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Asia-Pacific Journal of Ophthalmology:
doi: 10.1097/APO.0000000000000052
Annual Review

Neuro-Ophthalmology Annual Review

Palau, Angelina Espino Barros MD*; Morgan, Michael L. MD, PhD*; Yalamanchili, Sushma MD*; Lee, Andrew G. MD*†‡§¶∥

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From the *Department of Ophthalmology, Houston Methodist Hospital, Houston, TX; †Baylor College of Medicine, Houston, TX; ‡Departments of Ophthalmology, Neurology, and Neurosurgery, Weill Cornell Medical College, Houston, TX; §University of Texas Medical Branch, Galveston, TX; ¶University of Texas M.D. Anderson Cancer Center, Houston, TX; and ∥The University of Iowa Hospitals and Clinics, Iowa City, IA.

Received for publication February 2, 2014; accepted March 26, 2014.

The authors have no funding or conflicts of interest to declare.

Reprints: Andrew G. Lee, MD, Department of Ophthalmology, Houston Methodist Hospital, 6560 Fannin St, Scurlock 450, Houston, TX 77030. E-mail: AGLee@HoustonMethodist.org.

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Abstract

The aim of this study was to update the practicing ophthalmologist on the English-language neuro-ophthalmology literature from the prior year. This study is a review of English-language literature from August 1, 2012, to August 1, 2013. The authors searched PubMed articles published from August 1, 2012, to August 1, 2013, limited to English-language publications including original articles, review articles, and case reports and excluding letters to the editor, unpublished work, and abstracts. We researched the following topics: pupillary abnormalities, eye movement dysfunction, neuromuscular diseases, optic neuropathies, optic neuritis and demyelinating disease including multiple sclerosis, lesions of the chiasm and posterior primary visual pathways, elevated intracranial pressure, tumors and aneurysms affecting the visual pathways, vascular diseases, higher visual functions, and neuroimaging advances. We intend to share clinically relevant literature of the past year with the practicing ophthalmologist. We aimed to highlight remarkable and interesting literature rather than exhaustively including all new neuro-ophthalmological publications of the year. We reviewed literature in the past year with a focus on relevance and novelty. This review updates the comprehensive ophthalmologist on neuro-ophthalmic topics.

In this review, we highlight new 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 (ON) and demyelinating disease including multiple sclerosis (MS), lesions of the chiasm and posterior primary visual pathways, elevated intracranial pressure (ICP), tumors and aneurysms affecting the visual pathways, vascular diseases, higher visual functions, and imaging advances.

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PUPIL

Pupil Abnormalities

Assessing the pupils is a critical part of the ophthalmic examination, and prior research has shown that a relative pupillary defect correlated strongly with actual retinal ganglion cell loss.2 However, smaller differences could go unappreciated by a skilled examiner, and automated pupillometry is likely to play an increasingly important clinical role in the future.

Subtle pupillary defects might be present in many diseases. In a study comparing 46 migraineurs with 37 control subjects, Cambron et al3 showed altered pupillary responses in migraineurs. Using automated infrared pupillometry, they were able to compare pupil responses both ictally during headaches and interictally as well as under the influence of apraclonidine. In both ictal and interictal testing, migraineurs and control subjects had similar pupillary responses. In contrast, treatment with apraclonidine revealed differences in pupillary responses of migraine patients. With apraclonidine treatment, the pupillary latency was increased in migraineurs ictally. Intraictal apraclonidine-treated pupillography showed statistically significant differences in the left eye, but the right eyes did not reach statistical significance. These findings argue that migraineurs might harbor subtle autonomic dysfunction.

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Horner Syndrome

Oculosympathetic paresis, well known as Horner syndrome (HS), is classically characterized by the triad of ipsilateral ptosis, miosis, and anhidrosis. Horner syndrome presents a diagnostic challenge because the circuitous anatomic pathway permits many potential etiologies to enter the differential diagnosis. Davagnanam et al4 proposed a unified approach to HS evaluation in adults. The overall proposal emphasizes the role of neighborhood signs in localizing the lesion to better direct evaluation. Arterial dissection must be considered when HS is accompanied by pain. They view pharmacological testing with cocaine or apraclonidine as problematic secondary to drug availability as well as limited sensitivity and specificity, particularly in the acute phase before denervation hypersensitivity. For imaging, they recommend modality choice based on localization. For first-order lesions, magnetic resonance imaging (MRI) of the brain and the cervical and the upper thoracic spine is recommended. They elect for computed tomography (CT) angiography from the aortic arch to the orbits and the circle of Willis for second- and third-order lesions for evaluation of the arteries as well as reasonable good evaluation of the soft tissues, including the lung apices, except when iodinated contrast is contraindicated.

The anatomy of HS also leads to continued novel presentations. As noted above, arterial dissection remains one of the most concerning etiologies. Gozke et al5 reported a 40-year-old man who had HS and eye pain as presentation of a postcoital internal carotid artery (ICA) dissection. Magnetic resonance imaging revealed blood in the false lumen. Creavin et al6 reported a 31-year-old woman presenting with headache and a metallic taste after a minor head injury after being kicked while playing soccer. Examination revealed HS with carotid dissection confirmed on MRI.

Trauma can also cause HS from direct injury without dissection. A 35-year-old man developed HS from a penetrating neck wound from a wire.7 Such presentations are concerning for carotid artery injury. However, CT angiography revealed no such injury. Ahmadi et al8 presented a case of HS in a 47-year-old man caused by a first rib fracture sustained in a boating accident. Subsequent imaging revealed healing of the fracture, and the HS improved as well.

Iatrogenic trauma is also a consideration. Thomas et al9 reported HS as a rare complication of tube thoracostomy in a 13-year-old boy with a massive parapneumonic effusion with subsequent recovery and in an 8-year-old boy with operative treatment of pectus excavatum whose HS resolved with chest tube repositioning. They found only 24 other cases of HS in association with chest tube placement, making overall conclusions difficult, but the authors argued against chest tube placement above the third intercostal space.

Pourfour Du Petit syndrome is excessive activation of the oculosympathetic system, somewhat the opposite of HS. Interscalene block was used for repair of a humerus fracture and resulted in transient Pourfour Du Petit syndrome.10 The 24-year-old man developed unilateral mydriasis, hemifacial perspiration, and eyelid retraction that resolved in concert with recovery from the anesthetic blockade.

As emphasized by Davagnanam et al,4 cervical pathology must also be considered. Horner syndrome can be secondary to a syrinx as in the report of a 19-month-old child presenting with an isolated HS and a C6 to T2 syrinx without associated Chiari or other malformation.11 Kumar and Verma12 presented a case of HS associated with syringomyelia and a Chiari I malformation with the notable feature of full hemibody anhidrosis, presumably secondary to disruption of descending sympathetic fibers.

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Mydriasis

The tonic pupil, often termed Adie tonic pupil when idiopathic, arises from disturbance of the pupil’s parasympathetic innervation. Wakerley et al13 provide images and video of an acute tonic pupil including mydriasis, poor light reaction, and vermiform movements. There was response to dilute pilocarpine. The patient also had hyporeflexia consistent with Holmes-Adie syndrome.

In addition to the sympathetic pupillary abnormalities noted above, migraineurs sometimes manifest parasympathetic dysfunction. Sobreira et al14 report a case of ophthalmoplegic migraine. The attacks started at age 9 years, with diplopia, ptosis, and mydriasis without response to light as well as dizziness, nausea, and vomiting. These episodes respond well to pulsed corticosteroids. The mydriasis, however, has persisted through age 15 years.

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EYE MOVEMENTS

Nystagmus

Nystagmus remains of central importance to ophthalmologists as well as neurologists and otolaryngologists because it can arise from a wide variety of serious pathologies although other causes are relatively benign. Vascular causes, both hemorrhagic and ischemic, can threaten life, and their prompt recognition is critical. Newman-Toker et al15 reported on a system for quantitative video-oculography for stroke diagnosis. They expanded on a prior study showing that the combination of horizontal head impulse, nystagmus, and skew testing outperforms MRI in acute evaluation of the acute vestibular syndrome.16 In this more recent study, they enrolled patients with acute vestibular syndrome within 1 week of onset. They measured vestibulo-ocular reflex gain during head impulse testing looking for right-left asymmetry in 12 patients, 5 with ischemia, 1 with hemorrhage, and 6 without either. The patients with posterior inferior cerebellar artery strokes did not have significant asymmetry. Anterior inferior cerebellar artery stroke patients did have significant asymmetry, but testing for direction-changing nystagmus and skew correctly classified them. Use of the device in combination with nystagmus and skew testing correctly identified the 6 patients with stroke and the 6 patients without. The study points to the possibility of device-based augmentation of nonexpert examiners in correctly identifying stroke.

In addition to ischemia and hemorrhage, aneurysm is another vascular disease that can present with nystagmus. Hyun et al17 presented a 28-year-old woman with upbeat nystagmus as a presenting symptom of a giant vertebral artery aneurysm.

Lee and Kim18 investigated the characteristics of superior cerebellar artery infarction in a series of 41 patients. Nineteen of the patients experienced vertigo, and 11 had either spontaneous nystagmus or gaze-evoked nystagmus. The spontaneous nystagmus always beats toward the lesion side. The authors propose disruption of vestibular output to the fastigial nucleus of the cerebellum as a possible mechanism. Tsuda et al19 presented a case of alternating skew in a 76-year-old woman with hemorrhage in and around the cerebellar vermis. She had bilateral gaze-evoked nystagmus and truncal ataxia as well as alternating skew with hypertropia in the abducting eye. They proposed bilateral damage to the utricular pathways as the underlying mechanism. Shaikh et al20 reported 2 patients with complaints of acute binocular diplopia found to have upbeat nystagmus, exotropia, and internuclear ophthalmoplegia due to ischemic strokes in the pontomesencephalic region. The authors proposed that these findings combined as distinctive for pontomesencephalic lesions, particularly as internuclear ophthalmoplegia and upbeat nystagmus, are rare occurrences in concert. They also proposed that sufficiently large lesions can disrupt both the medial longitudinal fasciculus and the paramedian tract normally carrying feedback to the flocculus.

Demyelinating disease is often a consideration in the differential diagnosis of nystagmus especially in young patients. Nakamagoe et al21 described downbeat nystagmus attributed to a lesion of the paramedian tract. The findings and anatomic lesion were notably similar to the cases reported by Shaikh and colleagues.20 The 66-year-old man had MS and presented with downbeat nystagmus and an internuclear ophthalmoplegia with a dorsal pontine lesion evident on MRI.

Neoplasms can cause nystagmus and other eye movement abnormalities both through structural causes from the primary or metastatic tumor and through autoimmune paraneoplastic disease. A 63-year-old woman presented with complaints of acute headache and dizziness with bilateral horizontal nystagmus and slurred speech on examination.22 She had a history of resected papillary thyroid carcinoma. Head CT revealed a cerebellar hemorrhage. She initially recovered well with conservative management but then developed Bruns nystagmus as well as diplopia and hypoacusis. Resection showed the mass to be metastasis of her prior cancer, and she was further treated with radiosurgery. Barata et al23 reported a paraneoplastic syndrome as the presentation of breast cancer. The 42-year-old woman presented with upward nystagmus along with left facial paralysis, spastic paraparesis with bilateral plantar extensor responses, and left foot dystonic posturing. Magnetic resonance imaging of the brain and the spine did not reveal explanatory lesions. However, positron emission tomography scan led to diagnosis of invasive breast ductal carcinoma. She underwent resection with resolution of those neurologic symptoms but then developed bilateral fatigable eyelid ptosis. With chemotherapy and radiation, her neurologic problems resolved. Cerebrospinal fluid (CSF) analysis was normal, and although the course suggests a paraneoplastic process, no known paraneoplastic antibody (Ab), including any acetylcholine receptor (AChR) Ab, was discovered.

The ophthalmologist must consider nutritional states in specific circumstances, particularly thiamine deficiency leading to Wernicke encephalopathy (WE) in malnourished patients. In contrast to the population with chronic alcoholism, other populations at risk for WE may be less familiar to ophthalmologists. Elefante et al24 present MRI findings in 3 nonalcoholic patients with WE, 2 with prolonged intravenous (IV) feeding, and 1 with gastric lymphoma. Lesions of multiple periventricular areas of WE were found on MRI. In a similar case, Kim et al25 presented a single case of WE with characteristic serial imaging. Initially, the patient had bilateral gaze-evoked nystagmus and truncal ataxia along with poor oral intake secondary to recent allogenic stem cell transplantation for leukemia. Magnetic resonance imaging showed bilateral medullary tegmental lesions. Thiamine was supplemented but only at 50 mg/d, and the case emphasizes the need for high-dose parenteral thiamine in cases of suspected WE. The patient developed right gaze paresis partially overcome by vestibular input, and MRI demonstrated extension to involve the bilateral tegmentum of the pons and the midbrain. Then, the patient developed upbeat nystagmus, and repeat MRI showed T2 changes of the bilateral medial thalami with near resolution of the prior brain stem lesions. Larsen et al26 present a case of WE in a 31-year-old patient with acquired immunodeficiency syndrome initially presenting with Pneumocystis pneumonia. He subsequently developed nystagmus and confusion during treatment with increased T2 signal in the medial thalami. His condition improved with administration of IV thiamine. The authors argue for a low index of suspicion for thiamine deficiency in the patient with acquired immunodeficiency syndrome given the frequency of an overall catabolic state. Sutamnartpong et al27 reported coincident WE and central pontine myelinolysis secondary to hyperemesis gravidarum. The patient presented with lethargy and upbeat nystagmus. The patient additionally had a history of significant alcohol consumption before pregnancy. Both findings were confirmed with T2 hyperintensities in the medial thalami and the central pons. She responded well to thiamine replenishment with persistent mild vertical nystagmus as the only sequela.

Acute intoxication is another cause of nystagmus, with alcohol likely being the most common agent. Nystagmus is not, however, typically associated with marijuana use. Kibby and Halcomb28 reported gaze-evoked nystagmus and ataxia in a patient 2 days after consumption of alcohol and cannabis. Urine drug screen testing was positive only for cannabinoids. There was no evidence of abnormalities on MRI or CT. His nystagmus resolved with lorazepam.

Congenital causes are also seen, although early onset and family history can facilitate diagnosis. Liu et al29 reported a novel mutation in a Chinese family with congenital nystagmus. The family was found to have a unique mutation in the FRMD7 gene at position T635C in affected members and female carriers, in line with an X-linked inheritance pattern.

Migraine, typically familial without a clear genetic etiology, remains an important consideration because of the variety of vision-related deficits that can accompany it. Boldingh et al30 examined vestibular function in patients with vestibular migraine (VM) and migraine without vertigo. They compared the groups of 38 patients with VM and 32 patients with migraine, using a battery of 14 vestibular tests, with 70% of the VM patients and 38% of the migraine patients showing abnormalities. Three tests, Romberg, fixation suppression of the vestibulo-ocular reflex, and positional nystagmus, showed abnormal results significantly more often in the VM patients. The authors argue that vestibulopathy is actually a common finding among migraineurs both with and without vertigo.

Seizure also enters the differential diagnosis of nystagmus in certain cases. Although convulsive seizures rarely present to ophthalmologists, nonconvulsive status epilepticus (NCSE) can be difficult to diagnose. Tu et al31 investigated factors predicting whether emergent electroencephalography (EEG) would discover NCSE. In 215 EEGs ordered to exclude NCSE, 21 patients were found to have the condition. They found several factors significantly correlated with NCSE. Preceding clinical seizures, active central nervous system (CNS) infection, and ocular movement abnormalities were found to predict NCSE. Ocular movement abnormalities including gaze preference and/or nystagmus yielded a 3.5 odds ratio (OR) of discovering NCSE on emergent EEG. Lee et al32 present a single case of NCSE in a 19-year-old woman. She initially presented with headache, fever, and altered mental status leading to diagnosis of herpes encephalitis. She subsequently worsened with spontaneous right beating nystagmus and right gaze deviation. Electroencephalography showed status epilepticus with prominent discharges in the left posterior region corresponding with the eye findings. These findings resolved with treatment of the seizure with IV lorazepam and phenytoin.

Volitional control must be considered in the differential diagnosis of nystagmus. In a brief video submission, Bassani33 shows voluntary nystagmus in a 53-year-old woman. The subject could not sustain this series of small horizontal saccades for extended periods. It required convergent effort, and the lid fluttered in concert.

Treatment of nystagmus remains challenging, and successful response to a drug is idiosyncratic and unpredictable. Nevertheless, the underlying etiology can be helpful in guiding treatment. Ehrhardt and Eggenberger34 reviewed treatments of acquired nystagmus. They outlined Meniere disease and vestibular neuronitis as causes of peripheral nystagmus versus central vestibular nystagmus, gaze-evoked nystagmus, acquired pendular nystagmus, periodic alternating nystagmus, and see-saw nystagmus. Possible agents such as benzodiazepines, memantine, baclofen, gabapentin, and 4-aminopyridine are matched to these conditions for guidance in pharmacological attempts to suppress acquired nystagmus.

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Opsoclonus

The presence of opsoclonus typically arises from an autoimmune etiology and always raises suspicion for an underlying neoplasm (paraneoplastic disease). Jen et al35 examined eye movements and serum in a series of 7 patients who presented with opsoclonus and either myoclonus or generalized tremor. Brain MRI results were normal in all patients, but 3 had a CSF lymphocytic pleocytosis. Occult neoplasm was diagnosed in 3 of the patients. Commercial assays were negative for paraneoplastic Abs in all patients. Serum from 3 of the patients, however, stained Purkinje cells, and there was punctate staining with the cerebellar molecular layer. The reactivity seems to localize to synapses between Purkinje cells and parallel fibers, although a specific epitope has not yet been identified. In all but 1 patient, the condition improved spontaneously or with either immunosuppression or tumor resection.

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DISEASE OF MUSCLE AND MUSCULOSKELETAL JUNCTION

Ocular Myasthenia Gravis

Myasthenia gravis (MG) is an autoimmune disease that targets the postsynaptic neuromuscular junction, most often affecting the AChR. Ocular findings, usually diplopia and ptosis, are the first evidence of MG in approximately 50% of patients. Ocular MG (OMG) refers to MG isolated to these ocular findings. Approximately 50% to 60% of OMG patients will progress to generalized muscle involvement within the first 2 years of diagnosis. The extraocular muscles (EOMs) are often the first muscle group to be involved for a variety of reasons. First, they have decreased complement inhibitory proteins, making them more susceptible to autoimmune attacks. Second, they are also at increased risk for muscle fatigue because of the unique structure of their neuromuscular junction. Finally, they are subject to very precise and frequent demands to produce coordinated, single, binocular vision. Binocular fusion is easily disrupted if muscles are not equally coordinated within just a few degrees.36

The 2 major objectives in the treatment of OMG are (1) improvement or resolution of symptomatic ocular dysfunction (blepharoptosis and diplopia) and (2) reduction of generalized MG disease risk. Disease generalization can be life threatening because of concurrent respiratory failure and/or swallowing impairment. Available treatments of OMG include cholinesterase inhibitors and immunosuppressive and immunomodulatory agents along with thymectomy when thymoma is present. The incidence of thymoma in MG patients has been reported to be 10% to 30%. A recent review by Mao et al37 found an overall incidence of thymoma of 21%. The pooled incidences were 17% [95% confidence interval (CI), 14%–20%], 12% (95% CI, 11%–13%), and 25% (95% CI, 24%–26%) in population-, hospital-, and surgery-based studies. Treatment of MG should be individualized, and side effect profile and costs should always be taken into account.

Cholinesterase inhibitors, such as pyridostigmine and neostigmine, are usually the first line of treatment in patients with MG or OMG. By inhibiting acetylcholinesterase, the enzyme responsible for the hydrolysis of acetylcholine, pyridostigmine prolongs the action of acetylcholine in the postsynaptic receptor. Overall, 20% to 40% of patients improve with anticholinesterase agents, with ptosis being much more responsive than diplopia. Patients with Abs to muscle-specific receptor tyrosine kinase, however, respond poorly. Cholinesterase inhibitors do not alter the natural history of the disease. Corticosteroids, on the other hand, have been shown to be very effective, producing marked improvement in 80% of patients. Unfortunately, they have an extensive side effect profile including diabetes, hypertension, osteoporosis, gastrointestinal disorders, and susceptibility to infection. Steroids have also been reported to reduce the incidence of disease generalization at 2 years compared with acetylcholinesterase inhibitors; only 7% of treated patients progress to the generalized form of MG.

A recent systematic review on the medical and surgical management of OMG found only 2 randomized controlled trials (RCTs) on this topic. The first RCT evaluated corticotropin versus placebo in the treatment of OMG. The ORs for improvement in area of eye movements among those treated with corticotropin compared with placebo were 2.7 (95% CI, 0.6–12) for the right eye and 10.3 (95% CI, 1.2–25.2) for the left eye. There was a relatively high rate of loss to follow-up (67% of right eyes and 77% of left eyes completed the study), and the results were difficult to interpret because of a lack of clinically meaningful measures of response to therapy. The second RCT evaluated the efficacy of intranasal neostigmine. However, the sample size was too small, only 3 participants, and no meaningful conclusions could be drawn.38

This systematic review also analyzed 10 observational studies, both case-control and cohort, that included patients with OMG. Corticosteroids were used as active therapy in 7 of these studies; azathioprine, in 2; and thymectomy, in the remaining 2. In the 2 studies that evaluated steroids for control of ocular symptoms, the OR favored steroids in 1 study but not in the other. Five of the 7 studies on steroids for OMG also showed a benefit in decreasing the risk for progression to generalized MG. The 2 studies that evaluated azathioprine found a beneficial effect on risk progression. The last 2 studies that evaluated thymectomy showed no benefit in improvement of ocular symptoms or risk for progression to generalized MG.38

Another recent retrospective study evaluated the safety profile of low-dose steroids, 10 mg of prednisone daily, for the treatment of OMG. It included 87 patients, 70% of whom had at least 24 months of follow-up. Tapering to 10 mg/d required at most 4 months. Complications potentially related to steroid use were reported in 35% of patients, corresponding to a rate of 6.6 complications per 100 person-years (95% CI, 4.2–9.0). Three patients had serious complications during follow-up, corresponding to a rate of 0.7 serious complications per 100 person-years (95% CI, 0.0–1.5). The authors concluded that low-dose prednisone for the treatment of OMG had an acceptable side effect profile and caused few serious complications.39

Immunoglobulin and plasma exchange (PEX) are sometimes indicated for cases of generalized MG or less commonly for refractory OMG. A recent systematic review on the efficacy of IV immunoglobulin found 3 RCTs that compared IV immunoglobulin with either PEX or placebo for the treatment of MG exacerbation. One study showed roughly the same efficacy of IV immunoglobulin and PEX in the scenario of worsening MG. The IV immunoglobulin versus placebo trial reported a very modest improvement with IV immunoglobulin. This modest improvement was probably due to the heterogeneity of the population because it included people with OMG or mild MG. Intravenous immunoglobulin was more effective in the moderate or severe MG exacerbation subgroup. The authors concluded that IV immunoglobulin is definitely useful in the management of MG exacerbation. However, it seems to be less effective in patients with mild-to-severe but stable MG.40

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Thyroid Eye Disease

Thyroid eye disease (TED) is a common manifestation of a systemic autoimmune process in which autoantibodies target receptors (eg, thyroid-stimulating hormone receptor) present on thyrocytes. Systemically, these autoantibodies can induce the production of excess thyroid hormone with resulting hyperthyroidism. In the orbit, they induce secondary inflammatory effects including glucosaminoglycan deposition, muscle edema and fibrosis, and adipogenesis. This systemic autoimmune hyperthyroid condition is known as Graves disease. Although TED is commonly associated with hyperthyroidism, up to 20% of patients can be hypothyroid (eg, Hashimoto thyroiditis or treated Graves disease) and up to 3% of TED cases are completely euthyroid. Thyroid eye disease carries a major risk for vision loss due to corneal exposure, orbital congestion, and compressive/ischemic optic neuropathy (ION).41

Thyroid eye disease typically has a self-limited course, with active disease lasting up to 24 months followed by an inactive disease phase. After the resolution of the active phase, there may be a mild but incomplete improvement of associated signs. Treatment does not necessarily prevent disease progression. Corticosteroids during the active phase may, however, provide symptomatic improvement but do not typically halt disease progression or produce complete remission. During the inactive phase, treatment of symptomatic and stable patients is surgical, aimed to correct proptosis, strabismus, and cosmetically unacceptable lid retraction. The management of TED requires a multidisciplinary approach involving both endocrinology and ophthalmology. Endocrinology must focus on achieving a euthyroid state by means of medication, radioactive iodine therapy, or thyroidectomy. Immunosuppressants or biological agents have also been implemented in the management of active TED. Patients should be encouraged to quit smoking because it has been shown to increase incidence and severity of TED.41

Immunomodulatory therapies are now considered as alternatives in the management of steroid-unresponsive active and symptomatic TED. Although the use of biological agents has been supported only by case reports and uncontrolled studies, rituximab (RTX) has been shown to decrease disease activity score in patients who did not respond to traditional TED therapy. Rituximab is a chimeric murine monoclonal antihuman CD20, a transmembrane protein present on immature and mature B cells. The constant region of RTX depletes circulating CD20 B cells within days by Ab-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and induced apoptosis. Circulating CD20 B cells are undetectable for a median of 4 to 6 months after RTX treatment.42

A recent review on RTX for TED found 10 clinical studies on the subject: 1 open non-RCT, 3 case series, and 6 case reports.43 A total of 38 patients in published studies had received RTX for TED treatment; 1 patient had concurrent stiff person syndrome. The dose of RTX varied as follows: 32 received RTX based on the rheumatoid arthritis regimen (2000 mg); 3 patients, based on the lymphoma regimen (2865 mg); and 3 patients, based on the latest Salvi et al44 series (100 mg). In this report, 18 patients received RTX because of poor response or disease progression on conventional therapy; 3 patients, because of disease recurrence during tapering; and 13, as first-line treatment. A total of 23 (92%) of 25 patients with active TED who received RTX alone and 8 (88.9%) of 9 patients with concurrent therapy responded to RTX treatment, with a reduction of clinical activity score from a mean of 5.3 to 1.3. Clinical improvement was seen as early as 1 day in the low-dose regimen and within 4 to 8 weeks in the rheumatoid arthritis or lymphoma regimen. Nine patients of the open study also showed improvement in exophthalmometry from 22.4 to 20.9 mm. One patient with inactive TED had radiological improvement. The 3 nonresponders had optic neuropathy before initiation of RTX. Two were from the RTX only group, and 1 had concurrent corticosteroid therapy. They had all received the rheumatoid arthritis RTX regimen. The initial response in 1 of these 3 patients suggests that RTX may have ameliorated disease activity, but other mechanisms may have led to progression. Salvi et al44 recently reported successful therapy and remission with a low 100-mg RTX dose. The side effect profile has also been comparable with IV steroids (33% vs 45%). However, RTX has been associated with serious adverse effects including myelosuppression, severe mucocutaneous reactions, and progressive multifocal leukoencephalopathy, none of which have been reported in the management of TED. The authors conclude that although RTX treatment of TED shows promise, no conclusions can be drawn because of lack of standardization and RCTs. Spontaneous improvement or deterioration in the 38 reported cases could reflect the natural history of TED. Another recent systemized review on the effectiveness and safety of RTX for TED found no RCTs, and therefore, no reliable conclusions could be made. There are, however, 3 ongoing studies that could meet inclusion criteria once completed.42

Radiotherapy has been used for the treatment of active TED since the early 1970s. A recent review evaluated the efficacy and safety of radiotherapy.45 Three systematic reviews have been published, and their conclusions, unfortunately, have been different. The authors concluded that radiotherapy is a well-tolerated and established therapy for TED; however, its efficacy remains controversial. They agree that it should be offered early in active cases and that it can enhance the effectiveness and allow faster tapering of steroids. It may improve compressive optic neuropathy, periocular inflammatory changes, and motility disruption. It has limited effect on lid retraction and proptosis.

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Ocular Myositis

Idiopathic orbital inflammatory syndrome (IOIS), or orbital inflammatory pseudotumor, is a benign, noninfective, nonspecific orbital inflammation without an underlying local or systemic cause. It can be focal (myositis or dacryoadenitis) or diffuse. Orbital myositis primarily involves the EOMs and most commonly affects young women in the third decade of life. Common presentations include orbital or periorbital pain, ophthalmoplegia, diplopia, proptosis, lid edema or conjunctival hyperemia. High-dose oral steroids are the preferred treatment of IOIS, and response is rapid. However, systemic steroids are associated with a variety of side effects. A recent prospective noncomparative interventional case study evaluated the response of various types of IOIS to local steroid injection. Among the 47 patients included in the study, 12 had orbital myositis; 31, dacryoadenitis; and 4, diffuse orbital inflammation. Betamethasone suspension (4–8 mg of betamethasone sodium phosphate and 10–20 mg of betamethasone dipropionate) was injected at the site of the inflamed tissue, and systemic nonsteroidal anti-inflammatory drugs were given for 2 weeks. The response was dramatic, and complete resolution was observed in all cases within 1 to 4 weeks. In the 8-year follow-up period, only 2 patients, 1 with myositis and 1 with diffuse orbital inflammation, had recurrence but improved with a second injection. The authors propose local steroid injection as first-line treatment of IOIS.46

Ophthalmic manifestations of inflammatory bowel disease (IBD) are seen in 2% to 10% of patients. Among these ophthalmic findings, orbital inflammatory disease is rare and mostly seen in patients with Crohn disease (CD). Bennion et al47 recently reported the third documented case of orbital myositis in a patient taking infliximab for ulcerative colitis (UC). The 2 previous cases included a 43-year-old white woman with a 12-year history of quiescent UC in whom isolated lateral rectus myositis was seen and a 32-year-old white man with a 3-year history of UC in whom left superior rectus myositis was detected. This third case was a 63-year-old white man with recently diagnosed UC (9 months) and bilateral diffuse EOM involvement. This disease presentation was atypical because orbital myositis usually affects only a single muscle, commonly the superior or lateral rectus. The patient responded adequately to systemic corticosteroids, IV methylprednisolone, followed by oral prednisone. Orbital inflammation completely resolved in 2 weeks, and infliximab was continued at a higher dose to control the underlying inflammatory disease. Pimentel et al48 described a 55-year-old woman with CD who had recurrent steroid-dependent orbital myositis. Remission was achieved by increasing her infliximab dose. A review of previously reported cases found CD-related ocular myositis (OM) to be more common in women with CD of the colon or the ileocolonic area based on clinical and radiological findings. High-dose steroid therapy is the first-line treatment, with typical rapid resolution of symptoms. Verma et al49 reported the first case of CD-associated OM in a patient during IBD remission. This 35-year-old white man had IBD remission with discontinuation of infliximab 13 weeks before OM presentation. Ocular myositis was successfully treated with a combination of systemic steroids and adalilumab, and no recurrence was reported.

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OPTIC NERVE DISORDERS

Nonarteritic Anterior Ischemic Optic Neuropathy

Ischemic optic neuropathy is the most common cause for an acute unilateral optic neuropathy in patients older than 50 years. They are classified as either anterior or posterior depending on the affected segment of the optic nerve. Optic disc edema (ODE) secondary to optic ischemia must be present in acute anterior ION (AION). Conversely, disc edema is not seen in posterior ION. Anterior ION is by far the most common form of ION and represents up to 90% of ION cases. It has an incidence of 2.3 to 10.2 per 100,000 people 50 years or older. Ischemic optic neuropathies can be further classified as nonarteritic or arteritic depending on their etiology. Arteritic AION (A-AION) is secondary to giant cell arteritis (GCA) and is considered an ophthalmological emergency because bilateral blindness can occur if patients are not promptly treated. The nonarteritic AION (NA-AION) is presumably secondary to small vessel ischemia and hypoperfusion of the anterior optic nerve head. Risk factors of NA-AION include hypertension, diabetes mellitus, ischemic heart disease, hypercholesterolemia, nocturnal hypotension, and small cup-disc ratio. Hypercoagulable states have also been reported in atypical NA-AION cases such as NA-AION in young patients, bilateral NA-AION, and NA-AION in patients without the common risk factors (eg, hypertension, diabetes). The risk for NA-AION recurrence in the same eye is low, less than 5%. The 5-year risk for fellow eye involvement is 15%, but the risk can be possibly lowered by controlling for the known vasculopathic risk factors.50

Obstructive sleep apnea (OSA) is described as repeated total (apnea) or partial (hypopnea) obstruction of the upper airway with decreasing oxygen saturation and increase in carbon dioxide saturation during sleep. It has a prevalence of 2% in women and 4% in men aged 30 to 60 years. Obstructive sleep apnea has also been associated with NA-AION. Obstructive sleep apnea–associated NA-AION is thought to be due to impaired optic nerve head blood flow autoregulation. Arda et al51 evaluated the possible association between OSA and NA-AION. Twenty newly diagnosed NA-AION patients were included in the study, and 20 age- and sex-matched subjects with similar risk factors formed the control group. All participants underwent an overnight polysomnography (PSG) to identify the presence of OSA. An obstructive apnea was defined as a drop in the peak thermal sensor excursion by 90% or greater of baseline, lasting at least 10 seconds, and accompanied by respiratory effort movement. An obstructive hypopnea was defined as a drop in nasal pressure signal excursion by at least 30% of baseline with at least a 4% desaturation or a 50% or greater drop from baseline with a 3% or greater desaturation with an arousal. An apnea-hypopnea index (AHI) of greater than 5 was diagnostic for OSA. No statistically significant difference was found between the patient and the control group. In the patient group, however, 85% were diagnosed with OSA, whereas in the control group, 65% had OSA (P > 0.05). Both were higher than the population prevalence. The authors concluded that OSA is not a risk factor of NA-AION per se but it could contribute to the endothelial damage present in patients with multiple vasculopathic risk factors.

Bilgin et al52 reviewed the possible association between OSA and NA-AION. They evaluated 27 recently diagnosed NA-AION patients and included 27 age-matched controls with similar risk factors. A PSG was done on all patients. The AHI was calculated using the total number of respiratory events per hour of sleep. An AHI of 20 or greater was regarded as diagnostic for OSA, a higher cutoff point than in the study of Arda et al.51 Fifteen (55.6%) of their 27 patients and 6 (22.2%) of their 27 control subjects met criteria for OSA (P < 0.05). The relative risk for sleep apnea in NA-AION patients was 2.5 compared with the control groups. They found that by using a higher cutoff (AHI ≥20 instead of AHI >5), they were able to reduce false-positive findings. The authors thus concluded that OSA should be considered as a significant risk factor of NA-AION and that PSG should be indicated in every newly diagnosed patient.

Although there is currently no accepted and proven treatment of NA-AION, Hayreh and Zimmerman53 advocated for the use of systemic steroids for the treatment of selected cases of NA-AION. In their 2008 study, they reported improvement in visual acuity in NA-AION patients treated with systemic steroids during the acute phase. In 2012, Rebolleda et al54 evaluated the use of systemic steroids in 10 NA-AION patients. They did not find any beneficial effect in visual and anatomic outcomes with the use of steroids. Furthermore, up to a third of their patients had steroid-related complications. No new studies regarding this controversial issue were reported in the past year. In 2007, Bennet et al55 proposed using bevacizumab for the treatment of NA-AION. They reported improvement of ODE and vision in an 84-year-old woman diagnosed with NA-AION after treatment with a single intravitreal injection of bevacizumab (1.25 mg/0.05 mL). Vision markedly improved from counting fingers at 1 ft to 20/70 nineteen days after injection. The authors proposed that by decreasing vascular permeability, bevacizumab diminished vasogenic edema and protected open nerve tissue. On the other hand, Prescott et al56 found no beneficial effect of bevacizumab injection in 5 of their NA-AION patients. Recently, Rootman et al57 also evaluated the use of bevacizumab in NA-AION. They included 25 patients (17 treatment group, 8 control group) and compared the use of 1.25 mg of bevacizumab with natural history. The authors found no difference between bevacizumab and natural history for change in visual field, visual acuity, or optic nerve optical coherence tomography (OCT) thickness. Currently, the use of bevacizumab for the treatment of NA-AION is not recommended, and there have even been prior cases of NA-AION reportedly associated with such treatments.

The natural history NA-AION was described by Hayreh and Zimmerman58 in 2008. At the initial visit, up to half of patients had normal visual acuity (≥20/30) and only 23% had a visual acuity of 20/200 or lower. Improvement in visual acuity and visual fields could be seen in the first 6 months after the event but not thereafter. Of those patients with visual acuity of 20/70 or lower, there was improvement in 41% at 6 months. Deterioration was seen in 9% of eyes with initial visual acuity of greater than 20/70 and in 18% of those with initial visual acuity of lower than 20/60. Central visual field remained stable in 68%, improved in 16%, and worsened in 16%. The authors also evaluated whether the visual outcome of the first eye could be used to predict visual outcome in the second eye in patients with bilateral sequential NA-AION. They investigated 174 consecutive patients and found that there were large differences between visual acuity and visual field findings in paired eyes at both the initial visits (60% had at least a 0.3 logarithm of the minimal angle of resolution difference). They concluded that it is impossible to predict visual outcome of the second eye based solely on the first eye. The systemic implication of NA-AION was evaluated by Hasanreisoglu et al.59 The authors investigated the incidence of cardiac and cerebrovascular events after NA-AION compared with published control data from the Framingham Heart Study, the United Kingdom Prospective Diabetes Study, and the National Vascular Disease Prevention Alliance. The authors found no increased incidence of cardiovascular or cerebrovascular events.

A recent review of ischemic optic neuropathies by Hayreh60 drew the following conclusions regarding NA-AION: (1) the pathogenesis of NA-AION is known but is highly complex, (2) high-dose steroid therapy during the initial stages has rationale and can be beneficial, (3) aspirin has no beneficial effect in NA-AION, (4) risk factors must be eliminated to reduce the risk for further visual loss (including nocturnal hypotension), and (5) it is not adequate to predict the second eye’s visual acuity and visual field based on the first eye.

A subgroup of intrinsically photosensitive retinal ganglion cells (ipRGCs) mediates the pupillary light reflex. These ipRGCs express the photopigment melanopsin, blue light sensitive, and project to the olivary pretectal nucleus in the midbrain, the well-known pupillomotor center of the brain.61,62 The postillumination response is considered an indicator of melanopsin activation. Recent studies have shown that outer photoreceptor disease impairs pupil redilation after exposure to bright blue light. However, in patients with ischemic optic neuropathies, pupil redilation is not affected.63 Herbst et al64 further investigated the pupil responses in patients with NA-AION. They compared pupil responses of patients with strictly unilateral NA-AION with the fellow nonaffected eye and with nonaffected age-matched healthy controls. Consensual pupil responses during and after exposure for 20 seconds to continuous blue (470 nm) or red (660 nm) light of high intensity (300 candela per square meter) were recorded in both eyes of 10 patients and 11 age-matched controls. Most of the pupil response parameters to both blue and red light were significantly reduced in the affected eye compared with the fellow nonaffected eye (P < 0.05). However, when comparing the affected eyes with the healthy control eyes, postillumination responses were not significantly different. The late postillumination pupil responses after blue light exposure were increased in the fellow nonaffected eye compared with the healthy controls. The authors concluded that, as expected, the pupil responses in patients with unilateral NA-AION were significantly reduced in the affected eye when compared with the fellow nonaffected eye. This reduced postillumination pupil response suggests ganglion cell loss and ipRGCs dysfunction in NA-AION eyes. The second and unexpected result was the absence of a significant reduction in the postillumination response to blue light in the affected eyes when compared with the healthy controls. In addition, the late postillumination responses in the fellow nonaffected eyes were increased when compared with control eyes. The authors postulated an adaptive mechanism acting to “normalize” pupil responses in NA-AION affected eyes.

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Optic Neuropathy

Leber hereditary optic neuropathy (LHON) is a mitochondrial degeneration that typically presents with a bilateral, simultaneous, or rapidly sequential, acute, or subacute optic neuropathy in young males. Most patients with Leber (90%–95%) have one of the following mitochondrial DNA point mutations: 3460G>A, 11778G>A, and 14484T>C. The most common LHON mutation in Northern Europe, Australia, and the Far East is the 11778G>A. This mutation represents up to 70% of LHON cases. Clinical recovery in LHON can occur but is less likely with the more common 11778G>A mutation. Recovery rates for the other mutations are 22% for the 3460 mutation and up to 65% for the 14484 variant.65 Sharkawi et al66 recently reported a case of LHON diagnosed in a 10-year-old boy. Mitochondrial DNA testing confirmed the presence of the point 3460G>A mutation, and electrophysiology testing confirmed optic nerve damage. Visual acuity at that time was hand movement in the right eye and counting fingers in the left eye. Eighteen months later, vision markedly improved to 6/18 and 6/12. Electrophysiological testing also showed improvement. It has been suggested that a subset of inactive, but viable, retinal ganglion cells may be responsible for visual recovery in LHON patients. Morris and Votruba67 also described visual improvement in a LHON confirmed case. Their patient was a 34-year-old man with a history of significant smoking (20 cigarettes per day) and drinking (60 U of alcohol weekly) for 18 months. The Leber 14484 mutation was found. Visual acuity at that time was 6/60 OD and 6/9 OS. The patient was counseled about the visual prognosis and was advised to discontinue smoking and alcohol consumption. Ten months after presentation, the patient stopped drinking and decreased smoking to approximately 5 cigarettes per day. Within 8 weeks, vision had improved to 6/6 OU. Pupil examination and color vision results were also normal. This case highlights the importance of environmental factors in triggering disease presentation. Patients predisposed to LHON should be counseled to avoid smoking tobacco and drinking alcohol because these conditions are thought to increase oxidative stress on the optic nerve.

Idebenone has been recently reported to aid the recovery of visual acuity in LHON patients. Idebenone, a synthetic analog of coenzyme Q10, is capable of shunting electrons from the cytosol to complex III of the electron transport chain. This shunt in the electron transport chain bypasses complex I, which is deficient in patients with LHON. Rudolph et al68 set out to investigate red-green (protan) and blue-yellow (tritan) color contrast sensitivity in a subgroup of patients enrolled in the Rescue of Hereditary Optic Disease Outpatient Study (RHODOS) study. Their first objective was to characterize color vision using baseline data and evaluate the degree of dyschromatopsia in relation to age, disease history, and visual acuity. Their second objective was to evaluate the therapeutic benefit of idebenone on color vision during the 6-month treatment period. They found that patients treated with idebenone experienced less impairment of protan color vision and statistically significant improvement in tritan color vision. Idebenone was also particularly effective in improving and preserving color vision in the subgroup of patients younger than 30 years and in recently diagnosed patients. As previously reported, treatment was also very effective in protecting visual acuity and color vision in patients with discordant interocular vision.

Methanol is a known cause of toxic optic neuropathy. It is metabolized in the body to formaldehyde by alcohol dehydrogenase and then into formic acid, which causes most associated toxicity. Ingestion is commonly accidental due to adulterated or homemade alcoholic beverages.69 Methanol toxicity is particularly common in developing countries such as India. Desai et al70 attempted to determine whether laboratory markers of methanol ingestion and subsequent toxicity could serve as predictors of visual outcome. A total of 122 patients (only 1 female) were studied. Patients were divided into 2 groups for analysis according to whether vision loss was transient (group 1) or permanent (group 2). In group 1, the variables did not demonstrate significant correlation because disturbances by definition were transient. However, in group 2, arterial pH seemed to influence final acuity and change in acuity. Patients with a pH greater than 7.2 at initial examination were more likely to have only transient visual disturbances (OR, 31; 95% CI, 6–149). Early presentation and treatment did not seem to alter the course of visual recovery.

Treatment of methanol toxicity includes antidotal therapy (ethanol or fomepizole), folic or folinic acid, and sodium bicarbonate. Hemodialysis can be used to correct acidosis and remove methanol and formate. Intravenous steroids have also been advocated to salvage vision, with encouraging but anecdotal results. Pakravan and Sanjari71 recently reported dramatic visual improvement in 2 patients treated with erythropoietin in addition to IV steroids, vitamins, and folic acid. In the first case, vision dramatically improved from no light perception to 20/20 OU 3 days after first erythropoietin infusion (10,000 IU twice a day for 6 days). Initial treatment included IV methylprednisolone (1 g/d), vitamin B6 (100 mg/d), vitamin B12 (100 mg/d), and folic acid (10 mg/d). Because no improvement in vision was noted, erythropoietin was started 2 days later. In the second case, the patient was treated with a similar regimen of IV erythropoietin (10,000 IU twice daily for 3 days), methylprednisolone (1 g/d for 5 days followed by oral prednisone for 2 weeks), vitamin B12 (100 mg/d), vitamin B6 (100 mg/d), and folic acid (10 mg/d) for 1 month. Vision improved from no light perception at presentation to counting fingers at 6 ft OD and 20/30 OS after 2 weeks of treatment. The authors believe that erythropoietin is beneficial in methanol toxicity because it suppresses neuronal apoptosis and decreases the toxic inflammatory response.

Cat scratch disease is an infectious systemic disease caused by the gram-negative bacillus, Bartonellea henselae. It is often transmitted by the bite or scratch of an infected cat, hence the name. It is characterized by a subacute regional lymphadenitis accompanied by systemic symptoms (fever, malaise) usually 2 to 3 weeks after inoculation. Ocular symptoms occur in 5% to 10% of patients. They include retinitis, ODE, angiomatous lesions involving the optic disc, retinal granuloma, uveitis, vasculitis, and Parinaud oculoglandular syndrome. Cat scratch neuroretinitis has a favorable prognosis and visual outcome; up to 67% to 93% of patients have visual acuity of 20/40 or greater.72 Antibiotic therapy is usually recommended because it has been shown to shorten the course of systemic disease in moderate-to-severe disease.73 However, no definite conclusions have been drawn regarding the use of antibiotics for this disease. Gulati et al74 recently reported 2 cases of cat scratch neuroretinitis in which characteristic clinical findings were observed (disc edema, peripapillary cotton wool patches, macular star) but serologies, both immunoglobulin G (IgG) and IgM, were negative or equivocal. In both cases, serologies were repeated 2 weeks after initial evaluation. At that time, IgG Abs were positive but IgM Abs remained negative in both cases. The authors recommend repeating serology 2 weeks after initial testing in cases of high suspicion for cat scratch neuroretinitis. The initial test could have been performed after the IgM titers returned to normal but before IgG titers were detectable. The authors also note the low sensitivity of the current available B. henselae tests. For the enzyme immunoassay, IgM sensitivities range from 65% to 71% and IgG sensitivities range from 9.5% to 28%. For the more commonly used indirect fluorescence assay, values range from 46% to 53% for IgM and from 32% to 67% for IgG. In equivocal cases, polymerase chain reaction can also be used to detect Bartonella DNA in lymph node specimens, showing both high specificity and sensitivity.

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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 neuromyelitis optica (NMO). Optic neuritis may be the initial clinical presentation in approximately 20% of MS cases. It occurs in the course of the disease in 50% of MS patients. Neuromyelitis optica IgG is a serum immunoglobulin Ab (NMO-Ab) that is directed against aquaporin-4 (AQP4) and is the pathologic effector in NMO.75 Neuromyelitis optica Abs are highly specific for NMO, and seropositive status is now part of the diagnostic criteria. Its broader clinical definition is known as NMO spectrum disorders (NMOSDs), which includes patients with single or recurrent events of longitudinally extensive myelitis and recurrent or simultaneous bilateral ON.76

A recent study set out to determine the proportion of patients positive for anti-AQP4 Ab who did not meet NMO/NMOSD criteria because these patients may be at high risk for misdiagnosis with MS.77 Among the 298 patients analyzed, 72 were seropositive for anti-AQP4 Abs, with cell-based assay (CBA) superior to enzyme-linked immunosorbent assay for Ab detection. Of these 72 seropositive patients, 45.8% fulfilled the criteria for definite NMO, 36.1% met NMOSD criteria, and the remaining 18.1% did not meet the criteria for either NMO or NMOSD. These patients had monophasic ON with severe visual impairment, attacks restricted to the brain/brain stem, or spinal cord lesions of fewer than 3 vertebral segments. The current NMOSD criteria are based only on clinical findings. The authors propose that patients with single or recurrent attacks suggestive of NMO with positive anti-AQP4 Abs should also be included in this category and treated with immunosuppression. They also advocated testing a higher number of patients with idiopathic inflammatory CNS disorders who do not meet criteria for NMO/NMOSD, particularly in populations in which NMO is common.

The CBA using recombinant human AQP4 is now considered the most reliable method to assess NMO-Ab status. Recently, it has been suggested that optimized CBA with AQP4-M23 isoform on live cells is more sensitive than the classic AQP4-M1 on fixed cells. Marignier et al78 set out to optimize the CBA for anti-AQP4 Ab detection and to assess the influence of the assay’s increased sensitivity on the demographic characteristics of patients negative for anti-AQP4 Ab. They found that the optimized AQP4-M23 CBA was the best detection method, increasing the sensitivity from 57.4% to 74.4% while maintaining 100% specificity. The positive predictive value (PPV) was 100%, and the negative predictive value (NPV) was 71%. When using the classic indirect immunofluorescence or the current AQP4-M1 CBA, only slight differences were found between the groups positive and negative for anti-AQP4 Ab. However, when using the newer AQP4-M23 CBA, specific differences could be found between the 2 groups. Patients negative for NMO-Ab were found to have an equal male-female ratio, had white ethnicity in all cases, and had an overrepresentation of simultaneous ON and transverse myelitis at first episode. They also had better visual acuity at last follow-up compared with the seropositive NMO patients. The authors concluded that, by improving the sensitivity of the anti-AQP4 Ab detection, they were able to detect different demographic and disease-related features in patients negative for anti-AQP4 Ab.

Diagnosis of NMOSD can be challenging because of overlapping similarities with relapsing-remitting MS (RRMS). It is important to distinguish between these 2 conditions because NMOSD patients require long-term immunosuppression, whereas RRMS typically requires immunomodulatory therapy (eg, interferons), which can worsen NMOSD. Matthews et al79 examined the utility of brain MRI in the diagnosis of NMOSD, comparing and contrasting imaging findings with those in RRMS. In their study, 63% of patients with NMOSD had brain lesions. Of these patients, 27% actually fulfilled the Barkhof criteria for “dissemination in space.” This finding stresses the importance of careful localization and consideration of lesion morphology in differentiating between the 2 disease processes. They proposed criteria to aid in the diagnosis and differentiation between RRMS and NMOSD. Relapsing-remitting MS should have at least 1 lesion on a T2-weighted scan in both the inferior temporal lobe and adjacent to the body of the lateral ventricle or either a subcortical lesion with a U-fiber–type morphology or an ovoid lesion perpendicular to the lateral ventricle (Dawson fingers). These MRI findings diagnose RRMS with 92% sensitivity and 92.6% specificity. The presence of a lesion adjacent to the fourth ventricle did not improve the accuracy of the criteria. It was surprising to find that only 9% of NMOSD patients positive for anti-AQP4 Ab had lesions considered to be “NMO typical.”

Storoni et al80 also recently evaluated the use of MRI in the differentiation of MS and NMOSD. In their pilot study, they compared the MRI appearance of the anterior visual pathways of both NMOSD and MS patients. They devised a scoring system to evaluate 2 aspects: the linear location and the thickness of the cross-sectional area. Although contrast-enhanced MRI is the criterion standard for inflammation detection, this study did not routinely use gadolinium. They based the presence of inflammation solely on cross-sectional area. The authors found a trend for more posterior involvement in the NMOSD group. Patients with NMOSD had a relative risk of 7.5 (CI, 0.3–17.3) of having a score of 4 or higher, and only NMOSD patients were found to have a score of 6 or higher. However, the study had important limitations including the lack of IV contrast. Another retrospective study found no distinguishing optic nerve features on MRI.81 However, bilateral optic nerve and chiasmal enhancement was seen only in NMO patients. The cohort was small (NMO, n=6, and MS, n=11), and no dedicated orbital imaging protocol was used. Further prospective studies, including an orbital imaging protocol with and without contrast, are needed to determine whether MRI evaluation of the anterior visual pathway can help distinguish between NMO and MS ON.

Fingolimod (FTY720, Gilenya, Novartis) is the first oral immunomodulating agent approved for the treatment of RRMS. It is an antagonist to the sphingosine-1-phosphate (S1P) receptor. In vivo, fingolimod is rapidly phosphorylated to fingolimod phosphate, which resembles S1P. Fingolimod phosphate then induces internalization and degradation of S1P receptors, which play an important role in lymphocyte liberation from lymphoid tissue to the CNS. Fingolimod thus blocks ongoing disease by inhibiting T-cell CNS migration. It has also been shown to reverse blood-brain barrier leakiness and to reduce demyelination.82 Although fingolimod has been proven to be efficacious in reducing MS relapse rate, even more than interferon, cystoid macular edema (CME) has been reported in 0.5% of patients taking the 0.5-mg dose. The mechanism is not known but could represent disruption of the vascular endothelial integrity leading to breakdown of the blood-retinal barrier.83 Although CME usually develops within the first 3 months of treatment, a recent case report featured a patient whose symptoms started as early as 5 days after initiating fingolimod treatment.84 This finding illustrates the importance of a baseline ophthalmology examination and close follow-up.

Zarbin et al85 analyzed current phase 2 and 3 core and extension studies for MS. Among 2615 patients assessed in their pooled analysis, 19 CME cases were confirmed. Among the 1176 patients who received 0.5 mg of fingolimod, 4 (0.3%) developed CME, and among the 1302 patients who received 1.25 mg of fingolimod, 15 (1.2%) developed CME. Fingolimod discontinuation alone usually resulted in CME resolution and return to baseline. In some patients, treatment also included topical anti-inflammatory agents, both steroidal and nonsteroidal. The authors suggested discontinuing fingolimod as first-line treatment of fingolimod-induced CME. If CME does not resolve within 6 to 8 weeks, treatment with anti-inflammatory medications should be considered. Patients at increased risk include those with MS, those with diabetes mellitus, and those older than 41 years. The authors recommend a baseline ophthalmic evaluation and 3 to 4 months after initiation of fingolimod.

When patients elect to not discontinue their disease-modifying treatment, other CME management strategies should be considered. Chui et al86 recently reported the case of a 67-year-old woman who elected not to discontinue fingolimod after developing CME on month 6 of treatment. She was treated with a topical nonsteroidal anti-inflammatory drop and a topical steroidal drop. Cystoid macular edema resolved 3 weeks after increasing the frequency of drop application. Unfortunately, attempts to wean topical drops failed while the patient was still on fingolimod. She later decided to discontinue fingolimod with complete resolution of CME 5 weeks later. The authors conclude that topical anti-inflammatory drops may be useful in the management of CME if the patient elects to continue on fingolimod treatment. Minuk et al87 reported another case of a patient who did not want to discontinue fingolimod after CME development. This 58-year-old woman was treated with bilateral subtenon triamcinolone injection. Cystoid macular edema completely resolved 1 month after treatment. She did, however, develop steroid-induced increased intraocular pressure that required trabeculoplasty in the right eye and glaucoma therapy in the left eye. The authors propose that triamcinolone stabilized the blood-retinal barrier and resolved CME.

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CHIASM AND POSTERIOR VISUAL PATHWAY

Pituitary adenomas are the most common pituitary tumor, with an annual incidence of 0.8 to 8 per 100,000. They are frequently seen and diagnosed in neuro-ophthalmology clinics because they may compress the optic chiasm and nearby visual structures. Automated visual field testing is commonly used in the evaluation and treatment of these patients. Chouinard et al88 recently evaluated the use of standard functional MRI (fMRI) retinotopic mapping to describe the effects of tumor compression and decompression on the optic chiasm. The patient was a 68-year-old woman who presented with recurrent macroadenoma that compressed the left anterior portion of the optic chiasm and the left optic nerve. A left lower visual field defect was described in the left eye; the right eye had no detectable visual field defect. On fMRI, most of the left primary visual cortex (V1) responded to retinotopic stimulation in her right visual field, but a large portion of the right V1 did not respond to retinotopic stimulation in her left visual field. After the surgery, fMRI results were consistent with a recovery in the right V1 responsiveness, particularly in the previously affected left lower visual field. There was a 282% increase in V1 recruited in this field. The authors state that although automated perimetry is useful for assessing compression of the optic chiasm, the observed deficits do not always coincide with the expected deficits. They conclude that fMRI may have some advantages over automated perimetry in this setting. Functional MRI may be more sensitive in detecting visual field defects before these are detectable with automated perimetry. It may also be a more objective examination of visual function. They proposed that fMRI could be used as a complementary tool in the evaluation of pituitary compressive lesions.88

Compressive lesions of the optic chiasm usually affect the crossing nasal fibers subserving the bitemporal visual fields. Recently, the neurologic hemifield test (NHT), an automated analysis of the quantitative differences across the vertical midline, has been used to differentiate this field defect from glaucomatous defects. In addition to the classic visual field defects, chiasm-compressing tumors can cause thinning of the papillomacular and nasal retinal nerve fiber layer (RNFL). This finding is commonly referred to as band or bowtie atrophy. Optical coherence tomography can identify band atrophy in this setting. Moon et al89 developed an algorithm using these 2 concepts and evaluated their use in the detection of chiasmal compression. The NHT score was established using the 30-2 visual field pattern deviation probability plot. Retinal nerve fiber layer thickness was scored from 0 to 10 according to the pattern of RFNL loss, with nasal and temporal defects scored high whereas superonasal defects were scored low. They compared the scores across groups of patients with compressive lesions, glaucoma, and glaucoma suspects. The authors found significantly higher scores in chiasmal compression than in glaucoma. They concluded that the NHT and RNFL scores can detect chiasmal compression.

When lesions compress the visual pathway, visual field defects are found in sectors corresponding to the damaged tissue. Two general assumptions are usually made, that perception is completely abolished in the blind field and that perception is normal in the intact field. However, evidence has shown that the intact field may have subtle perceptual deficits. The intact field may also show decreased contrast sensitivity, impaired ability to detect targets on a noisy background, impaired figure-ground segregation, and maladaptive patterns of visual field search. Bola et al90 recently studied the temporal processing deficits in the intact visual field of patients with prechiasmatic and postchiasmatic lesions. The patients were tested with high-resolution perimetry, and reaction time in the intact visual field was measured to judge processing time. The authors showed that visual processing speed is impaired in the intact visual field. Two correlations were described, with longer reaction time associated with more defective surrounds and larger scotomas. The authors argued that compressive lesions have consequences for visual function even in the visual field presumed to be intact.

McCune-Albright syndrome (MAS) is a genetic disorder that manifests as a triad of café au lait pigmentation, polyostotic fibrous dysplasia, and single or multiple endocrinopathies. Fibrous dysplasia/MAS is associated with acute and chronic optic neuropathy. Progressive optic canal narrowing was thought to cause the chronic optic neuropathy in these patients. However, it has been shown that narrowing of the optic canal in craniofacial fibrous dysplasia may not be causally associated with visual loss. The mechanism of vision loss and optic neuropathy may be due to optic nerve stretching from bone expansion secondary to growth hormone excess.

Ma et al91 recently reported improvement of visual fields after transsphenoidal surgery in 3 patients with MAS growth hormone–secreting pituitary adenoma. The patients were followed for 6 to 18 months after surgery. Visual field improvement was noticed in all 3 patients, although no change in visual acuity or color vision was noted. The authors concluded that chiasmal compression is also a potential contributing factor to the visual impairment in MAS patients.

The optic tract syndrome (OTS) is described when injury to the unilateral optic tract causes an incongruous homonymous hemianopsia, a relative pupillary defect in the contralateral (or ipsilateral) eye depending on the degree of visual field loss in each eye, and bilateral optic atrophy. The uncrossed temporal fibers in the ipsilateral eye result in preferential atrophy of the superior and inferior rim of the optic disc. The crossed nasal fibers of the contralateral eye in turn lead to atrophy of the papillomacular bundle and nasal parts of the rim, known as band atrophy. Kanamori et al92 evaluated the use of spectral domain OCT (SD-OCT) in 4 patients with OTS. All their cases exhibited marked changes in the ganglion cell complex that were compatible with OTS. However, the difference in the presumed RNFL reduction rate in the temporal or nasal quadrants did not reach statistical significance between eyes with temporal hemianopsia and those with nasal hemianopsia. They concluded that SD-OCT could be a useful tool in the diagnosis of OTS.

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INCREASED INTRACRANIAL PRESSURE AND RELATED ENTITIES

Idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri, is characterized by symptoms and signs of increased ICP. The modified Dandy criteria include the following: (1) cranial CT and/or MRI confirming the absence of radiographic hydrocephalus or mass lesion; (2) elevated opening pressure upon ventricular or lumbar spinal tap with normal CSF profile; and (3) intact neurologic examination with the exception of visual disturbance, sixth cranial nerve palsy, and papilledema. Papilledema however, is not a necessary criterion for the diagnosis of IIH. The most common presenting symptoms are headache, pulse synchronous tinnitus, and blurred vision. Headache is often present in the morning, and patients typically have already tried multiple headache remedies without success. Acute visual loss can be present in the fulminant form of IIH, which may require more aggressive and urgent medical or surgical treatment than typical IIH. Patients can also describe transient visual obscurations precipitated by positional changes. Pulsatile tinnitus has also been described and may be related to flow disturbances in the cerebral venous system. Idiopathic intracranial hypertension is more common in obese women.93 African American men may have a more precipitous course of IIH. Recently, IIH has been reported in prepubertal and pubertal children. A recent review of records from the Kaiser Permanent Southern California Children’s Health Study (N=913,178) identified 78 children with IIH.94 They were mostly females (84.5%), aged 11 to 19 years (84.5%), non-Hispanic white (47.4%), and overweight or obese (73.1%). Similar to previous reports, prepubertal IIH showed little or no association with obesity and only a slight female predilection.

One theory of IIH development is intracranial venous drainage abnormalities. Whether it represents a primary mechanism or a secondary effect of the underlying pathologic process is unknown. Kerty et al95 recently proposed that IIH could be associated with specific AQP4 gene variants. Clinical data and blood and CSF samples were collected from 28 IIH patients. Genetic sequencing was performed for the AQP4 gene on chromosome 18. The χ2 test and linear discriminant analysis were used to search for a genotype-phenotype association. Full cross-validation of the linear discriminant analysis modeling resulted in only 55.1% correct classification of cases and controls. No association was thus found between AQP4 gene variants and IIH.

The treatment of IIH is focused on preserving vision and providing adequate symptom relief for headache. In patients with mild headaches and stable vision, a 6% weight loss alone can result in reversal of papilledema. Medical therapy is used with more severe symptoms or with a visual-threatening condition. Acetazolamide (a carbonic anhydrase inhibitor) and furosemide inhibit the production of CSF and consequently reduce ICP.93 The use of acetazolamide during pregnancy is controversial because of its teratogenic potential but is often used clinically in consultation with obstetrics. Acetazolamide is classified as Food and Drug Administration pregnancy category C. Category C classification indicates that animal reproduction studies have shown an adverse effect on the fetus, but there are no adequate and well-controlled studies in humans. Class C drugs should be used only if the potential benefit justifies the risk to the fetus. Falardeau et al96 recently evaluated teratogenicity outcomes in patients treated with acetazolamide during pregnancy. A total of 101 patients consented, and acetazolamide was used in 63 pregnancies. Use of acetazolamide before 13 weeks was reported in 50 patients. They found that the total abortion rate was not higher in acetazolamide users. Offspring abnormalities were also similar between the acetazolamide and the nonacetazolamide group. In the acetazolamide group, abnormalities were reported in 5 patients, 1 child with asthma; 1 with cerebral palsy; 1 with hydronephrosis; 1 with craniosynostosis; and 1 with juvenile rheumatoid arthritis, heart murmur, and esotropia. No case of forelimb or other axial skeletal malformations was identified. Limitations of the study included the small sample size, evaluation limited to the acetazolamide 1 g/d dose, the self-reporting method of data collection, and the fact that mental and learning disabilities are usually not apparent until at least 2 years of age. They concluded that evidence of the teratogenicity of acetazolamide is lacking and the avoidance of acetazolamide during the first trimester has little medical justification. However, they stressed that acetazolamide should be administered with caution during pregnancy and that the risk-benefit ratio should always be considered.

Idiopathic intracranial hypertension is more common in obese individuals, but it is unclear whether obesity is also an independent risk factor of poor visual outcomes. A recent retrospective review of 414 IIH patients evaluated whether a higher body mass index (BMI) at diagnosis was a risk factor of worse visual outcome in IIH.97 A total of 158 IIH cases had a BMI of greater than 40 kg/m2, and 172 had a BMI of 30 to 39.9. Patients with BMI of greater than 40 were more likely to have severe papilledema at first encounter than those with lower BMI (P=0.02). There was also a trend toward more severe visual loss at last follow-up in the higher BMI group (18% vs 11%, P=0.067). Logistic regression modeling found that, for each 10-kg/m2 increase in BMI, the odds of severe visual loss increased by 1.4 times (CI, 1.03–1.91, P=0.03) after controlling for confounding variables (sex, race, hypertension, and sleep apnea). They concluded that a higher BMI at diagnosis is independently associated with increased risk for severe visual loss in IIH patients.

Intracranial venous hypertension has been implicated as a potential final common pathway in IIH. Several mechanisms for the increased venous pressure have been investigated, including dural venous sinus stenosis. Focal stenosis has been found in 30% to 93% of IIH patients, commonly in the transverse or the upper sigmoid sinus. It is still not known whether the stenosis causes the increased ICP or is actually secondary to the elevated ICP. Regardless, venous hypertension proximal to the stenotic area leads to further increase in ICP. This has led to the assumption that treatment by endovascular venous stenting of the sinus stenosis could resolve or ameliorate the condition. Studies have shown that dural venous sinus obstruction resolves after CSF removal.98 A recent systematic review assessed the current status of venous sinus angioplasty and stenting for the treatment of IIH.99 A total of 143 patients were evaluated, with a mean BMI of 31.6 kg/m2 and a mean age of 41.4 years. Eighty-seven percent of patients were women. Headache and papilledema were the most common presentations at 90% and 89%, respectively, followed by visual changes in 62% and pulsatile tinnitus in 48% of patients. Endovascular venous stenting had a technical success rate of 99%. The venous pressure gradient dropped from 21.8 mm Hg before the procedure to 2.8 mm Hg after stent placement. Improvement or resolution of symptoms was reported in 88% of patients. Resolution of papilledema was seen in 97% of patients, and restoration of normal vision was achieved in 87% of cases. The overall complication rate was 6%, with a 2% rate of subdural hematoma requiring surgical intervention. The authors concluded that endovascular stent placement is an effective strategy with an acceptably low complication rate.

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Obstructive Sleep Apnea in Idiopathic Intracranial Hypertension

Obstructive sleep apnea has been previously associated with IIH. A recent study evaluated whether the prevalence and severity of OSA were greater than expected in IIH patients.100 They included 24 patients with newly diagnosed IIH who underwent PSG. The AHI was calculated for each patient on the basis of age, sex, race, BMI, and menopausal status. Eight patients (33.3%) had OSA by PSG. However, AHIs were not significantly different from those predicted by the model. The authors concluded that the prevalence and severity of OSA in IIH patients were not greater than expected. Abraham et al101 evaluated the incidence of sleep breathing disorders in patients with IIH. They performed overnight respiratory monitoring in 22 untreated IIH patients and compared results with age-matched control subjects. Variables included heart rate, respiratory rate, oxygen saturation, and continuous end-tidal capnography. Neither group was found to have significant hypoxia or hypercarbia during sleep. There were no differences in mean carbon dioxide levels or minimal oxygen saturation. The study group did, however, have significantly more apnea events per hour of sleep (1.21±1.38 and 0.92±0.56, respectively; P=0.02), although values in the study group were still within reference range (<5 per hour). The authors concluded that although IIH was not associated with a clinically significant nocturnal breathing abnormality, subtle increase in paroxysmal sleep apnea events could be sufficient to cause cerebral blood vessel vasodilatation and a secondary increase in ICP. Screening of OSA in IIH may be appropriate, but further investigation is still warranted.

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TUMOR AND ANEURYSM

Tumor

Neuro-ophthalmic presentations for tumors of course depend on location, and meningioma is the most common type, representing approximately one fifth of all intracranial tumors.102 Meningiomas near the visual apparatus pose special treatment challenges because nearby structures can be damaged by intervention, and both surgical and radiotherapy approaches must be carefully considered.

Bloch et al103 reviewed fractionated radiotherapy for optic nerve sheath meningiomas (ONSMs). They reviewed the classic presentation for ONSM of vision loss, optic nerve atrophy, and “optociliary shunt vessel” (retinochoroidal venous collateral), although noting that these findings are not specific for ONSM. Their review of surgical therapy found that 94% of subjects experienced visual decline, although noting that individual cases might still merit operative intervention. Fractionated stereotactic radiotherapy is considered by many to be the standard treatment of symptomatic ONSM. In their review of past studies, they report a trial of stereotactic radiosurgery, with higher complication rates and lower visual recovery rates than most trials of fractionated radiotherapy. They raise the possibility that fractionated radiosurgery might hold more promise.

Soldà et al104 assessed outcomes in patients with ONSM treated with fractionated stereotactic radiotherapy. They examined 51 involved optic nerves across 45 patients treated with 50 Gy in 30 or 33 fractions. Although 4 patients were lost to follow-up, 5-year progression-free survival was 100%. No patient with blindness had recovery. However, 30% had objective or subjective improvement at a median of 5 months. One patient became blind 10 years after treatment from an embolic retinal artery occlusion. Overall, in patients with some residual vision, 58% had stable vision, and vision deteriorated in 11%. Two patients developed radiation retinopathy. The study argued for stabilization of vision, with major side effects and worsening being uncommon.

Jo et al105 reported on multiple sessions of radiosurgery for treatment of benign orbital tumors. They report on 23 cases including 9 meningiomas, 9 cavernous hemangiomas, 3 schwannomas, and 1 each of a granular cell tumor and a solitary fibrous tumor. Size reduction was obtained with a median of 57.1% for cavernous hemangiomas and 12.6% for meningiomas. Of the patients, there were 16 with vision loss, 11 with proptosis, 8 with diplopia, and 4 with headache or orbital pain. Improvement was seen in 7 of the 11 with proptosis, 3 of the 4 with pain, and 7 of the 11 with visual field abnormalities. This study points to the possibility of successful fractionated radiosurgery in select cases.

Maclean et al106 present a prospective series examining outcomes of intensity-modulated radiotherapy in 30 patients with meningiomas affecting vision with a 28-month median follow-up time. The prescribed dose was 50.4 Gy in 28 fractions. Twenty-six patients (86.7%) had anterior visual pathway tumors including sphenoid wing, cavernous sinus (CS), parasellar, parasagittal, and frontal locations, with 3 of them with ONSM. Visual deficits judged by acuity, fields, and Ishihara color plates improved in 40% of patients and remained stable in the other 60%. Brief toxic effects included keratitis in 4 patients and diplopia in 2 patients, with persistent side effects of keratitis in 1 patient and dry eye in 5 patients. One patient had a contralateral temporal hemianopsia, thought to have resulted from chiasmal toxicity, and 3 patients had cataract. Other complications included herpes zoster and a posterior vitreous detachment followed by retinal detachment thought to be unrelated. Overall, treatment was effective in stabilizing or improving vision, with relatively few toxic effects.

Although radiation therapy remains an important modality, 2 recent studies argue that surgery can play an important role in certain cases. Lehmberg et al107 examined visual effects of anterior clinoidectomy (AC) for meningioma resection. Their series included 46 patients with meningiomas of the CS (9%), anterior clinoid process (39%), sphenoid wing (9%), and tuberculum sellae (9%). Forty-six percent of patients had gross total resections. Of the 57% of patients with preoperative acuity impairment, 79% had improvement, whereas 17% remained the same and 4% (1 patient) worsened. All patients without preoperative visual deficits stayed the same. Of the 67% of patients with field deficits, 54% improved, whereas 25% remained unchanged and 21% worsened. Similar to acuity, patients without preoperative field deficits remained unchanged. They looked more closely at whether AC, used in 53% of the sample, improved visual outcome. For acuity, AC resulted in 61% with improvement and 39% unchanged, whereas without it, only 25% improved whereas 70% remained unchanged and 5% worsened, for a statistically significant difference. For visual fields, the visual field differences with and without AC did not reach significance. The authors argued that bony decompression of the optic canal can also be beneficial.

Because many meningiomas have hormonal receptors and may grow in response to change in estrogen state, treatment in pregnancy is particularly challenging.102 Moscovici et al108 examined visual and surgical outcomes of parasellar meningiomas in pregnancy. They compared 20 patients who underwent resection during or after pregnancy. Six of the women were diagnosed in the second or early third trimester. The 4 who underwent operations had near total visual recovery, whereas 2 who delayed operations developed unilateral blindness. Three patients diagnosed later in pregnancy had spontaneous visual improvement after delivery. Although a small study, it emphasizes the possibility of surgery relatively early in pregnancy to avoid permanent vision loss.

Optic pathway gliomas (OPGs) comprise another class of tumors likely to present primarily with vision complaints. Liu et al109 published an argument that OPGs are true neoplasms rather than hamartomas. They argued that OPGs can grow faster than surrounding structures, causing destruction and functional decline. These also have histopathologic characteristics of true neoplasms. In particular, they are often positive for markers of cellular proliferation. Although they can improve spontaneously, this characteristic is seen in other neoplasms. They also respond to chemotherapy and radiation therapy. This view of OPG as neoplasms was argued as necessary to channel patients toward consideration of treatment rather than observation alone.

Observation does play a role in many cases, however, both because of individual patient preferences and physician judgment. Fard et al110 looked at SD-OCT for monitoring of OPG. They examined 38 eyes across 27 patients. Comparing progressing with nonprogressing eyes, they found statistically significant differences in the RNFL thickness and posterior pole retina. In a separate analysis of 26 eyes with corresponding sequential MRI, 6 had both radiological and clinical progression. Receiver operating characteristic analysis showed RNFL and posterior pole retina areas under the curve of 0.96 and 0.98, respectively. Optical coherence tomography does seem useful in discriminating progression of OPG.

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Aneurysm

Aneurysms are dilations of arterial walls, with cerebral aneurysms most often occurring at bifurcations. Rupture is a major medical emergency, with mortality as high as 45%.111 Mass effect from the unruptured aneurysm leading to ophthalmological deficits can herald its presence, and prompt diagnosis can avert rupture and the dreaded subarachnoid hemorrhage.

Although rare, aneurysm can imitate stroke and mass lesions. Opalski syndrome comprises features typical of a lateral medullary lesion together with ipsilateral hemiplegia. Dembo and Tanahashi112 report a single patient with this syndrome with an unusual pathology of lateral medullary compression by a tortuous and dolichoectatic vertebral artery. They were able to further show a difference on diffusion tensor imaging between corticospinal fibers on the affected side versus the unaffected side, a finding not previously reported. Acute and follow-up imaging showed no evidence of frank infarction. Although surgical decompression was considered, the patient’s symptoms improved with medical management of hypertension.

In recent years, treatment has primarily consisted of clipping versus endovascular treatment. Li et al113 performed a meta-analysis to examine the enduring question of clipping versus coiling for treatment of ruptured intracranial aneurysms. They included 4 randomized trials and 23 observational studies, for a total of 11,568 subjects, to address measures of mortality; poor outcome, judged as death or dependency at 1 year; and rebleeding. The mortality slightly favored coiling but did not reach statistical significance. The poor outcome measures favored coiling. However, rebleeding rate as an outcome measure favored clipping. Vasospasm, a secondary outcome measure, occurred more often after clipping. However, other secondary outcomes of ischemic infarction, shunt-dependent hydrocephalus, and procedural complications were not significantly different.

The Barrow Ruptured Aneurysm Trial presented its 3-year results.114 Patients were randomly assigned to clipping or coiling, but crossover was allowed based on clinical judgment. Thirty-eight percent of intent-to-coil patients crossed over to clipping. Subjects included 238 patients assigned to clipping and 233 assigned to coiling. It examined outcomes judged by the modified Rankin Score at 3 years. Poor outcome was not significantly different on the basis of assignment, 35.8% for clipping and 30% for coiling. However, aneurysm location was a factor. Posterior aneurysm patients assigned to coiling had a 25% poor outcome rate, whereas ones assigned to clipping had a 61.8% poor outcome rate, with similar 26.9% and 58.3% rates, respectively, when looking at actual treatment rather than assignment. The poor outcome rates for anterior circulation aneurysms were not significantly different at 29.3% versus 27.9%, respectively, by assignment and 23.6% versus 30.7%, respectively, by actual treatment.

Sturiale et al115 addressed the question of endovascular treatment of aneurysms in a more limited group, patients 65 years or older, in a meta-analysis. They pooled a total of 1511 patients, 1080 with subarachnoid hemorrhage, across 21 studies examining good recovery and moderate disability with 78% of patients, 66% of patients with ruptured aneurysms and 93% with unruptured aneurysms, reaching 1 of these 2 favorable outcomes at greater than 12 months. Occlusion at greater than 12 months was obtained in 86% of patients, with 87% considering both ruptured and unruptured cases individually. However, these findings contain no comparison with a control group to gauge the relative magnitude. Darsaut et al116 reported the study protocol for the International Subarachnoid Aneurysm Trial Part II. It aims to further address the question of clipping versus coiling by looking at poor outcome (modified Rankin Score >2) at 1 year with secondary measures of safety and efficacy secondary endpoints. It will involve 50 international centers with a planned duration of 12 years. The original International Subarachnoid Aneurysm Trial was influential in favoring coiling. This study will broaden the patient groups and questions of the original trial to further address this open question. Ferrell et al117 looked specifically at visual complications of stent-assisted endovascular aneurysm treatment of ophthalmic segment ICA aneurysms in 57 patients. A total of 63 aneurysms were treated. Interestingly, 89.5% of the patients were female. A total of 68.3% were completed occluded, and another 20.6% had a small residual neck leading to 4.8% with a significant residual neck at 6.3% incompletely or partially treated. The ophthalmic artery was preserved in 96.5% of cases. The overall visual complication rate was 5.3% with a 3.5% rate of permanent complications. Overall, the study argues that visual complications are not significantly different compared with clipping or standard endovascular treatment, but it was not a head-to-head comparison.

Although clipping is thought to be definitive, recurrence after coiling remains a concern, and repeated clinical and imaging monitoring is necessary.111 Pierot et al118 examined follow-up magnetic resonance time-of-flight angiographic imaging of coiled aneurysms at 3 T versus 1.5 T in comparison with digital subtraction angiography. This prospective study followed 126 aneurysms in 96 patients. They examined the sensitivity, specificity, and PPV and NPV for judging adequate occlusion versus remnant and for judging total occlusion versus remnant. For the assessment of adequacy, sensitivity, specificity, and PPV and NPV, the findings were 0.74, 0.93, 0.81, and 0.90 at 3 T versus 0.54, 0.98, 0.90, and 0.85 for 1.5 T. For total occlusion assessments, the same respective findings were 0.74, 0.81, 0.82, and 0.72 at 3 T versus 0.65, 0.88, 0.86, and 0.68 at 1.5 T. The study clearly shows superiority of 3-T imaging. However, both techniques will incorrectly classify a number of aneurysms compared with the criterion standard of digital subtraction angiography.

Many aneurysms with wide necks, large size, and complex morphologies are difficult to treat with traditional clipping and coiling techniques. The newer Pipeline device provides another treatment option. The Pipeline for Uncoilable or Failed Aneurysm trial was multicenter and prospective but had only a single arm of 108 patients.119 Its outcome measures were effectiveness defined as successful aneurysm occlusion without major stenosis at 180 days and safety defined as major ipsilateral stroke or neurologic death within 180 days. The effectiveness measure was met in 73.6% of cases, and the negative safety outcome was limited to 6 of 107 patients. However, 44 patients had various serious adverse events. Of course, these results are difficult to interpret in the absence of any control group.

Occlusion of the parent vessel can be another option in selected cases. Matouk et al120 presented a series of 28 patients from July 1992 through December 2009 whose intracranial aneurysms were treated with parent vessel occlusion. This approach is limited to aneurysms not able to be clipped or coiled. Eight of the subjects presented with cavernous aneurysms, with successful obliteration in 6 cases and complications including small strokes and transient HS as well as growth of other aneurysms in 2 cases. Presentation included cranial neuropathies in 6 cases and vision loss in 3 cases, 1 patient having both. Four paraophthalmic aneurysms, including 2 presenting with vision loss, were treated successfully without serious complications. Sixteen of the patients had posterior circulation aneurysms. Six presented with subarachnoid hemorrhage, but brain stem findings were noted in 7 cases, cranial nerve palsy in 1, brain stem compression in 5, and brain stem infarction in 1. Complications of note to the ophthalmologist included 3 brain stem infarctions and 2 patients with transient vision loss. Mortality in posterior circulation aneurysms presenting with mass effect was 28.6%, with 28.6% rate of permanent major deficits. These data argue that, with the growing availability and use of flow-diverting stents, parent vessel occlusion remains an option except in the case of posterior circulation aneurysms presenting with mass effect. Most of those cases resulted in death or significant disability, but the authors caution that the natural history is quite grave.

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VASCULAR DISEASE

Arteriovenous Malformations and Fistulas

Abnormal direct communications between the arterial and venous systems lead to high flow states. An arteriovenous malformation (AVM) is a congenital abnormal communication, whereas an acquired one is an arteriovenous fistula (AVF), with the carotid-cavernous fistula (CCF) being of special interest to ophthalmologists.

Arteriovenous malformations in the brain can cause visual symptoms when located near the visual apparatus. However, more distant ones can cause visual complications through indirect means. Inci et al121 present an unusual presentation of a spinal dural AVM presenting with headache and vision loss secondary to papilledema. Brain imaging results were normal, but cervical spine MRI revealed the AVM. Although rare, it is a consideration for the differential diagnosis of elevated ICP when more common causes have been excluded.

When a patient presents with combined deficits of cranial nerves III, IV, VI, V1, and V2, CCF must be suspected and evaluated, although other lesions can mimic CCF. Williamson et al122 present the rare intraorbital AVF mimicking the more common CCF. The 81-year-old woman presented with an abducens palsy along with proptosis and chemosis. Enlargement of the superior ophthalmic vein, a sign characteristic of CCFs, was noted. However, angiography demonstrated the fistula to be completely intraorbital. The fistula was successfully embolized with a transvenous approach, which they report as the first such treatment of an intraorbital AVF. Although rare, it represents another consideration when CCF is in the differential diagnosis.

Carotid-cavernous fistula diagnoses can be difficult when coincident with conditions presenting similarly. Celik et al123 present a case of coincident TED and CCF.

Although AVM and AVF are etiologically distinct, they can present similarly. Mohd-Tahir et al124 report a temporal lobe AVM, a lesion congenital rather than acquired, that mimicked a contralateral CCF. The patient presented with a painful, red proptotic left eye with diplopia in left gaze. Computed tomographic scan revealed a temporal AVM fed by the right middle cerebral artery. It was successfully embolized with improvement in signs and symptoms.

Endovascular methods have revolutionized AVF treatment. Korkmazer et al125 present a short review of the endovascular treatment of CCF. They first reviewed the anatomy and Barrow classification into type A, direct fistulas between the ICA and the CS; type B, indirect connections between the ICA and the CS; type C, indirect connections between the external carotid artery circulation and the CS; and type D, indirect connections between both the ICA and external carotid artery circulations and the CS. They present the common signs and symptoms including exophthalmos, bruit, chemosis, pain, elevated intraocular pressure, subconjunctival hemorrhage, and more. They provided alternatives for the differential diagnosis and discuss treatment options. Although CT, MRI, CT angiography, and MR angiography can be helpful, catheter angiography remains the criterion standard for evaluation, and endovascular treatment has become standard, with detachable balloons, coil, and/or material embolization stenting and even parent artery occlusion as major options for direct fistulas. Embolization has become the leading treatment of indirect fistulas, with both arterial and venous approaches being used on the basis of the exact anatomy. These approaches offer good long-term outcomes for most CCFs.

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Vascular Disease

Stroke remains a worldwide cause of great disability and mortality as well as expense.126 Some cases presenting primarily with visual manifestations can come to the attention of ophthalmologists, particularly strokes involving the posterior fossa. However, amaurosis fugax can warn the clinician, and permanent monocular vision loss is even more concerning. Helenius et al127 examined the rate of brain infarcts in patients with monocular vision loss. One hundred twenty-nine patients with monocular vision loss secondary to ischemia were studied retrospectively. The patients underwent brain MRI after presenting to the emergency department with monocular vision complaints judged ischemic in origin. Thirty-one patients (24%) were found to have diffusion-weighted imaging lesions, and 3 had lesions outside the territory of the suspected ICA. Of the remainder, they tended be small lesions, multiple in 65% and single in 35%. The relative commonness of concurrent strokes argues that evaluation for brain involvement is reasonable in patients with ischemic monocular vision loss.

Optic atrophy can be seen with lesions anterior to the geniculate. New evidence from Park et al128 examined retinal ganglion cell loss after cerebral infarction using OCT, suggesting that transsynaptic degeneration occurs as well. They examined 46 patients with stroke versus 46 control subjects with exclusion of glaucoma patients. Compared with the control subjects’ mean RNFL thickness of 100.48 μm, the stroke subjects’ mean thicknesses were 75.41 μm in the contralateral eyes and 74.02 μm in the ipsilateral eyes. Changes were seen both for strokes affecting the occipital lobes and other lobes. Sectoral analysis showed the loss in the contralateral eye to affect the superior, inferior, and nasal sectors, whereas the superior, inferior, and temporal sectors were affected in the ipsilateral eye. This pattern argues for the interesting phenomenon of transsynaptic degeneration of the retina. It also argues that allowances might be made in stroke patients when other possible causes of RNFL thinning, such as glaucoma, are being considered.

Although ischemic stroke presumed secondary to risk factors such as age, hypertension, and diabetes mellitus often underlies sudden-onset neurologic deficits, other etiologies and risks must not be neglected. Silver et al129 present a case of varicella zoster virus vasculopathy in a 69-year-old man who initially presented with ION. He subsequently had 4 ischemic strokes, causing multi-infarct dementia. He later was found to have anti–varicella zoster virus IgG with evidence of intrathecal synthesis discovered 26 months into his course. He was treated with acyclovir without further events.

Walsh et al130 report on reversible cerebral vasoconstriction syndrome as a novel cause of Balint syndrome, the triad of simultagnosia, optic ataxia and ocular apraxia, and visual allochira, the perceptual transposition of visual stimuli to the opposite visual hemifield. Magnetic resonance imaging showed a right parietal and occipital infarct, opposite of expectation. Later MR angiography showed multiple segmental stenoses in the circle of Willis, consistent with reversible cerebral vasoconstriction syndrome. Her examination findings were attributed to either cerebral diaschesis or a direct effect of the unusual pattern of multiple infarcts.

Recurrent attacks of symptoms referable to the posterior intracranial circulation including vertigo, nystagmus, and syncope occur with head turning in rotational vertebral artery occlusion. Choi et al131 analyzed a series of 21 rotational vertebral artery occlusion patients in terms of clinical and radiographic characteristics. Rotary vertigo with head rotation and resolution with return to the neutral position was common to all subjects with various fractions having tinnitus, blurred vision, nausea and vomiting, and syncope. The patients underwent dynamic cerebral angiography, with only a slight majority of 12 patients having clear findings of compression of the dominant vertebral artery at C1 to C2. Other patients showed compression at C1 to C2 and other levels or at other levels or with head tilt rather than rotation. Twenty of 21 subjects developed nystagmus within several seconds of head turning, with a variety of downbeat, torsional, and rotational findings. The authors report success with conservative management of antiplatelet agents and behavioral modification to avoid exacerbating positions while acknowledging that interventions including vertebral artery stenting, cervical fusion, and decompression are possible options.

Other vascular lesions can cause ophthalmological deficits. Pandey et al132 presented a summary view of cavernous malformations (CMs) of the brain stem, the thalamus, and the basal ganglia in a series of 176 patients. They examined the outcomes of resection with special attention to hypertrophic olivary degeneration. A total of 52.3% of the CMs were pontine, and of note to the ophthalmologist, 51.1% of the patients presented with cranial nerve deficits including 38.1% of the patients presenting with diplopia. Postoperatively, 31.2% of the patients had additional neurologic deficits. Nine of 134 patients developed delayed hypertrophic olivary degeneration. Palatal myoclonus, nystagmus, and oscillopsia occurred in 3 such patients. In the longer term, 61.8% of the patients improved, with 25.9% remaining unchanged and 11.2% worsening. This report adds to understanding of the natural history of CMs and their long-term response to intervention.

In stroke recovery, visual function seems to have prognostic significance. Dong et al133 examined stroke recovery prognosis based on ocular motor function in 15 patients with first-time ischemic stroke without evident visual defect or gaze palsy. Performance on visually guided and volitional saccades was compared with the National Institutes of Health Stroke Scale and the modified Rankin scale for prognosis. Although saccades to targets were relatively normal, more complex saccades, such as saccades to a location opposite a target or to a remembered location, were abnormal. These measurements improved during 3 months. Ocular motor testing can provide some quantifiable measure of larger cognitive dysfunction during stroke and subsequent recovery.

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Vasculitis

Vasculitis refers to inflammation of vessel walls and can predispose affected patients to ischemia. Hughes et al134 report a case of granulomatosis with polyangiitis presenting with ophthalmic complications. At age 27 years, the woman initially presented with a rash and bilateral uveitis and scleritis, with results of biopsies showing a necrotizing vasculitis consistent with the diagnosis. She subsequently developed a pituitary mass also thought to arise from granulomatosis with polyangiitis (formerly Wegener granulomatosis). She was planned to undergo treatment with RTX, but she then developed ptosis, ophthalmoplegia, and loss of visual acuity on the right, with subsequent imaging showing involvement of the CS and the optic chiasm and canal. Pulsed methylprednisolone for 3 days was given along with continued RTX. She subsequently experienced significant, although incomplete, recovery. Lee et al135 document a case of AION in a patient with Churg-Strauss syndrome. The patient was a 54-year-old man presenting with decreased right eye acuity to 20/50, with pallid edema of the eye noted on examination. Fluorescein angiography showed defects in the optic nerve head and the peripapillary choroid. Sedimentation rate, C-reactive protein, and eosinophil count were all elevated, and there was bronchial eosinophilic infiltration leading to the diagnosis. Treatment with corticosteroids resulted in recovery of acuity to 20/25 with resolution of the fundus abnormalities.

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Giant Cell Arteritis

Giant cell arteritis is a vasculitis of people older than 50 years, being the most common vasculitis in this age group, and vision loss, particularly from A-AION, is among its most disabling effects.136 Prompt initiation of corticosteroid treatment is the mainstay of treatment. Hayreh and Biousse137 presented arguments for oral steroids versus high-dose IV steroids, in cases of acute vision loss in GCA. Hayreh argued for limiting IV corticosteroids to particular cases of amaurosis fugax without vision loss, complete or marked vision loss in 1 eye, and early signs of involvement of the second eye. In contrast, Biousse favored induction with IV corticosteroids based on rapid administration, monitoring for side effects and rapidity of action along with the possibility shown in a clinical trial of reduced cumulative corticosteroid dosing. Both agreed, however, that the overall goal should be avoidance of delay in treatment.

Although A-AION is a classic presentation of GCA, many others are seen. Kumar et al138 presented a case of GCA in a 74-year-old man presenting with fever, headache, jaw claudication, and bilateral vision loss as well as necrosis of the scalp, the lip, and the tongue. The authors believed it to be the first such case in India. Kopsachilis et al139 present a case of GCA with choroidal infarction. They found pallor of the temporal retina with confirmation of infarction on fluoroscein angiogram and without evidence of A-AION. Kumarasinghe et al140 present a case of tongue necrosis as the presenting sign of GCA. The 74-year-old woman also had systemic symptoms including headaches and jaw claudication. She did not experience ophthalmic complications of the disease. Stengl et al141 report a 73-year-old woman presenting with a lateral medullary syndrome stroke. She presented again 3 months later with presumed brain stem transient ischemic attack, and subsequent evaluation with echocardiography revealed evidence of aortitis, with subsequent CT and positron emission tomography scans revealing more diffuse arteritis along with elevated inflammatory markers.

As in the case above, the aortic arch and its branches all can be affected in GCA. Kermani et al142 examined large vessel involvement of GCA. In a cohort of 204 patients spanning 54 years, they examined large artery stenosis and aortic aneurysm/dissection. Occurrence of large vessel involvement was 5 per 100 person-years in the first year, with a relatively constant risk after the first 5 years. However, rates of aortic aneurysm/dissection increased after 5 years. Although the overall survival of GCA patients was similar to that of the general population, large vessel involvement was a risk of decreased survival. This study serves as a reminder of systemic complications of GCA and their long duration.

The causes of GCA remain unclear. One recent case raises questions about the underlying factors. Chen et al143 observed 2 cases of GCA in a husband and wife. The 76-year-old husband presented with vision loss associated with new headaches beginning 10 years after his wife was diagnosed with GCA at age 66 years. Both patients were of Scottish-English extraction, and northern European ancestry is a known risk of the disease. The study raises the question of whether environmental exposures, particularly to tobacco smoke, sunlight, and infections, serve as disease triggers.

Presentation coincident with other autoimmune diseases is not the rule. Tripodaki et al144 present coexistent GCA and MG in a patient hospitalized for stroke. Although myasthenia is associated with other autoimmune diseases, GCA is not a common one. The 79-year-old woman presented with strokes in the right posterior parietal and occipital lobes, but her history was also remarkable for generalized weakness, malaise, headache, and ptosis. Subsequent testing revealed elevated inflammatory markers and a positive temporal artery biopsy result as well as anti-AChR Abs. Such overlap seems to be quite rare based on the authors’ review.

The need for long-term immunosuppression in a population especially sensitive to corticosteroid side effects remains a major problem, and if proven effective, steroid-sparing agents could provide great benefits. Ashraf et al145 reported on a patient with polymyalgia rheumatica and aortitis successfully treated with tocilizumab, a monoclonal Ab directed against interleukin 6. He underwent surgical reconstruction of his aorta. The patient experienced remission of disease with combined corticosteroid and tocilizumab treatment, highlighting a possible additional treatment. Seror et al146 reported the negative results of a multicenter RCT comparing prednisone plus adalimumab against prednisone plus placebo for GCA. Patients within 14 days of initiation of corticosteroid treatment also received a 10-week course of placebo or adalimumab, a monoclonal Ab against tumor necrosis factor α. Patients with visual manifestations were excluded. The authors measured rates of remission at week 26 and prednisone dose at that time point. The results for the adalimumab and placebo groups were not statistically significant.

Weaning of corticosteroids can be difficult because of the possibilities of both relapse and withdrawal. Jamilloux et al147 addressed the question of adrenal function recovery with weaning of long-term corticosteroids for GCA. They retrospectively analyzed 150 cases examined with the corticotropin stimulation test to assess for adrenal function recovery when each patient was successfully weaned to 5 mg of prednisone daily, taking 17.1 months on average. Forty-nine percent of their subjects failed the initial corticotropin stimulation test. Of these nonresponders, 53% failed to recover within an additional year. The nonresponders tended to have lower baseline cortisol levels, and they tended to have had higher prednisone dosing, both in terms of total dose and duration. The study emphasizes the need for vigilance even in the later stages of corticosteroid tapering.

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HIGHER VISUAL FUNCTIONS

Patients with cortical lesions present a special challenge to ophthalmologists because they can present with visual complaints and eye examination results that are normal or nearly so. Dementia is a prime example. Reñé et al148 report on 5 patients diagnosed with posterior cortical atrophy. Many of them presented initially to ophthalmologists, and diagnosis was made only 1 to 5 years after symptom onset. The report reminds of the important consideration of cortical pathology in patients with visual complaints out of proportion to any ocular pathology. Rajagopal et al149 present a case of corticobasal syndrome (CBS) with visual involvement. The 60-year-old woman presented with visual problems including problems reading and performing daily chores. She had previously been diagnosed with dementia of the Alzheimer type (DAT) but then developed gait and extrapyramidal motor deficits leading to the diagnosis of CBS. She had difficulty with locating and reaching for visual targets, including optotypes and Ishihara plates during examination. She had saccadic apraxia and square wave jerks as well as simultagnosia. Magnetic resonance imaging revealed diffuse cortical atrophy with a posterior parietal predominance. This degree of cortical visual processing deficits is unusual because abnormalities similar to progressive supranuclear palsy are more typical of CBS.

Resulting impairment from cortical pathology, especially from dementing illnesses, leads to questions about functional impacts. Fernandez et al150 examined event-related potentials from EEG during simulated changes in visual heading in Alzheimer patients versus healthy young and old controls. Visuospatial processing and navigational impairments are known features of DAT. Subjects were shown visual stimuli simulating changes in movement direction. Patients with DAT had decreased electrical potentials, whereas older control subjects had only slightly delayed responses. These findings correlated with worse psychophysical performance in DAT subjects. The study shows electrophysiological correlation to known deficits, and it shows that these deficits are clearly different from normal aging. Friedman et al151 examined the question of motor vehicle accidents in the elderly and their connection to higher-order visual processing. They examined a 2000-person population sample of drivers 70 years or older with 3 visual processing screening tests, the Motor Free Visual Perception Visual Closure Subtest, Trails B, and Useful Field of View Subtest 2. Test subjects with impairments in these tests were found to have significantly higher rates of motor vehicle accidents. Even after adjustment for additional factors including demographic influences, Trails B remained significantly associated with a higher rate of accidents. The study emphasizes the need for assessment of matters beyond simple visual acuity and field testing to assess the safety of potential drivers.

Migraine is a chronic condition seen across many ages that can impact vision. Messina et al152 examined structural cortical abnormalities in migraineurs. The study compared 63 right-handed migraineurs with 18 control subjects. The migraineurs had increased mean cortical thickness specifically in the left middle frontal sulcus and the left temporo-occipital incisure with reduced thickness in the left superior frontal sulcus. They also found cortical surface area differences between the 2 groups in specific areas. The authors argue that the thickness differences are potentially acquired, whereas the surface area differences are congenital, arguing for a combination of underlying disposition toward migraine with processes correlated to the disease itself.

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ADVANCES IN NEUROIMAGING

Ultrasound

Ultrasound offers attractive features including freedom from ionizing radiation and relatively low expense. Its availability varies, and results can be operator dependent. However, where available, it can provide quick and low-cost diagnosis. Neudorfer et al153 examined the utility of ultrasound for differentiating papilledema from pseudopapilledema. They prospectively examined 45 patients for optic nerve width as measured on ultrasound. Positive signs of papilledema were a doughnut or crescent sign in B-mode, an optic nerve width of greater than 3.3 mm in A-mode, or a reduction of at least 10% in the optic nerve width with 30-degree turning of the eye toward the probe. Ultimately, lumbar puncture was performed in 32 of the patients, with 20 having increased opening pressure. Using that upper limit of 3.3 mm, ultrasound was 85% sensitive and 63% specific. Reduction of the cutoff to 3.0 mm resulted in a sensitivity of 95% with a specificity of 58%. Both of these sensitivities exceeded other findings including headache, visual disturbances, general examination, funduscopy, and other imaging studies. Ultrasound remains a reasonable screening tool for true papilledema in patients with elevated optic nerve heads.

Mounting evidence argues for the use of ultrasound in evaluating for intracranial hypertension in acute settings. Amini et al154 examined use of the diameter of the optic nerve sheath on ultrasound to estimate ICP. They examined 50 patients with ultrasound immediately before lumbar puncture with measurement of opening pressure. In their sample, a 5.5-mm cutoff predicted opening pressure greater than 20 cm H2O with 100% sensitivity and specificity. Roque et al155 examined the use of ultrasound for detecting elevated ICP in a specific population, hypertensive patients. In a prospective, observational study, they examined 150 patients in the emergency department setting. They found that symptoms were poor predictors of the optic nerve sheath diameter (ONSD). However, systolic and diastolic blood pressures did correlate with increased ONSD. The distinction is important because evidence of papilledema leads to the diagnosis of hypertensive emergency, rather than hypertensive urgency, and subsequently to more aggressive treatment. They used a higher cutoff of 5 mm. Each arm of the study (normotensive/asymptomatic, hypertensive/asymptomatic, and hypertensive/symptomatic) included 50 participants. Optic nerve sheath diameter correlated with blood pressure, especially for blood pressures higher than 166/82. The authors argue for more aggressive blood pressure management when increased ONSD is found. Qayyum and Ramlakhan156 also examined ultrasound for predicting intracranial hypertension in the emergency department setting, also using a 5-mm cutoff. They included patients with moderate or severe traumatic brain injury, malignancy with new confusion, any clinical evidence of intracranial hypertension and neurologic deterioration. They recruited a total of 24 patients, finding a PPV of 95.4% and an NPV of 100% for prediction of CT scan evidence of elevated ICP. Resulting sensitivity and specificity were 100% and 75%, respectively.

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Optical Coherence Tomography

Optical coherence tomography is available within many ophthalmology practices and can provide immediate information about ocular anatomy. Cull et al157 report an animal study correlating optic nerve axon counts with RNFL thickness in rhesus macaques. Through unilateral disruption of the trabecular meshwork with laser, the intraocular pressure was increased in 1 eye. They found a strong linear relationship between axon count and OCT RNFL thickness, although 10% to 15% axon loss had to occur before becoming detectable with OCT.

Lee et al158 examined SD-OCT characteristics of optic nerve head drusen (ONHD). They examined 99 eyes in 61 patients, finding buried drusen in 95 eyes and visible ones in 4 eyes. They found a broad variety of characteristics of buried drusen, including both homogenous and nonhomogenous internal reflectivity.

Sarac et al159 looked at the question of using OCT to differentiate ODE from ONHD. They enrolled 25 participants in each category as well as 25 healthy control participants and compared the following parameters: (1) peripapillary RNFL thickness; (2) subretinal hyporeflective space (SHYPS) thickness; (3) SHYPS area; and (4) the angle between the temporal RNFL and the optic nerve head, termed the alpha angle. Mean, temporal, and nasal RNFL thicknesses were significantly different between ODE and ONHD and between ODE and controls, as were SHYPS thickness and area and the alpha angle. Merchant et al160 reported on enhanced depth imaging (EDI) OCT for ONHD. They compared both EDI and non-EDI modes as well as ultrasound in 68 eyes. Enhanced depth imaging provided clearer images of the posterior surface hyperreflective bands of ONHD. Enhanced depth imaging OCT exceeded ultrasound B-scan in detection of suspected ONHD, detecting 12 eyes with ONHD not seen on ultrasound. Enhanced depth imaging OCT might supplant B-mode ultrasound for diagnosis of buried ONHD.

Casas et al161 used OCT to examine patients with OSA. In 96 eyes of 50 patients compared with 64 eyes in 33 control subjects, peripapillary nasal RNFL thickness was decreased. Optic nerve head area and volume were increased. The study provides more evidence for OSA potentially predisposing to visual impairment.

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Magnetic Resonance Imaging and Computed Tomography

Magnetic resonance imaging and CT remain mainstays of imaging the CNS, but choice of the proper modality, attention to the correct anatomic structures, and appropriate choice of contrast versus noncontrast studies are important. McClelland et al162 examined the appropriateness and interpretations of imaging studies in 84 consecutive new patients referred for neuro-ophthalmological evaluations. They considered appropriateness in terms of whether the study was confirmatory of the suspected diagnosis and whether it excluded alternative diagnoses. The potential errors identified included wrong modality of MRI versus CT, poor-quality study, failure to administer contrast, failure to image the region suspected, failure to include the necessary sequences (eg, fat suppression when examining the orbits), and unnecessary imaging. Overall, 38.1% of studies were judged to be “inadequate,” with the most common limiting factors being incomplete visualization of the area in question, incorrect modality, and low quality. Consequently, 25% of patients underwent further imaging. The neuro-ophthalmologists disagreed with official radiology interpretation of prereferral studies in 22.6% of cases, with intraorbital optic nerve and the brain stem being the most common sites of disagreement. The suspected referring diagnosis, present in 68 participants, was changed in 69.1% of the cases. The study argues for the need of specificity in ordering of testing to avoid inadequate neuroimaging.

Storoni et al80 developed a scoring system for differentiating ON in NMO versus MS. They included 27 patients, 15 diagnosed with MS and 12 diagnosed with NMO. The scoring system evaluated involvement of the orbital, canalicular, intracranial chiasmal, and tract segments, for a total of 10 possible points. Multiple sclerosis ON mean score was 2.2 compared with 4.0 for NMO. Scores greater than 6 were seen exclusively in NMO and were in agreement with the trend of the means. Magnetic resonance imaging and CT are increasingly able to measure smaller elements of the visual apparatus. Yiannakas et al163 examined the intraorbital optic nerve at 3-T MRI in 8 healthy participants. Cross-sectional areas were 5.3 and 5.0 mm2 for the right and the left, respectively. Intraobserver coefficients of variation were 1.8% and 2.1%, respectively. This pilot study shows that the optic nerve can be measured reliably on MRI, and future studies in disease states should be possible. Legrand et al164 examined ONSD evaluated on CT for prognosis in traumatic brain injury. In 77 patients, ONSD was statistically higher, 7.8 mm, in 22 nonsurvivors compared with 6.8 mm in 55 survivors. A cutoff of 7.3 mm had sensitivity of 86.4% and specificity of 74.6% in predicting survival. Although imperfect, this measurement adds to prognosis.

Newer 7-T MRI holds promise for increasing detail in imaging of both anterior and posterior structures. Christoforidis et al165 used 7-T MRI with a dedicated eye coil to examine the retrobulbar vasculature. They were able to discriminate the retina, the sclera, and the choroid as well as the ophthalmic artery and its branches. The study points to the possibility of MRI for examining smaller retrobulbar structures, with higher resolution as the availability of MRI with higher field strength increases. Grams et al166 examined MRI of the cranial nerves at 7 T. They compared different MRI sequences including magnetization preparation rapid gradient echo, constructive interference in steady state, true fast imaging with steady state precession, and proton density T2-weighted turbo spin echo. Examining the number of cisternal segments of cranial nerves identified, true fast imaging with steady state precession had the highest rate of certain identification, whereas turbo spin echo had the highest failure rate.

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CONCLUSIONS

With this annual review, we provide an update on a variety of neuro-ophthalmic diseases of potential interest to the practicing comprehensive ophthalmologist.

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“Try your best to do good regardless how trivial it is and avoid evil no matter how insignificant it looks.”

— Liu Bei

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Keywords:

pupil; diseases of muscle and musculoskeletal junction; optic neuritis and multiple sclerosis; increased intracranial pressure; advances in neuroimaging

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