Cerebral arteriopathies

Cerebral arteriopathies are among the most challenging group of conditions encountered by the vascular neurologist. They are collectively the most common cause of stroke, accounting for 30% to 40% of strokes in young adults (149; 221; 134; 77) and over 50% in children (89). In older adults, atherosclerosis alone accounts for 20% to 50% of stroke (304) and lipohyalinosis another 15%. This article will focus on cerebral arteriopathies that most commonly affect young adults (see Table 1). Premature atherosclerosis will be very briefly reviewed; however, lipohyalinosis, Binswanger disease, cerebral amyloid angiopathy, and other arteriopathies that typically affect the elderly are not discussed here. Similarly, pediatric cerebral arteriopathies such as transient cerebral arteriopathy and post-varicella angiopathy are beyond the scope of this review.

Premature cerebral atherosclerosis. Premature cerebral atherosclerosis is gaining recognition as an important cause of stroke in the young. Accumulating evidence suggests that the incidence of traditional vascular risk factors such as diabetes, hyperlipidemia, obesity, and hypertension is increasing in young adults and is related to early atherosclerosis (26; 219; 274; 133; 134; 216).

Simultaneously, national databases have documented rising trends in stroke hospitalizations in both genders for children, adolescents, and young adults (96; 148; 239). As a consequence, it is not surprising that atherosclerotic etiologies are now the main cause of stroke in the young, with a prevalence of 40% to 42% of large artery atherosclerosis etiology, and 16% to 28% of small-vessel disease etiology in this population (167; 249). There is no gold standard for diagnosis. Intracranial arterial imaging findings of calcification in the intracranial carotid and proximal circle of Willis arteries, in a patient with vascular risk factors such as hypertension and diabetes, suggests atherosclerosis. High-resolution vessel wall MRI may provide further clues (122).

There has been an increase in incidence rates of first-time hospitalizations for ischemic stroke and TIA in young adults worldwide, especially in the last years (96; 137; 148; 220; 238; 240; 297; 22; 284; 224; 34; 76; 78). Data from the Helsinki cohort study have shown a high prevalence of silent infarcts and cerebral white matter disease in the young. The highest rates of stroke recurrence and mortality have been observed in stroke caused by carotid atherosclerosis and small-vessel disease, again emphasizing the contribution of premature atherosclerosis to stroke in the young (96; 240; 148; 220; 137; 238; 297). Patients below 55 years of age can also present with severe, fatal, and recurrent ischemic and hemorrhagic strokes secondary to advanced atherosclerosis-related pathologic changes (208). Consequently, aggressive control of atherosclerotic risk factors and treatment with antiplatelet agents and statins are warranted even in young individuals (293; 288).

Nonatherosclerotic cerebral arteriopathies. Nonatherosclerotic cerebral arteriopathies deserve special attention because their natural history, prognosis, and treatment differ considerably from atherosclerosis. They accounted for 5.6% of strokes in the Baltimore-Washington Co-operative Young Stroke Study (149), 19% percent of strokes in a population-based epidemiological survey in Sweden (156), 24% in a retrospective single-center study in Boston (137), and 27.8% in a prospective study of young stroke in The Netherlands (77). The significant differences in percentages may be attributed to the different stroke etiological schema used in these studies. One third of children with ischemic strokes have arteriopathy, of which dissection is the most common (27%), followed by moyamoya (24.5%), inflammatory focal cerebral arteriopathy (15%), and diffuse cerebral vasculitis (15%) (223). They can be classified according to etiology or the affected age group; however, from the standpoint of diagnostic approach, it is important to distinguish large- and medium-vessel from small-vessel cerebral arteriopathies (262). Medium-vessel arteriopathies induce visible abnormalities on angiography, whereas small-vessel arteriopathies affect distal vessels that are beyond the current resolution of angiography. Some arteriopathies, eg, the reversible cerebral vasoconstriction syndromes (RCVS) and primary angiitis of the central nervous system (PACNS), can affect both the medium and the small vessels. The final clinical manifestation of cerebral arteriopathies may be similar (ischemic or hemorrhagic stroke, seizures, brain edema); however, the key to diagnosis rests on the detection of associated signs and symptoms and recognition of their clinical and radiologic features.

Table 1. Common Cerebral Vasculopathies in Young Adults

Approach to diagnosis

In general, a high index of clinical suspicion, careful examination of the skin, eyes, ears and other organ systems, and a multi-disciplinary approach involving neurologists, neuroradiologists, rheumatologists, geneticists, and others is required for the appropriate diagnosis and management of cerebral arteriopathies (42).

The diagnosis of a small-vessel cerebral arteriopathy requires a high index of clinical suspicion, usually in patients presenting with recurrent focal neurologic deficits with or without encephalopathy and headache. Imaging typically shows small acute and chronic infarcts located in deep territories. Astute neuroradiology interpretation is key. Clinically, a careful skin, eye, and organ system examination is required.

Patients typically develop recurrent strokes from small-sized infarctions or micro-hemorrhages (292) and often have chronic headaches, cognitive deficits, or psychiatric manifestations. MRI findings of scattered small-vessel infarcts or micro-hemorrhages with or without white matter lesions should raise suspicion for small-vessel arteriopathy. Genetic arteriopathies may be suggested by funduscopic abnormalities, eg, retinal arteriolar irregularities (CADASIL and RVCL or “retinal vasculopathy with cerebral leukoencephalopathy”) or branch retinal artery occlusions (Susac syndrome). Skin examination may reveal characteristic lesions, eg, atrophic white papules in Degos disease, or livedo reticularis in systemic lupus erythematosus. Abnormal cerebrospinal fluid (CSF) examination results are common in cerebral vasculitis and infectious arteriopathies. Several small-vessel arteriopathies (eg, CADASIL) have established diagnostic criteria (45) or can be confirmed with specialized tests such as skin or brain biopsy, or genetic, immunological, or microbiological tests. Some small-vessel arteriopathies are diagnosed solely with clinical-imaging correlation, eg, lipohyalinosis in patients with chronic hypertension, a well-defined lacunar stroke syndrome, and a corresponding small cerebral infarction in the distribution of a “penetrator” artery. Others such as PACNS continue to pose diagnostic challenges, because definitive diagnostic tests like brain biopsy often produce false negatives, and tests like CSF examination and angiography have low specificity.

Medium-vessel cerebral arteriopathies typically come to attention when CT-angiography or MR-angiography (CTA or MRA) performed during a routine stroke or headache evaluation show ectasia, beading, or irregularities of the intracranial vessels. Common clinical features of medium-sized arteriopathies include recurrent thunderclap headaches (RCVS); stroke in the setting of recent headache, infection, recent pregnancy, vasoconstrictive medication exposure or illicit drug use; stereotyped transient ischemic attacks; or imaging findings of unilateral deep borderzone infarcts (303). As with small-vessel arteriopathies, the skin and eye examination can be informative, eg, ectopia lentis (Marfan syndrome); iris hamartomas, optic nerve tumors and café au lait spots (Neurofibromatosis-1); or cataracts, corneal opacities, and angiokeratomas (Fabry disease).

Unfortunately, in the absence of validated diagnostic criteria or confirmatory tests, for most nonartherosclerotic arteriopathies, their diagnosis and management of arteriopathies remains variable and uncertain. Patients with suspected cerebral arteriopathy typically undergo a battery of expensive diagnostic tests, most of which have relatively low sensitivity and specificity, often culminating in a brain biopsy or empiric treatment for conditions like cerebral “vasculitis,” which is not without risks. Ongoing studies are evaluating whether arteriopathies can be diagnosed on basis of different patterns of arterial contrast enhancement on high-resolution (3-Tesla) MRI (197). Prospective studies are still needed to refine diagnostic criteria and develop treatment algorithms. The next section provides an overview of selected nonatherosclerotic cerebral arteriopathies.

Carotid and vertebral artery dissection

The term "dissection," from the Latin verb disseco, refers to separation of anatomic structures along natural lines by disruption of the connective tissue framework. In the context of arterial pathology, it implies separation of the different layers that constitute the arterial wall. Subintimal dissections can cause lumen stenosis, and subadventitial dissections can cause aneurysmal dilatation. Some studies suggest that the media and adventitia, rather than the intima, are primarily affected in cervical artery dissections (296). It is estimated that carotid and vertebral artery dissection accounts for approximately 2% of all ischemic strokes and up to 25% of stroke in young adults. Population-based data from the Mayo Clinic in Rochester reveal an annual incidence rate of only 1.72 and 0.97 per 100,000 individuals for internal carotid artery and vertebral artery dissections respectively (252; 164). A study of the largest reported series of cerebral artery dissection (696 patients) showed that cerebral artery dissection more commonly affects males (57%) (11). 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). Simultaneous dissection of two cerebral arteries can occur in approximately 20% of cases; some patients, particularly women, can develop dissection in three or even four cerebral arteries (10). Outcome and mortality were similar in both sexes (11; 31). Intracranial dissections account for approximately 10% of all published cases, occur at an age of approximately 30 years, and have a slight male preponderance. The published literature suggests a higher frequency in Asians and in children (64). Influenza-like illness have been associated with an increased risk of dissection, especially in the first 15 days after infection (129). A few case reports associated cervical artery dissection with Covid-19 infection, but whether the infection precipitated the dissection is still a matter of debate (58; 209).

Carotid and vertebral artery dissection can occur spontaneously in otherwise healthy individuals or after "minor" trauma or torsion of the neck from innocuous physical activities such as coughing, sneezing, hiccups, sexual activity, yoga, racquet games, trumpet playing, and even prolonged neck tilting. Carotid and vertebral artery dissection has also been associated with roller-coaster rides and visits to hair salons (259). The wide range of associations, the presence of recall and publication bias, and lack of control populations make it difficult to draw firm conclusions about such risk factors. The potential hazard of chiropractic manipulation in precipitating vertebral artery dissection has been recognized since the early 1980s (20). However, this association is controversial because neck pain from a spontaneous dissection may motivate the initial visit to the chiropractor. The incidence of dissection after spinal manipulation is believed to be less than 1 in 20,000, but despite this low risk it is advisable to inform patients of a statistical association prior to undergoing neck manipulations (27; 36).

Hypertension may be an important modifiable vascular risk factor for CAD; however, hypercholesterolemia and obesity are associated with a lower risk (66). Several studies have found an association between migraine and cervical artery dissection, raising the possibility that an arteriopathy predisposes one to both disorders (290; 214; 13; 57). The increased risk of dissection in patients with higher frequency of migraine attacks seems to be reduced by migraine preventive medications, namely beta-blockers (71). Other conditions associated with CVAD include fibromuscular dysplasia (found in approximately 15% of patients), Ehlers-Danlos type IV and Marfan syndromes, cystic medial necrosis, polycystic kidney disease, osteogenesis imperfecta, giant cell arteritis, polyarteritis nodosa, meningovascular syphilis, reversible cerebral vasoconstriction syndrome, and moyamoya disease (67). The international CADISP-genetics study has been designed to uncover genetic risk factors for CVAD (70). Polymorphisms in ICAM-1 and COL3A1, and an association with the MTHFR 677TT genotype, have been reported (68). Although these studies support a role for connective tissue disorders, the association seems rare even after considering the familial occurrence of dissections (65). Genetic imbalances affecting arterial development are more frequent in patients with cervical artery dissection, particularly those with a familial history (108). Infections and hyperhomocysteinemia are implicated as systemic risk factors for carotid and vertebral artery dissection (105; 94; 213). Clinical signs suggesting connective tissue abnormalities such as craniofacial dysmorphisms, 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) (101). A systematic review of 31 case-control studies found the following risk factors for CVAD: 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), elevated homocysteine (OR 1.3), and recent infection (OR 1.60) (237).

The most common clinical features of extracranial carotid dissection include ipsilateral headache or neck pain, partial Horner syndrome (present in 40% of cases, but associated with a benign course), and cerebral or retinal ischemia (88; 152). An estimated 50% of cases develop stroke, and 30% present with transient ischemic attack (TIA) 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. Spontaneous vertebral artery dissections more commonly present with ischemic stroke (89%); male gender, increasing age, and smoking appear to increase the risk for ischemic events (12). 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) (21). The headache is typically dull and non-throbbing, can simulate migraine, and can precede ischemic symptoms. Other symptoms include isolated pulsatile tinnitus and cranial neuropathies from either direct compression of the evolving hematoma on cranial nerves IX, X, XI or XII in the region of the jugular foramen or local ischemia to the vasa nervorum of the oculomotor nerves that are supplied by the internal carotid artery (250; 211). Dysautonomia can occur (43). Intracranial carotid artery dissection seems to develop at a mean age of 50 years and is characterized by severe ipsilateral headaches (observed in 80%) and major stroke or recurrent TIAs (64). Patients with vertebral artery dissection typically develop posterior head or neck pain followed by ischemia in the vertebrobasilar territory and rarely cervical myelopathy. Intracranial extension of vertebral artery dissections can result in subarachnoid hemorrhage (SAH), which carries a much higher risk of death (20% to 50%). In older patients, dissections are often painless and associated with few mechanical triggers (285).

The clinical profile of carotid and vertebral artery dissection was compared in the ongoing CADISP study (69). 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.

The diagnosis of carotid dissection rests on neuroimaging findings. Transfemoral cerebral angiography is the gold standard for diagnosis; however, most physicians prefer relatively noninvasive tests such as contrast CT angiography and MR angiography, which can be repeated over time.

MRI with axial T1 fat-suppressed sequences can detect small hematomas in cervical vessels that can be missed with conventional angiography.

Diffusion-weighted MRI can show high signal intensity within the affected artery, and high-resolution MRI at 3.0 Tesla provides high spatial resolution that may help to distinguish intramural hematoma from luminal thrombus (16; 51). Patients with dissection may show perivascular contrast enhancement in high-resolution MRI. Generalized vessel wall enhancement has been described in patients with multiple dissections (215).

Multidetector row CT angiography may be even more sensitive than MR angiography in demonstrating the site and extent of dissection, as well as complications such as pseudoaneurysm formation (80). In a study, CT angiography identified more intimal flaps, pseudoaneurysms, and high-grade stenosis as compared to MRA and was the preferred technique, particularly for vertebral artery dissections (294). The classic angiographic findings of carotid artery dissection include the “string” sign, dissection “flaps,” and aneurysmal dilatation of the involved segment of the artery. Multivessel dissections may be seen in up to 28% of cases. Angiography may disclose underlying conditions such as fibromuscular dysplasia. The most frequent stroke topography is acute multiple brain infarcts (territorial infarcts), typically in a borderzone distribution, suggesting a combination of low-flow hemodynamic and thromboembolic mechanisms (23). Carotid duplex ultrasound may show reduced or absent distal carotid artery flow and rarely may show a tapering luminal stenosis, a double lumen, or an intimal flap. Transcranial Doppler studies may be useful in detecting high-intensity transient signals in the middle cerebral artery downstream from the carotid dissection, which are believed to represent microembolic events and correlate with stroke risk (273). Evidence-based guidelines for the management of carotid artery dissection have been published (60).

An international randomized controlled trial compared the efficacy of antiplatelet agents versus anticoagulation in patients with dissection (35; 179). 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. A total of four strokes occurred in the three-month follow-up period: three in the antiplatelet arm and one 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. The results of the CADISS trial are supported by several prior analyses (97; 171). On the basis of these data, most clinicians preferred antiplatelet agents as long-term treatment for spontaneous extracranial cervical artery dissection.

However, a randomized, multicentric study published in May 2021 showed different results (84). The TREAT-CAD trial compared treatment with either aspirin 300 mg daily or vitamin K antagonist started within two 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 (mostly within a day, emphasizing the high-risk early period for stroke) and in no patients from the other group, whereas major hemorrhage only occurred in the vitamin K antagonist group (one patient) (84).

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 has influenced the results. It should be noted that randomization occurred a few days after onset, so anticoagulation (eg, heparin) may still be useful to prevent hyperacute stroke in the first three to four days when stroke risk is highest. Although there are no randomized controlled trials evaluating direct oral anticoagulants in cervical artery dissection, a systematic review and metaanalysis evaluating 11 studies with 699 patients showed comparable efficacy and safety of direct oral anticoagulants and vitamin K antagonists (85). Still, more data are awaited regarding the safety and efficacy of direct oral anticoagulants in cervical artery dissection (198; 258). At this time, it is clinician’s choice to initiate either anticoagulation or antiplatelet therapy in patients with carotid artery dissection.

In the hyperacute setting, intravenous tissue plasminogen activator (iv tPA) therapy appears safe (83; 98; 222). However, thrombolysis was not found to improve outcomes (82). Endovascular thrombectomy has also been performed safely in patients with dissection (287). Neurointerventional procedures such as balloon angioplasty and stenting have been used to treat severe stenotic or symptomatic lesions and lesions complicated by pseudoaneurysm formation; however, the long-term safety and durability remains to be determined (203).

The outcome of carotid and vertebral artery dissection varies according to the location of the dissection, severity of initial ischemia, and extent of collateral flow (260). Recanalization of occluded vessels and improvement of relevant vessel stenosis occurs in more than half the patients in the first year (277). Serial neurovascular ultrasound studies show that complete or hemodynamically significant recanalization occurs in over 70% of patients, typically within the first few months (18). The mortality from intracranial carotid dissection is much higher than that of extracranial dissections. Approximately 5% to 6% of survivors have major residual neurologic deficits and 15% have minor residual deficits, leaving approximately 70% of patients with normal neurologic examinations. However, 50% of survivors are left with an impaired quality of life (87).

The risk of recurrent dissection is about 2% per month during the first month and 1% per year for at least one decade after the initial dissection. A collaborative German study found a recurrent stroke rate of 11% during the first year and 14% over three years (300). Patients with multiple and early recurrent dissections (within six months) are more likely to have recurrent cerebral ischemia within three to six months than patients with single dissections (55). Patients with occlusion of the dissected artery have a higher risk for stroke and unfavorable outcome (286). However, pulsatile tinnitus and Horner syndrome are associated with benign outcome (141).

Recurrence of dissection in a previously affected artery is extremely rare. Younger patients and those with a family history of spontaneous dissections have a greater risk of recurrence (251). Dissecting aneurysms carry a benign prognosis (161).

Inflammatory and infectious vasculitis of the CNS

Giant cell (temporal) or Horton arteritis. Giant cell (temporal) arteritis, or Horton arteritis, is a chronic systemic vasculitis of large- and medium-sized arteries, typically the superficial temporal, posterior ciliary, ophthalmic, internal maxillary, facial, and occipital arteries. It has a complex, overlapping relationship with polymyalgia rheumatica (248). Dendritic cells within the adventitia-media border of medium-sized arteries play a pivotal role in the initiation of giant cell arteritis (GCA).

Gene polymorphisms in the toll-like receptor 4 expressed by these dendritic cells have been associated with the pathogenesis of giant cell arteritis (205). Some studies suggest that varicella zoster infection may play a pathogenic role (100).

The incidence of giant cell arteritis rises sharply above the age of 50 years and peaks between the ages of 70 and 80 years. A Mayo clinic study found the age- and sex-adjusted incidence to be 17 per 100,000 in individuals above 50 years of age (172). Women are affected twice as often as men, and the incidence is higher in Caucasians. The American College of Rheumatology criteria for giant cell arteritis was updated in 2022 and included age of 50 years or older at onset, as an absolute requirement for classification. A weight was attributed to each criteria item and a cumulative score of greater than or equal to six points is diagnostic of giant cell arteritis. The criteria items and corresponding weights are: positive temporal artery biopsy or temporal artery halo sign on ultrasound (+5); erythrocyte sedimentation rate 50 mm/hour or C reactive protein greater than or equal to 10 mg/L (+3); sudden visual loss (+3); morning stiffness in shoulders; a neck, jaw, or tongue claudication; new temporal headache; scalp tenderness; temporal artery abnormality on vascular examination; or bilateral axillary involvement on imaging and fluoro-deoxy-glucose positron emission tomography activity throughout the aorta (+2 each) (44; 217). Sudden visual loss can occur in up to 20% and is a feared complication. Stroke can develop in up to seven percent of cases. In a study of 287 consecutive biopsy-proven giant cell arteritis cases, three percent developed strokes (one in the carotid and seven in the vertebrobasilar territory) between the onset of systemic symptoms and four weeks after the onset of corticosteroid therapy (104). The best predictors of stroke were permanent visual loss and arterial hypertension. Women and anemic patients had a reduced risk for stroke. Low socio-economic status appears to increase the risk for ischemic complications, perhaps due to a delay in seeking medical attention (173).

Although elevated ESR is a useful diagnostic marker, as many as 25% of cases can have a normal ESR; therefore, all suspected cases must be subjected to a temporal artery biopsy. Treatment should not be delayed for purposes of biopsy because pathological abnormalities persist for at least two weeks after initiation of therapy. Because “skip” areas of involvement are common, a long-segment biopsy, directed to sites of visible or palpable abnormalities of the temporal artery, should be obtained. If the clinical suspicion is high, the contralateral artery should be biopsied. Color duplex ultrasonography of the temporal artery can show the “dark halo” sign. This sign has 100% specificity for giant cell arteritis, but only 10% to 17% sensitivity, and it should be used as a substitute for temporal artery biopsy in screening or diagnosing giant cell arteritis (177). MRI of the temporal arteries appears to have high accuracy, especially before therapy is initiated (151).

Treatment generally involves the use of oral high-dose corticosteroids, which can be tapered gradually over one to two years. Initial treatment of pulsed intravenous methylprednisolone (1000 mg daily for 3 days) or 40 to 60 mg/day prednisone equivalent must be given to patients to avoid impending visual loss (123). Tocilizumab, a humanized monoclonal antibody against the interleukin-6 receptor, has been shown effective, especially in refractory cases, and improves the therapeutic efficacy of steroids (295; 276; 40). A trial showed a delayed time to flare and reduced cumulative glucocorticoid dose with weekly tocilizumab in patients with relapsing and new-onset giant cell arteritis, supporting the medication as part of first-line therapy in patients with giant cell arteritis (275). Methotrexate is another useful adjunctive treatment that enables reduction of the oral steroid dose (175). Rituximab, anakinra, and other monoclonal antibodies are being investigated for treatment of giant cell arteritis (194). Although tumor necrosis factor is present in affected arteries, treatment with inhibitors such as infliximab has not proven useful (125). Changes in ESR do not necessarily parallel the clinical course, and the role of C-reactive protein as a more reliable index is being investigated. Relapses can occur in 30% to 50% of patients (180).

Isolated primary or granulomatous angiitis of the CNS (PACNS). Isolated primary or granulomatous angiitis of the CNS is an idiopathic vasculitis restricted to the small and medium arteries and veins of the brain, spinal cord, and leptomeninges (39; 246; 116). It is a rare condition, with an annual incidence rate of 2.4 cases per 1,000,000 person-years (246). It is twice as frequent in males as in females, and the peak incidence is between the ages of 40 and 60 years. The disease has also been described in children (24), although it is not known whether children have different clinical-radiological features as compared with adults (289). Most authors believe that primary angiitis of the CNS results from an immunological nonspecific T-cell mediated inflammatory reaction. Approximately 5% of cases may present as a tumor-like mass lesion (195), and there is an association with beta-4 amyloid deposition (amyloid-beta related angiitis or ABRA) (253).

The 1988 diagnostic criteria by Calabrese and Mallek states patients should have a (1) history of clinical findings of an acquired, otherwise unexplained neurologic deficit, (2) presence of classic angiographic or histopathologic features of angiitis within the CNS, and (3) no evidence of systemic vasculitis or of any other disorder that could cause or mimic the angiographic or pathologic features (39). A revised criteria was suggested in 2009 by Birnbaum and Hellmann, aiming to differentiate PACNS from RCVS. They sub-divide the level of certainty of diagnosis into “definite” and “probable”: a “definite” diagnosis of PACNS requires histopathological confirmation of vasculitis; a “probable” diagnosis requires a high-probability angiogram with abnormal findings on magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) profile consistent with PACNS. The high probability angiographic pattern was defined as: alternating areas of smooth-wall segmental narrowing and dilatation of cerebral arteries; arterial occlusions affecting many cerebral vessels and absence of proximal vessel atherosclerosis or other recognized abnormalities (28). The 2023 European Stroke Organization Guidelines suggest the utilization of the revised criteria (207).

Several studies have provided insights about the clinical and imaging features and treatment of primary angiitis of the central nervous system (63; 269; 247). Typical features include insidious-onset, mild-to-moderate dull aching headaches; encephalopathy; and multifocal neurologic deficits from ischemic stroke (63). Three clinical patterns have been described: (1) acute or subacute encephalopathy, (2) a multiple sclerosis-like picture, and (3) a rapidly progressive space-occupying lesion. Consistent with these clinical presentations, brain MRI can show diffuse bihemispheric grey and white matter hyperintensities, multifocal punctate strokes, as well as mass lesions mimicking tumors (195; 317; 269). Parenchymal and subarachnoid brain hemorrhage is uncommon (and particularly uncommon at the time of presentation) but can occur from necrotizing angiitis (245). CSF examination is abnormal in over 90% of cases and typically shows elevated protein (often over 100mg/dl) with moderate lymphocytic pleocytosis. Primary angiitis of the CNS is frequently diagnosed on the basis of abnormal cerebral angiography results (39). However, the sensitivity of cerebral angiography in the setting of primary angiitis of the CNS may be as low as 10% to 20% (37). This is because primary angiitis of the CNS predominantly affects small caliber arteries that are below the resolution of angiography. Angiographic findings of multiple areas of alternating stenosis and ectasia (eg, beading or sausaging) are frequently attributed to primary angiitis of the CNS (305); however, these findings are more typical of a wide array of nonvasculitic conditions such as the reversible cerebral vasoconstriction syndromes discussed further in this article. In most biopsy-proven cases, cerebral angiography is normal or shows subtle multifocal nonconcentric arterial irregularities in the distal branch arteries. Intracranial vessel wall MRI usually shows concentric wall thickening and contrast enhancement and may help distinguishing PACNS from nonvasculitic conditions (140). A brain biopsy, ideally a 1 cm wedge of cortex including leptomeningeal vessels, is required for definitive diagnosis but has a high false-negative rate because of segmental involvement. A biopsy is recommended in patients with clinical suspicion of PACS, with a normal DSA and leptomeningeal enhancement. In the absence of leptomeningeal enhancement, the suggestion is to perform a targeted biopsy of gadolinium-enhanced lesions (207). Typical findings include lymphocytic and plasma cell infiltration of the arterial wall, usually affecting arteries below 500 µm in diameter, with or without multinucleated giant cells and granuloma formation. Fibrinoid necrosis can be seen in the acute stages. Three pathological subtypes are reported: granulomatous, lymphocytic, and acute necrotizing; however, the response to therapy does not appear to depend on the subtype (186).

The clinical course of primary angiitis of the CNS is typically progressive. Until recently, it was believed that patients not treated aggressively with immunosuppressive agents would have a uniformly fatal outcome; however, studies suggest otherwise (63). The results of a cohort study of 19 children with small vessel childhood primary angiitis of the CNS suggest that it is feasible and possibly effective to treat children with a standardized protocol of induction therapy with steroids and pulse intravenous cyclophosphamide, followed by maintenance with azathioprine or mycophenolate mofetil (130). Maintenance therapy with an immunosuppressant combined with glucocorticoids is associated with the best long-term outcome (61) and may be continued for two years before considering cessation (207). Anecdotal reports suggest that rituximab, methotrexate, and other immunomodulatory treatments may also be effective. Despite the low quality of evidence, expert consensus guidelines suggest adding aspirin to immunosuppressive therapy (207).

Polyarteritis nodosa (PAN). Polyarteritis nodosa is a systemic necrotizing vasculitis affecting small and medium arteries. It can affect almost any organ, including the peripheral nerves, muscles, joints, skin, kidney, intestines, heart, and eyes. Some studies have shown an association between systemic inflammation, polyarteritis, and early-onset stroke with adenosine deaminase-2 (ADA2) deficiency resulting from loss-of-function mutations in CECR1 (201; 315). According to the American College of Rheumatology criteria (168), polyarteritis nodosa can be diagnosed when three or more of the following are present: livedo reticularis, weight loss of more than 4 kg, testicular pain or tenderness, myalgia, muscle weakness, neuropathy, hypertension, abnormal renal function, positive hepatitis B serology, angiographic abnormalities, or biopsy showing polymorphonuclear neutrophils within small or medium sized arteries. Peripheral neurologic system involvement occurs in 50% to 70% of cases, whereas the central nervous system is involved in 20% to 40% of cases. Approximately 3% of patients with polyarteritis nodosa develop stroke after diagnosis (04). Stroke can result from the vasculitis itself or be related to longstanding hypertension or to cardioembolism secondary to cardiac involvement. Intracranial and spinal artery aneurysms can cause thunderclap headaches and myelopathy (117). CNS symptoms typically develop after a latent period of one to two years and include a diffuse encephalopathy, seizures, cognitive impairment, and focal deficits. Treatment consists of immunosuppression with corticosteroids, cyclophosphamide, or azathioprine or methotrexate (230; 282; 283). Tocilizumab may be effective in relapsing and/or refractory cases (114). With the advent of immunosuppressive therapy, survival rates have improved from 10% to over 80% (109). Antiviral therapy with interferon gamma-2b plus ribavirin and plasma exchange should be considered for viral hepatitis-associated polyarteritis nodosa.

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Churg-Strauss syndrome is an allergic granulomatosis and angiitis characterized by severe asthma, fever, hypereosinophilia, and multisystem vascular involvement (166). Approximately 70% of cases have a positive p-ANCA. Males are more frequently affected, and the mean age of onset is 47 years (166). The 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria takes into account the following items and weights: maximum eosinophil count ≥1×109/L (+5), obstructive airway disease (+3), nasal polyps (+3), cytoplasmic antineutrophil cytoplasmic antibody (ANCA) or anti-proteinase 3–ANCA positivity (−3), extravascular eosinophilic predominant inflammation (+2), and mononeuritis multiplex/motor neuropathy not due to radiculopathy (+1) and hematuria (−1). A score of greater than or equal to six points was diagnostic for eosinophilic granulomatosis with polyangiitis in the presence of small- or medium-vessel vasculitis (106).

Neurologic complications occur in over 60% and include mononeuritis multiplex, asymmetric polyneuropathy, demyelinating optic neuritis, and ischemic and hemorrhagic strokes that frequently occur in the cerebellar hemispheres (256; 302). Approximately 5% of patients develop stroke after diagnosis (04). Central retinal artery occlusion, compressive dorsal myelopathy due to extradural granulation tissue, and sensorineural hearing loss have also been described (102). Corticosteroids are the mainstay of treatment (81). In a prospective clinical trial of 72 patients, corticosteroid therapy alone achieved remission in 93%. Approximately one third relapsed, mainly during the first year, and adjuvant treatment with oral azathioprine and intravenous pulse cyclophosphamide was equally efficacious in treating relapses (229). The 2023 guidelines for the diagnosis and management of EGPA recommends corticosteroids as initial therapy and addition of cyclophosphamide or rituximab in severe cases (81). The IL-5 inhibitor mepolizumab is recommended in combination with glucocorticoids to induce remission in patients with relapsing-refractory EGPA without organ- or life-threatening manifestations. Intravenous immunoglobulin (IVIg) and recombinant interferon-alpha are additional treatment options (127; 184).

Wegener granulomatosis (granulomatosis with polyangiitis). Wegener granulomatosis is characterized by the triad of granulomatous vasculitis of the upper and lower respiratory tract, focal and segmental glomerulonephritis, and small vessel vasculitis. The 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria and their weights are as follows: bloody nasal discharge, nasal crusting or sino-nasal congestion (+3); cartilaginous involvement (+2); conductive or sensorineural hearing loss (+1); cytoplasmic antineutrophil cytoplasmic antibody (ANCA) or anti-proteinase 3 ANCA positivity (+5); pulmonary nodules, mass or cavitation on chest imaging (+2); granuloma or giant cells on biopsy (+2); inflammation or consolidation of the nasal/paranasal sinuses on imaging (+1); pauci-immune glomerulonephritis (+1); perinuclear ANCA or antimyeloperoxidase ANCA positivity (-1); and eosinophil count ≥1×109 /L (-4). A cumulative score of greater than or equal to 5 points is diagnostic of GPA in a patient with a diagnosis of small- or medium-vessel vasculitis after excluding mimics of vasculitis (233).

Cerebrovascular disease (including ischemic infarct, subarachnoid and parenchymal hemorrhages, and venous thrombosis) can result from necrotizing vasculitis, hypertensive small vessel disease, or contiguous extension of granulomas. Approximately 5% of patients with Wegener granulomatosis develop stroke after diagnosis (04). C-ANCA has a specificity of 98% and sensitivity of 96% for active disease and sensitivity of 65% for initial or inactive disease. Angiography is usually normal. Tissue diagnosis (lung, renal, sural nerve) is often required. Corticosteroids and cyclophosphamide are the mainstay of treatment. A comparative effectiveness study showed higher rates of remission in induction therapy with rituximab than cyclophosphamide (218). Rituximab, infliximab (an inhibitor of TNF-alpha), azathioprine, leflunomide, trimethoprim-sulfamethoxazole, and methotrexate are efficacious in preventing relapses.

Takayasu arteritis (pulseless disease). Takayasu arteritis affects the aortic arch and its branches and is predominantly seen in Japan, China, India, and other Asian countries (138). The female to male ratio is 11:1, with thoracic aortic involvement more common in women and abdominal aortic involvement more common in men. Most patients present in the third or fourth decade of life. Four types of aortic arch involvement have been described, with type I affecting the ascending aorta; type II, the infra-diaphragmatic aorta; type III, the supra and infra-diaphragmatic aorta; and type IV restricted to the pulmonary trunk. Patients may present with limb claudication, paresthesia, fever, and stroke. Cerebral infarction can be present in up to 34% of patients (154). Hyperlipidemia, a higher number of involved arteries, and MCA involvement have been independently associated with ischemic stroke (154). In a large case series of 60 patients, headache was present in 42%, the erythrocyte sedimentation rate was elevated in 70%, and the subclavian artery was involved in 90% of patients (143). The common carotid artery is affected in over half the cases, nearly always involving the left side. Carotidynia symptoms and prolonged time to diagnosis has been associated with stroke and transient ischemic attack in a large French cohort (188). Up to 20% of patients have intracranial artery involvement, especially those with coronary artery involvement, extracranial segment lesions of internal carotid artery, and higher Vasculitis Damage Index (VDI) score (111). Because stroke and transient ischemic attack frequently occur before the diagnosis of Takayasu arteritis, the importance of palpating arterial pulses, measuring blood pressure in both arms, doing a funduscopic examination, and considering the diagnosis of vasculitis in young individuals with stroke cannot be overstated (236). The pathogenesis is unknown; however, an overlap with giant cell arteritis is speculated based on overlapping clinical features, sites of arterial involvement, and characteristic imaging abnormalities (176). Imaging techniques are the most important diagnostic tools because tissue biopsy is not readily available. Digital subtraction angiography used to be the gold standard but has been replaced by noninvasive exams. Computed tomography angiography and magnetic resonance angiography show vascular stenosis, occlusions, and aneurysms. Vascular ultrasound can show arterial thickening, especially in the carotid, proximal subclavian, and femoral arteries. The 2022 American College of Rheumatology/EULAR classification criteria for Takayasu arteritis included the following: female sex (+1), angina (+2), limb claudication (+2), arterial bruit (+2), reduced upper extremity pulse (+2), reduced pulse or tenderness of a carotid artery (+2), blood pressure difference between arms of greater than or equal to 20 mm Hg (+1), number of affected arterial territories (+1 to +3), paired artery involvement (+1), abdominal aorta plus renal, or mesenteric involvement (+3). A cumulative score of greater than 5 points is diagnostic of Takayasu arteriopathy (107). Cardiovascular disease (heart failure, myocardial infarction, and stroke) is the main cause of mortality in patients with Takayasu arteritis (135). Treatment consists of antiplatelet agents, steroids, and disease modifying agents, as well as surgical revascularization and endovascular interventions (242; 123). Data suggest potential efficacy of infliximab and the interleukin-6 receptor antibody tocilizumab in treating this condition (199; 183).

Susac syndrome (retinocochleocerebral arteriopathy). Susac syndrome consists of the triad of encephalopathy, branch retinal artery occlusions, and hearing loss (280; 150). Encephalopathy features include headache, confusion, dementia, and behavioral changes. Eye and ear symptoms can be bilateral and may be the presenting symptoms. The female to male ratio is 3:1, and the age of presentation ranges from 15 to 60 years. The disease is typically self-limited, with most patients developing one to eight acute exacerbations and then stabilizing over a period of two to four years with varying degrees of residual neurologic dysfunction. The encephalopathy can be exacerbated after pregnancy, and isolated retinal arteriolar involvement may occur as a very late manifestation (14). Pathological studies of the affected tissues reveal microvascular damage with occlusive endothelial cell swelling, capillary destruction, and perivascular infiltrates leading to microinfarcts (226). CSF analysis typically shows pleocytosis and elevated proteins levels (182). Brain MRI is invariably abnormal, with a distinctive pattern of supratentorial ischemic white matter lesions involving the corpus callosum (small to large “snowballs,” linear defects, and “spokes,” eventually progressing to central callosal “holes”) and “studding” of the internal capsules with microinfarcts (162). There is frequent involvement of the grey matter, posterior fossa, and enhancement of the leptomeninges and brain parenchyma (279). High resolution vessel wall MRI may find small vessel/perivascular enhancement, and cochleovestibular enhancement may be seen in patients with hearing loss (306). Anecdotal reports suggest an association with immune responses directed against the endothelium (136). Steroids are the mainstay of therapy, but aggressive treatment with intravenous immunoglobulin, mycophenolate mofetil, cyclophosphamide, and rituximab should be considered to prevent progressive deficits (228; 226). Corticosteroids are most useful for encephalopathy but may not prevent hearing loss or new retinal arteriolar occlusions (14). Cochlear implants may help patients with hearing loss. An international collaborative registry was formed to better characterize this syndrome and understand its natural history (227).

Kohlmeier-Degos disease (malignant atrophic papulosis). Kohlmeier-Degos disease is a rare multisystem vasculopathy of unknown etiology that primarily affects the skin, gastro-intestinal tract and brain. The pathognomonic feature is painless eruption of cutaneous umbilicated papules with atrophic “porcelain white” centers resulting from progressive occlusion of small- and medium-sized arteries and veins. The gastrointestinal system is most commonly involved. In a case series from the Mayo Clinic, the mean age of presentation was 24 years (range 10 to 64 years), and 10 of 16 patients had neurologic symptoms (278). Neurologic complications include multifocal cerebral infarctions, venous thrombosis, subdural hematoma, cortex calcifications, meningitis, and rarely myelopathy and neuropathy. CNS involvement usually portends a poor outcome. Degos disease is often associated with autoimmune diseases such as systemic lupus erythematosus; it is important to exclude antiphospholipid antibody syndrome because papules can also occur in the latter condition. CSF examination frequently shows pleocytosis and elevated protein. Biopsy reveals extensive small vessel occlusions and thrombosis with intimal proliferation. No definitive treatment exists; glucocorticoids and immune modulators are often administered (33). Treatment with treprostinil and eculizumab is the most promising strategy to stop disease progression. Dual antiplatelet therapy with dipyridamole and aspirin may reverse platelet function abnormalities and stop the development of new skin lesions (232).

Behçet disease. Behçet disease is a multisystem vasculitis of unknown etiology occurring most commonly in Turkey and the Mediterranean region (80 to 300 per 100,000 individuals), and in Japan and other Asian countries (10 to 15 per 100,000 individuals). Genome-wide association studies have found a link with HLA-B*51, the MHC class I region, and loci on chromosomes 1p31.3 and 1q32.1 (193; 225). The International Study Group criteria for diagnosis include recurrent oral ulceration at least three times within 12 months, plus any two of the following: recurrent genital ulceration, eye lesions (eg, uveitis, retinal vasculitis), skin lesions (eg, erythema nodosum-like lesions, papulopustular lesions), or a positive pathergy skin test. Neurologic involvement occurs in 10% to 50% of cases, but the disease can affect virtually any organ system. CNS involvement can be either parenchymal (80% of cases) or vascular (20% of cases) (271). Typical neurologic manifestations of parenchymal disease (Neuro-Behçet disease) are subacute meningoencephalitis, headache, and signs of brainstem, pyramidal, and cerebellar dysfunction. CSF examination is invariably abnormal, and brain MRI shows scattered or confluent T2-hyperintense lesions in the white matter (70% of cases), brainstem and cerebellum (60%), and basal ganglia or thalamus (40%), which can progress over time (99). MRI studies may show a lesion extending from the midbrain to thalamus entitled the “cascade sign” (54). The serum myelin basic protein (MBP), an indicator of central nervous system myelin damage, showed a high diagnostic yield for Neuro-Behçet disease with demyelination (313). Management is largely guided by observational data and expert opinion; acute treatment consists of immunosuppression with steroids, azathioprine, and cyclosporine, and TNF-alpha blockade (121; 09). A trial suggested efficacy of oral apremilast (phosphodiesterase-4 inhibitor) in reducing ulcers; however, the trial was not designed to assess effects on other manifestations (120). Colchicine 1mg per day may reduce relapses. Vascular-Behçet disease typically manifests with cerebral venous sinus thrombosis or benign intracranial hypertension (03). Arterial involvement is rare. Treatment with heparin and anticoagulation is indicated for acute venous sinus disease, and aspirin 100 mg daily is often instituted for vascular prophylaxis.

Systemic lupus erythematosus (SLE). In a cohort of 4451 patients with systemic lupus erythematosus, 139 had strokes (3.1%), with an incidence rate of 1.25 per 1000 person-years (112). The most prevalent subtype was ischemic stroke (58.3%), followed by subarachnoid hemorrhage (13.7%), cerebral venous thrombosis (12.2%), and intracerebral hemorrhage (9.4%). In systemic lupus erythematosus patients, the most important cause of stroke is antiphospholipid antibody syndrome. Complement deposition and neuroinflammation involving the blood-brain and traditional cardiovascular risk factors have also been related to stroke in systemic lupus erythematosus. Primary prevention with antiplatelet therapy and control of disease activity is the main management strategy, whereas anticoagulation with warfarin is a tool for secondary prevention and treatment of antiphospholipid antibody syndrome (79).

Antiphospholipid syndrome (APS). Antiphospholipid syndrome (APS) is a well-established cause of acute ischemic stroke in younger patients characterized by a prothrombotic autoimmune state with heterogeneous clinicopathological manifestations. A wider spectrum of antiphospholipid syndrome-associated cerebrovascular lesions has been described, including white matter hyperintensities, cortical atrophy, and infarcts, with clinically important neurocognitive sequela (190). The ACR/EULAR has published a 2023 classification criteria including an entry criterion of at least one positive antiphospholipid antibody (aPL) test within three years of identification of an aPL-associated clinical criterion, followed by additive weighted criteria (score range 1 to 7 points each) clustered into six clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and two laboratory domains (lupus anticoagulant functional coagulation assays, and solid-phase enzyme-linked immunosorbent assays for IgG/IgM anticardiolipin and/or IgG/IgM anti-β2-glycoprotein I antibodies). Patients with at least three points each from the clinical and laboratory domains are classified as having antiphospholipid syndrome (19). Warfarin is the main antithrombotic treatment in antiphospholipid syndrome-associated stroke, although uncertainties remain regarding the optimal INR goal and efficacy of direct oral anticoagulants (190).

Eales retinopathy. Eales retinopathy is characterized by retinal perivascular sheathing with veins being affected more than arteries; neurologic involvement is rare and comprises the only extra-retinal manifestation of this disease. The disease is most common in India, affecting mostly males in the third or fourth decade, and an association with tuberculosis has been noted. The typical neurologic picture consists of an acute or subacute myelopathy occurring predominantly at the dorsal level at an interval of a few weeks to years after the onset of visual symptoms. CSF pleocytosis is relatively common. Pathological studies have shown extensive vasculitis affecting the veins of the spinal cord, brainstem, and cerebellum, associated with demyelination, as well as venous proliferation, dilatation, hemorrhage, and thickening with hyalinization (59; 59). Angiographic arterial occlusion with ischemic stroke is a rare complication.

Infectious arteritis. Infectious arteritis can complicate meningovascular syphilis, tuberculous meningitis, cysticercosis, aspergillosis, mucormycosis, varicella zoster virus infection, pneumococcal meningitis, and a variety of other bacterial, parasitic, and fungal diseases. Small-artery as well as large-artery stroke can result from arterial thrombosis and occlusion. HIV-infected patients can develop an infectious or inflammatory arteritis, aneurysmal dilatation, small-vessel arteriopathy, a moyamoya pattern, as well as premature atherosclerosis from metabolic disorders associated with long-term, highly active antiretroviral therapy (204; 257). The diagnosis of infectious arteritis rests on the results of CSF analysis and cultures. Prognosis is variable and depends on whether the underlying infection can be successfully treated.

Reversible cerebral vasoconstriction syndromes

Reversible cerebral vasoconstriction syndromes comprise a diverse group of conditions associated with reversible segmental vasoconstriction and vasodilatation (“beading”) of the circle of Willis arteries and their branches on cerebral angiography (41; 261; 38; 74; 301; 264).

Postpartum angiopathy is a typical cerebral vasoconstriction syndrome affecting women around the time of pregnancy (265; 301; 268). Other conditions associated with cerebral vasoconstriction include thunderclap headache, migraine, carotid endarterectomy (235), and the use of vasoactive drugs such as cocaine, pseudoephedrine, sumatriptan, selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors, ergot derivatives, and immune-suppressor immunomodulating drugs such as tacrolimus, cyclophosphamide, and fingolimod (266). In the literature, the syndrome has been reported as “Call-Fleming syndrome,” “migraine angiitis,” and “benign angiopathy of the central nervous system” (115). The condition predominantly affects women, usually between 20 and 60 years of age. Children can be affected (170). The estimated incidence of hospitalization for RCVS in the United States is three cases per million adults per year (174). Typical symptoms include severe “thunderclap” headache, focal deficits, cortical blindness, and seizures (262). “Thunderclap” headaches can recur for weeks to months and are often precipitated by Valsalva maneuver. Brain imaging can be normal or show ischemic strokes in arterial watershed or borderzone territories, presumably resulting from hypoperfusion distal to severe large artery vasoconstriction. FLAIR-MRI sequences may reveal linear or dot-shaped hyperintensities in the sulcal spaces due to slow flow within dilated surface arteries (262). The risk for stroke appears highest at the onset or within the first few days of symptom onset; hemorrhages typically occur earlier than infarcts. Worsening arterial “spasm” has resulted in progressive infarction and death in some patients. Parenchymal and minor cortical subarachnoid hemorrhages (75), as well as brain edema (ie, reversible posterior leukoencephalopathy), can result from reperfusion injury and disturbed autoregulation (263). Patients with reversible cerebral vasoconstriction are often misdiagnosed as primary (inflammatory) cerebral vasculitis and treated with long-term immunosuppressive therapy because features like headache, stroke, and angiographic vasoconstriction are common to both conditions. Highly accurate criteria for distinguishing these conditions have been published (269) and externally validated (63; 62). The more recently published RCVS2 diagnostic score and clinical approach is a highly specific and sensitive tool to differentiate reversible cerebral vasoconstriction syndrome from other intracranial arteriopathies (234). The score ranges from -2 to 10 and includes the following variables: recurrent or single thunderclap headaches (5 points); intracranial carotid artery involvement (-2 points); vasoconstrictive trigger (3 points); subarachnoid hemorrhage (1 point); and female sex (1 point). RCVS2 scores of 5 and higher are highly specific (99%) and sensitive (90%) for diagnosing reversible cerebral vasoconstriction syndrome, whereas scores two or lower are highly specific (100%) and sensitive (85%) for excluding reversible cerebral vasoconstriction syndrome. Intermediate RCVS2 scores of 3 or 4 have a lower specificity (86%) and sensitivity (10%) for diagnosing reversible cerebral vasoconstriction syndrome. For patients with intermediate scores, using a clinical approach based on the presence of recurrent thunderclap headaches, vasoactive triggers with normal brain imaging, or the presence of convexity subarachnoid hemorrhage improved diagnostic accuracy. It is important to note that reversible cerebral vasoconstriction syndrome is a noninflammatory and usually self-limited condition and that glucocorticoid therapy has been associated with worse outcome in reversible cerebral vasoconstriction syndrome patients (262; 269; 90). CSF examination is normal or near normal, and extensive histopathological studies have failed to show any arterial abnormality. The diagnosis can be confirmed by excluding mimics such as aneurysmal subarachnoid hemorrhage and primary angiitis of the CNS and documenting spontaneously reversible cerebral vasoconstriction, which typically occurs within six to 12 weeks. Serial transfemoral-, CT-, or MR-angiography, and transcranial Doppler ultrasound have been used for this purpose (47). An increase in certain urine metabolites has been shown in the acute phase of RCVS, mostly associated with endothelial dysfunction and sympathetic overactivity. However, it is not certain if theses metabolites may play a role in the pathogenesis of RCVS or aid in the diagnosis (128). Patients with RCVS also seem to have micro-RNA signatures that were linked to headache blood brain barrier integrity and vasomotor function (46). Oral and intravenous calcium-channel blockers such as nimodipine are often administered, although it should be noted that resolution often occurs spontaneously. Transluminal angioplasty and intra-arterial application of calcium channel blockers has been attempted with variable success in acutely deteriorating patients (91; 86; 169). Recurrence of this syndrome with complications such as stroke after complete symptomatic and angiographic resolution is virtually unknown; although isolated thunderclap headaches with mild vasoconstriction can be seen in up to 5% of patients (48). Therefore, long-term treatment or prophylaxis is not indicated. It may be important to counsel patients regarding use of illicit drugs and to instruct them to avoid further use of vasoconstrictive drugs.

Moyamoya disease

Moyamoya disease is an idiopathic, nonatherosclerotic, noninflammatory condition characterized by chronic progressive stenosis of the terminal internal carotid artery and the proximal portions of the anterior cerebral and middle cerebral arteries with formation of a fine network of collateral blood vessels at the base of the brain that angiographically resembles a puff of smoke – “moyamoya” in Japanese (159; 254). The disease is usually bilateral but can be unilateral; the posterior circulation is rarely involved. The term "moyamoya phenomenon," or “angiographic moyamoya,” is used to describe severe unilateral or bilateral internal carotid artery stenosis associated with conditions such as sickle-cell disease, atherosclerosis, cranial irradiation, Down syndrome, neurofibromatosis type 1, use of vasoactive drugs, neonatal anoxia, meningitis, head tumors, autoimmune disorders, and head trauma (103). Moyamoya disease is the most common vascular etiology of childhood stroke. The annual incidence in Japan is estimated at one patient per 1,000,000. Although most prevalent in Asian countries (73), moyamoya disease has been reported in various races and countries, including the United States (309; 30). A bimodal age of presentation occurs, with the first peak in the first decade of life and the second during the fourth decade. A slight female predominance is seen (female to male ratio of 1.4:1). A family history of moyamoya disease is found in 7% to 12% of cases (131), and the mode of inheritance is autosomal dominant with incomplete penetrance (187) or X-linked recessive (124). A study has suggested modifiable risk factors for moyamoya, such as increased body mass index and homocysteine levels (95). Epidemiological studies have shown that nearly 18% of individuals with moyamoya disease are asymptomatic (15; 157). However, asymptomatic disease is not benign, imparting an annual stroke risk exceeding 3% (158). The disease may begin as an asymptomatic, isolated stenosis of the middle cerebral artery stem and progress to symptomatic moyamoya disease over a few years (52). Pediatric patients may experience signs of orthostatic intolerance, such as headache, vertigo/dizziness on standing, fatigue, and difficulty with getting out of bed (291).

The etiology is unknown; however, genetic factors are being uncovered, and infectious and inflammatory processes and mechanical trauma are believed to play a role (02). Sera from patients with moyamoya disease show a higher incidence of anti-alpha-fodrin autoantibodies, suggesting a role for chronic endothelial cell apoptosis (202). Genome-wide association studies have identified RNF213 as the first susceptibility gene for moyamoya disease (139; 192). The homozygous variant is associated with early onset and more severe phenotype (146; 299). Genetic linkage studies of moyamoya disease have shown that susceptibility loci are located on chromosomes 3p, 6q, 17q, 8q, and 12p (131; 132; 308; 187; 244). A metanalysis evaluating 4711 patients with moyamoya disease found RNF213 rs112735431 and rs148731719 positively associated, and TIMP-2 rs8179090, MMP-2 rs243865, and MMP-3 rs3025058 inversely associated with moyamoya disease (298). An X-linked moyamoya syndrome characterized by moyamoya angiopathy, short stature, facial dysmorphism, hypogonadism, hypertension, and dilated cardiomyopathy has been shown to result from Xq28 deletions (189). Genetic studies have found an association between moyamoya disease and mutations in the NF-1 gene and the smooth muscle alpha-actin gene ACTA-2, which promotes smooth muscle proliferation, suggesting a role for hyperplastic vasculopathy (110; 185). Factors that trigger the opening of arterial collateral pathways or the development of new collateral pathways are not well defined, but may be related to chronic hypoperfusion and the release of growth factors, such as basic fibroblast growth factor, transforming growth factor-beta-1, and hepatocyte growth factor (311; 126; 200). Histologic examination of the distal internal carotid artery reveals intimal thickening from smooth muscle cell proliferation and reduplication of the elastic lamina. Lipid deposition is minimal or absent (181).

As stated, nearly a fifth of individuals are asymptomatic (15; 157). The disease may begin as an asymptomatic isolated stenosis of the middle cerebral artery stem, progressing to symptomatic moyamoya disease over a few years (52). The annual risk for stroke is 3%; however, nearly one-third of children can develop recurrent stroke within one year (92). Symptoms typically result from brain ischemia or hemorrhage, depending on the adequacy or the rupture of the delicate developing collateral vessels. There appears to be a higher susceptibility for transient ischemic attacks and ischemic strokes at younger ages. Ischemic symptoms are usually motor related, affecting one side or alternating sides, and are often precipitated by hyperventilation. Limb-shaking transient ischemic attacks may result from cerebral cortical hypoperfusion. The 5-year risk for stroke is 65% after initial symptom onset and 27% after angiographic diagnosis (118). In a study, 40% of patients with unilateral disease showed progression to bilateral disease over a mean follow-up period of 12.7 months (142). The risk for stroke may exceed 80% for patients who prove to have bilateral disease; however, after surgery the risk drops to 17%, suggesting a potential benefit for prophylactic surgery (118).

Other symptoms include intellectual dysfunction, transient sensory deficits, dysarthria, and headaches (49). Epilepsy is reported in about 25% of pediatric cases and in 5% of adult cases. Some patients may present with movement disorders, including hemichorea, dystonia, and parkinsonism (281). Patients with moyamoya phenomenon might manifest signs and symptoms of the associated condition, for example, neurofibromatosis, sickle cell anemia, and Down syndrome. Ocular abnormalities such as morning glory disc anomaly and choroidal coloboma have been associated with moyamoya disease (155; 32). The risk of hemorrhage increases with age, and older patients may present with altered sensorium from subarachnoid, parenchymal, or intraventricular hemorrhage (309). The risk of recurrent hemorrhage is high (30% to 60% in patients not surgically treated), and rebleeding can occur as late as 20 years after the initial bleed (153).

Conventional angiography remains the gold standard for the diagnosis. MRI and MRA are important for longitudinal follow-up and may be adequate for diagnosis (307). Ongoing research is investigating the utility of 3T MRI in distinguishing the various intracranial arteriopathies, such as moyamoya, atherosclerosis, and vasculitis (241). A study with artificial intelligence has assisted in distinguishing moyamoya from atherosclerotic intracranial disease. A deep learning-based approach evaluating two axial continuous slices of T2-weighted MRI at the level of the basal cistern, basal ganglia, and centrum semiovale has shown high accuracies for distinguishing between patients with moyamoya disease, atherosclerotic disease or controls (92.8, 84.8, and 87.8%, respectively) (05). Imaging may reveal nonspecific abnormalities such as sulcal or ventricular dilatation, anterior borderzone infarctions, or deep infarctions in regions of the penetrating arteries. Abnormal periventricular collaterals have been associated with hemorrhagic presentations (93). In patients with brain hemorrhage, the location of the bleed can be intraparenchymal (typically in the basal ganglia, with or without intraventricular extension) or primarily intraventricular. Subdural hematomas and subarachnoid hemorrhages are not uncommon. Microbleeds on susceptibility-weighted MRI are found in over 40% of patients, and higher numbers appear to predict future symptomatic brain hemorrhage (144; 145; 196). Contrast-enhanced T1-weighted and FLAIR images often reveal diffuse enhancement of the basal ganglia and the "ivy sign" of leptomeningeal contrast enhancement, which represents a fine vascular collateral network over the pial surface (310). Medullary streaks, believed to represent dilated medullary vessels due to chronic hypoperfusion, can be seen on high-resolution T2 images (119). Transcranial Doppler ultrasound imaging may be a useful, noninvasive test to follow the progression of intracranial vascular stenosis over time (212). Assessment of cerebral blood flow and tissue metabolic status with tests such as perfusion-MRI, bold-MRI, arterial spin-labeling MRI, PET, and SPECT are useful in the assessment of collateral circulation and “reserve” capacity and help to guide therapy (316; 163; 312).

Guidelines on the management of moyamoya disease have been published (272; 103). Medical treatment includes the use of antiplatelet agents, such as aspirin and ticlopidine, and calcium channel antagonists, such as nimodipine and nicardipine (254; 103). Warfarin is relatively contraindicated because of the risk for spontaneous bleeding from abnormal moyamoya vessels. Steroids have been successfully used in a few cases of movement disorders (210). A number of surgical interventions have been designed to improve collateral flow to the cortical surface using the external carotid circulation as a donor supply, including extracranial to intracranial anastomoses and superficial temporal artery to middle cerebral artery bypass (255; 206). Guidelines issued by the American Heart Association Stroke Council recommend indirect revascularization techniques for younger children whose small caliber vessels make direct anastomosis difficult (231). The European guideline suggest direct/combined revascularization in adults and combined revascularization whenever technically possible instead of indirect strategies in pediatric patients (25). Indications for surgery include progressive ischemic symptoms or evidence for tissue “at risk” for ischemia, eg, poor cerebrovascular reserve (06; 56). Guidelines suggest that revascularization surgery should be considered in patients with ischemic presentation in case of clinical symptoms or hemodynamic impairment on neuroimaging. In adult asymptomatic patients, the treatment of choice is conservative except in patients with both cerebral hemodynamic impairment and silent ischemic lesions in the same brain region (25). Early surgical intervention (eg, encephalo-duro-arterio-synangiosis) before the establishment of irreversible hemodynamic change has shown benefit in preventing stroke in children and adults, in delaying cognitive decline, and in improving performance in activities of daily living (118; 113; 147) (113; 118; 147; 50; 72; 160; 191; 29; 165; 243; 314). Acute stroke in the preoperative period, and reduced cerebrovascular reserve, are associated with poor surgical outcome (07). Some authors believe that the risk for stroke is higher in pregnancy. Care should be taken to avoid hypocapnia, hypotension, or hypertension during delivery. Whether cesarean section lowers the risk for complications is unknown. A combined spinal and epidural technique has been advocated because it allows better analgesia than epidural anesthesia and more hemodynamic stability than either general or spinal anesthesia (01). High rates of hypertensive disorders of pregnancy (19.2%) have been shown, many of them requiring and emergency cesarean sections (08). Prognosis appears to be related to the age of onset and the type of symptoms. Patients who present at less than five years of age appear to have a worse outcome. Patients who have repetitive transient ischemic attacks, without stroke, have a benign outcome. Patients who present with hemorrhage have a high mortality and high risk of recurrence of the hemorrhage.

Genetic and inherited conditions

Several monogenic disorders have been related to stroke. Although they collectively account for less than 1% of stroke, identification of these monogenic disorders is important for therapeutic decision-making, assessing prognosis and recurrent stroke risk, and genetic counseling. The diagnosis rests on determining the mode of inheritance, clinical and imaging phenotype, and stroke mechanism (17). Table 2 provides a summary of genetic arteriopathies (53; 178). The following characteristics are suggestive of a genetic stroke etiology: recurrent strokes, younger age (less than 50 years), absence of common etiologies, presence of family history, and presence of small vessel disease neuroimaging features (white matter disease, lacunes, small subcortical infarcts, dilated perivascular spaces, microbleeds, brain atrophy) (178).

Table 2. Genetic arteriopathies