Intracranial Aneurysms of Neuro-Ophthalmologic Relevance

Intracranial saccular aneurysms are acquired lesions that often present with neuro-ophthalmologic symptoms and signs. Recent advances in neurosurgical techniques, endovascular treatments, and neurocritical care have improved the optimal management of symptomatic unruptured aneurysms, but whether the chosen treatment has an impact on neuro-ophthalmologic outcomes remains debated. A review of the literature focused on neuro-ophthalmic manifestations and treatment of intracranial aneurysms with specific relevance to neuro-ophthalmologic outcomes was conducted using Ovid MEDLINE and EMBASE databases. Cavernous sinus aneurysms were not included in this review. Surgical clipping vs endovascular coiling for aneurysms causing third nerve palsies was compared in 13 retrospective studies representing 447 patients. Complete recovery was achieved in 78% of surgical patients compared with 44% of patients treated with endovascular coiling. However, the complication rate, hospital costs, and days spent in intensive care were reported as higher in surgically treated patients. Retrospective reviews of surgical clipping and endovascular coiling for all ocular motor nerve palsies (third, fourth, or sixth cranial nerves) revealed similar results of complete resolution in 76% and 49%, respectively. Improvement in visual deficits related to aneurysmal compression of the anterior visual pathways was also better among patients treated with clipping than with coiling. The time to treatment from onset of visual symptoms was a predictive factor of visual recovery in several studies. Few reports have specifically assessed the improvement of visual deficits after treatment with flow diverters. Decisions regarding the choice of therapy for intracranial aneurysms causing neuro-ophthalmologic signs ideally should be made at high-volume centers with access to both surgical and endovascular treatments. The status of the patient, location of the aneurysm, and experience of the treating physicians are important factors to consider. Although a higher rate of visual recovery was reported with neurosurgical clipping, this must be weighed against the potentially longer intensive care stays and increased early morbidity.

State-of-the-Art Review Section Editors: Valérie Biousse, MD Steven Galetta, MD Intracranial Aneurysms of Neuro-Ophthalmologic Relevance Jonathan A. Micieli, MD, Nancy J. Newman, MD, Daniel L. Barrow, MD, Valérie Biousse, MD Background: Intracranial saccular aneurysms are acquired lesions that often present with neuro-ophthalmologic symptoms and signs. Recent advances in neurosurgical techniques, endovascular treatments, and neurocritical care have improved the optimal management of symptomatic unruptured aneurysms, but whether the chosen treatment has an impact on neuro-ophthalmologic outcomes remains debated. Evidence Acquisition: A review of the literature focused on neuro-ophthalmic manifestations and treatment of intracranial aneurysms with specific relevance to neuro-ophthalmologic outcomes was conducted using Ovid MEDLINE and EMBASE databases. Cavernous sinus aneurysms were not included in this review. Results: Surgical clipping vs endovascular coiling for aneurysms causing third nerve palsies was compared in 13 retrospective studies representing 447 patients. Complete recovery was achieved in 78% of surgical patients compared with 44% of patients treated with endovascular coiling. However, the complication rate, hospital costs, and days spent in intensive care were reported as higher in surgically treated patients. Retrospective reviews of surgical clipping and endovascular coiling for all ocular motor nerve palsies (third, fourth, or sixth cranial nerves) revealed similar results of complete resolution in 76% and 49%, respectively. Improvement in visual deficits related to aneurysmal compression of the anterior visual pathways was also better among patients treated with clipping than with coiling. The time to treatment from onset of visual symptoms was a predictive factor of visual recovery in several studies. Few reports have specifically Department of Ophthalmology and Vision Science (JAM), University of Toronto, Toronto, Ontario, Canada; and Departments of Ophthalmology and Neurology (NJN, VB) and Neurological Surgery (DB, NJN), Emory University School of Medicine, Atlanta, Georgia. Supported in part by an unrestricted departmental grant (Department of Ophthalmology) from Research to Prevent Blindness, Inc., New York, and by NIH/NEI core grant P30-EY06360 (Department of Ophthalmology). The authors report no conflicts of interest. Address correspondence to Valérie Biousse, MD, Neuroophthalmology Unit, Emory Eye Center, The Emory Clinic, 1365-B Clifton Road NE, Atlanta, GA 30322; Email: [e-mail] Micieli et al: J Neuro-Ophthalmol 2017; 37: 421-439 assessed the improvement of visual deficits after treatment with flow diverters. Conclusions: Decisions regarding the choice of therapy for intracranial aneurysms causing neuro-ophthalmologic signs ideally should be made at high-volume centers with access to both surgical and endovascular treatments. The status of the patient, location of the aneurysm, and experience of the treating physicians are important factors to consider. Although a higher rate of visual recovery was reported with neurosurgical clipping, this must be weighed against the potentially longer intensive care stays and increased early morbidity. Journal of Neuro-Ophthalmology 2017;37:421-439 doi: 10.1097/WNO.0000000000000515 © 2017 by North American Neuro-Ophthalmology Society I ntracranial saccular aneurysms are acquired vascular lesions that occur in 3% of the adult population worldwide with a mean age of detection of 50 years (1). They are usually isolated, although various pathological entities have been associated with intracranial aneurysms, including arteriovenous malformations (AVMs), polycystic kidney disease, coarctation of the aorta, bicuspid aortic valve, aortic aneurysms, fibromuscular dysplasia, moyamoya disease, Marfan syndrome, Ehlers-Danlos syndrome types II and IV, and neurofibromatosis type I (2-4). The preferred locations of intracranial aneurysms are at the branching points of major arteries coursing through the subarachnoid space at the base of the brain (5). The majority are located in the anterior circulation (80%-85%), most commonly at the junction of the internal carotid artery (ICA) and the posterior communicating (PComm) artery, the anterior communicating (AComm) artery complex, or the bifurcation of the middle cerebral artery (MCA) (5,6). Although most patients with intracranial aneurysms have single lesions, 20%-30% have multiple aneurysms (4). Unruptured aneurysms are more common in women than men (3:1) and in the elderly (7,8). When they occur in children, 421 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 1. In this patient, an unruptured right posterior communicating aneurysm causes an ipsilateral painful third nerve palsy (A). On the catheter angiogram (B), the aneurysm has an irregular shape with protrusion of the wall of the aneurysm (daughter sac) (arrows), suggesting high risk of rupture. The daughter sac would have made endovascular coiling technically difficult and possibly incomplete, and the patient was treated with surgical clipping. Her third nerve palsy completely resolved over 3 months. they are often associated with other conditions (e.g., Marfan syndrome and type IV Ehlers-Danlos syndrome), have a higher occurrence in the posterior circulation (40%-45%), and have a male to female ratio of about 2:1 (9,10). The pathogenesis of intracranial aneurysm formation is thought to begin with hemodynamically induced endothelial dysfunction (11). This explains why aneurysms are found at the arterial junctions, bifurcations, or abrupt vascular angles where excessive hemodynamic stress is exerted on vessel walls (12). Endothelial dysfunction is followed by an inflammatory response in the vessel wall, which leads to disruption of the internal elastic lamina, a hallmark feature (13). A critically important step in aneurysm formation is phenotypic modulation of vascular smooth muscle cells to pro-inflammatory and matrix remodeling cells (14,15). These pathways lead to cell death and vessel wall degeneration and may ultimately result in aneurysmal rupture. Although most intracranial aneurysms are sporadic, approximately 15% of aneurysms are familial. When they run in families, there is likely a genetic predisposition for aneurysmal formation (16). Spontaneous rupture of an intracranial aneurysm causes subarachnoid hemorrhage (SAH), which is a devastating event, with mortality rates approaching 50% and substantial neurologic morbidity in survivors (6,17). This is not the case for aneurysms that are wholly confined to the cavernous segment of the ICA. These aneurysms are extradural and, therefore, do not cause SAH. If they bleed, they cause a carotid cavernous fistula and are usually not life threatening (5). Such intracavernous aneurysms are not covered in this review. 422 While it is estimated that 3% of the general population could develop an intracranial aneurysm, the rupture incidence is only 9 in 100,000 cases per year (1). The discrepancy between intracranial aneurysm prevalence and rupture rate suggests that some aneurysms are more prone to rupture than others. Much controversy exists about the mechanisms involved in the growth and rupture of intracranial aneurysms. Intrinsic factors such as hemodynamic stresses and blood flow turbulence appear to be of critical importance (18,19), as supported by the preferential occurrence of enlarging aneurysms on the feeding arteries of coexisting AVMs, where blood flow rates are higher (20). Extrinsic factors may also play a role, as seen with ophthalmic artery and cavernous segment ICA aneurysms having less risk of rupture (21), likely because of the protection afforded by the anterior clinoid process and dura of the cavernous sinus, respectively (22). Various elements in the subarachnoid space also may influence the growth or rupture of an aneurysm, including bone, brain, and dura (18,23). It is also likely that a genetic profile could contribute to intracranial aneurysm rupture susceptibility. Indeed, studies have suggested that a positive family history of SAH represents a strong risk factor for SAH from ruptured intracranial aneurysm (24). Intracranial aneurysms are often discovered incidentally on brain imaging or may present with neuroophthalmic manifestations (such as cranial neuropathies) allowing for treatment before a devastating SAH. Recent advances in neurosurgical techniques and endovascular treatments have improved the optimal management of symptomatic unruptured aneurysms, but whether the Micieli et al: J Neuro-Ophthalmol 2017; 37: 421-439 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review chosen treatment has an impact on neuroophthalmologic outcomes remains debated. This article provides a short review of asymptomatic and symptomatic unruptured intracranial aneurysms of neuroophthalmologic relevance and discusses in detail the outcomes of cranial neuropathies related to intracranial aneurysms, with the exception of cavernous sinus aneurysms, which are not included. ASYMPTOMATIC INTRACRANIAL ANEURYSMS With the common use of noninvasive vascular imaging such as MRA and CT angiography in clinical practice, intracranial aneurysms are increasingly detected incidentally (1,25,26). A recent study performed in Chinese adults between the age of 35 and 75 years showed that as many as 7% of patients undergoing MRA were found to have an intracranial aneurysm (27). After the discovery of an asymptomatic aneurysm, the clinician must consider the risk of rupture and the risks of treatment in the decision algorithm. There are no randomized clinical trials that define the optimal management of these asymptomatic lesions, but several large prospective and retrospective studies have provided important information in identifying risk factors for rupture (4). One of the largest of these studies was the International Study of Unruptured Intracranial Aneurysms (ISUIA), a prospective study from North America and Europe, which included 1,692 patients with 2,686 unruptured aneurysms over a mean of 4.1 years (8). ISUIA demonstrated larger aneurysm size and location as predictors of rupture (8,21), with the highest risk of rupture for aneurysms located in the posterior circulation or PComm artery. Numerous studies have addressed this issue and suggested an annual rupture risk ranging from 0.9% to 1.1% for aneurysms less than 10 mm in diameter and from 2.8% to 6.7% for those larger than 10 mm in diameter (28). A meta-analysis of 19 studies published between 1966 and 2005 included 4,705 patients with 6,556 unruptured aneurysms and found an overall annual rupture rate of 1.2%, with diameter .5 mm and posterior circulation aneurysm being the highest risk factors for rupture (29). Another large study from Japan (the Unruptured Cerebral Aneurysm Study [UCAS]) included 6,697 patients followed for a mean of 1.7 years (30). UCAS corroborated the finding of increased risk of rupture for larger aneurysms as well as those located on the PComm and AComm arteries. Older age, cigarette smoking (31,32), and characteristics of the aneurysm such as the presence of a daughter sac (an irregular protrusion of the wall of the aneurysm) were identified as risk factors for rupture in some studies (Fig. 1) (8,21,30,32,33). A recent Japanese study prospectively followed 1,960 aneurysms for 10 years Micieli et al: J Neuro-Ophthalmol 2017; 37: 421-439 and confirmed aneurysm size, specific location, history of SAH, and the presence of a daughter sac as independent risk factors for rupture (34). Interestingly, although the average rupture size of the aneurysm was 7.5 ± 5.74 mm, 39 of the 56 ruptures (69.6%) occurred in aneurysms ,7 mm in size, including 4 ,5 mm (34). Growth of a known unruptured untreated intracranial aneurysm on serial imaging also is an important risk factor for aneurysmal rupture, emphasizing the need to repeat noninvasive vascular imaging (35). Estimation of the absolute risk of aneurysm rupture based on a combination of risk factors is complex. A clinical risk score called PHASES was published in 2014 to help estimate the risk of rupture in asymptomatic patients (Table 1) (36). This score was based on data from 8,382 TABLE 1. PHASES risk score for the prediction of intracranial aneurysm rupture (36) Risk Factors Points Population North American, European (other than Finnish) Japanese Finnish Hypertension No Yes Age, yr ,70 $70 Size of aneurysm, mm ,7.0 7.0-9.9 10.0-19.9 $20 Earlier SAH from another aneurysm No Yes Site of aneurysm ICA MCA AComm/PComm/posterior PHASES Risk Score #2 3 4 5 6 7 8 9 10 11 $12 0 3 5 0 1 0 1 0 3 6 10 0 1 0 2 4 5-yr Risk of Aneurysm Rupture, % 0.4 0.7 0.9 1.3 1.7 2.4 3.2 4.3 5.3 7.2 17.8 (0.1-1.5) (0.2-1.5) (0.3-2.0) (0.8-2.4) (1.1-2.7) (1.6-3.3) (2.3-4.4) (2.9-6.1) (3.5-8.0) (5.0-10.2) (15.2-20.7) AComm, anterior communicating; ICA, internal carotid artery; MCA, middle cerebral artery; PComm, posterior communicating; SAH, subarachnoid hemorrhage. 423 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 2. Intraoperative photographs showing surgical clipping of an unruptured, large ophthalmic artery aneurysm causing a progressive ipsilateral optic neuropathy. A and B. A large ophthalmic artery aneurysm originates from the junction of the internal carotid artery and the ophthalmic artery. The aneurysm elevates the ipsilateral optic nerve that appears atrophic. C and D. A clip is placed across the large aneurysmal neck. E. After clipping, the aneurysm is excluded and can be safely perforated to empty it and decrease the mass effect on the adjacent optic nerve. F. The optic nerve appears free without compression by the decompressed aneurysm. Visual function did not improve. participants in 6 prospective cohort studies (21,30,32,37- 39), with SAH as the outcome. The most important prognostic information was based on older age, geographical origin of the patient (with Finland or Japan having the highest risk), the presence of hypertension, larger aneurysm size, and aneurysm location (with AComm, PComm, and posterior circulation having the highest risk). Male or female sex, the presence of multiple aneurysms, and smoking status did not provide additional value for the prediction of aneurysm rupture. However, patients with familial aneurysms, young smokers, and those with life expectancy greater than 5 years were underrepresented in the PHASES score. The more recent unruptured intracranial aneurysm treatment score (UIATS) includes key factors for clinical decision making in the management of unruptured intracranial aneurysms (40). Unlike the PHASES score, the UIATS is not a predictive model of intracranial aneurysm rupture. The UIATS model includes the risk of rupture, the clinical symptoms related to aneurysm, as well as the risk of treatment and the predicted life expectancy of the patient. This score was derived from consensus and from current practice of unruptured intracranial aneurysm management among specialists and not exclusively on data from published studies. It was found to have excellent consensus among experts in the field and may prove useful to clinicians by providing "advice from experts in the field" for a particular patient 424 (40). Applicability and clinical accuracy of the UIATS will need to be prospectively tested before it can be used routinely. NEURO-OPHTHALMOLOGY AND INTRACRANIAL ANEURYSMS It is not unusual for unruptured intracranial aneurysms to be first detected by neuro-ophthalmologists. (41,42) Unruptured aneurysms represent a small proportion of causes of cranial nerve palsies (CNPs), compressive optic neuropathies, or chiasmopathies, but their detection has important implications; a change in morphology of an unruptured aneurysm sufficiently large to cause compressive symptoms signals an increased risk of impending rupture (Figs. 1-4) (26, 42-44). A meta-analysis published in 2007 estimated the risk of rupture of symptomatic aneurysms to be approximately 6% per year, which is 4.4 times higher than that of asymptomatic aneurysms (29). Indeed, symptoms and signs of compression traditionally have been regarded as indications for urgent treatment to prevent SAH and to maximize the potential for recovery of the deficit (45-48). The interval between presenting signs of an aneurysm causing mass effect and rupture varies from 1 day to 4 months (median 14 days) (26, 43). Micieli et al: J Neuro-Ophthalmol 2017; 37: 421-439 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review One of the most recognized neuro-ophthalmic signs caused by an intracranial aneurysm is a third nerve palsy from a lesion located at the junction of the ICA and PComm artery (41,42). Because of the close proximity of the third cranial nerve and the PComm artery, even small aneurysms in this location may cause symptoms and signs. Most reports have suggested that a PComm aneurysm needs to be at least 3-4 mm in size to cause a third nerve palsy (Fig. 1) (41,49,50). A third nerve palsy also may be caused by intracavernous carotid artery, ICA- anterior choroidal artery, basilar artery, superior cerebellar artery, and posterior cerebral artery aneurysms. Patients typically present with ipsilateral frontal headache associated with a complete or partial, often pupil involving, third nerve palsy (42,51,52). The absence of pain is also unusual but does not exclude an aneurysm as the cause of the third nerve palsy (5). The sixth cranial nerve is more often affected by aneurysms of the cavernous sinus than from involvement in the subarachnoid space (42,52). Cavernous sinus aneurysms causing a sixth nerve palsy will often have an associ- ated ipsilateral Horner syndrome due to the proximity of the sympathetic pathways. Vision loss may be the first sign of an aneurysm, typically one arising from the ICA near the junction of the ophthalmic or superior hypophyseal arteries, at its terminal bifurcation or within the cavernous sinus, with resultant compressive optic neuropathy, junctional scotoma, or bitemporal defect (Figs. 2, 4) (52-54). Compression of the intracranial portion of the optic nerve, optic chiasm, or optic tract by an AComm artery aneurysm also may occur. Visual loss is usually slowly progressive, and patients may be unaware of their deficit until the advanced stages. Rarely, aneurysms can cause acute vision loss with pain, occasionally mistaken for optic neuritis, when there is sudden expansion of the aneurysm with anterior visual pathway compression or even bleeding into the optic nerve or chiasm (54,55). Less commonly, distal emboli from the aneurysm sac may cause visual loss from retinal ischemia in cases of ICA/ophthalmic artery aneurysm or cerebral ischemia when the aneurysm involves the posterior circulation FIG. 3. Ruptured left posterior communicating (PComm) aneurysm presenting with sudden headache and complete left third nerve palsy. The subarachnoid hemorrhage and aneurysms were diagnosed on brain CT without contrast and CT angiography with contrast, respectively. The catheter angiogram (A and B) shows an irregular aneurysm originating from the left PComm artery (arrow). The aneurysm has 3 lobes (arrows) and a wide neck making endovascular coiling difficult. The aneurysm was treated with surgical clipping. C. Intraoperative angiogram showing the lack of filling of the clipped aneurysm. D. A postoperative CT shows the clip (arrow). The third nerve palsy resolved within 6 months. Micieli et al: J Neuro-Ophthalmol 2017; 37: 421-439 425 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review (42). This is a very rare event and occurs almost exclusively with large thrombotic aneurysms. The rupture of an intracranial aneurysm leads to SAH, which produces an acute increase in intracranial pressure. SAH associated with any intraocular hemorrhage is called Terson syndrome and is thought to result from orbital venous hypertension leading to distention and rupture of papillary, peripapillary, and retinal capillaries (56). Terson FIG. 4. Giant unruptured suprasellar aneurysm with subacute visual loss from chiasmal compression. A. Automated visual field test (Humphrey 24-2 SITA fast program) shows a bitemporal hemianopia. Sagittal T1 MRI with contrast (B) demonstrates an enhancing homogeneous round suprasellar mass suggesting a large aneurysm. The catheter angiogram (C) confirms the diagnosis and shows the origin of the aneurysm at the junction of the right internal carotid artery (ICA) and ophthalmic artery. The patient tolerated a balloon test occlusion of the right ICA (D and E), and the right ICA was sacrificed after attempted surgical clipping was unsuccessful. D. Endovascular placement of a balloon occluding the right ICA. E. Brain single photon emission CT performed after placement of the balloon in the right ICA and showing a slight relative decrease in radiotracer uptake within the right parietal lobe (arrows) as compared with the contralateral side. ICA, internal carotid artery. 426 Micieli et al: J Neuro-Ophthalmol 2017; 37: 421-439 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 5. Endovascular coiling of an intracranial aneurysm with a small neck. A. The aneurysm is accessed with a catheter introduced via the femoral artery. B. The aneurysm is filled with coils under x-ray guidance. The coils cause a clot to form and occlude the aneurysm. C. Catheter angiogram reveals a large unruptured posterior communicating aneurysm (arrow) diagnosed after the patient developed an isolated third nerve palsy. D and E. The arrows show the coiled aneurysm, which is now excluded from the circulation. Over time, the coiled aneurysm tends to shrink, resulting in decreased mass effect of the coiled aneurysm on adjacent structures. Coiling also eliminates vascular pulsations compressing adjacent structures. syndrome has been reported in 20%-40% of patients with SAH and may be associated with a poorer prognosis for the patient (42,57). Papilledema from raised intracranial pressure occurs in 10%-24% of patients with SAH and can lead to secondary optic atrophy with irreversible vision loss if the raised intracranial pressure is not treated in a timely fashion (42). TREATMENT OF INTRACRANIAL ANEURYSMS The main goal of the treatment of an unruptured intracranial aneurysm is to exclude the aneurysm from the circulation in order to prevent aneurysmal rupture and SAH and restore neurologic and visual function. The excluded aneurysm eventually thromboses and shrinks, thereby reducing the mass effect on adjacent structures such as cranial nerves. The decreased pulsatility of the sac that occurs once the aneurysm is excluded from the circulation plays a major role in recovery of cranial neuropathies (58,59). This likely explains why endovascular coiling procedures often result in improvement of the cranial neuropathy despite not always decreasing the size of the coiled aneurysm. Aneurysm clipping was first described by Dandy in 1937 (60). The procedure has evolved over the years to include refinements in microsurgical and bypass techniMicieli et al: J Neuro-Ophthalmol 2017; 37: 421-439 ques, micro-instruments, operating microscopes, the application of intraoperative imaging, and adjunct anesthesia (61). Microsurgical clipping is the application of a small spring clip across the neck of an intracranial aneurysm during an open craniotomy. The clip, once placed, excludes the aneurysm from the parent blood vessel. It is then possible to puncture large aneurysms to immediately reduce the mass effect (Figs. 2, 3). Since Guglielmi detachable coils were introduced in the 1990s, endovascular treatments have become very popular and have progressively replaced neurosurgical clipping (63). Endovascular intervention has the advantage of reducing the surgical risks of craniotomy while still treating the intracranial aneurysm (62). Endovascular coiling is a minimally invasive procedure in which the aneurysm is accessed with a catheter via the femoral artery. The aneurysmal sac is then packed with thrombogenic embolic coils to prevent blood from entering the aneurysm. Successful coiling leads to thrombosis within the aneurysm (Fig. 5). The decrease in pulsatility and gradual shrinkage of the aneurysm after treatment are thought to be responsible for reduced risk of rupture and the clinical improvements from mass effect (63). Various coil embolization techniques have been developed since the 1990s, including balloon-assisted and stentassisted coiling (Fig. 6). 427 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 6. Stent-assisted endovascular coiling of an intracranial aneurysm with a large neck. A. The aneurysm is accessed with a catheter introduced via the femoral artery, and a stent is placed at the level of the aneurysmal neck. B. Once the stent is in place, the aneurysm is filled with coils to occlude the aneurysm. Another option in the treatment of intracranial aneurysms is the use of flow-diverting devices. These endovascular devices are endoluminal implants placed in the parent artery rather than in the aneurysmal sac. They redirect the flow past the aneurysm and into the normal distal artery, resulting in gradual thrombosis and involution of the aneurysm. Subsequent inflammation and endothelialization occur, with the vessel intima overgrowing the device while preserving the perforators and side branches in most cases (Fig. 7) (64-66). Flow diverters frequently allow treatment of previously deemed untreatable wide neck and giant aneurysms. One of the drawbacks of stent-assisted coiling and flow diversion is the need for dual antiplatelet therapy, which complicates the management of patients with SAH. Decisions regarding the choice of aneurysm therapy are ideally made by a team of experienced clinicians who consider the clinical status of the patient, the availability of surgical and endovascular expertise, and the anatomic characteristics of the aneurysm. Aneurysms in the distal arterial segments are typically not amenable to endovascular therapy, and surgical therapy is usually preferred in these cases (67). Surgical therapy may also be preferred for aneurysms at the bifurcation of the MCA, which are difficult to coil without complication (68). In contrast, some intracranial aneurysm locations in the posterior circulation are typically less amenable to surgical treatment, and endovascular treatment is generally preferred (69). Risks associated with surgical treatment include new or worsened neurologic deficits related to brain manipulation or retraction, temporary arterial occlusion, and intraoperative hemorrhage (70). The most devastating technical complication during surgery is intraprocedural aneurysm rupture, which is associated with periprocedural disability and, at times, death (71). Intraoperative hemorrhage during surgery can usually be handled without sequelae, particularly if the aneurysm ruptures after it has been exposed, which is most common. Intraprocedural hemorrhage during endovascular therapy can be more difficult but is often managed by rapidly coiling the remaining sac. In a prospective study comparing surgical clipping and coiling in patients with similar baseline characteristics and aneurysms judged to be treatable by either clipping or coiling, surgical treatment was associated with a higher postprocedural disability score, longer length of stay and number of days in intensive care, and higher hospital costs (72). In a large, national, multihospital database study in the United States, there was no difference in in-hospital mortality rates between patients with aneurysms treated with clipping or coiling but surgical clipping patients had a significantly higher likelihood of unfavorable outcomes, including discharge to long-term care, ischemic complications, postoperative neurologic complications, and ventriculostomy (73). The major risks associated with endovascular therapy FIG. 7. Treatment of an intracranial aneurysm with a large neck with a flow diverter device. A. Before treatment, blood flow continuously fills the aneurysm, which is pulsating, resulting in mass effect on adjacent structures. B. After endovascular placement of a flow diverter device across the large neck of the aneurysm, the aneurysm is excluded from the circulation and progressively thromboses and shrinks. 428 Micieli et al: J Neuro-Ophthalmol 2017; 37: 421-439 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review TABLE 2. Summary of studies comparing surgical clipping and endovascular coiling for aneurysms causing a third nerve palsy Authors, Year No. of Patients Full Recovery Partial Recovery Overall Outcome Tan et al, 2015 (84) 176 patients with 3NP Clip: 123/132 (93%) Clip: 7/132 (5%) Clipping: 132 Coil: 14/44 (32%) Coil: 16/44 (36%) Coiling: 44 Surgical clipping superior McCraken et al, 2015 (85) 93 patients with 3NP Clip: 41/70 (59%) Clipping: 70 Coil: 10/22 (45%) Not stated Surgical clipping superior Assessed in conjunction with literature review Coiling: 23 Mino et al, 2015 (86) 17 patients with 3NP Clip: 7/9 (78%) Clipping: 9 Coil: 5/8 (62%) Coiling: 8 Clip: 2/9 (22%) Coil: 3/8 (38%) No difference in treatments Engelhardt et al, 2015 (87) 23 patients with 3NP Clip: 7/9 (78%) Clipping: 9 Coil: 4/14 (28%) Clip: 2/9 (22%) Coil: 7/14 (50%) Surgical clipping superior Coiling: 14 Patel et al, 2014 (88) 18 patients with 3NP Clip: 6/9 (67%) Clipping: 9 Coil: 5/9 (55%) Coiling: 9 Clip: 3/9 (33%) Coil: 4/9 (44%) No difference in treatments Brigui et al, 2014 (89) 21 patients with 3NP Clip: 6/7 (86%) Clipping: 7 Coil: 8/13 (62%) Clip: 1/7 (86%) Coil: 2/13 (15%) No difference in treatments Delayed recurrence with coiling Coiling: 14 Khan et al, 2013 (90) 17 patients with 3NP Clip: 7/8 (88%) Clipping: 8 Coil: 4/9 (44%) Coiling: 9 Not stated Surgical clipping superior Guresir et al, 2011 (91) 11 patients with 3NP Clip: 4/4 (100%) Clipping: 4 Coil: 3/7 (43%) Clip: NA Coil: 4/7 (57%) Surgical clipping superior Coiling: 7 Nam et al, 2010 (92) 19 patients with 3NP Clip: 6/9 (67%) Clipping: 9 Coil: 6/10 (60%) Coiling: 10 Clip: 2/9 (22%) Coil: 1/10 (10%) No difference in treatments Tsang et al, 2017 (93) 7 patients with 3NP Clipping: 4 Clip: NA Coil: 2/4 (50%) Not stated, small sample Clip: 4/4 (100%) Coil: 2/4 (50%) Coiling: 3 Chen et al, 2006 (94) 13 patients with 3NP Clip: 6/7 (85%) Clipping: 7 Coil: 2/6 (33%) Coiling: 6 Clip: 1/7 (86%) Coil: 4/6 (67%) Surgical clipping superior Ahn et al, 2006 (95) 17 patients with 3NP Clip: 3/7 (43%) Clipping: 7 Coil: 6/10 (60%) Clip: 4/7 (57%) Coil: 3/10 (30%) No difference in treatments Clip: 6/14 (43%) Coil: 0/1 (0%) Not stated, small sample Coiling: 10 Yanaka et al, 2003 (50) 15 patients with 3NP Clip: 7/14 (50%) Clipping: 14 Coil: 0/1 (0%) Coiling: 1 Total 447 patients with 3NP Clip: 227/289 (78%) Clip: 28/289 (10%) Clipping: 289 Coil: 69/158 (44%) Coil: 46/158 (29%) Coiling: 158 3NP, third nerve palsy; NA, not assessed. Micieli et al: J Neuro-Ophthalmol 2017; 37: 421-439 429 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review are thromboembolism and intraprocedural aneurysm rupture, with the greatest risk of rupture occurring with aneurysms greater than 10 mm and with a neck size of greater than 4 mm (72-74). Both risks are greater in those patients with SAH compared with those with unruptured aneurysms. Coiled aneurysms also appear to be more likely than surgically clipped aneurysms to recur and require additional intervention (75,76). In a systematic review that assessed aneurysm reopening after coiling in 8,161 aneurysms, reopening occurred in 21% and retreatment was performed in 10% (77). Although generally safe, risks of flow diverters include perforator occlusion, device migration, wire perforation, in-stent thrombosis, distal emboli, and perianeurysmal edema with local compression (78). A rare complication of flow diversion for ophthalmic artery aneurysms is permanent occlusion of the ophthalmic artery (79). Dual antiplatelet therapy is mandatory with flow diverters, and delayed fatal hemorrhages have been reported with their use. All treatments for intracranial aneurysms carry a risk of neuro-ophthalmologic complications, such as new-onset or worsening CNPs and retinal or cerebral ischemia. TREATMENT OF ANEURYSMS CAUSING NEURO-OPHTHALMOLOGIC SIGNS When specifically considering the treatment of aneurysms causing neuro-ophthalmologic signs, the goal is not only to treat the aneurysm to prevent SAH but also to maximize the chances of functional neuro-ophthalmic recovery. All reports in the literature comparing surgical clipping vs endovascular coiling for the treatment of aneurysms causing neuro-ophthalmologic conditions are retrospective studies. Because of an increased interest in this topic, a few comprehensive reviews and meta- analyses have been published over the past few years (80-83). Surgical Clipping vs Endovascular Coiling of Aneurysms Causing Ocular Motor Cranial Nerve Palsies The results of 13 studies (50,84-95) that compared surgical clipping and endovascular coiling for the treatment of aneurysms causing a third nerve palsy are shown in Table 2. Among a total of 447 patients, complete recovery was achieved in 227/289 (78%) patients with surgical clipping compared with 69/158 (44%) with endovascular coiling (50,84-95). In a study from our institution, among patients with a complete third nerve palsy, the recovery rate was much higher in patients treated with surgical clipping compared with those treated with endovascular coiling (47% vs 20%), but there was no difference in the recovery rate when analyzing patients with partial third nerve palsies (85). Another finding from this study was that patients who sought treatment earlier in the course of their third nerve palsy tended to have a more significant recovery regardless of treatment modality. The time to recovery was assessed in 3 other studies and was significantly shorter in the surgically treated group in only one report (84 vs 137 days) (84), whereas no statistically significant difference was detected between the treatment groups in the 2 other studies (57 days for clipping vs 88 days in the coiling group [86] and 66 days for clipping vs 50 days for coiling, [92]). Complications were reported in detail in only one other study (84), with higher rate in the surgical clipping group of 132 patients (vasospasm in 6 patients, hemiparesis in 2 patients, hydrocephalus in 16 patients requiring a ventriculoperitoneal [VP] shunt in 2 patients) compared with the coiling group of 44 patients (vasospasm in 2 patients, aphasia in TABLE 3. Summary of studies evaluating surgical clipping for aneurysms causing a third nerve palsy Author, Year No. of Patients Full Recovery Partial Recovery Predictors of Recovery Early intervention NA NA Partial 3NP Degree of deficit Timing to surgery and severity of 3NP NA NA NA NA NA NA Timing to surgery Chang et al, 2014 (96) Guresir et al, 2012 (97) Park et al, 2011 (98) Javalkar et al, 2010 (99) Yerramneni et al, 2010 (100) Yang et al, 2008 (101) 10 6 13 26 13 74 7/10 (70%) 5/6 (83%) 12/13 (92%) 15/26 (58%) 10/13 (77%) 67/74 (90%) 1/10 (10%) 1/6 (17%) 1/12 (8%) 5/26 (19%) 3/13 (23%) Not stated Grunwald et al, 2008 (102) Bhatti et al, 2006 (103) Dimopoulos et al, 2005 (104) Kraus et al, 2004 (105) Arle et al, 2002 (107) Friedman et al, 2001 (106) Leivo et al, 1996 (45) Total 1 1 5 1 1 7 28 186 1 of 1 0 of 1 4/5 (80%) 1/1 (100%) 1/1 (100%) 3/7 (43%) 16/28 (57%) 142/186 (76%) NA 1/1 (100%) 1/5 (20%) NA NA 4/7 (57%) Not stated 17/186 (9%) 3NP, third nerve palsy; NA, not assessed. 430 Micieli et al: J Neuro-Ophthalmol 2017; 37: 421-439 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Micieli et al: J Neuro-Ophthalmol 2017; 37: 421-439 Author, Year No. of Patients Full Recovery Partial Recovery Predictors of Recovery Wang et al, 2015 (108) Hassan et al, 2013 (109) Chalouhi et al, 2013 (110) 27 - 3NP 11/27 (41%) 39 - ophthalmoplegia 29/39 (74%) 37 - 3NP 14/37 (38%) Not stated 6/39 (15%) 19/37 (51%) Gu et al, 2013 (111) Panagiotopoulos et al, 2011 (112) 17/36 (47%) 15/30 (50%) 15/36 (42%) 12/30 (40%) Ko et al, 2011 (113) Santillan et al, 2010 (114) Zhang et al, 2010 (115) Kassis et al, 2010 (116) Kang et al, 2009 (117) 36 - 3NP 30 - 3NP ± other cranial neuropathy 10 - 3NP 11 - 3NP 13 - 3NP 20 - 3NP 8 - 3NP NA NA Complete aneurysm occlusion, partial 3NP, increasing follow-up time Length and degree of preoperative 3NP Partial 3NP 1/10 (10%) 2/11 (18%) 6/13 (46%) 12/20 (60%) NA Time to treatment and partial 3NP Partial 3NP or cardiovascular risk factors not predictive Initial severity, time to treatment, SAH SAH and early management NA Hanse et al, 2009 (118) van Rooij et al, 2008 (119) Mansour et al, 2007 (120) 21 - 3NP 8 - 3/4/6NP 11 - 3/4/6NP 7/10 (70%) 7/11 (64%) 7/13 (54%) 7/20 (35%) 7/8 full recovery 1 lost to follow-up 8/21 (38%) 3/8 (38%) 7/11 (64%) 11/21 (52%) 5/8 (62%) Not stated Suzuki et al, 2007 (121) Bhatti et al, 2004 (122) Kim et al, 2003 (123) Stiebel-Kalish et al, 2003 (124) 15 - 3/4/6NP 1 - 3NP 7 - 3/6NP 11 - 3NP 6/15 (40%) 0/1 2/7 (28%) 0/11 7/15 (47%) 1 of 1 3/7 (43%) 10/11 (91%) Inamasu et al, 2002 (125) Uda et al, 2001 (126) Mavillio et al, 2001 (127) Total 1 - 3NP 2 - 3NP 6 - 3NP 314 - 3NP 1 of 1 2/2 (100%) 5/6 (83%) 155/314 (49%) NA NA 1/6 (17%) 111/265 (42%) NA NA Duration of cranial neuropathy, SAH, complete cranial nerve palsy, intracavernous aneurysm worse outcome NA NA NA Worse outcome with older patients and microvascular risk factors NA NA NA 3NP, third nerve palsy; 4NP, fourth nerve palsy; 6NP, sixth nerve palsy; NA, not assessed; SAH, subarachnoid hemorrhage. State-of-the-Art Review 431 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 4. Summary of studies evaluating endovascular coiling for aneurysms causing a third, fourth, and sixth cranial nerve palsy State-of-the-Art Review TABLE 5. Summary of studies evaluating endovascular flow diverters for the treatment of aneurysms causing third, fourth, and sixth cranial nerve palsies Author, Year Binyamin et al, 2016 (129) Moon et al, 2014 (128) Szikora et al, 2013 (130) Total No. of Patients Full Recovery Partial Recovery 2 with 3NP 16 with 3/4/6NP 10 with 3/6NP 28 2/2 (100%) 3/16 (19%) 7/10 (70%) 12/28 (43%) 10/16 (62%) 3/10 (30%) 13/28 (46%) Predictors of Recovery NA NA NA 3NP, third nerve palsy; 4NP, fourth nerve palsy; 6NP, sixth nerve palsy; NA, not assessed. 1 patient, hydrocephalus in 9 patients requiring a VP shunt in 2 patients). Surgical Clipping of Aneurysms Causing Ocular Motor Cranial Nerve Palsies Surgical clipping for the treatment of aneurysms causing third nerve palsies evaluated in several retrospective studies has been summarized in Table 3 (45,96-107). Among a total of 186 patients, complete recovery of the third nerve palsy was achieved in 142 (76%). Predictors of recovery were partial third nerve palsy and a shorter interval to surgery (96,99,100). No difference was found in cases in which the aneurysm was simply clipped at the neck vs those in which the sac was punctured and decompressed after surgical clipping (101). Endovascular Coiling of Aneurysms Causing Ocular Motor Cranial Nerve Palsies Endovascular coiling evaluated for the treatment of aneurysms causing third, fourth, or sixth nerve palsies in 20 retrospective studies is summarized in Table 4 (108-127). Among 314 patients (most had a third nerve palsy), 155 (49%) had a complete recovery and 111 (42%) had a partial recovery. In 2 publications, the mean time to resolution of symptoms was reported to be 69 days and 3.8 months (112,115). Ptosis was the first symptom to resolve in 2 of the case series (118,123), whereas pupillary function recovered first in another (125). Five studies found that the most consistent predictor of recovery was partial third nerve palsy at onset (110-113,115). Flow-Diverting Devices of Aneurysms Causing Ocular Motor Cranial Nerve Palsies Flow-diverting devices have been evaluated in a large number of patients (64), but few publications have specifically addressed their effect in patients with isolated cranial neuropathies (Table 5) (128-131). In a retrospective study of 20 patients with cranial neuropathies, 16 had involvement of third, fourth, or sixth cranial nerves (128). Three patients experienced resolution of their deficits, 10 had improvement, and 3 remained stable at a mean follow-up time of 9.55 months. In an additional 432 case series (130), 7 of 10 patients with third or sixth nerve palsies had resolution of their symptoms. A recent publication addressed the neuro-ophthalmologic outcomes of patients treated with a flow diverter in the PUFS (the Pipeline for Uncoilable or Failed Aneurysms) trial (131), but the presentation of the results does not allow detailed analysis of each specific neuro-ophthalmologic sign. In the PUFS trial, most patients with neuroophthalmologic deficits improved after the procedure (131). Complications reported in the flow diverter studies include in-stent thrombosis and subacute occlusion of the parent artery. Treatment of Aneurysms Causing Optic Neuropathies Anterior visual pathway compression by intracranial aneurysms is also amenable to treatment with either surgical or endovascular techniques (Table 6). In 5 studies directly comparing surgical clipping with endovascular treatment for patients with visual symptoms due to aneurysm compression of the optic pathways, resolution or improvement in symptoms was achieved in 36 of 49 (73%) patients by surgical clipping alone and in 10 of 22 (50%) patients by endovascular coiling (132-136). Studies that reviewed the outcomes of surgical clipping found resolution or improvement of symptoms in 64 of 99 (65%) patients (106,137- 146). Slightly lower results of resolution or improvement of visual symptoms in 28 of 54 (52%) patients were found in studies assessing outcomes of endovascular coiling (109,119,121,147-151). Very few studies specifically reported the visual outcome of patients treated with a flowdiverting device, and 3 of 9 patients (33%) with compressive optic neuropathies had resolution of their symptoms (128,130). Previous reports and systematic reviews have found no significant relationship between aneurysm location, aneurysm size, or the presence of SAH on visual outcome (133). A shorter time to treatment after onset of symptoms has been reported to be a positive predictive factor for visual outcome in several studies (14,141,149), but this was not confirmed in a multivariate analysis combining many studies (133), probably because of the difficulty in precisely identifying the timing of onset of symptoms. Micieli et al: J Neuro-Ophthalmol 2017; 37: 421-439 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Micieli et al: J Neuro-Ophthalmol 2017; 37: 421-439 Author, Year No. of Patients Intervention Full Recovery Improvement No Change Worsened Park et al, 2015 (135) 33 Clipping: 23 Coiling: 10 Clip: 17/23 (74%) Coil: 2/10 (20%) Clip: 4/23 (17%) Coil: 4/10 (40%) Clip: 2/23 (9%) Coil: 4/10 (40%) Schuss et al, 2011 (133) 20 Clipping: 12 Coiling: 8 Clip: 4/12 (33%) Coil: 3/8 (38%) Clip: 1/12 (8%) Clip: 2/12 (17%) Coil: 2/8 (38%) 9 Clipping: 1 Coiling: 8 Clip: 1/1 (100%) Coil: 4/8 (50%) Coil: 4/8 (50%) Clip: 3/12 (33%) Coil: 1/4 (25%) Clipping vs coiling Yadla et al, 2011 (136) Clip: 5/12 (42%) Coil: 3/8 (38%) Hoh et al, 2001 (132) 16 Clipping: 12 Coiling: 4 Clip: 8/12 (67%) Coil: 3/4 (75%) Chan et al, 1997 (134) 3 Clipping: 1 Coiling: 2 Clip: 1/1 (100%) Coil: 1/2 (50%) Coil: 1/2 (50%) 81 Clipping: 49 Coiling: 32 Clip: 31/49 (63%) Coil: 13/32 (41%) Clip: 8/49 (16%) Coil: 10/32 (31%) 1/5 (20%) 11/14 (79%) 12/23 (52%) 8/10 (80%) 7/15 (47%) 8/10 (80%) 3/7 (43%) 4/5 (80%) Total 5 14 23 10 15 10 7 3 3 3 6 99 10 9 3 3 16 2 3 8 54 Clip: 5/49 (10%) Coil: 3/32 (9%) 7/15 (47%) 1/3 (33%) 8/99 (8%) 1/3 (33%) 2/2 (100%) 3/6 (50%) 56/99 (57%) 10/10 (100%) 5/9 (56%) 8/23 (35%) 1/10 (10%) 1/15 (7%) 2/10 (20%) 1/7 (14%) 2/3 (67%) 2/3 (67%) 2/6 (33%) 23/99 (23%) Clip: 1/12 (8%) Clip: 7/49 (10%) Coil: 6/32 (19%) 3/14 (21%) 3/23 (13%) 1/10 (10%) 3/7 (43%) 1/6 (17%) 11/99 (11%) 4/9 (44%) 3/3 (100%) 2/3 (66%) 6/16 (38%) 1/2 (50%) 8/54 (15%) 4/8 (50%) 20/54 (37%) 1/3 (33%) 4/16 (25%) 1/2 (50%) 3/3 (100%) 3/8 (38%) 16/54 (30%) 6/16 (38%) 1/8 (12%) 10/54 (18%) State-of-the-Art Review Clipping Aboukais et al, 2014 (137) Mattingly et al, 2013 (138) Lai et al, 2013 (139) Dehdashti et al, 2012 (140) de Oliviera et al, 2009 (141) Park et al, 2009 (142) Nonaka et al, 2007 (143) Friedman et al, 2001 (106) Lownie et al, 2000 (144) Bakker et al, 1999 (145) Date et al, 1998 (146) Total Coiling Hassan et al, 2013 (109) van Rooij et al, 2008 (119) Turner et al, 2008 (147) Suzuki et al, 2007 (121) Heran et al, 2007 (148) Kazekawa et al, 2003 (149) Gruber et al, 1999 (150) Malisch et al, 1998 (151) Total 433 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 6. Summary of studies evaluating the visual outcome after surgical clipping or endovascular coiling for aneurysms causing compression of the optic nerves, chiasm, or tracts State-of-the-Art Review 434 1/3 (33%) 1/6 (17%) 2/9 (22%) 2/3 (67%) 2/6 (33%) 4/9 (44%) 3/6 (50%) 3/9 (33%) 3 6 9 Flow-diverting device Moon et al, 2014 (128) Szikora et al, 1993 (130) Total Author, Year (Continued ) No. of Patients Intervention Full Recovery Improvement No Change Worsened CONCLUSIONS Intracranial aneurysms are frequently discovered because of neuro-ophthalmologic symptoms and signs. A higher rate of complete recovery has been reported with surgical clipping of aneurysms causing ocular motor CNPs and those causing compressive optic neuropathies, but most studies are retrospective. Although numerous studies provided information on the visual outcomes of patients with unruptured aneurysms, the lack of detail regarding the type of visual deficit in many studies limits the number of studies analyzed in this review. Decisions regarding the choice of therapy should be made at high-volume centers that have access to both neurosurgical and endovascular treatments. Neuro-ophthalmologists, neurologists, interventional radiologists, and neurosurgeons should work collaboratively to best treat patients with ruptured and unruptured intracranial aneurysms (59). Clinicians must consider the condition of the patient and the location, size, and configuration of the aneurysm when deciding on the preferred treatment to optimize the neurologic and visual outcome of the patient. Clinical tools such as the PHASES (36) and the UIATS (40) scores can help factor in these variables. Certainly, if an aneurysm is amenable to either treatment option, the higher risk of serious complications and the longer hospital stay and costs associated with neurosurgical treatment should be considered in the decision-making process. SEARCH STRATEGY AND SELECTION CRITERIA References for this review were identified by searches of Ovid MEDLINE from 1946 to October 10, 2016, and Ovid EMBASE from 1980 to October 10, 2016, with the terms "intracranial aneurysm*," "subarachnoid hemorrhage," "Terson syndrome," "third nerve palsy," "sixth nerve palsy," "fourth nerve palsy," "optic neuropathy," "optic atrophy," "endovascular treatment," and "surgical clipping." Additional references were identified by hand search of journals and relevant articles. Only articles published in English were reviewed. The final reference list was generated on the basis of originality and relevance to the topics covered in the review. Priority was given to the most recent references and those specifically addressing the issue of visual symptoms and signs. Cavernous sinus aneurysms were not included in this review. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: J. A. Micieli, V. Biousse, N. J. Newman, and D. L. Barrow; b. Acquisition of data: J. A. Micieli, V. Biousse, and N. J. Newman; c. Analysis and interpretation of data: J. A. Micieli, V. Biousse, N. J. Newman, and D. L. Barrow. Category 2: a. Drafting the manuscript: J. A. Micieli; b. Revising it for intellectual content: V. Biousse, N. J. Newman, and D. L. Barrow. Category 3: a. Final approval of the completed manuscript: V. Biousse, N. J. Newman, and D. L. Barrow. Micieli et al: J Neuro-Ophthalmol 2017; 37: 421-439 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review 18. REFERENCES 1. Vlak MH, Algra A, Brandenburg R, Rinkel GJ. 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