In this review, we highlight new clinically relevant literature in neuro-ophthalmology from the past year. It follows last year’s review using a similar format to update the comprehensive ophthalmologist.1 Topics covered are pupillary abnormalities, eye movement dysfunction, neuromuscular diseases, optic neuropathies, optic neuritis, demyelinating diseases including multiple sclerosis (MS), lesions of the optic chiasm and posterior primary visual pathways, elevated intracranial pressure (ICP), tumors and aneurysms affecting the visual pathways, vascular diseases, higher visual function, and imaging advances.
Relatively little was published regarding pupil abnormalities and examination. Chu and Sadun2 reported a patient with corectopia, a displacement of the pupil from its center, which when acquired is usually due to midbrain lesions with poor prognosis. However, their patient had a dural arteriovenous fistula with ectatic cortical draining veins. Corectopia persisted despite treatment of the lesion. Initially, it was thought that this pupil abnormality might represent Adie tonic pupil but dilute pilocarpine testing showed no denervation supersensitivity. The authors’ point is that acquired corectopia should prompt neuroimaging. Of course, this is a single report of a rare entity, and thus, evaluation for other common causes of corectopia (eg, trauma, Adie tonic pupil) should be considered first.
Multifocal pupil perimetry (mfPOP) is a new diagnostic technique that assesses visual function from the pupillary response to stimuli at 44 locations in the visual field. Ali et al3 used mfPOP to evaluate patients with MS and correlated results with disability scores. They found decent predictive power of mfPOP in relation to disability scores. Further investigation is needed, but this technique may have wider clinical implications.
Downbeat nystagmus (DBN) is the most common type of acquired nystagmus encountered by the ophthalmologist. It may be idiopathic but is typically seen in association with craniocervical junction abnormalities (eg, Chiari malformation), magnesium deficiency, and as part of a paraneoplastic syndrome (anti-Purkinje cell antibodies). Cai et al4 reported DBN due to cerebellar swelling and cervicomedullary junction compression in a patient with familial hemophagocytic lymphohistiocytosis. This is a rare autosomal recessive disorder characterized by severe inflammation due to defective natural killer cell function. Common manifestations include fever, splenomegaly, cytopenia, hypertriglyceridemia, hemophagocytosis, low natural killer cell activity, elevated ferritin, and elevated CD25. The DBN improved with treatment of the cerebellar edema.
The treatment of DBN can be frustrating, in particular when no underlying cause is found. A randomized double-blind, crossover trial looked at the effect of 4-aminopyridine on DBN in 27 patients.5 Five milligrams of 4-aminopyridine 4 times a day reduced slow phase velocity and improved near visual acuity.
Although not nystagmus, superior and inferior oblique myokymia may be mistaken for nystagmus. These conditions are both monocular, high-frequency, low-amplitude contractions that produce torsional oscillopsia. Smith and Cornblath6 reported a patient who presented with alternating left versus right hypertropia. Testing and treatment for myasthenia gravis (MG) were negative. Several months later, she developed both intermittent incyclotorsion and excyclotorsion of the right eye. The authors felt that this represented both superior and inferior oblique myokymia. The exact mechanism of this phenomenon is not clear.
Ocular Motor Cranial Nerves/Brainstem
Presumed microvascular or vasculopathic cranial nerve palsies are considered a common cause of spontaneously resolving diplopia in patients older than age 50. These patients may undergo minimal evaluation except for a check of vascular risk factors (eg, diabetes mellitus, hypertension, hypercholesterolemia). Tamhankar et al7 reported a prospective, multicenter observational series of 109 patients with acute isolated ocular motor cranial nerve palsy. Eighteen (16.5%) had a cause other than microvascular ischemia. Other causes included midbrain ischemia, pituitary apoplexy, neoplasm, inflammation, and giant cell arteritis. They suggest that magnetic resonance imaging (MRI) should be part of the evaluation in such patients. There is controversy regarding this recommendation, and an alternate approach would be to observe these patients and if they do not have spontaneous improvement in 6 weeks, then imaging may be necessary.
Anagnostou et al8 looked retrospectively at 149 patients presenting with painful ophthalmoplegia in the emergency department. Thirty-four met the criterion of acute (ie, ≤3 days’ duration). Common etiologies were presumed microvascular, migraine, sarcoidosis, and Tolosa-Hunt syndrome. However, few recommendations could be made regarding a cookbook approach to evaluation of these patients.
Chhabra and Golnik9 retrospectively reviewed 18 patients from a single practice with herpes zoster–related diplopia to provide prognostic information on resolution of the diplopia. Fourteen patients had single ocular motor cranial neuropathy and 4 patients had more than 1 nerve involved. Seventeen (94%) of the patients had resolution of diplopia in primary position although 8 (44%) of these patients had diplopia in some position of gaze.
Ocular neuromyotonia is a fairly rare condition in which there is sustained undesired contraction of 1 or more muscles innervated by a single ocular motor cranial nerve. Although most often reported after irradiation of the parasellar region, Cruz et al10 reported a partial third nerve palsy and ocular neuromyotonia due to third nerve compression by a displaced posterior communicating artery. The neuromyotonia resolved after treatment with carbamazepine but the third nerve palsy persisted.
Patients with seemingly isolated sixth nerve palsies may have small vertical misalignments that might suggest some other cranial nerve dysfunction or other pathophysiology. Pihlblad and Demer11 retrospectively reviewed 79 patients with isolated, unilateral sixth nerve palsy. Alternate cover or Krimsky testing demonstrated vertical misalignment in 15 (19%) of 79 patients and Hess screen showed vertical misalignment in 32 (57%) of 56 patients.
Internuclear ophthalmoplegia due to disruption of the medial longitudinal fasciculus is most commonly due to demyelination in patients younger than age 50 and to lacunar stroke in older patients. Although there is a high rate of spontaneous improvement, symptoms and signs may persist chronically. Serra et al12 treated 3 patients with chronic bilateral internuclear ophthalmoplegia due to MS with dalfampridine (a potassium channel blocker). Eye movement recordings showed substantial improvements in binocular conjugacy and led the authors to suggest a randomized clinical trial.
Aberrant innervation is well known to occur in Duanes retraction syndrome and Marcus Gunn jaw-winking. Bursztyn and Makar13 report the unusual occurrence of congenital trochlear nerve-oculomotor nerve synkinesis in a 6-year-old boy. No ocular misalignment was present in any gaze but the right upper eyelid retracted in attempted down and left gaze. The authors propose a central origin to this phenomenon.
Diseases of Extraocular Muscles and the Neuromuscular Junction
Myasthenia gravis commonly presents to the ophthalmologist as diplopia and/or ptosis. Wong et al14 reviewed the data on ocular MG converting to systemic MG and potential disease-modifying treatments. The authors conclude that no good prognostic model exists regarding the likelihood of conversion to systemic MG. Although debate exists regarding corticosteroids’ “protective” effect in preventing systemic MG, the authors suggest that previous studies have many flaws and heterogenous patients. Alkhawajah and Oger15 reviewed “late-onset” MG defined as older than age 65. They found that the incidence of late-onset MG seems to be increasing and that treatment can be more difficult because of comorbidities. They stress the need for early intervention. Wang et al16 reported 1108 patients with MG seen in 1 hospital in China for a 3-year period. There was no overall sex predilection, but females were more likely to be diagnosed in their 30s and men in their 60s.
Myasthenia gravis in the non-Asian population is much less common in the pediatric or juvenile age group but it does occur. VanderPluym et al17 studied pediatric MG in Canada by using the established Canadian Pediatric Surveillance Program. In 2 years, 57 patients were confirmed. Thirty-four had generalized MG, 18 had ocular MG, and 5 had congenital myasthenic syndromes. Pyridostigmine was fairly effective in both systemic and ocular MG. Marina et al18 reviewed the juvenile MG literature and found that ocular symptoms are common at onset.
Thyroid eye disease often causes diplopia due to extraocular muscle enlargement and restriction. Strabismus surgery is often postponed until after orbital decompression because this surgery might effect ocular alignment. Mainville and Jordan19 retrospectively reviewed 123 patients with thyroid eye disease who underwent orbital decompression surgery by 1 surgeon. They found that 26% had diplopia before surgery as compared with 41% after surgery. Interestingly, 9 patients (28% of those with preoperative diplopia) had complete resolution of diplopia after surgery, whereas 30% developed new diplopia postoperatively. They found that opening the periorbita significantly increased the risk of new-onset diplopia.
Congenital facial weakness is uncommon and can be present in a wide variety of conditions, and eye movement abnormalities can coexist. Moebius syndrome is characterized by nonprogressive facial weakness and unilateral or bilateral abduction deficits. Rucker et al20 studied 40 patients with Moebius syndrome to categorize patterns of eye movement abnormalities. They found that the most common pattern was bilateral horizontal palsy although vertical movement impairment, abduction deficits, and normal motility were also observed.
Divergence insufficiency pattern esotropia is a common cause of diplopia in elderly patients, but can lead to extensive investigation and is underappreciated by neurologists who may see these patients. Godts and Mathysen21 prospectively collected 87 elderly patients (age range, 62–91 years) with adult-onset distance esotropia. Sixty (69%) were female and none had diplopia at near. Esodeviation ranged from 2 to 18 prism diopters with a median of 6.75. All patients were successfully treated with prism and there were no additional long-term neurologic problems. These patients do not require extensive evaluation if the diplopia is slowly progressive and there are no other neurologic symptoms or signs.
OPTIC NERVE DISORDERS
Ischemic Optic Neuropathy
Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common optic nerve disorder in patients older than age 50. Nevertheless, we do not know the exact etiology and have no effective treatment. Hayreh offered his opinion regarding the pathogenesis of NAION as acute ischemia of multifactorial cause.22 He discussed systemic risk factors (eg, diabetes mellitus, atherosclerosis, hypertension) and local risk factors [eg, poor optic nerve head blood supply, raised intraocular pressure (IOP)]. Another precipitating factor may be nocturnal hypotension. He also provided detailed reasoning behind the results of his previous study showing that corticosteroid treatment is beneficial in patients with NAION who present with 20/70 or worse visual acuity.23 This study was a “patient choice” design looking at 613 consecutive patients with NAION who chose either no treatment or systemic corticosteroids (80 mg/d for 2 weeks then tapered for approximately 8 weeks). At 6 months from the onset of NAION, 69.8% of eyes with an initial visual acuity of 20/70 or worse and seen within 2 weeks of onset in the treated group had visual acuity improvement [95% confidence interval (CI), 57.3%–79.9%]. This was in contrast to the control group of untreated patients who had a 40.5% (95% CI, 29.2%–2.9%) visual improvement. Inherent bias in this study design limits the validity of this data. Kinori et al24 reported on 24 patients treated with intravenous methylprednisolone 1 gm/d for 3 days followed by a 2-week oral prednisone taper. They compared visual recovery versus 24 controls who received no treatment. No differences in visual outcomes were identified. Radoi et al25 retrospectively evaluated visual results of 36 patients with NAION [15 untreated and 21 treated with intravitreal triamcinolone (4 mg)]. They noted statistically significant improvements in both visual acuity and visual fields at 6 months in the treated group. The authors recommend a prospective controlled clinical trial. Inherent bias in the Hayreh study23 and disparity in other studies leave corticosteroid treatment for NAION controversial.
Risk factors for NAION include diabetes mellitus, hypertension, hypercholesterolemia, and a small, crowded optic disc (the disc-at-risk). Bilgin et al26 compared 27 patients with NAION and 27 age/sex/disease-matched controls. They found that patients with NAION had a statistically higher prevalence of obstructive sleep apnea. One must consider this disorder in patients with NAION, especially if there are few other risk factors.
Previous studies regarding whether visual outcomes are similar in eyes of patients with sequential NAION have conflicted. Hayreh and Zimmerman27 reported on 174 consecutive patients with sequential NAION. They found large differences between first and second eye involvement in both visual acuity and visual fields. They concluded that it is not possible to predict acuity and visual field grade in the second eye based on the first eye.
Although NAION is generally thought to occur primarily in individuals older than age 50, Arnold et al28 reported a retrospective comparative case series comparing 108 cases of NAION in patients younger than age 50 with 108 cases in people older than age 50. Interestingly, in their total group of 848 patients, 108 (12.7%) were younger than age 50 so perhaps this is not that unusual. They also found that chronic renal failure and migraine were more common in young people with NAION. In addition, younger patients with NAION were more likely to have second eye involvement.
In contrast to NAION, posterior ischemic optic neuropathy (PION) is much rarer and usually occurs in the setting of giant cell arteritis, dialysis, or prolonged surgical procedures (eg, spine and cardiac bypass). Al-Zubidi et al29 described a patient with PION associated with presumed alcohol abuse–related seizures and subsequent rhabdomyolysis-related renal failure. Diffusion-weighted MRI showed restricted diffusion in the optic nerve. Joos et al30 also reported a patient with magnetic resonance diffusion weighted imaging (MR-DWI) findings of PION associated with posterior reversible encephalopathy syndrome and hypertensive emergency.
This category of optic neuropathy is very heterogenous, and incidences vary greatly depending on where one lives. The spectrum of “autoimmune” optic neuropathies is expanding and was recently reviewed by Petzold and Plant.31 They discuss the following 6 phenotypes: (1) single isolated optic neuritis, (2) relapsing isolated optic neuritis (RION), (3) chronic RION, (4) neuromyelitis optica (NMO), (5) MS-associated optic neuritis, and (6) unclassified optic neuritis. Neuromyelitis optica and MS-associated optic neuritis will be discussed in a separate section of this review. They recommend testing for NMO antibodies (aquaporin 4 antibodies) in all patients with severe, atypical, or recurrent optic neuritis. In a different publication, the same authors reviewed 122 reported cases of chronic RION.32 They found that it is an idiopathic entity dependent on immunosuppression for control. They propose revised criteria for diagnosis including at least 2 episodes of optic neuritis, NMO-IgG negative, contrast enhancement of the inflamed optic nerve, and response to immunosuppressive treatment with relapse on withdrawal of treatment.
IgG-4 disease is an increasingly reported distinct entity characterized by elevated serum IgG-4 levels and IgG-r positive lymphoplasmacytic infiltration. The most common ophthalmic findings include enlargement of the lacrimal gland, extraocular muscles, and/or the infraorbital nerve. Takahashi et al33 reported a patient with presumed bilateral optic nerve involvement. He had biopsy-proven IgG-4 disease and evidence of bilateral optic nerve dysfunction. Vision improved after treatment with intravenous corticosteroids and slow oral corticosteroid taper.
Paraneoplastic optic neuropathy is mediated by antibodies directed against an underlying malignancy that cross-react with the optic nerve. Rahimy and Sarraf34 reviewed the literature and found that small cell lung cancer is the most common malignancy encountered. Visual loss is typically subacute, bilateral, and painless and progresses for days to weeks. Optic discs may seem normal, swollen, or atrophic. Most patients test positive for the antibody to a 62-kDa neuronal antigen, collapsing response-mediating protein 5 (CRMP-5, sometimes called CV2). Treatment consists of managing the underlying malignancy and immunosuppression.
Thyroid eye disease frequently results in optic neuropathy from compression by enlarged extraocular muscles in the orbital apex. Although orbital decompression can result in diplopia, it is still generally considered to be the treatment of choice to alleviate this compressive optic neuropathy. Curro et al35 retrospectively evaluated the efficacy of pulsed methylprednisolone for thyroid optic neuropathy. Forty eyes of 24 patients were treated with either 500- or 1000-mg pulsed intravenous methylprednisolone for 3 consecutive days and then repeated in 1 week. Steroids were then “tapered orally or intravenously” (no doses given). Forty percent of patients had resolution of optic neuropathy and did not require orbital decompression surgery. Persistently active orbital disease at 2 weeks after initial methylprednisolone was a poor prognostic factor. Shams et al36 retrospectively investigated whether orbital radiation affects the development of optic neuropathy in thyroid eye disease. They reviewed 351 patients with active thyroid eye disease but without optic neuropathy. Patients were divided into 2 groups, those who received corticosteroids alone and those who received both corticosteroids and orbital radiotherapy (20 Gy in 10 fractions for 2 weeks). After a mean follow-up of 3.2 years, 17% of the patients receiving only corticosteroids developed optic neuropathy versus 0% of those receiving both steroids and radiotherapy (P > 0.001). This does not mean that prophylactic radiation should be considered in all patients with thyroid eye disease because there are potential risks, and certainly more data are needed.
Invasive fungal sinusitis can be difficult to diagnose and cause optic neuropathy and even death. Thurtell et al37 retrospectively reviewed 14 consecutive patients to better characterize this entity and facilitate earlier diagnosis. Twelve of their patients were immunocompromised but 2 patients were not. Twelve of the 14 patients presented with painful orbital apex syndrome (optic neuropathy and dysfunction of cranial nerves 3, 4, or 6). Magnetic resonance imaging may show only orbital apical enhancement. The authors suggest that anyone presenting in this fashion (especially if immunocompromised) should be imaged immediately and have a biopsy promptly. Twelve of their 14 patients died, emphasizing the emergent nature of this condition.
Rappoport et al38 reported their experience with parainfectious optic neuritis and compared adults versus children. Ten children and 8 adults were seen for an 8-year period. Parainfectious optic neuritis is defined as optic neuritis occurring after an infectious disease (within 1 month), presumably on an autoimmune basis. They found that all patients had optic disc swelling and good visual outcomes. Children were more likely to have bilateral optic neuritis and acute disseminated encephalomyelitis.
Miscellaneous Optic Neuropathy
Radiation optic neuropathy is fairly rare and usually occurs 3 to 18 months after radiation of skull base tumors. Doses below 5200 cGy delivered in multiple small fractions are usually thought to be safe. Although rare, visual prognosis is usually poor. Leavitt et al39 investigated the risk of radiation optic neuropathy after single-fraction stereotactic radiotherapy for skull base tumors. They retrospectively reviewed 222 patients who underwent gamma knife radiosurgery. At a mean follow-up of 83 months, the rate of optic neuropathy was 0% if less than 12 Gy and 10% if greater than 12 Gy. Sanda et al40 reported a patient with a history of bilateral sequential optic neuritis years before radiation for cystic adenoid carcinoma. The right optic nerve was reported to receive 19.9 Gy and the left received 53 Gy. It is unclear whether these doses are accurate because the authors then conclude that a history of optic neuritis might lower the threshold for radiation optic neuropathy. If these doses are correct, they are far above threshold and either way, 1 case is not convincing.
Kisimbi et al41 reported optical coherence tomography (OCT) findings in an epidemic of optic neuropathy occurring in younger individuals in Dar es Salaam, Tanzania, characterized by bilateral subacute central visual loss. This “endemic optic neuropathy” was noted to present similar to both nutritional and Leber optic neuropathy. However, testing for these conditions was negative. They found microcystic macular changes in 12.5% of 128 patients although similar changes can be seen in a variety of other optic neuropathies. Further work needs to be conducted to elucidate the cause of this condition.
Haines and Longmuir42 reported an unusual case of biotinidase deficiency causing optic neuropathy in a 19-year-old man. His condition was diagnosed as a newborn and given the appropriate supplementation. At age 10, these were discontinued without apparent ill effect. At the age of 19, he developed bilateral optic neuropathy for several weeks. The authors speculate that occasional binge drinking of alcohol may have played a role. Presentation was similar to Leber optic neuropathy, and biotin is important for normal mitochondria function and maintaining mitochondrial complex IV.
Moloney et al43 reported a woman who developed bilateral optic disc swelling 2 weeks after starting docetaxel (Taxotere) for breast cancer. The findings from extensive evaluation including MRI and lumbar puncture were normal. The authors speculate that the pathophysiology was either ischemic or neurotoxic (mechanism unclear). The relatively good recovery would speak more toward the neurotoxic etiology.
Skidd et al44 provided a good review of the genetics and clinical manifestations of autosomal dominant optic neuropathy (ADOA). They emphasize the clinical presentation, findings, and what is referred to as ADOA+, when additional clinical manifestations accompany ADOA. These manifestations include sensorineuronal deafness, progressive external ophthalmoplegia ataxia, and/or myopathy. The OPA1 gene (chromosome 3) mutations are found in 32% to 89% of patients with typical features of ADOA. New mutations in this gene are being discovered frequently. Unfortunately, at least in the United States, the testing is expensive and as yet does not lead to effective treatment.
Optic nerve cupping is typically associated with glaucoma, but a variety of neuro-ophthalmic conditions can produce this finding. Fraser et al45 reviewed the nonglaucomatous causes of cupping. Their extensive review covers congenital and acquired causes of cupping and distinguishing historical and clinical findings. In particular, they emphasize that neuro-ophthalmic pathology should be considered when visual fields do not correlate with cupping and neural rim pallor is present.
OPTIC NEURITIS, MULTIPLE SCLEROSIS, NEUROMYELITIS OPTICA
In Europe and North America, optic neuritis is a term usually used to refer to demyelinating optic neuropathy. In distinction to inflammatory optic neuropathies discussed previously, optic neuritis is not dependent on corticosteroids and usually improves without treatment. A significant percentage of patients go on to develop MS. Moss et al46 analyzed Optic Neuritis Treatment Trial data to investigate the associations of age, sex, and race/ethnicity with visual outcomes in this prospective controlled clinical trial conducted in North America. They found no relationship between age, sex, or treatment and visual outcomes. Black race/ethnicity was significantly associated with poorer visual acuity and contrast sensitivity. Malik et al47 retrospectively reviewed 291 patients with MS who presented with optic neuritis as a first symptom. They found that men and patients who presented with severe visual loss (worse than 20/200) had worse recovery. Pediatric patients had better visual recovery. Interestingly, they found that low vitamin D levels were associated with more severe visual loss but not with visual recovery. The pathophysiology of this association is unclear.
In North America, most people have good visual recovery after an episode of optic neuritis (20/40 or better). Kupersmith et al48 prospectively studied the retinal nerve fiber layer (RNFL) with OCT in 25 patients 1 month and 6 months after they had acute optic neuritis. They found that 1-month RNFL thickness correlated with 6-month thickness and thus predicted the outcome of the optic neuritis attack. In other regions, visual prognosis is less well known. Saxena et al49 reported their prospective experience with 83 Indian patients thought to have optic neuritis. Subjects were included if they presented with evidence of unilateral or bilateral optic neuropathy of less than 4 weeks’ duration. Other optic neuropathies (eg, ischemic, infective, traumatic, toxic, hereditary, compressive) were excluded from the study, although it is not clear how these diagnoses were determined. All patients were treated with intravenous dexamethasone, 200 mg/d for 3 days. Papillitis was more common than retrobulbar optic neuritis (54% vs 46%). Only 64% of eyes improved to 20/40 or better. Magnetic resonance imaging was not performed and mean follow-up duration was 10.8 months. Thus, it would seem that there are some differences between optic neuritis in the Indian population and North Americans. However, the limited information on how patients were excluded from this study makes it difficult to be more specific. Toosy et al50 provided an extensive and detailed review of the optic neuritis literature for the past 10 years. They provided crucial differentiating features of typical versus atypical optic neuritis and related treatment ramifications.
The association between optic neuritis and MS has been well established. Marques et al51 retrospectively evaluated patients with normal brain MRI at the time of the first episode of optic neuritis to determine conversion to MS. Ten of the 42 patients developed MS during an 8-year follow-up. Conversion was more likely if there were previous symptoms suggestive of MS, presence of cerebrospinal fluid oligoclonal bands, and incomplete visual recovery. Presence of optic disc swelling correlated with a lower MS conversion rate. This represents a conversion rate similar to the reported 15-year rate observed in the Optic Neuritis Treatment Trial.
Gabilondo et al52 studied OCT images of the RNFL in 100 patients with MS and posterior visual pathway damage as measured by 3T brain MRI. They found that RNFL thinning was associated with atrophy of the posterior visual pathways and visual cortex. This suggests the possibility of transsynaptic degeneration.
Much has been learned about NMO since the association between it and the aquaporin-4 molecule antibody (NMO-Ab) was established. Patients with NMO can initially be confused as having optic neuritis. Lim et al53 tried to identify factors that distinguish between optic neuritis and NMO. They found female sex and bilateral optic nerve involvement more likely in NMO patients. The optic chiasm was more likely to be affected in NMO and brain MRI abnormalities were less likely. Patients with NMO were more likely to have persistent severe loss of vision. Sato et al54 found that during attacks, the cerebrospinal fluid (CSF) aquaporin-4 levels correlated with markers for inflammatory response whereas serum levels did not. They suggest that blocking the binding of aquaporin-4 antibodies to their antigen in the central nervous system may reduce subsequent damage.
There were 2 well-done reviews of the pathogenesis, clinical manifestations, and treatment for NMO.55,56 Recommended first-line treatments include azathioprine and rituximab. Other agents including methotrexate, mycophenolate mofetile, and mitoxanthrone are considered second-line. Kim et al57 reported data on a 5-year follow-up of rituximab showing a marked reduction in the relapse rate. Ramanathan et al58 reported their 18-month experience using methotrexate and also found a decrease in the annualized relapse rate. Mealy et al59 reported a retrospective multicenter analysis of 90 NMO patients looking at relapse rates in patients treated with azathioprine, mycophenylate, and/or rituximab. They found a marked reduction in the relapse rate for both rituximab and mycophenylate with 66% of patients using rituximab having complete remission. Azathioprine was less effective with a higher failure rate. They also found that when 1 of these drugs fails, switching to another can achieve remission.
Recently, myelin-oligodendrocyte glycoprotein antibodies (MOG-Abs) have been found in some patients with the clinical presentation of NMO but without the NMO antibody (NMO-Ab). Kitley et al60 reviewed clinical characteristics of their patients who tested positive for either NMO-Ab or MOG-Abs. They found that women were more likely to have NMO-Ab than MOG-Abs. The MOG-Abs–positive patients were more likely to present with bilateral or sequential events. The MOG-Abs–positive patients were more likely to have better outcomes and a lower relapse rate. Sato et al61 also investigated clinical characteristics of MOG-Abs–positive versus NMO-Ab–positive patients and found similar results. They found MOG-Abs–positive patients were more likely to be male, have bilateral optic neuritis, and have a single attack and better recovery. Thus, it would seem that a portion of patients who seem to have an NMO-type presentation with negative NMO-Ab may have MOG-Abs.
CHIASM AND POSTERIOR VISUAL PATHWAY
Optic chiasm disorders are typically compressive in nature. However, other entities can cause chiasmal dysfunction. Purvin and Kawasaki62 reviewed noncompressive chiasmal disorders. They grouped these entities into inflammation (eg, demyelination), infiltration by neoplasm (eg, glioma), toxic (eg, ethambutol), radiation, trauma, herniation, hereditary, and rarely, ischemia. Although MRI is very helpful in detecting compressive lesions, it is less specific for these other causes of chiasmal dysfunction.
The most common cause of chiasmal dysfunction is compression by pituitary macroadenoma. Ogra et al63 prospectively analyzed the demographics and pattern of visual field loss in 103 patients. Mean age was 54 years and the most common reason for presentation was visual loss (39%). Although bitemporal visual field defects were the most common abnormality (41%), homonymous hemianopsia was not rare (13%). Visual field loss was unilateral in 33% of patients with field loss, often altitudinal. The authors point out that a variety of visual presentations can occur, not just the typical bitemporal defect. Garcia et al64 investigated the prognostic value of OCT measurements of RFNL thickness in patients with chiasmal compression. Nasal RNFL thickness was a good prognostic factor for peripheral visual field recovery.
Several groups found abnormal RFNL thickness in patients with posterior visual pathway lesions suggesting transynaptic degeneration. Two groups looked at patients with MS and posterior visual pathway lesions.52,65 They studied OCT images of the RNFL in the setting of posterior visual pathway damage as measured by 3T brain MRI.52 They found that RNFL thinning was associated with atrophy of the posterior visual pathways and visual cortex. Keller et al66 performed a similar study but their patients had a variety of lesions including stroke, postsurgical, and infection. They also found a strong correlation between visual field defects and thinning of the corresponding RFNL.
Most posterior pathway lesions causing visual defects are well delineated on MRI, but the Heidenhain variant of Jakob-Creutzfelt disease and the visual variant of Alzheimer disease are exceptions. The visual variant of Alzheimer disease is fairly common whereas the Heidenhain variant is very rare. Parker et al67 reported a 3-patient case series of the latter condition. They found that all 3 patients had MR-DWI abnormalities and rapid neurologic and visual deterioration. Criterion standard diagnosis is made by pathologic findings of spongiform degeneration, gliosis, and neuronal loss, but MR-DWI may be a helpful adjunct.
HIGHER VISUAL FUNCTION
Tzekov and Mullan68 provided a good review of the myriad visual function abnormalities occurring in Alzheimer disease (AD). This disease of elderly patients will be encountered more frequently by ophthalmologists as average life expectancies increase. The pathogenesis of AD is thought to be related to the production of amyloid beta aggregates and accumulation of neurofibrillary tangles. Although vision is usually affected later in AD, there is a subset of patients who present with early visual symptoms. This has been called the visual variant of AD but has also been referred to as posterior cortical atrophy. Symptoms include difficulty reading, visual agnosia, and visual neglect. Partial homonymous hemianopsia may occur. Pal et al69 conducted a cross-sectional study of 55 patients with AD in India. They found visuoconstructional and visuoperceptual deficits were the most common forms of visual dysfunction. Thus, ventral visual pathway symptoms were more common than dorsal pathway symptoms. Other frequent but less common findings included object agnosia, prosopagnosia, visual hallucination, and simultanagnosia.
Kraft et al70 studied deficits in 128 patients with occipital, occipitotemporal, and occipitoparietal infarction. In addition to the common visual field defects and phosphenes, patients often reported anomia, difficulty reading, and memory deficits. Anomia and memory deficits were associated with lesions of the occipital inferior gyrus or the lingual gyrus of the hippocampus. This study emphasizes the importance of neuropsychological deficits in addition to the expected visual field abnormalities.
Bartolomeo et al71 studied cerebral achromatopsia in a patient with consecutive hemorrhagic lesions in bilateral occipitotemporal regions. They compared their case with a case published more than 100 years ago and speculated that the problem occurred in the V4 area. Although cortical lesions may affect color vision, this would seem to be fairly rare.
Schankin et al72 studied patients with “visual snow” who describe continuous tiny flickering dots in their entire visual field. Seventy of 120 patients also had migraine, and migraine was associated with symptoms of palinopsia as well. Typical migraine aura was associated with an increased likelihood of spontaneous photopsia. They found brain hypermetabolism in the right lingual gyrus and left cerebellar anterior lobe on positron emission tomography (PET) scan. The authors conclude that visual snow, migraine, and typical migraine aura are distinct syndromes.
INCREASED INTRACRANIAL PRESSURE AND RELATED ENTITIES
The Neuro-ophthalmology Research Disease Investigator Consortium Idiopathic Intracranial Hypertension (IIH) Study Group reported results of the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT).73 The IIHTT was a multicenter, double-masked, randomized, placebo controlled study of acetazolamide in patients with mild visual loss. All participants also participated in a lifestyle modification program focusing on weight loss. Patients received either placebo or acetazolamide at a maximally tolerated dose (up to 4 g/d). The main visual outcome was change in mean deviation as measured by Humphrey Field Analyzer. Grade of papilledema, quality of life, headache disability, and weight were also monitored for 6 months. They found that the use of acetazolamide in addition to weight loss compared with weight loss alone resulted in modest improvements in visual function. This “modest” improvement was the difference between 1.43 decibels (dB) in the acetazolamide group versus 0.71 dB in the placebo group, statistically but perhaps not clinically significant. The acetazolamide group also did better in terms of improvement in papilledema and quality of life. Keltner et al74 reported baseline visual field findings in the IIHTT. Most defects were nerve fiber bundle type (arcuate) combined with enlarged physiologic blind spot. Inferior defects were more common than superior. Wall et al75 reported the clinical profile of patients in the IIHTT. Mean age was 29 years and only 2.4% were men. Average body mass index was 39.9 and headache was the most common symptom. Transient visual obscurations occurred in 68%, back pain in 53%, and pulsatile tinnitus in 52%. Only 32% reported visual loss in this selected group of patients with mild perimetric defects.
McGeeney and Friedman76 reviewed proposed mechanisms of IIH pathophysiology. They concluded that it must be multifactorial including vascular and hormonal factors. Kelly et al77 looked at patients without IIH to characterize those with incidental transverse cerebral venous sinus stenosis. They found a very low rate of stenosis and concluded that this is uncommon outside of IIH, and patients found to have stenosis should be checked for papilledema.
The MRI findings in IIH include flattening of the posterior sclera, distension of the perioptic nerve subarachnoid space, tortuosity of the optic nerve sheath complex, and an empty sella. Saindane et al78 studied 46 patients with IIH and correlated visual outcome with MRI findings. They found that no MRI finding was predictive of visual outcome. Similarly, Padhye et al79 studied 35 patients with IIH and also found no correlation between MRI findings and vision.
Treatment of IIH can include weight loss (including bariatric surgery), medication (acetazolamide, Lasix), optic nerve sheath fenestration, cerebrospinal fluid diversion (ventriculo-peritoneal and lumbo-peritoneal shunting), and venous sinus stenting. Moreau et al80 retrospectively evaluated the safety and efficacy of optic nerve sheath fenestration in 568 eyes, 455 of which were for IIH, and concluded it to be relatively safe. Eight patients did require strabismus surgery to correct postoperative misalignment. No patient had permanent visual loss related to the surgery. Fonseca et al81 compared surgical outcomes of optic nerve sheath fenestration versus cerebrospinal fluid diversion surgery. Postoperative visual acuity did not differ between the 2 groups. Each group had an approximately 6-dB improvement in mean deviation measured by automated static perimetry. Gailloud and Miller82 provided a good review of emerging interventional neuroradiologic techniques including stenting for IIH. They reported their procedure and parameters for stenting, which includes a greater than 4 mm Hg gradient across the stenosis. Ahmed et al83 compared the cost of transverse venous sinus stenting versus cerebrospinal fluid diversion surgery. There was no significant difference in cost between stenting and shunting, either for the initial procedure or for subsequent stents or shunt revision. However, 87% of the stents placed required just 1 procedure whereas 45% of the shunts required only 1 surgery. Thus, stenting costs less than shunt surgery overall. This study did not evaluate visual outcomes.
There were several reports of spontaneous CSF leaks in patients with IIH. Perez et al84 reported 2 patients who presented with CSF rhinorrhea. After it was repaired, they both developed IIH. A third patient with known untreated IIH developed CSF rhinorrhea that resolved after placing the CSF shunt and repairing the leak. Allen et al85 reported 38 patients with spontaneous CSF otorrhea. Of the 22 who underwent postoperative lumbar puncture, 8 (36%) had elevated ICP. Of the 27 patients with MRI available for review, findings of increased ICP were present in 13 (48%). Chaaban et al86 prospectively evaluated 46 patients with 56 spontaneous CSF leaks for a 5-year period. All 21 of their patients who presented with recurrent CSF leaks had IIH. The other patients had an average ICP of 24.3 cm H2O before CSF leak repair and 32.3 mm H2O after repair. Individual ICP values were not given. Thus, it seems clear that ICP is associated with spontaneous CSF leaks. Direct causation has yet to be proven.
TUMOR AND ANEURYSM
Pituitary tumors are one of the most common intracranial lesions to cause neuro-ophthalmic deficits. Lee et al87 studied 170 eyes of 85 patients who underwent transsphenoidal resection of pituitary adenomas. Systemic and visual symptom duration, tumor size, and age did not correlate with postoperative visual acuity or visual field score (measured with Goldmann kinetic perimetry). Preoperative visual acuity did correlate with postoperative acuity and visual field score.
Avery et al88 reported 4 patients with pediatric optic pathway glioma (2 neurofibromatosis and 2 sporadic). They each underwent treatment with bevacizumab (intravenously 10 mg/kg per dose) because of progressive visual loss after other chemotherapy or proton-beam radiation. Interestingly, 3 patients had complete resolution of acuity or visual field loss in at least 1 eye. The authors speculate that bevacizumab’s antiangiogenic activity and resultant decreased blood vessel permeability may stop tumor expansion and decrease the inflammatory response.
Traynis et al89 reported an 18-year-old man who presented with seizures and gliomatosis cerebri. He was treated with subtotal resection of the tumor, radiation, and temozolamide. He did well for 20 months and then began to lose vision. The MRI showed infiltration of the optic chiasm and nerve. Funduscopy demonstrated massive optic disc infiltration. The authors are unaware of a similar case with optic disc infiltration.
Normal peripapillary nerve fiber layer as measured by OCT has been shown to correlate with better visual recovery in patients with pituitary tumors. Loo et al90 reported the prognostic value of OCT in patients with optic neuropathy due to skull base meningiomas. They retrospectively analyzed 14 eyes of 12 patients. Eyes with normal OCT of the peripapillary nerve fiber layer were more likely to improve after treatment. Fard et al91 used OCT to monitor nerve fiber layer (NFL) thickness in patients with optic pathway gliomas for 24 months. They found that changes in NFL thickness correlated with progression of disease and suggested that this may be a useful way to monitor these children.
Endovascular stenting is a well-established method of treating intracranial aneurysms. Heller et al92 reported on the safety of stenting across the origin of the ophthalmic artery. They retrospectively looked at 104 patients treated for a 5-year period. Eighty-nine patients had at least a 1-month follow-up. Patients with any visual symptoms postoperatively (n = 46) had a neuro-ophthalmologic evaluation. Five patients experienced new neuro-ophthalmic abnormalities including retinal infarct, transient hemianopia, and anisocoria, and 3 patients had subjective visual complaints. The authors conclude that endovascular stenting across the ophthalmic artery origin is relatively safe from a neuro-ophthalmic point of view.
Morofuji et al reported 2 patients with orbital infarction syndrome after intracranial aneurysm surgery.93 Both patients had anterior communicating artery aneurysms treated with frontotemporal craniotomy. Both patients awoke with complete ophthalmoplegia, ptosis, proptosis, and no light perception vision. One patient had a documented central retinal artery occlusion (RAO). The exact pathophysiology is unclear, but both these authors and others recommend an eye shield be placed before surgery to minimize external pressure on the orbit.
ADVANCES IN IMAGING
Ocular coherence tomography has shown utility in characterizing a wide variety of retinal conditions but is being increasingly used in neuro-ophthalmology. Merchant et al94 used enhanced depth OCT to study 34 patients with definite or suspected optic disc drusen. They found that this technique was better than ultrasound B-scan and nonenhanced depth OCT. However, Kulkarni et al95 tried to differentiate optic disc drusen from mild papilledema using OCT in 16 eyes of 9 patients. Five experienced clinicians reviewed OCT in a blinded fashion. Interrater agreement was poor, and the authors conclude that OCT is not helpful for this determination. Gili et al compared B-scan ultrasonography with autofluorescence as means to detect buried drusen in children.96 They considered B-scan ultrasonography to be the criterion standard and found autofluorescence to reliably detect drusen in children.
Lee et al97 evaluated the co-occurrence of acute ischemic stroke and acute RAO. Thirty-three patients presented with RAO and all underwent MR-DWI within 7 days of visual symptoms. Eight patients (24.2%) had MR-DWI abnormalities consistent with acute stroke and 3 of these patients had no symptoms of stroke. The authors recommend MR-DWI for patients with RAO given these findings.
Hassold et al98 used MR-DWI to investigate metastases of rhabdomyosarcoma to extraocular eye muscles in a 15-year-old patient. The MR-DWI showed restricted diffusion as the first sign of such metastases. They reviewed the literature and concluded that MR-DWI is an increasingly helpful tool in differentiating malignant from benign orbital tumors.
Tuberculomas of the brain are a common cause of space-occupying lesions in developing countries. Joseph et al99 reported 3 patients who developed optochiasmatic tuberculomas during treatment for tuberculous meningitis (n = 2) and pulmonary tuberculosis (n = 1). The 2 patients with tuberculous meningitis had previous MRIs showing no tuberculoma at the onset of therapy. Treatment with intravenous methylprednisolone, 500 mg twice a day for 5 days (n = 2) or oral prednisone (dose not given), resulted in good recovery of vision. The authors point out that visual loss during treatment for tuberculosis could be due to ethambutol toxicity and one must consider the possibility of paradoxical tuberculoma occurrence.
Olsen et al100 reviewed 57 eyes of 40 patients with chorioretinal folds to better characterize their associations. Mean age was 64 years and 18 eyes (32%) were hyperopic. Fifty percent of patients had some form of autoimmune disease. Rheumatoid arthritis, posterior scleritis, thyroid eye disease, and inflammatory bowel disease were most common. Only 6 patients (15%) were thought to have idiopathic folds. The authors suggest that the presence of chorioretinal folds warrants a careful search for systemic or associated disease.
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