% CI: 0.9 to 4.2), and 3.5 per 100,000 for those aged 20 years and older (95% CI: 1.3 to 5.8).³ The incidence of vertebral artery dissection is believed to be even lower at 1.0 per 100,000 per year (95% CI 0.4-1.7).³ The pathophysiology of cervical dissection is poorly understood, but some hypothesize that a genetically inherited blood vessel weakness makes them susceptible to pathophysiologic exacerbations such as infection or minor trauma, chiropractic manipulation, whiplash injury, and various sporting activities.⁴ Hereditary connective tissue disorders such as Ehlers-Danlos syndrome (EDS) are associated with an increased risk of cervical dissection; however, the association is rare and responsible for less than 2% of cases.^5,6 Carotid dissection is found in 1-5% of patients with a bicuspid aortic valve, but even more common is the association between fibromuscular dysplasia (FMD) and cervical dissection, estimated to be the initial clinical manifestation of FMD in approximately 15% of cases.⁷

Regardless of the etiology, a dissection is either an intimal tear or bleeding of the vaso vasorum. Subintimal dissection tends to cause stenosis, whereas aneurysmal degeneration appears to result from subadventitial dissection.⁸ Patients who develop cervical dissection typically present with local signs and symptoms and then progress to ischemia. For instance, sudden-onset Horner's syndrome or cranial nerve palsy in the context of headache or neck pain should be investigated immediately for carotid artery dissection. Dissection can be diagnosed using computed tomography (CT) or magnetic resonance (MR) angiography and it can be most commonly seen as a long tapered stenosis, a tapered occlusion, or less frequently a dissecting aneurysm.²

Once diagnosed, management is usually conservative. Anticoagulation or antiplatelet therapy is generally recommended in the acute phase to prevent primary or recurrent ischemic events.⁹ The CADISS trial found no significant difference in efficacy of antiplatelet or anticoagulant drugs at preventing death or disability.¹⁰ However in practice, anticoagulation is often preferred when there is a severe stenosis or occlusion, and antiplatelet agents are favored when there is a contraindication to therapeutic anticoagulation or there is a high risk of hemorrhagic conversion.¹⁰ In 2011, two multi-societal guidelines were published for the management of carotid disease and they both recommend initial management with antithrombotic treatment with either an anticoagulant (heparin, low-molecular-weight heparin, or warfarin) or a platelet inhibitor (aspirin, clopidogrel, or the combination of extended-release dipyridamole plus aspirin) for at least 3 to 6 months in patients with extracranial carotid or vertebral arterial dissection associated with ischemic stroke or transient ischemic attack.^9,11 Less clear is the role of beta blockers, angiotensin inhibitors, or calcium channel blockers to lower blood pressure to the normal range to theoretically reduce the stress on the vessel wall and prevent dissection progression or worsening ischemia. Carotid angioplasty and stenting are reserved for when ischemic neurologic symptoms are refractory to antithrombotic therapy following acute carotid dissection.^9,11 Although unable to make firm recommendations due to paucity of data, the Society of Vascular Surgery expert committee unanimously agreed that balloon angioplasty and stenting is currently preferred over open surgery after failed medical management.¹¹ Prognosis is overall favorable for patients who experience spontaneous cervical dissection, and with antithrombotic therapy, complete resolution of the arterial abnormality is expected in about half of patients with stenosis and a third of patients with occlusion.³ Recurrence is estimated to be between 0 and 13.3% at 1 year, but if a recurrent dissection does happen, it is most often during the first few weeks.²

Trauma

Trauma is an important cause of non-atherosclerotic stroke and can result from both blunt and penetrating trauma. It has been estimated that cervical dissection occurs in about 1-2% of patients who experienced blunt trauma.¹² The risk of carotid dissection is higher when there is associated major thoracic injuries while the risk of vertebral dissection is more likely with cervical spine fracture or spinal cord injury.¹² Traumatic dissection is diagnosed and managed similarly to spontaneous dissection with the mainstay of treatment being antithrombotic therapy. Again, endovascular intervention is reserved only for patients with persistent neurologic deficits despite pharmacologic treatment.¹¹ The risks and benefits of any therapy must be weighed carefully in all patients, but the management of trauma patients can be particularly challenging given the increased odds of there being an absolute or relative contraindication to therapeutic anticoagulation as a result of the initial trauma or subsequent procedures. Multi-disciplinary discussions with the care teams and the patient and/or family should occur prior to initiating therapy to ensure shared decision making and informed consent in light of the potential devastating consequences of the disease itself and the recommended therapy.

Fibromuscular Dysplasia

FMD is a non-inflammatory angiopathy that is characterized by segmental, nonatheromatous, and dysplastic changes to small- and medium-sized arteries.¹³ FMD has been reported in nearly every vascular bed, but most commonly affects the renal and extracranial carotid and vertebral arteries almost equally, which is a recent divergence from the classical paradigm of renal FMD being the primary manifestation.⁷ The cause of FMD is unknown, but since most patients with cerebrovascular FMD are young and 80-90% are women, hormonal factors have been implicated, yet there is little supporting evidence for this hypothesis.⁷

The diagnosis of cerebrovascular FMD was classically made on the basis of cerebral angiography with the archetypal "string of beads" appearance.¹⁴ In contrast, the phenotype of cerebrovascular FMD is highly variable, ranging from asymptomatic (most common), to headache, dizziness or neck pain, to the most feared and serious sequelae including transient retinal or cerebral ischemia, cerebral infarction, cervical artery dissection, or subarachnoid hemorrhage.¹⁵ The association of FMD and dissection is well described in published case series. It has been estimated that about 15-20% of cervical artery dissections are FMD-related.^2,8 However, focal neurologic events in FMD can also be related to severe stenosis, embolization, thrombosis or aneurysm rupture.¹³ The optimal strategy for noninvasive diagnosis of cerebrovascular FMD is debatable, as few studies have directly compared them to the gold standard of catheter-based angiography, but techniques using duplex ultrasound and CT and MR angiography are reasonable for ongoing annual surveillance to monitor disease progression.⁹

Evidence for the treatment of FMD is largely based upon case reports and small retrospective case series, but most experts agree that in patients who have had an ischemic event, antiplatelet therapy should be prescribed for future risk-reduction. A writing group was recently commissioned by the Society for Vascular Medicine (SVM) and the working group 'Hypertension and the Kidney' of the European Society for Hypertension (ESH) to create a single expert consensus document¹⁶ that outlines the following for the diagnosis and management of FMD:

1. The presence of at least one focal or multifocal arterial lesion (stenoses) is required to establish the diagnosis of FMD. The presence of aneurysm, dissection, or tortuosity alone is inadequate to establish the diagnosis.
2. If a patient has a focal or multifocal lesion in one vascular bed to establish the diagnosis of FMD, the presence of aneurysm, dissection, or tortuosity in another/other vascular bed is considered multivessel involvement of all affected vascular beds.
3. Regardless of initial site of vascular bed involvement, patients with FMD should undergo brain to pelvis imaging, at least once and usually with CTA or contrast enhanced MRA, to identify other areas of FMD, as well as to screen for occult aneurysms and dissections.
4. Treatment with antiplatelet therapy (aspirin 75–100 mg/day) is reasonable to prevent thrombotic and thromboembolic complications, in the absence of contraindication.

In contrast to atherosclerotic vascular disease for which surgical or endovascular procedures are advised for risk reduction in both asymptomatic and symptomatic patients, revascularization is performed only in symptomatic FMD patients who experience ipsilateral cerebral ischemic symptoms.^11,13

Vasculitis

The vasculitides encompass a heterogenous group of disorders related pathologically by inflammation of the blood vessel walls with reactive damage to mural structures.¹⁷ Vasculitis is a rare (responsible for 3-5% of strokes in patients < 50 years old), but potentially treatable cause of stroke.¹⁸ Central nervous system (CNS) vasculitis can be primary in etiology (rarer and more challenging to diagnose) or secondary to a systemic disorder such as systemic lupus erythematosus (SLE), polyarteritis nodosa, Takayasu's arteritis or temporal arteritis.¹⁹ The vasculitides are typically classified according to the size of the affected blood vessels, and stroke secondary to vasculitis can result from direct involvement of the diseased cerebral vessels through aneurysm rupture or parenchymal hemorrhage, or through arterial occlusion/infarction secondary to dissection or thromboembolic phenomena.¹⁹

Primary CNS vasculitis is a complex and challenging diagnosis to make, and often incorrect: one observational study found that only 17% of 77 consecutive patients referred for further evaluation with a presumptive diagnosis of primary CNS vasculitis ultimately had the disease.²⁰ Brain MRI scans reveal non-specific findings of infarction or hemorrhage; thus, diagnosis frequently requires invasive procedures, specifically catheter angiography, lumbar puncture, and brain and meningeal biopsy.²⁰ Biopsy is the gold standard for diagnosis, but it also functions to help exclude other conditions with similar presentations, and the morbidity associated with biopsy has been found to be less than that associated with the immunosuppression necessary to treat the condition.²⁰

A secondary CNS vasculitis is suggested when patients lack the traditional risk factors for stroke and there is evidence of a systemic rheumatologic disorder or a secondary viral infection such as Herpes zoster.²⁰ For instance, stroke can occur in patients with SLE through a variety of mechanisms such as cardiogenic embolism, a prothrombotic state, or dissection, in addition to direct involvement of intracranial vessels or secondary effects of disease sequelae (e.g. severe hypertension secondary to renal disease).^21,22 Polyarteritis nodosa is a systemic, necrotizing form of vasculitis affecting medium-sized arteries and is associated with viral hepatitis infection.¹⁹ Similar to SLE, ischemic stroke secondary to polyarteritis nodosa can occur through direct or indirect insults to the cerebral vasculature, but more commonly neurological involvement of the disease is in the periphery in the form of myalgias and polyneuropathy multiplex.²³ Takayasu's arteritis is a giant cell granulomatous pan-arteritis of the aorta and its main branches, and it predominantly affects patients under 50 years of age.¹⁷ Takayasu's arteritis classically contributes to stroke pathogenesis through extracranial stenosis and micro-emboli to the cortices.²⁴ Temporal arteritis is a chronic, granulomatous vasculitis of large and medium sized arteries that affects patients older than 50 years of age and women more frequently than men (4:1), and may present with headache, jaw claudication, visual symptoms, or more rarely blindness and stroke.²⁵ In contrast to the other vasculitides, high dose corticosteroids (prednisone or prednisolone) are the only effective therapy in temporal arteritis and it should not be delayed by temporal artery biopsy.¹⁹

Immunosuppression is the cornerstone of treatment for cerebral vasculitis, although the protocols themselves were developed initially for systemic vasculitides. In general, a combination of steroids and pulse cyclophosphamide is recommended for induction, and more recently rituximab, an anti-CD20 monoclonal antibody, has become a viable alternative.¹⁹ Once remission is achieved, then methotrexate, azathioprine and mycophenolate mofetil are suggested alternatives to cyclophosphamide.¹⁹

Moyamoya Disease

Moyamoya disease (MMD) is a nonatherosclerotic, noninflammatory, nonamyloid vasculopathy characterized by chronic progressive stenosis or occlusion of the distal internal carotid arteries and/or proximal portions of the middle and/or anterior cerebral arteries.²⁶ It is most prevalent in Japan and other Asian countries.²⁷ The name "moyamoya" means "puff of smoke" in Japanese and describes the look of the tangle of tiny vessels at the base of the brain on catheter angiography, formed to compensate for the blockage.²⁷ MMD presents most commonly in children around age 5 years with a second smaller peak in the third decade.²⁸ MMD in childhood usually presents with a transient ischemic attack (TIA) or cerebral infarction, whereas more than half of adult patients with MMD present with cerebral hemorrhage.^28,29

The natural history of MMD is largely unknown, and the clinical course and outcomes of surgical revascularization procedures differ substantially between children and adults.³⁰ Aspirin has been widely used in patients with ischemic symptoms, and a variety of surgical revascularization procedures have been used in both children and adults with recurrent ischemia, however, there is some concern about using antiplatelet agents in adults since they are at higher risk of brain parenchymal hemorrhage.³¹ The preventive effect of surgical revascularization treatment for ischemic MMD has been clinically demonstrated. For example, a recent systematic review and meta-analysis of 2258 pediatric MMD patients reported that direct, indirect, and combined indirect/direct bypass techniques were all effective revascularization options for pediatric MMD and reduced the risk of future stroke.³² The best bypass approach and the decision to operate at all in adult patients is less clear, but evidence is accumulating regarding the benefits of surgical treatment for both ischemic and hemorrhagic MMD compared to conservative therapy.³³

Conclusion

Diagnosis and treatment of non-atherosclerotic stroke relies heavily upon history and physical exam as well as CT/MR and catheter angiography. Treatment depends upon the etiology of the ischemia but is in general focused on managing the underlying condition and reducing the risk of future stroke either through antithrombotic therapy or revascularization.

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Clinical Topics: Anticoagulation Management, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Vascular Medicine, Lipid Metabolism, Interventions and Vascular Medicine

Keywords: Aneurysm, Platelet Aggregation Inhibitors, Carotid Artery, Internal, Dissection, Aspirin, Fibrinolytic Agents, Ischemic Attack, Transient, Platelet Aggregation Inhibitors, Warfarin, Cerebral Angiography, Calcium Channel Blockers, Vertebral Artery Dissection, Moyamoya Disease, Fibromuscular Dysplasia, Giant Cell Arteritis, Constriction, Pathologic, Methotrexate, Stroke, Polyarteritis Nodosa, Prednisone, Azathioprine, Mycophenolic Acid

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