This review highlights the recent literature in neuro-ophthalmology over the last year. We included the following topics in our review: pupil abnormalities, eye movements, diseases of muscle and musculoskeletal junction, optic nerve disorders, optic neuritis (ON) and multiple sclerosis (MS), chiasm and posterior primary visual pathway lesions, increased intracranial pressure (ICP) and related entities, tumors (eg, meningioma) and aneurysms affecting the visual pathways, vascular diseases, higher visual functions, advances in neuroimaging, and miscellaneous topics in neuro-ophthalmology.
The pupil is a key part of the ocular examination, and the presence or absence of a relative afferent pupillary defect (RAPD) is an important indicator of optic nerve function. Ichhpuiani et al1 studied methods to detect an RAPD. Three techniques were studied: a standard transilluminator light at high intensity, a transilluminator light at high intensity with a magnification lens (+20 diopter lens), and a direct ophthalmoscope (+10 diopter setting 1 ft away from the patient). The authors concluded that the most sensitive method to detect an RAPD was the transilluminator light with a +20 diopter magnifying lens concurrently.1 Although the “gold standard” for quantitative RAPD grading has been neutral density filters, the most commonly used grading system in clinical practice is only semiquantitative (eg, the “plus” system from grades 1+ to 4+). A recent study investigated the correlation between the clinical plus scale grading and quantified RAPD using the neutral density filter bar. The 2 scales were found to be closely correlated with grade 1+ equivalent to less than 0.6 log unit (94.7%), grade 2+ equivalent to 0.6 to 0.9 log unit (85%), grade 3+ equivalent to 1.2 to 1.5 log unit (88.3%), and grade 4+ equal to or greater than 1.8 log unit (84.6%) RAPD.2
A tonic pupil is one that poorly reacts to light but contracts slowly to a near stimulus and then slowly redilates. The idiopathic tonic pupil is called an “Adie tonic pupil.” In contrast, the combination of a tonic pupil with absent deep tendon reflexes is called the “Adie syndrome” or “Holmes-Adie syndrome.” In a review of the work of neurologist William John Adie, however, he intended to describe the Adie syndrome and not the tonic pupil itself. Thus, it was suggested that the tonic pupil be called tonic alone and to leave Adie’s name for the syndrome.3
Topical pharmacologic agents are commonly used in neuro-ophthalmology to aid in the diagnosis of sympathetic or parasympathetic pupil dysfunction [eg, the Horner syndrome (HS), pharmacologic blockade, or a tonic pupil]. Apraclonidine has emerged as an important topical diagnostic test for distinguishing the HS from physiologic anisocoria and has supplanted the classic topical cocaine test in many centers. Apraclonidine is a sympathetic α-agonist and, in normal patients, has stronger α-2 receptor agonism and weaker α-1 agonism. The more predominant α-2 receptor agonism usually causes the normal pupil to constrict. In contrast, in a positive test, apraclonidine 1% dilates the involved pupil because of denervation supersensitivity and secondarily enhanced α-1 agonist activity. This results in a reversal of anisocoria.4
Cambron et al4 used pupillometry to study 1% apraclonidine. A significant miotic effect and increased amplitude of constriction to light were found after apraclonidine 1% was instilled in healthy eyes, with the greatest miotic effect occurring between 30 and 60 minutes after instillation. The affected pupil in HS typically dilates after topical apraclonidine 1%, and this study suggests that the best time to evaluate for the greatest relative anisocoria is within 30 to 60 minutes after apraclonidine 1% instillation. Another topical α-2 agonist, brimonidine tartrate 0.2%, was compared in a pupillometry study with a lower concentration of apraclonidine, 0.5%. Maximal miosis was observed at 90 minutes after the instillation of brimonidine tartrate 0.2%, but no miosis was observed using apraclonidine 0.5%. This highlights the importance of concentration when using apraclonidine since the previously mentioned study by Cambron et al4 demonstrated a miotic effect using apraclonidine 1%.5 The dissimilar responses of the pupil to 0.5% and 1% apraclonidine could limit the ability of the clinician to appreciate a reversal of the anisocoria in the HS if they are not aware of these differences.
Although apraclonidine testing has been used for some time to diagnose HS because of the inconvenience and difficulty with cocaine testing, there has been some debate in the literature as to apraclonidine’s use in the acute setting.6 Cooper-Knock et al7 recently demonstrated a positive apraclonidine test result in a patient who presented with a 3-hour history of blurred vision in the right eye associated with neck pain 4 days after a road traffic accident. Magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) demonstrated a right-sided carotid artery dissection. Most previous reports of apraclonidine testing were at least 1 week and usually more than 1 month after the onset of symptoms, so this case represents a relatively acute diagnosis of HS using apraclonidine. Although the symptoms were only 3 hours in onset, it may be that the actual onset of the HS had occurred 4 days prior, at the time of the initial motor vehicle accident. Thus, further studies on apraclonidine testing in the acute setting may be necessary to define the sensitivity for the diagnosis of HS of less than 1 week’s duration.7
Kang et al8 reported right sixth nerve palsy followed by ipsilateral HS suggesting the classic localization within the cavernous sinus (Parkinson sign). The MRI showed an enhancing thickening in both sphenoidal sinuses, bony destruction of the skull base, and extension into the right cavernous sinus with encasement of the right internal carotid artery (ICA). Biopsy revealed invasive squamous cell carcinoma of nasopharyngeal origin.8
Another case of HS was described 9 weeks after a prior cesarean delivery with epidural anesthesia. Although previous cases have been reported of HS after cesarian sections (up to 4%), the typical onset is within 30 minutes to a few hours. The most common theory for this phenomenon is that changes during pregnancy lead to a decreased epidural space capacity with increased epidural venous engorgement. The engorgement is exacerbated during labor with Valsalva maneuver and uterine contractions, presumably resulting in local anesthetic traveling more superiorly than expected. This disrupts the oculosympathetic pathway at the second-order neurons, which exit the spinal cord in transit to the superior cervical ganglion. Unlike prior reports, this case was unusual in that the HS persisted over a period of more than 8 months, had a delayed onset, and showed laterality to the elevated rather than dependent side.9
Horner syndrome has also been a well-documented, albeit rare, finding in MS. Agarwal et al10 described an alternating HS in MS. Horner syndrome was reported 4 weeks after a black widow spider bite in which an extensive workup for alternative etiologies was negative. The authors postulated secondary autonomic nerve injury as a mechanism.11 Patients with symptomatic palmar hyperhidrosis treated with thoracic (T3) sympathectomies also developed asymptomatic HS.12 Ophthalmologists should be aware of the potential adverse effect of this procedure to avoid unnecessary additional testing in these patients.
A number of studies also reported interesting presentations of HS in children. Kava et al13 reported a 7-year-old previously healthy girl with a transient left-sided HS due to Streptococcus pyogenes acute otitis media. Another case developed HS after complicated pneumonia with placement of pleural tubes and internal jugular vein catheter.14 An infant developed HS after receiving extracorporeal membrane oxygenation, a procedure used for cardiac or respiratory failure that involves inserting catheters in both the ICA and internal jugular vein.15 These cases illustrate the complex anatomy of the oculosympathetic pathway and the need for ophthalmologists to consider HS after seemingly unrelated nonocular disorders (eg, otitis media), chest or neck disease, or surgical or invasive procedures involving any of the structures within or in close anatomical proximity to the sympathetic pathway.
Other Unusual Pupil Findings
A 41-year-old man presented with 2 weeks of headache, photophobia, and symmetrically dilated pupils (5 mm) equal in light and dark and minimally reactive to light or accommodation. The pupils constricted to topical pilocarpine 1%, although no response was found with pilocarpine 0.125%. He had decreased tendon reflexes diffusely. He had been treated for respiratory syncytial virus–mediated upper respiratory tract infection. Serology was positive for anti-GQ1b antibodies consistent with a Miller Fisher variant.16
Dunlop observed ipsilateral, paradoxical pupillary dilation during periods of intermittent exotropia. The effect seemed to be more pronounced in younger patients with lighter colored irides. The patients were otherwise healthy and had no anisocoria in primary gaze while orthotropic. The author postulated that patients with intermittent exotropia may have a heightened light sensitivity. Pupillary dilation during exotropic episodes could be related to the retinal ganglion cell (RGC) pathway containing melanopsin, which mediates sustained constriction of the pupil in bright light.17
Seizures can also commonly affect the pupil in various ways. Symptomatic pupillary hippus during seizure was reported by Centeno et al.18 No other autonomic-mediated responses were involved. The epileptogenic region localized to the right posterior parietooccipital areas.18 Although pupillary motor responses are primarily mediated within the Edinger-Westphal nucleus, it was postulated that cortical areas could override this control of pupillary function.19 Another unusual finding recently reported is seizure-induced miosis compared with the more typical postictal pupillary dilation. Focal seizures in this case localized to the left middle parietal gyrus by electroencephalography.20 This case gives further credence to cortical-based regions of pupillary control.
Head-Shaking Nystagmus in Cerebellar Infarction
Horizontal head shaking is a powerful way to produce a latent spontaneous vestibular nystagmus and can induce nystagmus in peripheral and central vestibular lesions. Huh and Kim21 investigated spontaneous nystagmus and head-shaking nystagmus (HSN) in central vestibulopathies in 72 patients with an isolated cerebellar infarction. Half of the patients with acute isolated cerebellar infarction developed HSN, which was mostly ipsilesional or downbeat, these authors postulated damage to the cerebellar uvula, nodulus, and inferior tonsil and asymmetric disinhibition of the uvula/nodulus over the velocity storage. The downbeat HSN could be explained by a build-up of vestibular asymmetry favoring upward bias due to disinhibition of the paraflocculus over the anterior canal vestibuloocular reflex pathway.21 Dissociated torsional-vertical nystagmus is characterized by conjugate torsional nystagmus with dissociated vertical components. In contrast, jerky seesaw nystagmus is a special form of nystagmus with conjugate torsional but disparate vertical components. A study described the patterns and mechanisms of jerky seesaw nystagmus in 33 internuclear ophthalmoplegia patients. In 11 patients, the nystagmus was ipsiversive torsional in both eyes with vertical components in the opposite direction; in 18 patients, there was ipsiversive torsional nystagmus with a larger upbeat component in the contralesional eye; and in 4 patients, there was ipsiversive torsional nystagmus with a greater downbeat component in the ipsilesional eye. Interestingly, most patients showed at least 1 component of contraversive ocular tilt reaction (30/33). The patterns of jerky seesaw nystagmus in internuclear ophthalmoplegia suggests a disruption of neural pathways from the contralateral vertical semicircular canals with or without concomitant damage to the fibers from the contralateral utricle in or near the medial longitudinal fasciculus.22
Both seesaw nystagmus and dissociated vertical divergence are cyclovertical eye movements characterized by vertical disconjugation and torsional conjugation. Seesaw nystagmus is known to occur with chiasmal disorders and an associated bitemporal hemianopsia. In contrast, dissociated vertical divergence is commonly encountered in infantile strabismus without visual loss (bitemporal hemianopsia). The vertical dissociation of both eye movement disorders is postulated to occur because of insufficiently developed neuronal coupling between the superior colliculi. In seesaw nystagmus, a functional differentiation between crossed and uncrossed RGCs fibers is presumed to cause diminished binocular coupling. The interstitial nucleus of Cajal may also play a role in explaining the distinct torsional eye movements in both conditions.23
Paraneoplastic Disorders of Eye Movements
Abnormal eye movements may be a feature of paraneoplastic syndromes involving the brainstem and cerebellum, including opsoclonus, slow or inaccurate saccades, impaired smooth pursuit, both gaze-evoked and downbeat nystagmus. Several mechanisms have been proposed to account for upbeat nystagmus, including an interruption of brainstem pathways from the labyrinthine semicircular canals mediating upward eye movements (ventral tegmental tract, medial longitudinal fasciculus, and brachium conjunctivum), an imbalance of central otolithic projections, or disturbed cerebellar influences upon otolithic projections from the vestibular labyrinths. Wray et al24 reported a case of upbeat nystagmus in pancreatic cancer presumed to be due to cerebellar-induced imbalance of otolithic pathways. The nystagmus was dependent on head position (being absent when supine and suppressed with convergence). The patient also showed marked retropulsion. In this case, anti-Hu antibodies and antibodies to a novel neuronal cell surface antigen were described.24
DISEASES OF MUSCLE AND MUSCULOSKELETAL JUNCTION
Ocular Myasthenia Gravis
Myasthenia gravis (MG) is of great importance to ophthalmologists because ocular involvement is seen in up to 80% of patients with MG in the disease course, with ocular problems being the presenting symptom in at least 50% of patients with MG. The extraocular muscles (EOMs) are often the first muscles to be affected because they have uniquely inherent decreased complement inhibitory proteins that predispose to a greater risk of autoimmune attack. They are also at increased risk for fatigue based on the unique structure of the EOM neuromuscular junction and are subject to very precise and frequent demands to produce coordinated, single, binocular vision. This binocular fusion is easily disrupted if muscles are not equally coordinated within just a few degrees. A pathognomonic sign of MG is the presence of eye movements that are rapid despite having a limited range of movements, described as “quiver movements” (small, fast eye movements followed by a rapid drift backward). In horizontal saccades in patients with MG, the initial portion of the movement is consistently conjugate, whereas the later component is significantly and variably disconjugate. This is in contrast to patients with isolated nerve palsies, in which early disconjugacy is demonstrated.25 One useful clinical sign in MG is the “Cogan lid twitch” (CLT). To elicit the CLT, the patient is instructed to maintain downward gaze for approximately 15 seconds and then return to primary gaze. A positive CLT sign describes an overshoot, or “twitch,” of the upper lid that occurs after the return to primary gaze from downgaze. Singman et al26 reported that the specificity of the CLT for MG was 99%, but sensitivity was slightly lower at 75%.
Another study of MG was conducted to determine the diagnostic sensitivity of repetitive nerve stimulation, single-fiber electromyography, and serum anti–acetylcholine receptor (AChR) antibody levels. Abnormal values in repetitive nerve stimulation, single-fiber electromyography, and AChR antibody level were detected in 62%, 93%, and 38% of ocular MG and 80%, 99%, and 73% of generalized MG cases, respectively. This demonstrates significantly higher sensitivities of all modalities of testing in generalized MG as compared with ocular MG. The authors also found higher sensitivities for all modes of testing in AChR antibody seropositive as compared with seronegative patients.27
Thyroid Eye Disease
Two recent reviews discussed thyroid-associated eye disease (TED). Most patients with TED are hyperthyroid but autoimmune hypothyroidism and even normal thyroid function (euthyroid Graves orbitopathy) can occur. The most common signs of TED are lid retraction (90%-98%), lagophthalmos and exposure symptoms, superior limbic keratoconjunctivitis, proptosis, and diplopia. Computed tomography (CT) of the orbit is the preferred imaging in TED and typically shows EOM belly enlargement, sparing of the tendon insertions, or an increase in orbital fat volume. Computed tomography is also especially useful for demonstrating crowding at the orbital apex in the evaluation of compressive optic neuropathy. The order and frequency of involvement of EOMs is typically inferior rectus, medial rectus, and superior rectus, with the lateral rectus muscle least likely to be affected. Smoking was also shown to exacerbate TED (up to 5-fold risk) and has been linked with the progression of TED and a poorer response to treatment.28–30 Nonsurgical treatment with orbital radiation therapy has been used in TED, but predisposing disease such as diabetes or optic nerve compression can increase the risk of postradiation optic neuropathy and retinopathy.31 Typically, orbital radiotherapy for TED should be performed in a low-dose and fractionated fashion.32
Although TED is a common cause of EOM enlargement, other etiologies can mimic the clinical and radiographic presentations. In a case of a 45-year-old man with diplopia, orbital CT revealed bilateral symmetrical enlargement of the medial and inferior rectus muscle bodies, but this patient had coarse facial features, macrognathia, enlarged hands, and a pituitary macroadenoma on cranial MRI. Although the thyroid gland was enlarged, all thyroid function testing including thyroid autoimmune antibody testing was normal. In this case, elevated serum insulin-like growth factor 1 was postulated to be the mechanism for thyroid enlargement, hypertrophy of skeletal muscle fibers, and EOM enlargement.33
Idiopathic orbital inflammatory syndrome (IOIS) can be focal (myositis or dacryoadenitis) or diffuse. Orbital myositis primarily involves the EOMs and most commonly affects young females in the third decade of life. Common presentations include orbital or periorbital pain, ophthalmoplegia, diplopia, proptosis, lid edema, or conjunctival hyperemia. In a recent series of patients with IOIS, 4 patients had myositis of 1 EOM but recurrent episodes of myositis in different EOMs in the contralateral orbit. One patient had recurrent myositis of a different EOM in the same eye. Two patients had recurrences at completely different structures (eyelid), whereas 1 patient had only eyelid involvement. This report emphasizes that IOIS is a dynamic disorder, can recur and relapse, and can affect the same or different anatomical sites or structures.34
OPTIC NERVE DISORDERS
Nonarteritic Anterior Ischemic Neuropathy
Cullen and Chung found the following in a study of 121 Singaporean patients with nonarteritic anterior ischemic optic neuropathy (NAION): 64.7% were male and 35.3% were female; 9.8% presented with sequential or bilateral disease; vision at presentation was normal in 40% but less than counting fingers in 28%; improvement in visual acuity occurred in only 7.5%, whereas worsening or no improvement occurred in 7.5% and 85% of patients, respectively. Visual field defects did not change in 77% of eyes and most commonly showed inferior nasal (45%), inferior altitudinal (30%), and superior altitudinal (7.5%) defects. The most common vascular disease present was hypertension (60%), followed by hyperlipidemia (50.9%) and diabetes mellitus (49%).35
The management and treatment of NAION have received significant attention over the past year, likely fueled by the prior publication by Hayreh and Zimmerman36 in 2008 suggesting the role of systemic corticosteroid in treating NAION. Although this 2008 study reported improvement in visual acuity in acute-phase treatment of NAION with corticosteroids, many still remain skeptical about these findings because of the lack of strong rationale for the mechanism of corticosteroid improvement. To further elucidate this mechanism, in his more recent discussion about vascular disorders in neuro-ophthalmology (February, 2011), Hayreh37 proposed that the mechanism for the beneficial role for corticosteroid use in acute-phase NAION was mediated by the corticosteroid-induced decrease in capillary permeability. Hayreh also discusses that, unlike a typical “stroke,” NAION is not a thromboembolic occlusive disorder and does not behave like diseases such as giant cell arteritis where fluorescein angiography often demonstrates little to no flow in the choroidal or optic disc vasculature. Thus, there is no benefit or rationale for aspirin or anticoagulants in NAION.37
Only 11 months later, Salgado et al38 proposed another mechanism to explain the possible role for corticosteroid-mediated improvement in acute-phase NAION. Salgado et al38 used a non–human primate model (male rhesus macaques) of NAION to reveal infiltration of acute inflammatory cells almost immediately after infarct induction, demonstrating that cellular inflammation may play a role in NAION. The finding of acute-phase inflammation demonstrated by Salgado et al could certainly support the theoretic use of corticosteroids in acute-phase NAION. However, a counter study was then published in March 2012 by Rebolleda et al,39 which challenged the benefit of corticosteroid use in treating NAION. This study prospectively evaluated the visual outcomes of 10 patients treated with high-dose corticosteroids (80 mg of prednisolone) in the setting of acute-phase NAION as compared with controls (untreated acute-phase NAION at the same institution). The authors concluded that no significant difference in visual outcome was found between the treated and untreated patients. In fact, the study was halted early because of a high rate of complications (almost one third of patients) observed in the treated group. Although the total number of patients included within this study was low and larger, more controlled trials need to be performed, the study of Rebolleda et al39 demonstrates that the use of corticosteroids in acute-phase NAION is an actively debated controversy.
Another retrospective literature review that included the results of the Ischemic Optic Neuropathy Decompression Trial found no benefit for surgery in visual acuity outcomes in NAION and a greater risk of adverse effects and adverse reactions from the surgical procedure than in controls.40
Very commonly, the ophthalmologist may have to distinguish between glaucomatous and nonglaucomatous optic neuropathy. In a case series of 6 patients misdiagnosed with glaucoma and later found to have anterior visual pathway compressive lesions, Choudhari et al41 reviewed several potential differentiating features of glaucomatous nerves including more symmetric cupping, visual loss in proportion to the degree of cupping, and typical glaucomatous nasal step or arcuate visual field (VF) defects; these changes are usually found in older patients. In contrast, anterior visual pathway compressive lesions demonstrate optic disc pallor (ie, rim pallor) and visual loss out of proportion from cupping, have vertically aligned (ie, hemianopic) VFs, are usually markedly asymmetric or unilateral, and occur in younger patients. Although routine imaging is not recommended in patients with normal tension glaucoma, imaging should be obtained in cases where there is a high clinical suspicion for nonglaucomatous optic neuropathy.41
Optic neuropathy can also occur from many infectious etiologies. Cat scratch disease is an infectious, systemic illness caused by a Gram-negative bacillus, Bartonella henselae, and is usually transmitted by the bite or scratch of an infected cat. Most immunocompetent people have no further sequelae, but ocular symptoms can occur in approximately 5% to 10% of patients [eg, optic neuropathy, neuroretinitis (macular star figure), vitreitis, focal retinitis, choroiditis, and intraretinal white spots]. Chi et al42 described the clinical presentations and features in 53 patients with cat scratch optic neuropathy. Visual acuity ranged from 20/20 to counting fingers (mean, 20/160). Most eyes (68%) had a favorable visual outcome with a final visual acuity of 20/40 or better. Interestingly, only 67% had a history of cat or kitten scratch. The classic neuroretinitis [optic disc edema (ODE) with a macular star figure] picture was seen in only 45% of eyes. No benefit was found for systemic antibiotic or steroid use on visual acuity at final follow-up examination.42 Zhang et al43 described a case of endemic typhus (a flea-borne bacterial disease caused by Rickettsia typhi) with acute, painless, monocular vision loss 3 weeks after being hospitalized for extensive illness (multiorgan failure, meningoencephalitis, and pancytopenia). The authors postulated an autoimmune reaction and perhaps Rickettsia-induced deposition of immune complexes as a potential mechanism.43
Amiodarone is one of the most commonly prescribed antiarrhythmic drugs and has been reported to produce an optic neuropathy that is similar to anterior ischemic optic neuropathy (AION). In a series investigating amiodarone optic neuropathy, the mean duration of amiodarone therapy was 9 months before the onset of vision loss, although nearly one third of these patients were asymptomatic when the diagnosis of optic neuropathy was made. Optic disc edema was present in 85% of cases. After the drug was discontinued, only 58% had improvement in visual acuity, whereas 21% worsened. In 20% of patients, legal blindness (<20/200) occurred in at least 1 eye.44
Methanol is a well-described cause of toxic optic neuropathy45 and typically occurs from intentional (eg, suicidal or homicidal attempt) or accidental ingestion of adulterated ethanol products (eg, “moonshine”). Typically, symptom onset is acute. In 2 cases of methanol poisoning recently reported by Koehrer et al,46 the onset of severely decreased vision occurred 2 to 3 days after methanol ingestion. Methanol was isolated from a sample of the ingested liquor product for 1 patient. Three months later, fundi showed the typical bilateral optic atrophy in both patients.46
Toxic damage to the optic nerve can also occur from endogenous mechanisms. Traber et al47 described a 23-year-old woman with methylmalonic acidemia since birth (an autosomal recessive disorder in which the body cannot break down certain proteins and fats). She had acute, bilateral vision loss over a period of 5 days to finger-counting vision in both eyes. Magnetic resonance imaging performed 2 weeks later revealed enhancement of both optic nerves with symmetric T2-hyperintense lesions in the posterior limb of each internal capsule. By 6 months after the initial onset of symptoms, she had developed bilateral subacute neurosensory hearing loss with new, bilateral optic nerve atrophy. Other possible etiologies were investigated [including, but not limited to, vitamin deficiencies and Leber hereditary optic neuropathy (LHON)], and treatment attempts (in the acute phase) with high-dose corticosteroids, coenzyme Q10, and vitamin E were unsuccessful. The authors postulated that the etiology of bilateral neurosensory hearing loss and optic atrophy was due to delayed progressive breakdown of mitochondrial function because an inhibition of mitochrondrial metabolism has previously been shown to occur in methylmalonic acidemia. Neuromyelitis optica (NMO) testing was not performed, however, and therefore could represent a diagnostic possibility in this case. However, this case demonstrates that methylmalonic acidemia could be the etiology of an endogenous toxic optic neuropathy and needs to be further investigated.47
Optic neuropathy can also occur in the setting of trauma. In a review of 8 cases of traumatic optic neuropathy (TON) after maxillofacial trauma, TON was found to be associated with zygomaticofacial, Le Fort II, and cranial bone fractures.48 Endoscopic optic nerve decompression was evaluated in 96 cases of TON and was described as “effective” in only 40.6% of cases, although this rate was significantly higher for patients with light perception vision (83.3%) than in those without light perception (26.4%). Patients with fractures in a single medial wall of the optic canal reportedly had better prognoses than patients with multiple fractures or those with a single fracture in the lateral wall. This demonstrates that although there could be a role for endoscopic decompression in the setting of TON, surgical intervention remains controversial, and treatment options must still be individualized for each patient.49
Leber hereditary optic neuropathy is a mitochondrial degeneration that typically presents with a bilateral, simultaneous or rapidly sequential, acute or subacute optic neuropathy in young males. McClelland et al50 reported an unusual case of presumed LHON in a 65-year-old African American woman who developed lower extremity pain, weakness, and ataxia. Although NMO antibody was negative in the cerebrospinal fluid, spinal MRI revealed enhancement of the posterior columns throughout the entire cervical spine. Approximately 1 year later, she presented again with a 3-month history of painless, sequential, subacute visual loss. Examination revealed bilateral cecocentral scotomas and optic discs that progressed from hyperemic to bilateral atrophy. Genetic testing for LHON showed the 14484 point mutation, demonstrating a rare subset of LHON patients that have MS-like features that can mimic NMO.50 Another report found that 15.4% of patients with tobacco or alcohol optic neuropathy were LHON positive, confirming the need for LHON testing even in patients with a presumptive toxic-nutritional etiology.51
Another hereditary disease that has been recently reported to cause optic atrophy is thalassemia intermedia. Although less severe than thalassemia major, this disorder can cause severe anemia and may lead to complications such as hepatosplenomegaly, expansion of medullary spaces, extramedullary hematopoiesis, and optic atrophy.52
OPTIC NEURITIS AND MULTIPLE SCLEROSIS
Optic neuritis is a demyelinating inflammation of the optic nerve that can be isolated or associated with acute inflammatory demyelinating diseases such as MS or NMO. NMO-IgG is a serum immunoglobulin autoantibody (NMO-Ab) that is directed against aquaporin-4 and is a pathologic effector in NMO. Myelin oligodendrocyte glycoprotein is another causative protein of MS. Myelin oligodendrocyte glycoprotein antigen is derived from oligodendrocytes that induced murine ON with myelitis. In a study of 23 patients with ON compared with 8 healthy adult controls, 11 patients were NMO-Ab seropositive, and 8 patients were MOG-Ab seropositive. Six patients were seropositive for both NMO-Ab and MOG-Ab. Ten patients were seronegative for both antibodies. Of 6 eyes in patients seropositive for both antibodies, 3 did not respond to corticosteroid pulse therapy and plasmapheresis, and their visual acuity remained unchanged. The authors hypothesized that patients who were seropositive for both NMO-Ab and MOG-Ab had poor visual recovery because of involvement of both astrocytes and oligodendrocytes. They also concluded that NMO-Ab and MOG-Ab could be considered as potential biomarkers to determine visual prognosis in patients with ON.53
Neuromyelitis optica (ie, Devic disease) is an idiopathic immune-mediated inflammatory disease that predominantly affects the spinal cord and optic nerves. A study of 33 patients with NMO and 30 patients with MS compared visual outcomes after a single episode of ON. The VF mean deviations were significantly worse in patients with NMO. After a single episode of ON, the VF tests were normal in only 2 of 36 eyes of patients with NMO compared with 17 of 35 eyes with MS (P = 0.001).54 Another study reported a case of familial anti–aquaporin-4 antibody–positive NMO. Disease onset occurred at different ages, even within the same family. The study suggested that the frequency of familial NMO is higher than expected in the general population. Therefore, family history must be carefully examined in patients with NMO.55
Multiple sclerosis is characterized by a wide range of clinical presentations ranging from benign to more aggressive courses. “Benign” MS has been traditionally defined on the Expanded Disability Status Scale (EDSS) with a score of less than or equal to 3 after a 15-year MS disease duration. A prospective longitudinal study evaluated the extent of visual pathway axonal loss in a benign MS cohort and examined the relationship to vision and quality of life. The authors concluded that patients with “benign MS” have similar and perhaps even greater degrees of visual pathway involvement.56
To evaluate the retinal neurodegeneration in patients with MS, measurement of the retinal nerve fiber layer (RNFL) thickness using optical coherence tomography (OCT) has been proposed as a potential biomarker of axonal damage in MS. A cross-sectional, case-control study of 39 patients with MS circumpapillary RNFL thickness in affected eyes was decreased compared with nonaffected eyes. The thickness of the macular ganglion cell complex (GCC) had the highest sensitivity and specificity in detecting axonal loss independent of ON. The EDSS score showed the strongest correlation with the ganglion cell layer (GCL), internal plexiform layer, and GCC thickness.57
The potential relationship between the degree of chronic demyelination and axonal degeneration was investigated using ON as a model. This study investigated 25 patients with a first episode of unilateral ON who also had good recovery of visual function and the presence of concurrent brain or spinal cord MRI lesions. The axonal loss was assessed using the change in RNFL thickness between 1 and 3 years after ON. Optic nerve conduction was evaluated using the latency of multifocal visual evoked potentials (VEPs). The RNFL thickness was significantly reduced in ON eyes at 12 months compared with controls but remained unchanged in fellow eyes. Average RNFL thickness demonstrated a small but significant reduction between 12 and 36 months for ON and the fellow eyes. Change in RNFL thickness between 12 and 36 months, however, did not correlate with the degree of multifocal VEP latency delay. In addition, there was no evidence that intravenous prednisolone significantly affected long-term outcome.58
A retrospective analysis was performed with full-field electroretinogram (ERG), pattern ERG (PERG), and pattern VEP findings from 46 patients with clinical and electrophysiologic unilateral ON. Standard ERG did not show significant differences between ON and fellow eyes nor between patients with and without MS. Differences were present in the negative component of the PERG at approximately 95 milliseconds (N95), which was significantly lower in the affected eye. The pattern reversal VEP showed significant longer latency in the affected eye.59
Loss of RGCs can be detected by OCT and scanning laser polarimetry (GDx). GDx is a noninvasive, quantitative technique that measures peripapillary RNFL thickness using polarized light that undergoes a phase shift after passing through the RNFL. In one study of 166 patients with MS, changes in the optic nerve were detected by structural measurements of the RNFL using OCT. Eyes with previous ON showed a greater reduction of parameters in the baseline evaluation, but RNFL thickness was not significantly greater in the longitudinal study. Patients with MS relapses showed a greater reduction of RNFL thickness and VEP amplitude compared with nonrelapsing cases. Patients with and without treatment showed similar reductions; the nontreated group had a significantly higher EDSS (P = 0.029).60 Another study of 73 MS eyes and 74 control eyes evaluated scanning laser polarimetry measurements of RNFL thickness and compared the results with VEP and VF results. GDx is a useful diagnostic tool to identify patients with a previous history of ON or patients with no fundus findings, such as patients with retrobulbar ON or patients with subclinical attacks of MS.61
CHIASM AND POSTERIOR VISUAL PATHWAY
Compressive lesions at the optic chiasm can cause visual loss or VF defects. Visual dysfunction is a consequence of damage to RGC and their axons. Moon et al62 investigated the time course of VF recovery and changes in RGCs after chiasmal decompression using standard automated perimetry and OCT photopic negative response (PhNR) in 23 patients with chiasmal syndrome and 20 controls. Postoperatively, the VFs were significantly improved, but RNFL thickness, GCC area, and PhNR/b-wave ratio were still reduced. Six months after surgery, average RNFL thickness, GCC area, and PhNR/b-wave ratio showed significant improvements by 2.82%, 2.66%, and 8.72%, respectively, than what was observed at 3 months postoperatively. Visual fields were significantly correlated with RNFL thickness, GCC area, and PhNR/b-wave ratio. Optical coherence tomography measurements of the RNFL thickness, GCC area, and PhNR were useful for predicting postoperative visual outcome in chiasmal compression.62
Multifocal transient pattern electroretinography (mfPERG) is a technique that uses multiple inputs to simultaneously record localized PERG responses from multiple areas of the retina to detect localized retinal damage. In one study, the ability of mfPERG to detect neural loss and the relationship between mfPERG and VF loss in eyes with chiasmal compression were evaluated. The study included 23 eyes from 23 patients with temporal VF defects and band optic atrophy and 21 controls. Significant correlations were found between VF relative sensitivity and mfPERG amplitude. The authors concluded that mfPERG might be used as an indicator of ganglion cell dysfunction.63
Pituitary apoplexy is a sudden neurologic impairment caused by hemorrhage or infarction of the pituitary gland and is a life- and sight-threatening medical emergency. It is a clinical syndrome that typically presents with sudden severe headache, nausea, vomiting, visual impairment, and diplopia. Simon et al64 reported neuro-ophthalmic manifestations in 23 patients (mean age, 54.1 years) with pituitary apoplexy. Symptoms included headache, which was the most common symptom but not universally present (82.6%); reduced visual acuity (55%); VF defects (47.6%); and cranial nerve palsies (60.9%). Pituitary apoplexy should be considered in the differential diagnosis of any sudden-onset neuro-ophthalmic manifestation.64
Disorders of the retrochiasmal visual pathways (eg, optic tract, lateral geniculate nucleus, optic radiations, and occipital lobe) are relatively common in general neurologic practice. Homonymous hemianopic VF defects were found in approximately 8% of stroke patients. Homonymous hemianopic VF defects can lead to impairment of visual functions. This type of field defect can have significant medical, legal, occupational, and financial consequences and can also limit the activities of daily living. Many patients are unable to read, drive, or return to work after sustaining retrochiasmal damage.65
INCREASED INTRACRANIAL PRESSURE AND RELATED ENTITIES
Idiopathic intracranial hypertension (IIH) typically affects obese, young women. It is also characterized by symptoms and signs of increased ICP, negative neuroimaging studies (eg, MRI and magnetic resonance venography), or a documented elevated ICP with normal cerebrospinal fluid content. Bruce et al66 emphasized the key features of IIH including that higher body mass and recent weight gain (5%–15%) increased the risk for IIH even in nonobese patients and that IIH can occur in prepubertal children, but unlike adults, IIH in children has no predilection for either sex or obesity. Idiopathic intracranial hypertension has also been associated with specific medications, systemic disorders (eg, anemia), and obstructive sleep apnea (OSA). Headache was the most common symptom, and papilledema was the most common sign. African American patients with IIH tended to have more aggressive disease.66,67
Idiopathic intracranial hypertension in a pregnant woman is a special circumstance that was reviewed. Evaluation of IIH in pregnancy should proceed in almost the same manner as IIH in the nonpregnant patient with few exceptions. Although traditional imaging studies with cranial MRI and CT have minimal risk to the mother and fetus, contrast material is still a category C agent for both imaging modalities. Papilledema in pregnancy can be a sign of cerebral venous sinus thrombosis or IIH, and in this circumstance, cranial MRI and magnetic resonance venography are recommended. When IIH is diagnosed during pregnancy, treatment options may differ slightly as compared with IIH diagnosed without pregnancy. For example, weight loss may not be an appropriate recommendation during pregnancy. Acetazolamide is a class C agent but still remains a treatment option when clinically indicated. However, all treatments’ risk/benefit ratio should be carefully weighed with the patient and obstetrician. Other ophthalmic changes related to pregnancy included the following: refractive variability is thought to be secondary to progesterone-mediated changes in corneal fluid content; reduced episcleral venous pressure, greater aqueous outflow, and effects from progesterone contribute to the reduced intraocular pressure (IOP) observed during pregnancy; pre-eclampsia, eclampsia, and HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) may occur; cranial neuropathies and HS may also occur because of pregnancy or pregnancy-related procedures; and an acquired Chiari type I malformation may occur.68
Obstructive Sleep Apnea in IIH
Obstructive sleep apnea may be associated with IIH. Polysomnography is considered the “gold standard” test. A simple screening test, however, the Berlin questionnaire, has been used to identify persons who are at high risk for OSA. Thirty patients with IIH were included in the study; 66.7% were found to have a high-risk Berlin questionnaire score and 60% exhibited OSA, only 30% have a low-risk score who had OSA. The sensitivity and specificity of the Berlin questionnaire for OSA in patients with IIH was 83% and 58%, respectively. The positive predictive value was 75%. A low-risk Berlin questionnaire score identified patients with IIH who were unlikely to have OSA. The authors, therefore, concluded that the Berlin questionnaire is a practical adjunctive tool to stratify patients with IIH for the risk of OSA.69
Papilledema Versus Pseudopapilledema
The differentiation of true optic disc edema (ODE) from pseudoedema (PODE) can be a clinical challenge. To assess the accuracy, sensitivity, and specificity of funduscopy in differentiating ODE from PODE, 74 patients with ODE and 48 subjects with PODE were included in an observational, cross-sectional study. The study showed that swelling of the peripapillary RNFL had the highest accuracy. The best 4-sign combinations were optic disc swelling, hemorrhage, papilla elevation, and congestion of peripapillary vessels (sensitivity, 0.95; specificity, 0.89). The presence of retinal or choroidal folds had 100% specificity and was considered a “pathognomonic” sign of true ODE.70
The spectral-domain OCT (SD-OCT) uses geometric morphometrics to analyze the shape of the peripapillary retinal pigment epithelium–Bruch membrane (RPE/BM) layer. The SD-OCT was recently used to compare 3 groups: 30 normal controls, 20 NAION cases, and 25 papilledema cases. The RPE/BM layer in the control and NAION groups had a “V shape” pointing away from the vitreous, whereas the RPE/BM layer in the papilledema group had an inverted U shape, skewed nasally inward toward the vitreous. These OCT differences were statistically significant. There were no significant differences, however, in shapes between control and NAION groups. Pretreatment and posttreatment OCT in papilledema showed that the inverted U-shaped RPE/BM moved posteriorly into a V shape as the papilledema resolved after weight loss or shunting procedure. This difference was believed to be the result of changes in the translaminar pressure gradient at the optic nerve head and the material properties of the peripapillary sclera. The authors proposed that OCT offers a novel way of assessing shape differences of the peripapillary optic nerve head and optic disc cup.71
Although there are different modalities that have been proposed to measure ICP (including CT, MRI, transcranial Doppler, sonography, near-infrared spectroscopy, and VEP), none of them have been proven equivalent to direct invasive ICP measurement. Multiple techniques to measure the optic nerve and the optic nerve sheath diameter have been studied. Optic nerve sheath ultrasound and Doppler flow imaging are promising noninvasive modalities for the indirect assessment of ICP.72
A study of 10 patients with IIH who had undergone lumbar puncture (LP) and continuous ICP monitoring with an intraparenchymal Codman ICP Monitoring System was performed. Intracranial pressure monitoring influenced the management in all patients studied. Lumbar puncture showed elevated opening pressures in 7 patients, but ICP monitoring failed to confirm a consistently high ICP. Subsequently, the decision was made in these patients to discontinue ICP-lowering agents or shunts or to advise against revisions of existing indwelling shunts. In another patient, ICP monitoring confirmed high ICP, justifying the placement of a ventriculoperitoneal shunt. In another, ICP monitoring was performed instead of LP because of the presence of a petroclival mass. In this patient, a shunt was subsequently placed because of elevated ICP. The study concluded that short-term (at least 24 hours), continuous ICP intraparenchymal monitoring was a useful adjunct in the management of IIH.73
TUMORS AND ANEURYSM
An aneurysm is a vascular disease that is characterized by local dilatation of arterial walls. Rupture of cerebral aneurysms causes intracranial hemorrhage, which is associated with high mortality and morbidity. Progress in medical imaging and information technology has enabled the prediction of flow fields in the patient-specific blood vessels using computational analysis. Recent computational hemodynamic studies on cerebral aneurysm initiation, progress, and rupture were reviewed. The study concluded that the computational analysis of hemodynamics in cerebral aneurysms provided valuable information for treatment planning and follow-up.74
To evaluate the prevalence of incidentally found unruptured intracranial aneurysms using MRA, a study was performed evaluating the MRA results in 3049 patients. Magnetic resonance angiography results were compared with intra-arterial digital subtraction angiography. Unruptured intracranial aneurysms were found in 137 patients. The prevalence of unruptured intracranial aneurysms was 5% in women and 4% in men. The most common aneurysm location was at the distal ICA, followed by the middle cerebral artery. Almost all (99%) aneurysms measured less than 12 mm. This study revealed a higher prevalence of unruptured intracranial aneurysms observed by MRA than what was previously reported.75
Unruptured intracranial aneurysms represent a dilemma for physicians. To study the biomechanical behavior and characteristics of ruptured and unruptured aneurysms, 18 patients treated for ruptured or unruptured intracranial aneurysms by surgical clipping were evaluated. Aneurysm rupture occurs when wall tension exceeds the strength limit of the wall tissue. Aneurysm computational hemodynamics studies make the assumption of rigid walls, which is arguably an oversimplification. All unruptured intracranial aneurysms presented more rigid tissue than ruptured or preruptured aneurysms. Wall thickness was also not correlated to aneurysmal status (ruptured/unruptured).76
Radiotherapy has shown efficacy in controlling optic nerve sheath meningioma growth. It has also helped achieve stable or improved visual function in symptomatic and progressive patients. In one study of 10 patients with optic nerve sheath meningioma treated with conformal radiotherapy, visual function significantly improved after radiotherapy. Visual acuity deterioration after radiotherapy was most commonly related to radiation-induced retinopathy, which was found in 2 patients. Another adverse effect, a radiation-induced mature cataract, was found in 1 patient. Long-term visual outcomes may be compromised by radiation-induced adverse effects. Therefore, mean eye radiation dose has to be considered as a limiting constraint in treatment planning.77
Meningiomas affecting the anterior visual pathways may not always be suitable for surgery. An alternate treatment using multisession stereotactic radiotherapy was discussed (including the Gamma Knife (Elekta Instruments AB, Stockholm, Sweden), CyberKnife (Accuray Co., Sunnyvale, CA), tomotherapy, and isocentric linear accelerator systems). Sixteen patients with anterior visual pathway meningiomas were treated with fractionated stereotactic radiotherapy (FSRT). Eleven had undergone surgery before FSRT, and 5 had undergone FSRT as first-line management. Tumor control was achieved in 14 of the 16 patients after a median follow-up time of 51 months. Visual function improved in 6 patients, stabilized in 8 patients, and worsened in 2 patients. Fractionated stereotactic radiotherapy is a safe and effective option for patients with meningiomas threatening the anterior visual pathways. However, long-term results are still pending.78
Carotid-cavernous fistulas (CCFs) can be classified by etiology (traumatic or spontaneous), speed of flow (high or low), or vessel architecture (direct or indirect). Indirect dural CCFs are usually fed by smaller meningeal arteries of the internal and/or external carotid arteries.79 Grumann et al80 retrospectively evaluated 47 CCFs and reported that 44.7% were direct and 55.3% were indirect CCFs. Direct CCFs had a younger age of presentation, whereas indirect CCFs were more common in middle-aged or postmenopausal women. In addition, 40% of direct CCFs and 80% of indirect CCFs were of spontaneous origin (ie, no history of trauma), which was a higher rate than what was previously reported especially for direct CCFs, which are more classically described as posttraumatic. The common ophthalmic symptoms were blurred vision (36.2%) and headaches (29.8%), and the most common signs were proptosis (78.7%), red eye (68.1%), ophthalmoparesis (61.7%), chemosis (42.6%), bruit (36.2%), and elevated IOP (31.9%). Elevated IOP was more commonly found in indirect CCFs, whereas bruits were more commonly found in direct CCFs. Decreased visual acuity at the initial visit was significantly associated with the persistence of ocular symptoms after CCF treatment.80 The most common treatment for CCFs is endovascular occlusion of the lesion using a transarterial or transvenous route.81 However, in certain cases, spontaneous closure can occur, so no treatment is needed.82 Barry et al83 reported 12 patients with direct and 12 patients with indirect fistulas, which were successfully endovascularly closed. Visual recovery was observed in all treated fistulas except in those who presented with no light perception vision.83
There were 2 case reports of orbital arteriovenous malformations (AVMs) that are of interest to the practicing ophthalmologist. The first was discovered when the patient presented with intermittent diplopia and was found to have acquired superior oblique restriction, with a diagnosis of Brown syndrome. Imaging was performed, and a supranasal orbital AVM was discovered as the cause of the syndrome.84 The second case was a 65-year-old woman who presented with chronic right eye proptosis and conjunctival vessel dilation. On examination, she was found to have decreased right eye visual acuity to 20/40 and an IOP of 40 mm Hg. The patient and multiple family members were found to have recurrent epistaxis and many telangiectasias on the lips and palate. Magnetic resonance imaging and cerebral angiographic imaging revealed a thrombosed right orbital AVM and other AVMs in the brain and chest, confirming the diagnosis of hereditary hemorrhagic telangiectasia or Rendu-Osler-Weber disease. Although steroid treatment and IOP-lowering drops were initiated on the affected eye, the patient ultimately experienced a central retinal artery occlusion in the eye 2 months later.85 These cases emphasize the wide scope of orbital AVM presentations, the importance of a careful, complete physical examination, and consideration for the possible adverse affects of treatment embolization in some types of orbital AVMs, although in this case, the thrombosis occurred spontaneously.
A 35-year-old left-hand–dominant woman reported difficulty recognizing the faces of her family (prosopagnosia). She had a right homonymous hemianopsia and lacked the inability to read or associate separate parts of a word into a whole word. However, no other difficulties in language skills were present (pure alexia). An occipital AVM was diagnosed, revealing an unusual and interesting combination of pure alexia, prosopagnosia, and right homonymous VF defect (HVFD).86
In some stroke syndromes, a well-known ophthalmic sign termed wrong-way deviation may occur, in which the eyes deviate conjugately in a direction contralateral to the affected side. The wrong-way deviation usually appears a few days after the initial insult and is frequently accompanied by transient downward eye deviation, which is perhaps due to damage in the rostral brainstem.87
In the wall-eyed bilateral internuclear ophthalmoplegia syndrome, there is a bilateral adduction deficit with exotropia, impaired convergence, and a bilateral horizontal dissociated abducting eye nystagmus elicited on horizontal gaze. Although a lesion of the rostral midbrain is a common cause of the wall-eyed bilateral internuclear ophthalmoplegia syndrome, a recent case report discussed an affected patient with a medial dorsal pontine lesion on diffusion-weighted imaging MRI.88
The Wallenberg syndrome, or lateral medullary syndrome (LMS), is a stroke syndrome usually caused by an infarction involving the posterior inferior cerebellar artery. A 45-year-old male construction worker presented with LMS after a period of prolonged neck extension. Magnetic resonance imaging confirmed a left lateral medullary infarction. However, cerebral angiogram revealed a patent, extracranial, extradural left posterior inferior cerebellar artery that was relatively small in diameter compared with the left vertebral artery. Therefore, this case demonstrates that neck manipulation or prolonged neck extension can cause an LMS, especially in the setting of anomalous vasculature.89
Artery occlusion can result in devastating vision loss, and treatments continue to remain controversial. A case with cilioretinal artery occlusion was reported after intranasal cocaine use.90 Lee et al91 reported an ophthalmic artery occlusion combined with brain infarction in a 44-year-old woman 1 hour after periocular autologous fat injection. A case of a branch retinal vein occlusion in a patient with MS taking fingolimod (FTY720; Novartis) was described but may have been coincidental rather than causal.92
Patients with ICA dissection, a life-threatening event, can often present with HS as one of their initial symptoms. To help quantify the incidence of HS in the setting of ICA dissection, Diviak et al93 reported that 10 of 22 patients with ICA dissection presented with an HS. The spectrums of clinical presentations of ICA dissection included facial pain, neck pain, and concurrent HS in 4 patients; facial pain, HS, and contralateral sensorimotor deficit in 6; headache and contralateral sensorimotor deficit in 2; and contralateral sensorimotor deficit with or without speech impairment in 10.93 Nizam et al94 reported a left, pupil-involving oculomotor palsy as a rare presenting sign of left ICA dissection.
Many vasculitic diseases can have ocular involvement. Systemic lupus erythematosus is a chronic systemic autoimmune dysfunction that can affect the visual system in 20% to 47.3% of patients. In one study of patients with systemic lupus erythematosus, the most common ocular manifestations were dry eye (39.5%), followed by lupus retinopathy (21%) and drug-induced ocular complications (21%).95 Other ocular involvement can include periocular skin lesions, orbital inflammation, retinal hemorrhages, vasculitis, iritis, scleritis, ON, or optic neuropathy. One patient with lupus presenting with ptosis was misdiagnosed with orbital inflammatory syndrome due to lupus erythematosus profundus.96
Antineutrophil cytoplasmic antibody–associated vasculitides are a group of autoimmune diseases affecting small to medium-sized vessels and can affect the eye and orbit. The antineutrophil cytoplasmic antibody–associated vasculitides include granulomatosis with polyangiitis (previously known as Wegener granulomatosis), microscopic polyangiitis, and eosinophilic granulomatous polyangiitis of Churg-Strauss.97 Another vasculitic disorder with common ocular manifestations is Behçet disease, a systemic inflammatory disorder characterized by a combination of recurrent oral or genital ulcers, ocular inflammation, or skin lesions (major criteria), or central nervous system lesions, vascular lesions, epididymitis, gastrointestinal lesions, or arthritis (minor criteria). Behçet disease most commonly causes recurrent nongranulomatous uveitis or necrotizing obliterative retinal vasculitis, but 1 case report described central retinal artery occlusion (CRAO), left eye recurrent papillitis, and recurrent oral ulcers.98 Another vasculitic disease with ocular manifestations is Susac syndrome. Two cases of Susac syndrome have recently been reported, each encompassing the typical clinical triad of encephalopathy, branch retinal artery obstruction, and hearing loss in the absence of prominent systemic manifestations. Susac syndrome is thought to be caused by localized arteriolar vasculitis secondary to circulating antiendothelial cell antibodies.99,100
Some ocular paraneoplastic disorders may be misdiagnosed as vasculitis. Anastasakis et al101 described a patient with symptoms of a shimmering photopsia and floaters. Examination revealed vitreous cells, peripapillary atrophy, a blunted foveal reflex with midperipheral nonspecific pigmentary abnormalities, and large choroidal vessels in both eyes. Retinal periphlebitis was present on fluorescein angiography, but flash ERG showed reduced b-wave amplitudes on both the dim flash and bright flash scotopic ERG. Photopic responses (single-flash a- and b-wave) showed a broad a-wave and a b-wave with normal amplitude, although with a sharpened appearance and lacking photopic oscillatory potentials. These findings prompted an oncologic workup, which revealed metastatic breast carcinoma. The patient was then started on chemotherapy with subsequent resolution of her visual symptoms and normalization of the b-wave on ERG.101
Giant Cell Arteritis
Giant cell arteritis (GCA) is the most common type of vasculitis in people older than 50 years, rarely affecting those younger, with incidence peaking in the eighth decade of life and more commonly affecting females. The highest frequencies have been reported in those of Scandinavian descent, whereas much lower frequencies are found in those of African, Asian, Hispanic, and Arab descent. Although large vessels can be involved such as the aorta and its proximal branches (dissection and/or rupture), the most commonly affected arteries in GCA are the superficial temporal, ophthalmic, posterior ciliary, and vertebral arteries. Unfortunately, vision loss is the presenting symptom in approximately 30% of patients with GCA. Amaurosis fugax may be the presenting sign of GCA and can herald an impending loss of vision secondary to arteritic anterior ischemic optic neuropathy. This is differentiated from NAION, which is not classically associated with amaurosis fugax. In GCA, a chalky-white appearance of the disc (ie, pallid edema) is seen, unlike the disc appearance of NAION, which presents with hyperemic sectoral or diffuse edema.102 Some patients with GCA-related visual loss can even present with a normal optic nerve (posterior ischemic optic neuropathy). In 1 case, fluorescein angiography revealed focal perfusion defects in the submacular choroid, with sparing of the optic nerve and retinal arteries.103
A recent retrospective review of 22 Mexican patients with GCA reported a mean (SD) age of 73 (7.9) years. The most frequent presenting symptoms included headache (90%), constitutional symptoms (86%), and polymyalgia rheumatica (59%). Other complications also included cranial ischemia in 32%, amaurosis fugax in 36%, and blindness in 27%, which are higher rates than reported for other GCA populations.104 Jaw claudication has recently been highlighted as a very specific feature of GCA and is due to ischemic involvement of the facial artery.105 Recently, a reduction in jaw opening (trismus) has also been proposed as a rare symptom for GCA.106 Intracranial arteries are usually spared in GCA; however, Goedhart-de Haan et al107 described a case with occipital infarction due to vertebral artery vasculitis caused by GCA.
In a study of 19 patients (9 men and 10 women) in a headache clinic in Japan, Imai et al108 reported a mean (SD) age of 78.1 (4.8) years for Japanese patients with GCA, but the female-to-male ratio (10:9) was much lower than that reported in other studies. The most common symptoms were headache (89.5%), ear pain (5.3%), jaw claudication (15.8%), polymyalgia rheumatica (15.8%), and jaw pain (5.3%). Ocular involvement was only found in 2 patients (10.5%), with no loss of vision. The much lower frequency of ocular involvement in Japanese GCA might be a factor contributing to underdiagnosis of GCA in this population.108 However, the results of this study must be interpreted cautiously because these data were taken from enrollment at a headache clinic and therefore may not be representative of the general patient population.
Lugo et al109 found that, in GCA, the positive predictive value of an elevated erythrocyte sedimentation rate (ESR), defined as 50 mm/h or greater, was 27% with a sensitivity of 100%. The authors therefore recommended screening patients with a normal ESR for etiologies other than GCA.109 This study did not report C-reactive protein levels or platelet counts, however, which have previously also been emphasized as being important predictors of positive temporal artery biopsies. Walvick110 reported that only 459 of more than 3000 temporal artery biopsies were positive for GCA. The prevalence of a positive biopsy in the setting of normal laboratory values was 20% with a normal ESR, 5% with a normal C-reactive protein, and 55% with normal platelets.110 In another study of GCA, 22.5% were found to have a normal ESR, and 3 (3.7%) of 80 patients with GCA-associated blindness had a normal ESR.111 Goslin and Chung112 reported in a retrospective review that, of all GCA patients undergoing temporal artery biopsy, only 38.3% were positive, which is fairly close to the percentages reported in other similar studies. To reduce the number of negative biopsies, the authors recommended a biopsy length of greater than 2 cm.112
Although temporal artery biopsy remains the “gold standard” for the diagnosis of GCA, Doppler ultrasound and positron emission tomography (PET) findings have been reported in cases of GCA. Color Doppler ultrasound of the temporal arteries in GCA can be used to show a “halo sign” around the patent arterial lumen but can also reveal stenosis or occlusion. In one study, the presence of a halo sign on color Doppler ultrasound yielded 81% sensitivity and 88% specificity, whereas the presence of a bilateral halo sign was 37% sensitive and 100% specific.113 In a 72-year-old woman with biopsy-proven GCA, Chaigne et al114 reported CT and PET scan findings that showed aortic wall thickening and increased metabolic uptake without clinical involvement of the temporal arteries. Because PET does not image the temporal artery well, this type of imaging can be helpful for identifying larger vessel involvement in the unusual or atypical presentation of GCA.
HIGHER VISUAL FUNCTIONS
The association between visual impairment and impaired activities of daily living are well known. Reading impairment after stroke is common and could be secondary to ocular or nonocular causes. Ocular causes include VF loss, eye movement impairment, or poor central vision. Nonocular causes may include cognitive errors or language. To identify patients with suspected visual impairment who reported reading difficulties and to establish the prevalence of ocular and nonocular causes, a prospective, multicenter observational case-cohort study included 915 patients. Reading difficulties were reported in 177 patients (19.3%). Reading difficulties were the only symptom in 39 cases. Fifteen patients were diagnosed either with expressive or receptive aphasia without a visual cause, 8 had alexia, 109 had VF loss, 85 had eye movement abnormalities, 27 had low vision, and 39 had visual perceptual impairments (eg, visual inattention, visual agnosia and hallucinations, depth perception impairment, and achromatopsia).115
In a study of 13 healthy subjects and 6 patients with left or bilateral occipital and/or temporal lesions, a correlation between mean reading time and the slope of the word-length effect was found in HVFDs.116 Although there are functional differences between right and left HVFDs, in a study of 30 patients with HVFDs, there was no significant difference in collision avoidance between patients with left- and right-hemispheric lesions.117
Posterior cortical atrophy is a progressive neurodegenerative syndrome that can present with cortical visual dysfunction (eg, homonymous hemianopsia or cortical blindness) due to neurodegenerative disease such as Alzheimer disease (AD). In a retrospective case series, Pelak et al118 reviewed VF records from 9 patients with documented posterior cortical atrophy and found that homonymous hemianopia or quadrantanopia was seen in patients with useful vision or bilateral constriction in patients with very poor vision. There was a predominance of left homonymous hemifield defects or left visuospatial neglect, suggesting preferential damage in the right visual cortical regions. This is interesting in the setting that 7 of 9 patients had early and prominent complaints of difficulty driving. Homonymous visual field defects (HVFD) defects showed probable AD in 7, definite AD in 1, and definite dementia with Lewy bodies associated with AD pathology in 1. Although 8 of 9 patients did progress to probable or definite AD, their VF remained distinct from a prior study that concluded that the most common VF defect in AD was bilateral constriction that is predominant inferiorly.118
ADVANCES IN NEUROIMAGING
Imaging Updates in Specific Disorders
Interpreting and applying imaging is of vital importance to the neuro-ophthalmologist and must begin with a basic understanding of the clinical relevance of different types of imaging. Pula et al119 thoroughly reviewed the mechanism of many different types of MRI protocols and their specific clinical use.
Al-Moosa and Eggenberger120 reported that imaging was most useful when the suspected pathology in HS was first localized to the first-, second-, or third-order neuron by a complete history and physical evaluation. First-order studies are usually limited to the brain and neck and are best evaluated with MRI with and without contrast. Second-order studies should be focused on the neck and upper chest to evaluate for possible dissection of the carotid arteries. Third-order lesions are best evaluated by scanning both the head and neck. The authors suggested that, in adults with HS who are asymptomatic or who have chronic and long-standing HS (as documented in old photographs), imaging may be of low yield and observation may be appropriate. In children with a HS, however, the authors recommended a thorough physical examination, homovanillic and vanillylmandelic acid testing, and imaging of the brain, neck, and chest.120
A case report demonstrated restricted diffusion on MRI in the optic nerve in a 44-year-old man with non–Hodgkin B-cell lymphoma, a finding that was only previously seen in optic nerve infarction or inflammation. The restricted diffusion persisted at least 4 months after the onset of visual symptoms, which would be atypical for infarction.121 Gupta et al122 performed a retrospective review of 7 patients with MRI or CT imaging demonstrating carcinoid tumor metastases to the EOMs. The authors’ findings suggest that well-defined, round, or fusiform masses of the EOMs should strongly suggest metastatic involvement in a patient with known carcinoid.122
Another emerging imaging modality growing in importance in neuro-ophthalmology is PET. This technology creates a 3-dimensional (3D) image of the metabolic activity within the body by detecting gamma rays emitted by a tracer, usually similar to glucose. Functional or metabolic alterations in the brains of patients with hemifacial spasm were investigated using PET to measure cerebral glucose metabolism. Magnetic resonance imaging was also used concurrently to measure the grade of neurovascular compression. Patients were scanned both before treatment (active state) and after treatment (suppressed state) with botulism neurotoxin type A. Hemifacial spasm was found to be associated with bilateral thalamic glucose hypermetabolism in both active and suppressed states, with a positive correlation between the severity of the spasm and the degree of neurovascular compression.123
A retrospective review investigated 54 patients with chronic uveitis who underwent PET for suspected sarcoidosis. Ten patients (18.5%) were diagnosed with presumed sarcoidosis, and 7 patients (12.9%), with indeterminate sarcoidosis. Increasing age at the diagnosis of uveitis, the presence of posterior synechiae, and a positive high-resolution CT of the chest were all factors that were significantly associated with an abnormal PET scan.124 Moisseiev et al125 described the benefits of using multiple imaging modalities together to confirm the diagnosis of transient or subtle CRAO. These can include Doppler ultrasound of orbital vessels, MRA to evaluate patency of the central retinal artery, high-resolution OCT to reveal retinal abnormalities or subclinical cotton wool spots, fluorescein angiography to show a filling delay, and indocyanine green chorioangiography.125
Orbital ultrasound (standardized A and B scan) was recently used in 15 patients to aid in the differential diagnosis of suspected orbital vascular lesions by Ko et al.126 Quantitative features, kinetic properties, and sizes of lesions before and after Valsalva maneuver were recorded. In all patients but 1, ultrasound examination correctly identified the lesion and was able to differentiate among low, medium, or high flow rates. Although dynamic MRI/MRA is an alternative and sometimes favored imaging modality for orbital vascular lesions, the authors demonstrated that ultrasound is an excellent first-line study. In fact, when CT and MRI are inconclusive, ultrasound is actually preferred based on cost and ease of examination for serial follow-up evaluations of orbital vascular malformations.126
Doppler uses the same, yet slightly modified, technology as ultrasound to quantify blood flow direction and velocity. This is accomplished by calculating both the time lapse between the ultrasound wave emission and return, in addition to the change in frequency (if the reflecting object is moving).127 Doppler ultrasound waveform changes have been recently used to show an association between retrobulbar blood flow and glaucomatous optic nerve damage. Ophthalmic artery color Doppler images were obtained and compared between patients with open-angle glaucoma, patients with normal tension glaucoma, and healthy controls. Doppler waveforms were much more sensitive to changes in IOP in patients with glaucoma, especially normal tension glaucoma. This suggests an inability to regulate blood flow in the face of blood pressure changes, implying intermittent periods of decreased ophthalmic artery perfusion. This theory of perfusion pressure volatility is also in agreement with the existing literature on blood flow velocities and arterial pressure instability in patients with normal tension glaucoma. Doppler studies on ophthalmic artery blood flow could assist with glaucomatous diagnosis or shed light on an underlying vascular dysfunction.128
Optical Coherence Tomography
Girkin et al129 reported that Indian and Hispanic patients had thicker global RNFL measurements, whereas people of African descent had thinner macular inner retinal thickness. Increasing age was associated with a reduction of rim area by 0.005 mm2/y, a decrease of RNFL thickness by 0.18 μm/y, and a reduction of inner retinal thickness by 0.1 μm/y.129 Another unique feature of OCT that was introduced was a novel, digital, 3D-enhanced depth imaging OCT based on SD-OCT technology.130 This technique was developed to visualize the full thickness of the choroid and the lamina cribrosa. With 3D images of the optic nerve head and lamina cribrosa, this method facilitates a better evaluation of glaucomatous and nonglaucomatous forms of optic neuropathy. Thus, the better detail and image quality could also be helpful in distinguishing between mechanisms.131 In a study that examined 25 patients with clinically definite MS and 25 healthy controls, SD-OCT measurements of RNFL thickness were recorded in the acute phase of ON and again after 3 months. The SD-OCT was able to detect optic nerve edema and prior, clinically unrecognized optic nerve injury within patients with MS. This suggests a possible role for SD-OCT in diagnosing clinically silent ON in patients with MS or following the severity of optic nerve damage in this disease.132 Another study investigated the use of SD-OCT in MS by manually measuring GCL volume in SD-OCT images and correlating these volumes to visual function. The results showed that patients with MS had significantly lower GCL volumes than control eyes and even lower volumes in eyes with a documented history of ON. Decreased GCL volumes were also associated with worse performance on low-contrast letter acuity testing, suggesting that SD-OCT images could possibly be used in the prediction of visual performance in MS.133
There has been an increased focus on the use of macular OCT in neuro-ophthalmology. A strong correlation has been shown between both RNFL thickness and visual threshold; similarly, a strong correlation is also shown between macular GCL thickness and visual sensitivity. Other disorders affecting the outer retina can also be correlated to the thickness of the photoreceptor layer. More specifically, in MS/ON, macular OCT can be used to quantify and monitor the demyelinating process. In NAION, the macular OCT cannot monitor peripapillary RNFL loss well because this portion of the RNFL is often acutely edematous. Therefore, in following up patients with NAION, RNFL thickness elsewhere must be preferentially monitored. Macular OCT might also help differentiate between arteritic and nonarteritic ischemic optic neuropathy because more outer retinal layer disruption would point toward an arteritic rather than nonarteritic etiology. Other potential uses for macular OCT might include a prognostic value in compressive optic neuropathy, differentiating papilledema from pseudopapilledema, and differentiating optic neuropathy from retinopathy.134 In cat-scratch disease neuroretinitis, macular OCTs from all patients showed flattening of the foveal contour, thickening of the neurosensory retina, and accumulation of subretinal fluid in all studied eyes, although not all of these elements were evident on clinical examination.135
Neuro-ophthalmic Findings During Space Flight
Mader et al136 reviewed the ophthalmic findings in 7 individuals after long-duration space flight and found disc edema, globe flattening, and choroidal folds (n = 5), cotton wool spots (n = 3), RNFL thickening by OCT (n = 6), and decreased near vision (n = 6). Five had a hyperopic shift greater than or equal to +0.50 diopters as compared with their preflight refractions. Lumbar punctures performed in 4 astronauts with disc edema documented opening pressures of 22, 28.5, 21, and 28 cm H2O. The LPs were performed at 60, 57, 19, and 12 days after mission, respectively. The authors proposed that these changes could be the result of microgravity-induced increased ICP, similar to increased ICP findings as described in IIH. However, in the microgravity environment, these changes could be due to the secondary result of cephalad shifts in blood fluid volume and increased venous congestion. The second possible explanation could be that the disc changes could be due to local factors at the level of the choroid and intraorbital optic nerve due to local fluid dysregulation, or less likely, secondary to ocular hypotony (although in flight IOP measurements have been normal in astronauts). Further study is needed to elucidate the exact mechanisms.136 Berdahl et al137 proposed a similar but combined mechanism for the ophthalmic findings observed during space flight and suggested that the combination of elevated ICP and decreased IOP was the cause of the findings because of the difference between these 2 pressures across the lamina cribrosa. The translaminar differences between the IOP and ICP could be causing a reversal of the normal translaminar pressure. This, in return, could lead to a slowing of orthograde axonal transport with resultant ODE.137
A New Neuro-ophthalmic Syndrome
A new neuro-ophthalmic syndrome has recently been described, consisting of congenital macular dystrophy, corpus callosum agenesis, and hippocampi hypoplasia in multiple members of a consanguineous family.138
Eye Closure–Induced Tinnitus
Symptomatically intermittent tinnitus while blinking was reported in 2 cases from Japan. In both patients, tinnitus was transient, only occurred during the movement of the eyelid, and did not last more than a few seconds after eyelid movement ceased. Electrophysiologic testing revealed the cause to be muscular tinnitus caused by abnormal stapedial muscle contraction. It was postulated that this was a form of synkinesis where the stimulus from the facial nerve to the orbicularis oculi muscle was redirected toward the stapedial muscle, causing tinnitus during eyelid blinking.139
Photophobia is a relatively common but poorly understood symptom in patients with normal ocular examination results. Different treatments for unexplained photophobia have been described including the use of tinted lenses to particular wavelengths, sedatives or antianxiolytic medications, or even injections [supraorbital nerve injection, orbital alcohol injection (1.5 mL), botulism toxin injection, or lidocaine-mediated superior cervical sympathetic blockade].140
This annual review provides a brief update on a number of neuro-ophthalmic conditions that might be of interest to the practicing clinical ophthalmologist.
1. Ichhpuiani P, Rome J, Jindal A, et al.. Comparative study of 3 techniques to detect a relative afferent pupillary defect. J Glaucoma
. 2011; 20: 535–539.
2. Yotharak P, Aui-Aree N. Correlation between clinical grading and quantification by neutral density filter of relative afferent pupillary defect (RAPD). J Med Assoc Thai
. 2012; 95 (Suppl 4): S92–S95.
3. Kelly-Sell M, Liu G. “Tonic” but not “Adie” pupils. J Neuroophthalmol
. 2011; 31: 393–395.
4. Cambron M, Maertens H, Crevits L. Apraclonidine and my pupil. Clin Auton Res
. 2011; 21: 347–351.
5. Besada E, Reed K, Najman P, et al.. Pupillometry study of brimonidine tartrate 0.2% and apraclonidine 0.5%. J Clin Pharmacol
. 2011; 51: 1690–1695.
6. O’Connor J, Rochford M, O’Connor G, et al.. Pharmacologic diagnosis of Horner’s syndrome in the emergency department. Emerg Med J
. 2011; 28: 729.
7. Cooper-Knock J, Pepper I, Hodgson T, et al.. Early diagnosis of Horner syndrome using topical apraclonidine. J Neuroophthalmol
. 2011; 31: 214–216.
8. Kang N, Lim K, Sung S. Horner’s syndrome with abducens nerve palsy. Korean J Ophthalmol
. 2011; 25: 459–462.
9. Goel S, Burkat C. Unusual case of persistent Horner’s syndrome following epidural anaesthesia and caesarean section. Indian J Ophthalmol
. 2011; 59: 389–391.
10. Agarwal P, Lim L, Park S, et al.. Alternating Horner’s syndrome in multiple sclerosis. Semin Ophthalmol
. 2012; 27: 40–41.
11. Strowd R, Scott B, Walker F. Black widow spider envenomation, a rare cause of Horner’s syndrome. Wilderness Environ Med
. 2012; 23: 158–160.
12. Ramos R, Ureña A, Rivas F, et al.. Impact of T3 thorascopic sympathectomy on pupillary function: a cause of partial Horner’s syndrome? Surg Endosc
. 2012; 26: 1146–1152.
13. Kava M, Bynevelt M, Lannigan F, et al.. Horner’s syndrome in a child with otitis media: an unusual complication. Pediatr Neurol
. 2011; 45: 209–210.
14. Knyazer B, Levy J, Rosenberg E, et al.. Horner’s syndrome in an infant with complicated pneumonia. Isr Med Assoc J
. 2011; 13: 504–506.
15. Ghosh P, Indulkar S. Horner’s syndrome as complication of extracorporeal membrane oxygenation in a neonate. J Pediatr
. 2012; 160: 349–349.e1.
16. Bulder M, Gijn J. The man in black with headache, photophobia and fixed pupils. Pract Neurol
. 2011; 11: 231–233.
17. Dunlop C. Ipsilateral pupil dilation associated with unilateral intermittent exotropia: a new observation. Clin Experiment Ophthalmol
. 2011; 39: 839–841.
18. Centeno M, Feldmann M, Harrison NA, et al.. Epilepsy causing pupillary hippus: an unusual semiology. Epilepsia
. 2011; 52: e93–e96.
19. Daniels L, Nichols D, Seifert M, et al.. Changes in pupil diameter entrained by cortically initiated changes in attention. Vis Neurosci
. 2012; 29: 131–142.
20. Sadek A, Kirkham F, Barker S, et al.. Seizure-induced miosis. Epilepsia
. 2011; 52: e199–e203.
21. Huh Y, Kim J. Patterns of spontaneous and head-shaking nystagmus in cerebellar infarction: imaging correlations. Brain
. 2011; 134 (Pt 12): 3662–3671.
22. Jeong S, Kim E, Lee J, et al.. Patterns of dissociate torsional-vertical nystagmus in internuclear ophthalmoplegia. Ann N Y Acad Sci
. 2011; 1233: 271–278.
23. Tusscher T. A neural model for cyclovertical eye movements and their disorders. Strabismus
. 2011; 19: 162–165.
24. Wray SH, Dalmau J, Chen A, et al.. Paraneoplastic disorders of eye movements. Ann N Y Acad Sci
. 2011; 1233: 279–284.
25. Serra A, Ruff R, Kaminski H, et al.. Factors contributing to failure of neuromuscular transmission in myasthenia gravis and the special case of the extraocular muscles. Ann N Y Acad Sci
. 2011; 1233: 26–33.
26. Singman E, Matta N, Silbert D. Use of the Cogan lid twitch to identify myasthenia gravis. J Neuroophthalmol
. 2011; 31: 239–240.
27. Witoonpanich R, Dejthevaporn C, Sriphrapradang A, et al.. Electrophysiological and immunological study in myasthenia gravis: diagnostic sensitivity and correlation. Clin Neurophysiol
. 2011; 122: 1873–1877.
28. Erdurmus M, Celebi S, Ozmen S, et al.. Isolated lateral rectus muscle involvement as a presenting sign of euthyroid Graves disease. J AAPOS
. 2011; 15: 395–397.
29. Maheshwari R, Weis E. Thyroid associated orbitopathy. Indian J Ophthalmol
. 2012; 60: 87–93.
30. Stan M, Garrity J, Bahn R. The evaluation and treatment of graves ophthalmopathy. Med Clin North Am
. 2012; 96: 311–328.
31. Sanchez-Orgaz M, Grabowska A, Royo-Oreja A, et al.. Optic neuropathy following orbital irradiation for Graves’ ophthalmopathy: a case report and literature review. Orbit
. 2012; 31: 30–33.
32. Cardoso C, Giordani A, Wolosker A, et al.. Protracted hypofractionated radiotherapy for Graves’ ophthalmopathy: a pilot study of clinical and radiologic response. Int J Radiat Oncol Biol Phys
. 2012; 82: 1285–1291.
33. Heireman S, Delaey C, Claerhout I, et al.. Restrictive extraocular myopathy: a presenting feature of acromegaly. Indian J Ophthalmol
. 2011; 59: 517–519.
34. Avni-Zauberman N, Tripathy D, Rosen N, et al.. Relapsing migratory idiopathic orbital inflammation: six cases and review of the literature. Br J Ophthalmol
. 2012; 96: 276–280.
35. Cullen J, CHung S. Non-arteritic anterior ischaemic optic neuropathy (NA-AION): outcome for visual acuity and visual field defects, the Singapore scene 2. Singapore Med J
. 2012; 53: 88–90.
36. Hayreh S, Zimmerman M. Nonarteritic anterior ischemic optic neuropathy. Role of systemic corticosteroid therapy. Graefes Arch Clin Exp Ophthalmol
. 2008; 246: 1029–1046.
37. Hayreh S. Vascular disorders in neuro-ophthalmology. Curr Opin Neurol
. 2011; 24: 6–11.
38. Salgado C, Vilson F, Miller N, et al.. Cellular inflammation in nonarteritic anterior ischemic optic neuropathy and its primate model. Arch Ophthalmol
. 2011; 129: 1583–1591.
39. Rebolleda G, Perez-Lopez M, Casas-Llera P, et al.. Visual and anatomical outcomes of non-arteritic anterior ischemic optic neuropathy with high-dose systemic corticosteroids. Graefes Arch Clin Exp Ophthalmol
. March 24, 2012 [Epub ahead of press].
40. Dickersin K, Manheimer E, Li T. Surgery for nonarteritic anterior ischemic optic neuropathy. Cochrane Database Syst Rev
. 2012; 1:CD001538.
41. Choudhari N, Neog A, Fudnawala V, et al.. Cupped disc with normal intraocular pressure: the long road to avoid misdiagnosis. Indian J Ophthalmol
. 2011; 59: 491–497.
42. Chi S, Stinnett S, Eggenberger E, et al.. Clinical characteristics in 53 patients with cat scratch optic neuropathy. Ophthalmology
. 2012; 119: 183–187.
43. Zhang J, Pau D, Lee A. Postinfectious optic neuropathy in endemic typhus. J Neuroophthalmol
. 2011; 31: 342–343.
44. Passman R, Bennett C, Purpura J, et al.. Amiodarone-associated optic neuropathy: a critical review. Am J Med
. 2012; 125: 447–453.
45. Sanaei-Zadeh H, Zamani N. A case of optic nerve atrophy with severe disc cupping after methanol poisoning. Korean J Ophthalmol
. 2011; 25: 463; author reply 463.
46. Koehrer P, Creuzot-Garcher C, Bron A. Methanol poisoning: two case studies of blindness in Indonesia. Int Ophthalmol
. 2011; 31: 517–524.
47. Traber G, Baumgartner M, Schwarz U, et al.. Subacute bilateral visual loss in methylmalonic acidemia. J Neuroophthalmol
. 2011; 31: 344–346.
48. Urolagin S, Kotrashetti S, Kale T, et al.. Traumatic optic neuropathy after maxillofacial trauma: a review of 8 cases. J Oral Maxillofac Surg
. 2012; 70: 1123–1130.
49. Yang Q, Zhang G, Liu X, et al.. The therapeutic efficacy of optic nerve decompression and its effects on the prognoses of 96 cases of traumatic optic neuropathy. J Trauma Acute Care Surg
. 2012; 72: 1350–1355.
50. McClelland C, Van Stavern G, Tselis A. Leber hereditary optic neuropathy mimicking neuromyelitis optica. J Neuroophthalmol
. 2011; 31: 265–268.
51. Amaral-Fernandes M, Marcondes A, Miranda P, et al.. Mutations for Leber hereditary optic neuropathy in patients with alcohol and tobacco optic neuropathy. Mol Vis
. 2011; 17: 3175–3179.
52. Pakdel F, Pirmarzdashty N, Sanjari M, et al.. Optic atrophy in thalassemia intermedia. J Neuroophthalmol
. 2011; 31: 252–254.
53. Kezuka T, Usui Y, Yamakawa N, et al.. Relationship between NMO-antibody and anti-MOG antibody in optic neuritis. J Neuroophthalmol
. 2012; 32: 107–110.
54. Fernandes D, Ramos Rde I, Falcochio C, et al.. Comparison of visual acuity and automated perimetry findings in patients with neuromyelitis optica or multiple sclerosis after single or multiple attacks of optic neuritis. J Neuroophthalmol
. 2012; 32: 102–106.
55. Yoshimine S, Sakai T, Ogasawara M, et al.. Anti–aquaporin-4 antibody–positive familial neuromyelitis optica in mother and daughter. Jpn J Ophthalmol
. 2011; 55: 647–650.
56. Galetta KM, Graves J, Talman LS, et al.. Visual pathway axonal loss in benign multiple sclerosis: a longitudinal study. J Neuroophthalmol
. 2012; 32: 116–123.
57. Tátrai E, Simó M, Iljicsov A, et al.. In vivo evaluation of retinal neurodegeneration in patients with multiple sclerosis. PLoS One
. 2012; 7: e30922.
58. Klistorner A, Garrick R, Paine M, et al.. Relationship between chronic demyelination of the optic nerve and short term axonal loss. J Neurol Neurosurg Psychiatry
. 2012; 83: 311–314.
59. Fraser C, Holder G. Electroretinogram findings in unilateral optic neuritis. Doc Ophthalmol
. 2011; 123: 173–178.
60. Garcia-Martin E, Pueyo V, Almarcegui C, et al.. Risk factors for progressive axonal degeneration of the retinal nerve fibre layer in multiple sclerosis patients. Br J Ophthalmol
. 2011; 95: 1577–1582.
61. Alpay A, Guney T, Unal A, et al.. Comparison of retinal nerve fibre layer thickness with visual evoked potential and visual field in patients with multiple sclerosis. Clin Experiment Ophthalmol
. 2012; 40: e25–e31.
62. Moon C, Hwang S, Ohn Y, et al.. The time course of visual field recovery and changes of retinal ganglion cells after optic chiasmal decompression. Invest Ophthalmol Vis Sci
. 2011; 52: 7966–7973.
63. Monteiro M, Hokazono K, Cunha L, et al.. Multifocal pattern electroretinography for the detection of neural loss in eyes with permanent temporal hemianopia or quadrantanopia from chiasmal compression. Br J Ophthalmol
. 2012; 96: 104–109.
64. Simon S, Torpy D, Brophy B, et al.. Neuro-ophthalmic manifestations and outcomes of pituitary apoplexy—a life and sight-threatening emergency. N Z Med J
. 2011; 124: 52–59.
65. Fraser J, Newman N, Biousse V. Disorders of the optic tract, radiation, and occipital lobe. Handb Clin Neurol
. 2011; 102: 205–221.
66. Bruce B, Biousse V, Newman N. Update on idiopathic intracranial hypertension. Am J Ophthalmol
. 2011; 152: 163–169.
67. Biousse V, Bruce B, Newman N. Update on the pathophysiology and management of idiopathic intracranial hypertension. J Neurol Neurosurg Psychiatry
. 2012; 83: 488–494.
68. Digre K. Neuro-ophthalmology and pregnancy: what does a neuro-ophthalmologist need to know? J Neuroophthalmol
. 2011; 31: 381–387.
69. Thurtell M, Bruce B, Rye D, et al.. The Berlin questionnaire screens for obstructive sleep apnea in idiopathic intracranial hypertension. J Neuroophthalmol
. 2011; 31: 316–319.
70. Carta A, Favilla S, Prato M, et al.. Accuracy of fundoscopy to identify true edema versus pseudoedema of the optic disc. Invest Ophthalmol Vis Sci
. 2012; 53: 1–6. Print 2012 Jan.
71. Sibony P, Kupersmith M, Rohlf F. Shape analysis of the peripapillary RPE layer in papilledema and ischemic optic neuropathy. Invest Ophthalmol Vis Sci
. 2011; 52: 7987–7995.
72. Rosenberg J, Shiloh A, Savel R, et al.. Non-invasive methods of estimating intracranial pressure. Neurocrit Care
. 2011; 15: 599–608.
73. Warden K, Alizai A, Trobe J, et al.. Short-term continuous intraparenchymal intracranial pressure monitoring in presumed idiopathic intracranial hypertension. J Neuroophthalmol
. 2011; 31: 202–205.
74. Jeong W, Rhee K. Hemodynamics of cerebral aneurysms: computational analyses of aneurysm progress and treatment. Comput Math Methods Med
. 2012; 2012: 782–801.
75. Jeon T, Jeon P, Kim K. Prevalence of unruptured intracranial aneurysm on MR angiography. Korean J Radiol
. 2011; 12: 547–553.
76. Costalat V, Sanchez M, Ambard D, et al.. Biomechanical wall properties of human intracranial aneurysms resected following surgical clipping (IRRAs Project). J Biomech
. 2011; 44: 2685–2691.
77. Abouaf L, Girard N, Lefort T, et al.. Standard-fractionated radiotherapy for optic nerve sheath meningioma: visual outcome is predicted by mean eye dose. Int J Radiat Oncol Biol Phys
. 2012; 82: 1268–1277.
78. Stiebel-Kalish H, Reich E, Gal L, et al.. Visual outcome in meningiomas around anterior visual pathways treated with linear accelerator fractionated stereotactic radiotherapy. Int J Radiat Oncol Biol Phys
. 2012; 82: 779–788.
79. Barrow D, Spector R, Braun I, et al.. Classification and treatment of spontaneous carotid-cavernous sinus fistulas. J Neurosurg
. 1985; 62: 248–256.
80. Grumann A, Boivin-Faure L, Chapot R, et al.. Ophthalmic outcome of direct and indirect carotid cavernous fistulas. Int Ophthalmol
. 2012; 32: 153–159.
81. Miller N. Dural carotid-cavernous fistulas: epidemiology, clinical presentation, and management. Neurosurg Clin N Am
. 2012; 23: 179–192.
82. Masaya-Anon P. Isolated oculomotor nerve palsy in a white-eyed patient with dural carotid-cavernous sinus fistulas: a case report. J Med Assoc Thai
. 2012; 95 (Suppl 4): S143–S146.
83. Barry R, Wilkinson M, Ahmed R, et al.. Interventional treatment of carotid cavernous fistula. J Clin Neurosci
. 2011; 18: 1072–1079.
84. Fard M, Kasaei A, Abdollahbeiki H. Acquired Brown syndrome: report of two cases. J AAPOS
. 2011; 15: 398–400.
85. Van Went C, Ozanne A, Saliou G, et al.. Spontaneous thrombosis of an orbital arteriovenous malformation revealing hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber disease). A case report. Interv Neuroradiol
. 2011; 17: 466–471.
86. Liu Y, Wang A, Yen M. “Seeing but not identifying”: pure alexia coincident with prosopagnosia in occipital arteriovenous malformation. Graefes Arch Clin Exp Ophtlmol
. 2011; 249: 1087–1089.
87. Johkura K, Nakae Y, Yamamoto R, et al.. Wrong-way deviation: contralateral conjugate eye deviation in acute supratentorial stroke. J Neurol Sci
. 2011; 308: 165–167.
88. Sakamoto Y, Kimura K, Iguchi Y, et al.. A small pontine infarct on DWI as a lesion responsible for wall-eyed bilateral internuclear ophthalmoplegia syndrome. Neurol Sci
. 2012; 33: 121–123.
89. Razak A, Clark D, Farooq M, et al.. Wallenberg’s syndrome with extradural-extracranial origin of the posterior inferior cerebellar artery. Neurol Sci
. 2011; 32: 711–713.
90. Kannan B, Balaji V, Kummararaj S, et al.. Cilioretinal artery occlusion following intranasal cocaine insufflations. Indian J Ophthalmol
. 2011; 59: 388–389.
91. Lee C, Hong I, Park S. Ophthalmic artery obstruction and cerebral infarction following periocular injection of autologous fat. Korean J Ophthalmol
. 2011; 25: 358–361.
92. Gallego-Pinazo R, España-Gregori E, Casanova B, et al.. Branch retinal vein occlusion during fingolimod treatment in a patient with multiple sclerosis. J Neuroophthalmol
. 2011; 31: 292–293.
93. Diviak I, Slankamenac P, Jovićević M, et al.. A case series of 22 patients with internal carotid artery dissection. Med Pregl
. 2011; 64: 575–578.
94. Nizam A, Yacoub H, McKinney J. Internal carotid artery dissection heralded by an oculomotor nerve palsy: case report and literature review. Neurologist
. 2011; 17: 333–337.
95. Sitaula R, Shah D, Singh D. The spectrum of ocular involvement in systemic lupus erythematosus in a tertiary eye care center in Nepal. Ocul Immunol Inflamm
. 2011; 19: 422–425.
96. Ohsie L, Murchison A, Wojno T. Lupus erythematosus profundus masquerading as idiopathic orbital inflammatory syndrome. Orbit
. 2012; 31: 181–183.
97. Schmidt J, Pulido J, Matteson E. Ocular manifestations of systemic disease in antineutrophil cytoplasmic antibody-associated vasculitis. Curr Opin Ophthamol
. 2011; 22: 489–495.
98. Tian G, Lu N, Yan R, et al.. Central retina artery occlusion and recurrent papillitis in a patient with incomplete Behçet’s disease. J Neuroophthalmol
. 2011; 31: 244–247.
99. Bienfang D, McKenna M, Papaliodis G, et al.. Case records of the Massachusetts General Hospital. Case 24-2011. A 36-year-old man with headache, memory loss, and confusion. N Engl J Med
. 2011; 365: 549–559.
100. Joe S, Kim J, Kwon S, et al.. Recurrent bilateral branch retinal artery occlusion with hearing loss and encephalopathy: the first case report of Susac syndrome in Korea. J Korean Med Sci
. 2011; 26: 1518–1521.
101. Anastasakis A, Dick A, Darnato E, et al.. Cancer-associated retinopathy presenting as retinal vasculitis with a negative ERG suggestive of on-bipolar cell pathway dysfunction. Doc Ophthamol
. 2011; 123: 59–63.
102. Borchers A, Gershwin M. Giant cell arteritis: a review of classification, pathophysiology, geoepidemiology, and treatment. Autoimmun Rev
. 2012; 11: A544–A554.
103. Gandhi J. The island of ischaemia: submacular choroidal nonperfusion in giant cell arteritis. Eye (Lond)
. 2012; 26: 480–481.
104. Alba M, Mena-Madrazo J, Reves E, et al.. Giant cell arteritis in Mexican patients. J Clin Rheumatol
. 2012; 18: 1–7.
105. Kermani T, Warrington K. Recent advances in diagnostic strategies for giant cell arteritis. Curr Neurol Neurosci Rep
. 2012; 12: 138–144.
106. Kraemer M, Metz A, Herold M, et al.. Reduction jaw opening: a neglected symptom of giant cell arteritis. Rheumatol Int
. 2011; 31: 1521–1523.
107. Goedhart-de Haan A, Pans SJ, Lensen KD, et al.. Vasculitis revealed by posterior stroke. Neth J Med
. 2012; 70: 81–83.
108. Imai N, Kuroda R, Konishi T, et al.. Giant cell arteritis: clinical features of patients visiting a headache clinic in Japan. Intern Med
. 2011; 50: 1679–1682.
109. Lugo JZ, Deitch JS, Yu A, et al.. Demographic and laboratory data may predict positive temporal artery biopsy. J Surg Res
. 2011; 170: 332–335.
110. Walvick M. Importance of clinical judgment in the diagnosis of temporal (giant cell) arteritis. J Neuroophthalmol
. 2011; 31: 397.
111. Helliwell T, Muller S, Hider S. ESR can be normal in giant cell arteritis and polymyalgia rheumatica. BMJ
. 2012; 344: e1408; author reply e1409.
112. Goslin B, Chung M. Temporal artery biopsy as a means of diagnosing giant cell arteritis: is there over-utilization? Am Surg
. 2011; 77: 1158–1160.
113. Habib H, Essa A, Hassan A. Color duplex ultrasonography of temporal arteries: role in diagnosis and follow-up of suspected cases of temporal arteritis. Clin Rheumatol
. 2012; 31: 231–237. 2011 Jul 9.
114. Chaigne B, Magnant J, Favelle O, et al.. 18 FDG PET/CT contribution in occult giant-cell arteritis. J Clin Rheumatol
. 2012; 18: 104–105.
115. Rowe F, Wright D, Brand D, et al.. Reading difficulty after stroke: ocular and non ocular causes. Int J Stroke
. 2011; 6: 404–411.
116. Sheldon CA, Abegg M, Sekunova A, et al.. The word-length effect in acquired alexia, and real and virtual hemianopia. Neuropsychologia
. 2012; 50: 841–851.
117. Papageorgiou E, Hardiess G, Wiethölter H, et al.. The neural correlates of impaired collision avoidance in hemianopic patients. Acta Ophthalmol
. 2012; 90: e198–e205.
118. Pelak VS, Smyth SF, Boyer PJ, et al.. Computerized visual field defects in posterior cortical atrophy. Neurology
. 2011; 77: 2119–2122.
119. Pula J, Daily J, DeSanto J. Radiology update in neuro-ophthalmology. Curr Opin Ophthalmol
. 2011; 22: 451–457.
120. Al-Moosa A, Eggenberger E. Neuroimaging yield in isolated Horner syndrome. Curr Opin Ophthalmol
. 2011; 22: 468–471.
121. Sudhakar P, Rodriguez F, Trobe J. MRI restricted diffusion in lymphomatous optic neuropathy. J Neuroophthalmol
. 2011; 31: 306–309.
122. Gupta A, Chazen J, Phillips C. Carcinoid tumor metastases to the extraocular muscles: MR imaging and CT findings and review of the literature. AJNR Am J Neuroradiol
. 2011; 32: 1208–1211.
123. Shimizu M, Suzuki Y, Kiyosawa M, et al.. Glucose hypermetabolism in the thalamus of patients with hemifacial spasm. Mov Disord
. 2012; 27: 519–525.
124. Rahmi A, Deshayes E, Maucort-Boulch D, et al.. Intraocular sarcoidosis: association of clinical characteristics of uveitis with findings from 18F-labelled fluorodeoxyglucose positron emission tomography. Br J Ophthalmol
. 2012; 96: 99–103.
125. Moisseiev E, Goldenberg D, Gold D, et al.. Imaging modalities in the diagnosis of transient central retinal artery occlusion. IMAJ
. 2012; 14: 329–330.
126. Ko F, DiBernardo C, Oak J, et al.. Confirmation and differentiation among primary vascular lesions using ultrasonography. Ophthal Plast Reconstr Surg
. 2011; 27: 431–435.
127. Stalmans I, Vandewalle E, Anderson DR, et al.. Use of colour Doppler imaging in ocular blood flow research. Acta Ophthalmol
. 2011; 89: e609–e630.
128. Abegao P, Vandewalle E, DeClerck E, et al.. Ophthalmic artery Doppler waveform changes associated with increased damage in glaucoma patients. Invest Ophthalmol Vis Sci
. 2012; 53: 2448–2453.
129. Girkin C, McGwin G Jr, Sinai M, et al.. Variation in optic nerve and macular structure with age and race with spectral-domain optical coherence tomography. Ophthalmology
. 2011; 118: 2403–2408.
130. Park S, De Moraes C, Teng C, et al.. Enhanced depth imaging optical coherence tomography of deep optic nerve complex structures in glaucoma. Ophthalmology
. 2012; 119: 3–9.
131. Lee E, Kim T, Weinreb R, et al.. Three-dimensional evaluation of the lamina cribrosa using spectral-domain optical coherence tomography in glaucoma. Invest Ophthalmol Vis Sci
. 2012; 53: 198–204.
132. Serbecic N, Beutelspacher S, Geitzenauer W, et al.. RNFL thickness in MS-associated acute optic neuritis using SD-OCT: critical interpretation and limitations. Acta Ophthalmol
. 2011; 89: e451–e460.
133. Davies E, Galetta K, Sackel D, et al.. Retinal ganglion cell layer volumetric assessment by spectral-domain optical coherence tomography in multiple sclerosis: application of a high-precision manual estimation technique. J Neuroophthalmol
. 2011; 31: 260–264.
134. Kardon R. Role of the macular optical coherence tomography scan in neuro-ophthalmology. J Neuroophthalmol
. 2011; 31: 353–361.
135. Habot-Wilner Z, Zur D, Goldstein M, et al.. Macular findings on optical coherence tomography in cat-scratch disease neuroretinitis. Eye (Lond)
. 2011; 25: 1064–1068.
136. Mader T, Gibson C, Pass A, et al.. Optic disc edema, globe flattening, choroidal folds, and hyperopic shifts observed in astronauts after long-duration space flight. Ophthalmology
. 2011; 118: 2058–2069.
137. Berdahl J, Fleischman D, Allingham R, et al.. Disc swelling and space flight. Ophthalmology
. 2012; 119: 1290; author reply 1291.
138. Bitoun P, Pipiras E, Rigaudiere F. Congenital macular dystrophy, corpus callosum agenesis, hippocampi hypoplasia—a novel neuro-ophthalmic syndrome: case report. Ophthalmic Genet
. 2012; 33: 39–43.
139. Ohki M, Kato H. Idiopathic tinnitus concomitant with eye closure. Otol Neurotol
. 2012; 33: 267–269.
140. Digre K, Brennan K. Shedding light on photophobia. J Neuroophthalmol
. 2012; 32: 68–81.