Neuro-Ophthalmic Manifestations of Intracranial Malignancies

Background: To describe the various neuro-ophthalmic presentations, key exam features, and clinical findings associated with 5 common primary and secondary intracranial malignancies. Evidence acquisition: Retrospective PubMed search and review of published case reports, case series, observational studies, book chapters, and review articles examining the neuro-ophthalmic features of intracranial malignancies including primary glial neoplasms (e.g., glioblastoma multiforme), primary and secondary lymphoma, intracranial metastases, carcinomatous/lymphomatous meningitis, and intracranial germ cell tumors. The search strategy used to perform the retrospective review included the aforementioned tumor type (e.g., glioblastoma multiforme) and the following terms and Boolean operators: AND ("visual loss" OR "papilledema" OR "diplopia" OR "ophthalmoplegia" or "neuro-ophthalmology" OR "proptosis"). Results: The rate of growth and the location of an intracranial tumor are essential factors in determining the neuro-ophthalmic presentation of certain intracranial malignancies. Primary malignant brain glial neoplasms commonly present with visual afferent complaints (e.g., unilateral or bilateral visual acuity or visual field defects, bitemporal or homonymous hemianopsia), pupil abnormalities (relative afferent pupillary defect), and optic atrophy or papilledema. Primary intraocular lymphoma (with or without central nervous system lymphoma) typically presents as a painless bilateral vitritis. Secondary intracranial malignancies have variable afferent and efferent visual pathway presentations. Carcinomatous/lymphomatous meningitis is associated with diplopia (e.g., multiple ocular motor cranial neuropathies with or without vision loss from papilledema or compressive/infiltrative optic neuropathy). Intracranial germ cell tumors can present with a chiasmal syndrome or dorsal midbrain syndrome. Conclusion: Intracranial malignancies can present with neuro-ophthalmic symptoms or signs depending on topographical localization. Specific neuro-ophthalmic presentations are associated with different malignant intracranial tumors. Clinicians should be aware of the common malignant intracranial tumors and their associated clinical presentations in neuro-ophthalmology.

Trainees' Corner Section Editors: Vivek R. Patel, MD Prem Subramanian, MD, PhD Neuro-Ophthalmic Manifestations of Intracranial Malignancies Christopher R. Dermarkarian, MD, Ashwini T. Kini, MD, Bayan A. Al Othman, MD, Andrew G. Lee, MD Background: To describe the various neuro-ophthalmic presentations, key exam features, and clinical findings associated with 5 common primary and secondary intracranial malignancies. Evidence Acquisition: Retrospective PubMed search and review of published case reports, case series, observational studies, book chapters, and review articles examining the neuro-ophthalmic features of intracranial malignancies including primary glial neoplasms (e.g., glioblastoma multiforme), primary and secondary lymphoma, intracranial metastases, carcinomatous/lymphomatous meningitis, and intracranial germ cell tumors. The search strategy used to perform the retrospective review included the aforementioned tumor type (e.g., glioblastoma multiforme) and the following terms and Boolean operators: AND ("visual loss" OR "papilledema" OR "diplopia" OR "ophthalmoplegia" or "neuro-ophthalmology" OR "proptosis"). Results: The rate of growth and the location of an intracranial tumor are essential factors in determining the neuro-ophthalmic presentation of certain intracranial malignancies. Primary malignant brain glial neoplasms commonly present with visual afferent complaints (e.g., unilateral or bilateral visual acuity or visual field defects, bitemporal or homonymous hemianopsia), pupil abnormalities (relative afferent pupillary defect), and optic atrophy or papilledema. Primary intraocular lymphoma (with or without central nervous system lymphoma) typically presents as a painless bilateral vitritis. Secondary intracranial malignancies have variable afferent and efferent visual pathway presentations. Carcinomatous/lymphomatous meningitis is associated with diplopia (e.g., multiple ocular motor cranial Department of Ophthalmology (CRD, AGL), Cullen Eye Institute, Baylor College of Medicine, Houston, Texas; Blanton Eye Institute (ATK, BAAO, AGL), Houston Methodist Hospital, Houston, Texas; and Departments of Ophthalmology, Neurology, and Neurosurgery (AGL), Weill Cornell Medicine, New York, New York; Department of Ophthalmology (AGL), University of Texas Medical Branch, Galveston, Texas; Department of Ophthalmology (AGL), UT MD Anderson Cancer Center, Houston, Texas; Department of Ophthalmology (AGL), Texas A and M College of Medicine, College Station, Texas; Department of Ophthalmology (AGL), University of Iowa Hospitals and Clinics, Iowa City, Iowa; Department of Ophthalmology (AGL), University of Buffalo, Buffalo, New York. The authors report no conflicts of interest. Address correspondence to Andrew G. Lee, MD, Blanton Eye Institute, Houston Methodist Hospital, 6565 Fannin Street, Houston, TX 77030; E-mail: [e-mail] Dermarkarian et al: J Neuro-Ophthalmol 2020; 40: e31-e48 neuropathies with or without vision loss from papilledema or compressive/infiltrative optic neuropathy). Intracranial germ cell tumors can present with a chiasmal syndrome or dorsal midbrain syndrome. Conclusion: Intracranial malignancies can present with neuroophthalmic symptoms or signs depending on topographical localization. Specific neuro-ophthalmic presentations are associated with different malignant intracranial tumors. Clinicians should be aware of the common malignant intracranial tumors and their associated clinical presentations in neuroophthalmology. Journal of Neuro-Ophthalmology 2020;40:e31-48 doi: 10.1097/WNO.0000000000000950 © 2020 by North American Neuro-Ophthalmology Society I ntracranial tumors (benign or malignant) may arise either intra-axially from the brain parenchyma or from the other (extra-axial) structures (e.g., meninges and pituitary gland) within the intracranial space (1). Although the origins of these intracranial masses are diverse, almost half of all patients with brain tumors will present with an ophthalmologic sign or symptom (1). Although much has been written about the common and often benign intracranial tumors of neuro-ophthalmic significance (e.g., meningioma, pituitary adenoma, craniopharyngioma, etc.), reviews of the intracranial malignancies are less common. For the purposes of this review, we confine our discussion to the direct neuroophthalmic manifestations of primary intracranial malignant tumors and secondary (e.g., metastatic) intracranial malignancies. Primary intraocular or intraorbital tumors and indirect paraneoplastic effects of tumors are not reviewed in this manuscript. Likewise, this article does not review malignant presentations of histopathologically benign tumors or the malignant variants of more typically benign intracranial tumors (e.g., pituitary carcinoma, malignant meningioma, or skull-based malignancies). Clinicians should be able to recognize the key clinical neuro-ophthalmic symptoms and signs of primary intracranial malignancies (PIM) and secondary intracranial malignancies (SIM). e31 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees' Corner CLINICAL MANIFESTATIONS OF INTRACRANIAL MALIGNANCIES PIM and SIM can affect the afferent, efferent, or both pathways of the visual system. Up to 50% of patients with a primary brain tumor present with an ophthalmic signs or symptom (2). The clinical presentation is largely dependent on tumor location, secondary mass effects, the rate at which a tumor expands within the parenchyma, hydrocephalus, or increased intracranial pressure (1-4). Common neuroophthalmic symptoms of PIM/SIM include blurred vision, dyschromatopsia, diplopia, or oscillopsia and the common signs include visual acuity or visual field loss, relative afferent pupillary defect (RAPD), ophthalmoplegia, nystagmus, optic disc edema, ptosis, or optic atrophy (2,5). Compared with the more benign intracranial mass lesions affecting the visual pathways, PIM and SIM are more likely to produce more rapid symptoms/signs and potentially acute vision or life-threatening problems (e.g., hydrocephalus, papilledema related visual loss, severe headache, and alternated mental status). However, symptom and sign onset can also be subacute to chronic in patients who have compensated (e.g., chronic hydrocephalus), who have less mass effect from their tumor burden or have disease in a less eloquent region of the brain (2). Recognition of these common presenting neuro-ophthalmic signs or symptoms is important, but management is variable and usually dependent on the underlying PIM/SIM. Table 1 describes general treatment recommendations for common neuro-ophthalmology findings seen on clinical examination. Although we attempt to correlate the neuro-ophthalmic signs and symptoms with a location, the topographical localization does not define any specific etiology. Demyelinating (e.g., multiple sclerosis), ischemic (e.g., stroke), inflammatory (e.g., sarcoid), infectious (e.g., herpetic), traumatic, degenerative, metabolic, or infiltrative lesions can present with identical symptoms and signs as PIM/ SIM in the same location. Our goal instead is to highlight the localizing value of these findings in PIM/SIM to direct neuroimaging (preferably MRI with and without contrast). Typically, histopathologic diagnosis from a surgical biopsy is necessary for the final diagnosis of PIM/SIM. Suspicion for SIM should be higher, however, if the patient has a history of prior primary malignancy (even if remote). Careful and detailed characterization of the primary lesion (e.g., melanoma, carcinoma, and sarcoma) in stage, grade, and treatment should be included in the past medical history. Nonspecific or specific constitutional (e.g., "B symptoms") or systemic findings such as a nonhealing or pigmented skin lesion (e.g., melanoma), a palpable nodule of unknown origin (e.g., lymphadenopathy), unusual bleeding, a persistent digestive problem, chronic cough of uncertain origin, unintentional weight loss, unusual fatigue, or unusual pain may all be suggestive symptoms/ signs of SIM (6). e32 Prechiasmatic Anterior Afferent Visual Pathway PIM and SIM affecting the prechiasmal afferent visual pathway can involve the intraocular (e.g., retina/choroid/ optic nerve), intraorbital, intracanalicular, or intracranial optic nerve in one or both eyes. Patients with an optic neuropathy may have variable visual acuity or visual field deficits, loss of color vision (dyschromatopsia), and an RAPD. Patients with PIM/SIM may have optic disc edema (e.g., compressive, infiltrative, or papilledema), optic atrophy, or a normal appearing optic nerve (retrobulbar optic neuropathy) (1,3,4). The most common primary optic nerve tumor in children is optic pathway glioma (OPG). OPG has a peak incidence between the age of 2 and 8 years and is commonly associated with neurofibromatosis (NF) type 1. In contrast, the most common primary optic nerve tumor in adults is optic nerve sheath meningioma, with a peak incidence between the age of 30 and 50 years (7). Unlike OPG in NF1, optic nerve sheath meningioma is more likely to be associated with NF2. Both OPG and optic nerve sheath meningioma may have a benign or malignant histopathology or clinical course. Less commonly reported PIM and SIM affecting the optic nerve include lymphoma, metastatic lesions, malignant OPG, medulloepitheliomas, schwannomas, hemangiopericytomas, and gangliogliomas (7,8). As with all conditions in neuro-ophthalmology, the history is typically more helpful than the exam in determining the etiology of an optic neuropathy. The tempo of the visual loss may suggest a PIM/SIM as the cause of the optic neuropathy rather than more benign etiologies (e.g., optic neuritis or anterior ischemic optic neuropathy [AION]). Acute onset optic neuropathy is more typical of demyelinating, inflammatory, ischemic, and traumatic causes, whereas a slow, gradual onset is more likely secondary to compressive PIM/SIM lesion (9). Younger patients are more likely to present with para-infectious, postvaccination, demyelinating (e.g., multiple sclerosis), or inflammatory (e.g., sarcoid, neuromyelitis optica) optic neuritis, whereas older patients with an acute optic neuropathy are likely to present with ischemia (e.g., arteritic or nonarteritic AION). Patients with suspected demyelinating or inflammatory optic neuritis would typically undergo neuroimaging as part of the usual evaluation and sometimes neuroimaging discloses a PIM/SIM compressive optic neuropathy mimicking optic neuritis or AION. Although neuroimaging is not typically performed in typical AION, patients with atypical presentations for nonarteritic AION (e.g., bilateral disease, progressive disease, persistent optic disc edema, lack of disc edema at presentation, lack of the small cup-to-disc ratio (or structural disc at risk), young age without vasculopathic risk factors, or proptosis) should undergo neuroimaging for PIM/SIM mimicking AION. Likewise, patients without optic disc edema (e.g., posterior ION) or who present with optic atrophy (and not optic disc edema) should be considered for neuroimaging. Dermarkarian et al: J Neuro-Ophthalmol 2020; 40: e31-e48 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees' Corner TABLE 1. Common neuro-ophthalmologic findings and associated management recommendations for primary and secondary intracranial malignancies Common Neuro-Ophthalmologic Findings Anisocoria Isolated third nerve palsy, fourth nerve palsy, or sixth nerve palsy Isolated seventh nerve palsy Papilledema Acquired nystagmus Transient visual obscurations (lasting seconds at a time) secondary to papilledema Headache Management Recommendations Tonic pupil: consider pilocarpine 0.125% QID for cosmesis and to aid with photosensitivity and accommodation Horner syndrome: consider topical apraclonidine for ptosis Treat underlying disorder If patient has symptomatic diplopia, consider occlusion patch or prism over involved eye If no improvement in symptoms or significant misalignment, consider strabismus surgery Monitor for amblyopia in children Treat underlying disorder Consider physical therapy or electrical stimulation of facial muscles If significant corneal exposure, consider artificial tears, moisture chamber, or temporary or permanent tarsorrhaphy Consider definitive lid surgery including gold weight placement and facial nerve reanimation procedures Treat underlying cause of increased intracranial pressure (CSF shunting for hydrocephalus, surgical resection, etc.) Consider corticosteroid therapy for brain edema Consider acetazolamide (diamox) for papilledema Consider CSF diversion procedures or optic nerve sheath fenestration for patients who fail, are intolerant of, or noncompliant with maximum medical therapy and have progressive papilledema-related visual loss Treat underlying disorder Consider baclofen for periodic alternating nystagmus Consider null point (the position where the nystagmus is least) surgery (e.g., Kestenbaum procedure) Treat underlying papilledema Treat Treat Treat Treat medically with headache analgesic therapy neuropathic pain underlying condition increased intracranial pressure Patients presenting with an unexplained unilateral or bilateral optic neuropathy should undergo initial neuroimaging (preferably MRI of the head and orbit with and without contrast and with fat suppression). Patients with orbital presentations (e.g., proptosis, combinations of ipsilateral afferent [optic neuropathy]) and efferent (anisocoria, ptosis, ophthalmoplegia) findings or in whom there may be both orbital and intracranial (e.g., perineural spread and intracranial extension) involvement should also have imaging of both the head and orbit (10). Patients of any age with an acute or subacute optic neuropathy and a history of prior malignancy (e.g., solid carcinoma, melanoma, or lymphoproliferative disorder) may have SIM in the differential until proven otherwise. Chiasmatic and Posterior Afferent Visual Pathway Providers should be concerned for a PIM/SIM affecting the chiasm in patients with progressive, bilateral visual loss Dermarkarian et al: J Neuro-Ophthalmol 2020; 40: e31-e48 (e.g., optic neuropathy, junctional visual loss, bitemporal hemianopsia, or homonymous hemianopsia). Up to 15%- 20% of all brain tumors are located in the sellar region and may involve the optic nerves or optic chiasm/tract (11). The most common tumors affecting the optic chiasm are benign (e.g., pituitary adenomas [50%], craniopharyngiomas [25%], meningiomas [10%] and gliomas [5%]); however, PIM and SIM may also occur in the optic chiasm (e.g., pituitary carcinoma, chordomas, dysgerminomas, lymphoma, or metastasis). Although bitemporal hemianopsia is the classic chiasmal visual field defect, compression of one or both optic nerves (optic neuropathy), the junction of the optic nerve and chiasm (junctional scotoma or junctional scotoma of Traquair), and the optic tract (homonymous hemianopsia) can occur from sellar and parasellar PIM/SIM (12,13). If the tumor involves the posterior macular-crossing fibers in the optic chiasm, it may produce a paracentral bitemporal visual field defect. Tumors involving the posterior aspect of the chiasm can e33 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees' Corner damage the optic tract leading to a contralateral, typically incongruous homonymous hemianopsia, an RAPD, and band atrophy of the optic nerve (1). Lesions producing compressive optic atrophy in one eye and contralateral optic disc edema (secondary to increased intracranial pressure) may present with true Foster Kennedy syndrome. Although typically associated with large anterior visual pathway meningiomas, the Foster Kennedy syndrome has rarely been reported in PIM/SIM (14). Posterior Afferent/Postchiasmatic Visual Pathway Compression of the optic tract can produce contralateral rAPD plus band-type optic atrophy in the eye with temporal visual field (15). PIM/SIM affecting the retrochiasmal afferent visual system, including the optic tract, optic radiations (temporal or parietal lobe), or occipital cortex will present with contralateral homonymous hemianopsia (1). Bilateral lesions (e.g., metastasis, lymphoma) can produce cortical visual loss or juxtaposed homonymous hemianopsia with or without macular sparing. Again, as described above, the pattern of visual field loss can help the provider determine the location of the postchiasmal lesion. Tumors involving the temporal lobe radiations (Meyer loop) produce incongruous, denser superiorly (i.e., "pie in the sky") homonymous hemianopsias, whereas tumors involving the parietal lobe radiations produce an incongruous denser inferior (i.e., "pie on the floor") homonymous hemianopsia (16). Occipital lobe tumors may produce macular sparing (rather than macular splitting), contralateral, congruous homonymous hemianopsia (4). Sparing or involvement of the anterior monocular temporal crescent may also occur in occipital lobe tumors (4). Patients with PIM/SIM in the retrochiasmal pathway may have other localizing and nonlocalizing symptoms and signs. A review of occipital lobe tumors reported headache as the most common symptom (95%) (17). Suspicion for PIM/SIM should increase when the headaches are always on the same side (i.e., "side locked") or when the headaches are associated with either visual hallucinations (seen in 25% of patients) or homonymous hemianopsia (seen in 50% of patients). Although visual hallucinations often present to ophthalmology, clinicians should also ask about auditory or gustatory hallucinations as well (e.g., temporal lobe seizures). In addition, some symptoms may represent neuropsychiatric manifestations of PIM/SIM. Up to 20%-25% of temporal lobe tumors can present with psychiatric symptoms including nonspecific anxiety or depression, feelings of dread, or panic attacks (17-19). Noll et al compared the neurocognitive changes seen in temporal lobe gliomas to the grade of the tumor and reported worse neurocognitive deficits with more malignant and higher grade tumors (18). e34 Although these symptoms can be wide-ranging and nonspecific, suspicion of PIM/SIM should be elevated in patients with visual complaints (e.g., homonymous hemianopsia) and new-onset psychiatric behavior or cognitive deficits. These patients warrant further testing and imaging that could reveal the underlying PIM/SIM. Table 2 reviews common neurological signs and symptoms associated with frontal, temporal, parietal, and occipital lobe lesions. Table 3 reviews neuroophthalmic findings associated with subcortical and periventricular or intraventricular lesions. Table 4 discusses neuro-ophthalmic findings associated with brainstem, cerebellopontine angle, and cerebellar lesions. Of note, PIM/SIM lesions may produce localizing, nonlocalizing (e.g., sixth nerve palsy from increased intracranial pressure), or false localizing (e.g., Kernohan notch related third nerve palsy in cerebral herniation from mass effect) signs (20). Table 5 reviews common false localizing signs that may be seen in neuro-ophthalmology. Efferent Visual Pathways The efferent visual pathway includes supranuclear, nuclear, and infranuclear components that may be affected by PIM/ SIM. Prior case reports documenting tumors causing third nerve nucleus or fascicular palsy (e.g., Benedikt syndrome, Claude syndrome, internuclear ophthalmoplegia (INO), WEMINO, WEBINO, and Parinaud syndrome) are also highlighted within Table 4 (20-27). NEURO-OPHTHALMIC MANAGEMENT OF INTRACRANIAL (PRIMARY INTRACRANIAL MALIGNANCIES/SECONDARY INTRACRANIAL MALIGNANCIES) MALIGNANCIES Patients who present with acute or subacute neuroophthalmic manifestations should undergo an expedited work-up involving neuroimaging (preferably MRI of the head and orbit with contrast and fat suppression sequences). Specific diagnostic studies recommended for the most common PIM/SIM are discussed below. Admission to the hospital may be warranted for tumors presenting with more acute presentations that may require urgent work-up (mass effect or shift, hydrocephalus) and treatment. Patients with a PIM/SIM with visual loss or visual field deficits need to be evaluated and treated for the underlying mechanism (e.g., compressive optic neuropathy, papilledema). Patients with brain edema, increased intracranial pressure, hydrocephalus, or mass effect may require medical (corticosteroids) and/or expedited surgical treatment (surgical decompression, CSF shunting). Patients with papilledema may benefit from acetazolamide therapy until definitive surgical treatment (e.g., decompression resection, CSF shunting procedure, optic nerve sheath fenestration) can be performed. We Dermarkarian et al: J Neuro-Ophthalmol 2020; 40: e31-e48 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees' Corner TABLE 2. Cerebral cortical lesions and their potential neuro-ophthalmic and neurologic signs and symptoms Cerebral Cortex Lesion Frontal lobe lesion Temporal lobe lesion Parietal lobe lesion Signs and Symptoms Ipsilateral visual neglect Foster-Kennedy syndrome (compressive optic atrophy and contralateral papilledema (from increased intracranial pressure) with or without anosmia or hyposmia) Decreased amplitude and slowing of contralaterally directed saccades (seen in tumors involving the unilateral frontal eye field) Conjugate gaze preference toward (destructive lesion) or away (irritative lesion and seizure focus) from the side of frontal lobe lesion Inability to voluntarily close eyelids (seen with a lesion in either lobe) Incomplete homonymous contralateral upper quadrantopia or homonymous upper quadrantanopia ("Pie-inthe-sky" visual deficit usually from lesions of either lobe between 4 and 8 cm from temporal tip) Complete homonymous hemianopia (usually from lesions of either lobe greater than 8 cm posterior to temporal tip) Wernicke aphasia (receptive aphasia marked by paraphrastic errors) Dysnomia (deficit in expressive language) Amusia (deficit in musical memory/recognition) Visual agnosia (inability to recognize objects) Auditory agnosia (inability to recognize sounds) Korsakoff syndrome (disproportionate memory loss when compared with other neurologic findings) Auditory hallucinations (usually occur contralateral to lesion) Visual hallucinations (usually occur in the contralateral visual field) Olfactory and gustatory hallucinations Focal temporal lobe seizures Kluver-Bucy syndrome (e.g., hypersexuality, hyperorality, loss of fear, increased hunger, visual distraction, and memory loss secondary to bilateral temporal lobe damage) Cortical deafness (secondary to bilateral lesions of the transverse gyri of Heschl) Decreased hearing of the contralateral ear (secondary to unilateral lesions of Heschl gyri) Inability to perceive time (secondary to a lesion in either temporal lobe) Impaired verbal memory (secondary to a lesion in the dominant temporal lobe) Inability to understand what a patient is reading (secondary to a lesion of the dominant temporal isthmus) Left homonymous hemianopia + left hemianesthesia + delusion of body scheme (secondary to a lesion of a right non-dominant temporal isthmus) Uncinate fit (aura consisting of abnormal sensation of smell or taste following by seizure that is seen with lesions of the uncinate gyrus or amygdaloid complex) Total contralateral hemianesthesia Mild contralateral hemiparesis or poverty of movement Contralateral homonymous hemianopia or inferior quadrantanopia ("pie on the floor") Abolition of optokinetic nystagmus (OKN) response with target moving toward unilateral side of parietal lobe lesion (seen as a reduced smooth muscle pursuit when a stimulus is moved toward the side of the lesion) Neglect of the opposite external space (seen usually with right parietal lobe lesions but can occur with frontal lobe lesions) Alexia (distinct inability to read only with intact vision, spelling and writing) Dysgraphia (dysfunction in writing skills) Dyscalculia (difficulty with arithmetic comprehension usually seen with right parietal lobe lesions) Finger agnosia (inability to name and recognize fingers) Tactile agnosia (inability to recognize objects by touch) Bilateral ideomotor and ideational apraxia (disorder of planning and sequencing complex motor events usually seen with left hemisphere lesions) Anosognosia (lack of insight), dressing, and constructional apraxias Balint syndrome (A lack of coordination between spatial and visual systems leading to poor hand and eye movements; defined by the following triad: oculomotor apraxia, an inability to voluntarily adjust gaze despite normal extraocular movements, optic ataxia, a lack of coordination between hand movements and visual input, and simultanagnosia (an inability to perceive more than one object at a single time.) Gerstmann syndrome (syndrome of acalculia, agraphia, left-right spatial disorientation, and finger agnosia seen with lesions in the left parieto-occipital region) Palinopsia (visual perseveration of images after brief presentation secondary to some parietal lobe lesions) Dermarkarian et al: J Neuro-Ophthalmol 2020; 40: e31-e48 e35 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees' Corner (Continued ) Cerebral Cortex Lesion Occipital lobe lesion Signs and Symptoms Contralateral homonymous hemianopia (visual deficit is usually contralateral to lesion) with or without macular or monocular crescent-sparing or involvement Hallucinations (usually occurs in the hemifield contralateral to the tumor) Alexia without agraphia (inability to write without inability to write and spell words secondary to a lesion of the splenium of the corpus callosum; this finding is also usually seen with a right homonymous hemianopia in left occipital lobe lesions) Visual object agnosia (inability to recognize objects seen with lesions in either lobe) Cortical blindness (juxtaposed homonymous hemianopsias with bilateral retrochiasmal lesions) Anton syndrome (lack of insight or denial of visual loss in a cortically blind patients) Cerebral achromatopsia (inability to recognize color) Prosopagnosia (inability to recognize familiar faces) Balint syndrome (as discussed above) Adapted from (20). recommend that patients with PIM/SIM-related visual loss be followed serially (e.g., every 1-2 months) until there is resolution of the underlying mechanism of the visual loss (e.g., papilledema). Appropriate multidisciplinary subspecialty management is generally required for PIM/SIM (e.g., oncology, neurosurgery, radiation oncology). The role of the ophthalmologist/neuro-ophthalmologist is to communicate both the findings and define the possible causes for the visual loss to help the primary treating services to decide on best treatment and monitor treatment effects after surgery, chemotherapy, or surgery. We recommend that formal visual fields be assessed in symptomatic patients and those with PIM/SIM lesions that are near or involve the visual pathways with serial automated visual field testing (e.g., Humphrey visual field 24-2 or 30-2) (29). Although there are no evidencebased recommendations for specific visual field testing, we typically obtain formal automated perimetry (e.g., Humphrey Visual Field) every 6-8 weeks until there is resolution/treatment of the underlying PIM/SIM mechanism for visual loss and stabilization of the visual field (29). In addition, patients with visual loss could undergo serial testing to document any treatment response or progression. If progression is seen, direct and timely communication is recommended to the appropriate treating subspecialties to determine any additional treatment options. More aggressive PIM/SIM tumors (e.g., glioblastoma multiforme) may require more frequent and more vigilant serial follow-up. The role of optical coherence tomography (OCT) in PIM/SIM has not been established in an evidence-based manner. Nevertheless, we generally use OCT of the optic nerve (retinal nerve fiber layer [RNFL] thickness) and macular ganglion cell (MGC) layer to define a patient's baseline optic nerve function and to follow patients for progression or stability. We correlate the functional changes on visual acuity and automated visual field testing with any structural changes (e.g., loss of RNFL or MGC) seen on serial OCT. e36 SPECIFIC PRIMARY AND SECONDARY INTRACRANIAL MALIGNANCIES The most common PIM are glial based neoplasms and the most common SIM are metastatic or lymphoproliferative tumors. Table 6 lists the various PIM and SIM discussed within this manuscript that can produce neuro-ophthalmic manifestations (30-32). GLIAL NEOPLASMS INCLUDING GLIOBLASTOMA MULTIFORME Glioblastoma multiforme (GBM) is the most common PIM seen worldwide, with an annual incidence of 5.26 cases per 100,000 individuals (33). The incidence is higher in white men and median age of presentation is 64 years (33,34). Histological examination demonstrates vascular proliferation, vast cellularity and mitotic activity and necrosis (33). GBM are typically unifocal and are found within the cerebral hemispheres (1,33). Less than 20% of GBMs are multifocal (with a neural or vascular connection) or multicentric GBM (35). Although less common, patients with multifocal GBM are at higher risk for frontal or temporal lobe involvement (35). Rarely, GBM can arise within the anterior visual pathway, optic nerve, optic chiasm, or optic tract (36-38). Other reported areas of GBM involvement include the oculomotor nerve, trigone, body, and occipital horn of the lateral ventricle, the third ventricle, and the frontal horn (39-47). DIAGNOSIS AND MANAGEMENT OF GLIOBLASTOMA MULTIFORME GBM can be associated with afferent or efferent visual pathway deficits, most notably subacute, progressive visual field deficits (1,33,48). Up to 5% of patients can present with papilledema secondary to increased ICP in GBM (33,49,50). In addition to papilledema, secondary visual loss can occur from either direct compression by GBM or Dermarkarian et al: J Neuro-Ophthalmol 2020; 40: e31-e48 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees' Corner TABLE 3. Orbital, intracranial, subcortical, and ventricular lesions and their potential neuro-ophthalmic and neurologic signs and symptoms Location of Lesion Anterior visual pathway Ventricles (lateral, third, and fourth ventricles) Basal ganglia Thalamus Pineal gland Hypothalamus Pituitary gland Supranuclear Signs and Symptoms Enophthalmos or exophthalmos (if orbital extension) Gaze-evoked amaurosis (orbital lesion) Optic disc edema or optic atrophy Decreased extraocular movements Visual acuity loss Visual field deficit Relative afferent pupillary defect Headache induced or relieved by changes in position of the head Papilledema Ocular motor dysfunction Nonlocalizing or localizing sixth nerve palsy Dorsal midbrain (Parinaud) syndrome (as described below) Dorsal pontine syndrome (horizontal gaze deficit, internuclear ophthalmoplegia, sixth nerve palsy) Nystagmus (as described below) Movement disorders Contralateral hemiparesis Abducens nerve paresis Hemiparesis Hemiplegia Dementia Apathy Vertical gaze impairments Skew deviation Paresis of upward conjugate movements Ptosis Convergence-retraction nystagmus Anisocoria Abnormal pupillary responses to light stimuli, near stimuli or both Parinaud syndrome (upper gaze paralysis + pseudo-Argyll Robertson pupils + convergence-retraction nystagmus + eyelid retraction + conjugate downgaze in primary position secondary to a lesion at the rostral interstitial nucleus of the MLF) Oculomotor nerve paresis Trochlear nerve paresis Disorders of temperature regulation Disorders of water or food intake Sleep disorders Disorders of consciousness Disorders of autonomic functioning Diabetes insipidus Delay or arrest of sexual development Russell diencephalic syndrome Visual loss (e.g., junctional visual field defects, bitemporal hemianopsia, and homonymous hemianopsia) Relative afferent pupillary defect Ophthalmoplegia (CN III, IV, VI) Ptosis (cavernous sinus involvement, third nerve palsy, and Horner syndrome) Endocrinologic manifestations (e.g., hyperprolactinemia, growth hormone hypersecretion, corticotrophin hypersecretion, glycoprotein hormone, hyperthyroidism) Pursuit and vergence may be affected but with preserved dolls head maneuver testing Adapted from (20). from treatment effects (e.g., radiation retinopathy, optic neuropathy, or brain necrosis). As noted previously, depending on location, GBM can produce a unilateral or Dermarkarian et al: J Neuro-Ophthalmol 2020; 40: e31-e48 bilateral optic neuropathy, chiasmal, or optic tract compression. Rarely, a midbrain (tectal) lesion can produce a tectal RAPD without visual loss. e37 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees' Corner TABLE 4. Brainstem, cerebellopontine angle, and cerebellar lesions and their potential neuro-ophthalmic signs and symptoms Localization of Lesion Brainstem Brainstem Midbrain Nucleus or fascicle of 3rd nerve of dorsal midbrain at level of superior colliculus, ventral to cerebral aqueduct Fasicular 3rd nerve + red nucleus and dentaterubral fibers (concomitant damage to surrounding mesencephalic structures causes specific localization syndromes) Fasicular 3rd nerve (larger rostral lesions that involve subthalamic nuclei) Fasicular 3rd nerve (larger caudal lesions that involve input to cerebellum) Fasicular 3rd nerve with anterior cerebral peduncle involved (ventro-medial midbrain) Nucleus of 4th nerve at dorsal midbrain at the level of inferior colliculus Parinaud syndrome Vertical gaze center seen at the rostral interstitial medial longitudinal fasciculus and interstitial nucleus of Cajal-tegmentum of the midbrain Dorsal midbrain at level of superior colliculus. Pons Nucleus of 6th nerve at pons Fasicular 6th nerve with involvement of pyramids) at ventral medial pons Fasicular 6th with associated 7th nerve palsy and with pyramidal involvement at ventral pons Fasicular 6th nerve involvement with concomitant involvement of other cranial nerves including the 5th, 7th, and 8th nerve with pyramidal involvement at caudal/medial pontine tegmentum Medial longitudinal fasciculus (MLF) e38 Signs and Symptoms Unilateral or bilateral motor loss (hemiparesis) Hemisensory loss Ophthalmoplegia Ptosis (CN III or Horner syndrome) Cranial nerve defects Ataxia Intention tremor Nystagmus Weakness of contralateral superior rectus with ipsilateral third nerve palsy Bilateral ptosis or no ptosis (with involvement or sparing of central caudate subnucleus of oculomotor nucleus) in third nerve palsy (21) Claude syndrome-complete ipsilateral 3rd nerve palsy with contralateral ataxia and tremor (22) Benedikt syndrome-complete ipsilateral 3rd nerve palsy with choreiform movements and contralateral hemiparesis (23,24) Nothnagel syndrome-complete ipsilateral 3rd nerve palsy with ipsilateral cerebellar ataxia Weber syndrome-complete ipsilateral 3rd nerve palsy with contralateral hemiparesis Contralateral superior oblique palsy (fourth nerve is crossed) Please refer to description provided in Table 3 Vertical gaze palsy (conjugate upgaze or down gaze palsy or both) Parinaud dorsal midbrain syndrome-Limitation of upgaze with convergence retraction nystagmus and lid retraction (Collier sign) Associated light near dissociation of the pupils (25,26) Ipsilateral horizontal gaze palsy Raymond syndrome-ipsilateral abduction deficit with contralateral hemiparesis. Could have concomitant internuclear ophthalmoplegia (medial longitudinal fasciculus) Millard Gubler syndrome- ipsilateral abduction deficit with facial palsy and contralateral hemiparesis Foville syndrome-ipsilateral abduction deficit, facial palsy with hypoesthesia, deafness with gaze palsy and Horner syndrome and contralateral hemiparesis. Can have concomitant internuclear ophthalmoplegia (INO-see below) Ipsilateral adduction deficit/lag and contralateral gaze, horizontal dissociated abducting nystagmus producing an internuclear ophthalmoplegia (INO) (27) Dermarkarian et al: J Neuro-Ophthalmol 2020; 40: e31-e48 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees' Corner (Continued ) Localization of Lesion Various combinations of deficits of pontine structures (e.g., parapontine reticular formation (PPRF), 6th nerve nucleus, MLF) with or without other brainstem signs (e.g., seventh nerve palsy) Medulla Medulla Cervicomedullary junction Cervicomedullary junction (28) Cerebellopontine angle Cerebellopontine angle Cerebellum Cerebellum Signs and Symptoms Combination deficits may also occur (e.g., "a one and a half syndrome [horizontal gaze palsy and INO] or "wall eyed unilateral [WEMINO] or bilateral INO [WEBINO] or paralytic pontine exotropia) Impaired voluntary saccadic and pursuit movements Skew deviation Nystagmus (e.g, rotary, downbeat) Lower cranial nerve palsy Myelopathy Horner syndrome Facial hypoesthesia Dysphagia Lower limb weakness Nystagmus (e.g., downbeat) Syndrome marked by dysfunction of cranial nerves V, VI, VII, and VIII with or without ataxia Nystagmus (e.g., Brun Cushing nystagmus) Diplopia (skew) Nystagmus (most commonly horizontal and conjugate) Facial neuropathy Truncal ataxia Adapted from (20). Because of the high-grade malignant histology (microvascular proliferation and/or necrosis) and rapid growth of GBM, the clinical findings may appear abruptly and progress rapidly (51). Patients who present with an acute, subacute, and progressive visual loss and an optic pathway mass should be evaluated for PIM/SIM (35,36,52). The pattern of the visual field defect(s) is dependent on tumor location (1,33). We recommend that patients with GBM in proximity to the afferent or efferent visual pathway should be considered for serial neuro-ophthalmic evaluations (e.g., every few months) to gauge response to treatment or progression of disease, particularly patients with lesions in the suprasellar region. Although direct intra-axial involvement of the anterior visual parenchyma is an uncommon presentation for GBM, Lyapichev et al reported a patient who presented with rapid onset visual loss and a RAPD secondary to a GBM extending from the suprasellar cistern into the left optic nerve (38). The role of the ophthalmologist/ neuro-ophthalmologist is to document the baseline examination and findings, determine the pathogenic mechanism for the visual loss (e.g., direct compression or indirect damage by elevated intracranial pressure causing papilledema), and to communicate the results to the other multidisciplinary members of the treating medical and surgical teams. Increased intracranial pressure-related papilledema may be seen on initial patient presentation or develop over time Dermarkarian et al: J Neuro-Ophthalmol 2020; 40: e31-e48 and it is important for the examining ophthalmologist to communicate the findings of the eye exam (including visual field loss) to the treating physicians to treat the associated visual loss independent of the treatment of the PIM or SIM. Although papilledema usually resolves after surgical intervention and reduction of ICP, the visual loss and papilledema can reappear or fail to resolve with relapse, rapid tumor growth, associated hydrocephalus, leptomeningeal disease, or venous sinus occlusion (1,33). Although uncommon, GBM can also present with efferent visual symptoms including diplopia. Cho et al discusses a case of a patient with GBM and leptomeningeal gliomatosis who presented with symptoms of diplopia and photophobia (53). Reifenberger et al describes a case of an elderly patient presenting with transient diplopia and an incomplete left-sided oculomotor nerve palsy secondary to a GBM at the left pontomesencephalic junction with destruction of the left oculomotor nerve (47). Yu et al notes a case of diplopia and left-sided exophthalmos in a 37-yearold man with GBM extending to the left temple and sphenoid, ethmoidal, and frontal sinuses (54). A summary of the various afferent and efferent neuro-ophthalmic presentations reported in the literature of typical PIM/SIM can be found in Table 7. The standard initial treatment for GBM is surgical resection for relieving mass effect and providing tissue for e39 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees' Corner TABLE 5. Common false localizing signs of tumors Common False Localizing Signs and Symptoms of Tumors Papilledema (e.g., hydrocephalus, mass effect, and venous sinus compression) Cranial neuropathies (Kernohan notch-related third nerve palsy) Parinaud dorsal midbrain syndrome (related to hydrocephalus) Adapted from (20). histological and molecular analysis (80). However, complete surgical resection is often limited by tumor infiltration into the surrounding brain tissue and wide-spread vascularization. As a result, surgery is usually coupled with adjuvant therapy (80). After resection, most patients will receive external beam irradiation 5 times a week for 6 weeks plus oral temozolomide daily or other chemotherapy (e.g., carboplatin, irinotecan, BCNU, etoposide, or procarbazine, lomustine, and vincristine combination) (81). However, most patients with GBM will recur within 6-12 months after initial diagnosis (81). Adjuvant therapy increases the two-year survival rate to 27%. but there is no cure (33). Current efforts are being made to investigate tumor resistance patterns and develop novel drug-delivering strategies, molecular-targeted agents, and immunomodulative treatments (81). Clinicians should be aware, however, that presenting neuro-ophthalmic symptoms and signs can be the result of tumor burden or of side effects secondary to treatment (e.g., chemotherapy or radiation damage). LYMPHOMA Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma confined to the CNS and the eyes and represents approximately 2% of all primary brain tumors (82,83). Approximately 90%-95% of all PCNSLs are classified as diffuse large B-cell lymphoma (82). Patients with PCNSL usually present with focal neurological deficits (56%-70%), behavioral changes (32%-43%), symptoms of increased intracranial pressure (32%-33%), or seizures (11%-14%) (84). Histopathology is necessary for treatment; diagnosis is usually made via stereotactic needle biopsy (83). Intraocular lymphoma (IOL) is a known rare subtype of PCNSL representing 1.86% of all ocular malignant tumors. IOL can arise from the retina, uvea, vitreous, Bruch membrane, or optic nerve (85,86). Mean age of presentation is 50-60 years and does not favor either gender (87,88). Obtaining a diagnosis of ocular lymphoma can be difficult, because this disease is known to masquerade as various conditions, including uveitis, white dot syndromes, and other metastatic diseases (86). IOL can be separated into 2 subtypes: primary intraocular lymphoma (PIOL) and secondary intraocular lymphoma (SIOL). e40 TABLE 6. Common primary and secondary intracranial malignancies Common Intracranial Malignancies With Neuro-Ophthalmic Manifestations Glial neoplasms (e.g., glioblastoma multiforme) (14.7% of all primary brain tumors) (30) Lymphoma (2.0% of all primary brain tumors) (30) Intracranial metastases (secondary intracranial malignancy) (present in 10%-35% of patients with a known primary malignancy) (31) Carcinomatous or lymphomatous meningitis (present in 5%-15% of systemic malignancies) (32) Intracranial germ cell tumors (0.4% of all primary brain tumors) (30) Primary and Secondary Intraocular Lymphoma The presenting symptoms and signs of PIOL are varied, but are generally associated with the afferent visual system. Most patients complain of nonspecific blurred vision (72.4%), floater symptoms (22.1%), and visual field disturbances (2.3%) on initial presentation (89). These visual impairments can be initially mistaken for more benign inflammatory vitreous opacities (90). Although less likely, some patients present with eye pain, injection, photophobia, or can even be clinically silent (91). Malignant invasion of the optic nerve and subsequent disc edema can also occur in PIOL (91). On histological exam (e.g., diagnostic vitrectomy), PIOL is typically a pleomorphic B lymphocyte infiltrate with large multilobular nuclei, prominent nucleoli, and scant cytoplasm (92). Although 15%-25% of PCNSL patients can develop ophthalmic manifestations of lymphoma, 56%- 90% of PIOL patients have or will develop CNS manifestations of lymphoma (93). PIOL can be further divided into subtypes depending on the site of involvement including primary vitreoretinal lymphoma (PVRL) and primary uveal lymphoma (PUL) (94). Primary Vitreoretinal Lymphoma and Primary Uveal Lymphoma PVRL is the most common type of PIOL and is known to affect middle-aged to older adults. Patients usually will present with blurring of vision, floaters, vitreous cells, retinal pigment epithelial pigmentary changes, subretinal infiltrates, and retinal pigment epithelial detachment. The anterior chamber is usually quiet, but the patient may have iritis or keratic precipitates. Some other unusual findings include neurotrophic keratopathy, secondary inflammatory glaucoma, hypopyon, hyphema, choroidal detachment, retinal vein occlusion, and optic disc edema (95). Roughly 29 months after initial onset, most patients will develop an array of CNS symptoms (86,92). PUL is primarily seen in elderly men ages 60-70 years with initial presentation of unilateral blurring of vision. Dermarkarian et al: J Neuro-Ophthalmol 2020; 40: e31-e48 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees' Corner TABLE 7. Reported afferent and efferent visual presentations of PIM/SIM Intracranial Malignancy Glioblastoma multiforme Lymphoma Intracranial metastases Carcinomatous meningitis Intracranial germ cell tumors Neuro-Ophthalmic Signs and Symptoms Visual field defects (29,35,52) Papilledema (1,33) Relative afferent pupillary defect (RAPD) (38) Diplopia and ophthalmoplegia (47,53,54) Exophthalmos (54) Oculomotor nerve palsy (47) Painless visual loss (55) "Floaters" secondarily to intravitreal involvement (55) Metamorphopsia secondary to retinal involvement (56) Iris infiltrates (55) Pseudohypopyon (55) Uveitis (57) Vitreous cells (55) Retinal/Choroidal infiltrates (55) Exudative retinal detachment (55) Papilledema (1) Visual field deficits (1,58,59) CN 3, 4, and 6 neuropathies Supranuclear, nuclear, infranuclear involvement (60-67) Internuclear ophthalmoplegia (INO) (68-70) Acute unilateral or bilateral visual loss (32,71-73) Papilledema (32,71,72) Scotoma (72) Homonymous or bitemporal hemianopsia (72) Ocular motor cranial nerve palsies (21,72,74) Ptosis (72) Anisocoria (72) Exophthalmos (72) Nystagmus (72) Papilledema (75) Parinaud syndrome (75-79) Hydrocephalus related visual problems (visual loss from optic atrophy or papilledema, non-localizing sixth nerve palsy) (77) PIM, primary intracranial malignancies; SIM, secondary intracranial malignancies. Most patients also present with ocular findings, including yellowish creamy choroidal lesions, choroidal folds, retinal detachment, and uveal effusion (94,96). Patients with iris involvement can present with symptoms and signs similar to anterior uveitis such as a painful red eye, blurring of vision, pseudohypopyon, posterior synechiae, and keratic precipitates (97). Features such as infiltrative iris lesions, abnormal iris vessels, salmon-patch lesions on the conjunctiva, and hyphema can also be helpful in establishing the diagnosis (97). A summary of signs and symptoms can be found in Table 7. Secondary Intraocular Lymphoma SIOL is defined as any lymphoma that originates outside of the central nervous system, but metastasizes to the eye. The most common lymphoma subtype seen in SIOL is diffuse large B-cell lymphoma, although rarely there are T-cell variants, and the iris, ciliary body, and choroid are usually involved in the disease (86). The original lymphoma could Dermarkarian et al: J Neuro-Ophthalmol 2020; 40: e31-e48 be primary cutaneous peripheral T-cell lymphoma, NK-Tcell lymphoma or adult T-cell leukemia/lymphoma. The immunophenotypical and morphological features of secondary lymphoma are similar to its primary systemic counterpart. The etiology is still unknown, but prior reports have suggested infectious antigens as the primary triggers of rapid B-cell expansion (98). Although secondary lymphoma usually has similar presentation to the primary type, some presentations such as pseudohypopyon and iris infiltrates are more commonly encountered in SIOL. Collaboration with the oncologist is important in diagnosis and treatment of the primary systemic counterpart. Diagnosis and Management of Primary Intraocular Lymphoma A physician must have high index of suspicion to diagnose PCNSL/PIOL. Cerebrospinal fluid (CSF) analysis for cytology, cytokine, and chemical analysis is usually e41 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees' Corner performed and several lumbar punctures with high volume fluid removal may be necessary to make the diagnosis. Most cases of PCNSL, however, are diagnosed via stereotactic biopsy. This modality is particularly useful if serial CSF analysis is negative and the patient presents with a highly suspicious brain lesion on neuroimaging (82). If CSF and/ or neuroimaging are negative, a diagnostic vitrectomy or vitreous aspiration needle tap could also be performed on the eye if there is high suspicion for IOL. Multiple biopsies (e.g., aqueous or vitreous fluids) could be required for a definite pathological diagnosis and should be sent quickly to the lab to avoid degradation of neoplastic cells (86). A cytokine analysis of vitreous fluid demonstrating elevated interleukin (IL-10) with an IL-10:IL-6 ratio .1 is suggestive of PIOL (89). Flow cytometry has limited use in diagnosing PCNSL and is largely limited to analysis of CSF for staging and long-term follow-up (83). Management of PIOL is largely dependent on the lymphoma subtype. Management of PVRL is usually with chemotherapy or radiotherapy. Most of the neoplasms are radiosensitive and respond well to methotrexate or rituximab. Unilateral ocular involvement can be treated with local therapy composed of intravitreal methotrexate and rituximab with or without 30-35 Gy external beam radiation therapy. Patients with bilateral ocular involvement can be treated with systemic chemotherapy preferably with intravitreal chemotherapy (94,99,100). If this subtype of lymphoma also involves the CNS, treatment is usually with systemic high dose methotrexate and rituximab with intravitreal chemotherapy (93,94). Management of PUL differs from PVRL, because this lymphoma subtype is typically less aggressive. If the disease is limited to the choroid, then treatment usually is low-dose external beam radiotherapy (101). Radiotherapy can be associated with complications, including radiation retinopathy, vitreous hemorrhage, neovascular glaucoma, and optic atrophy (90). During the follow-up period, neuroimaging and serial examination by the ophthalmologist/ neuro-ophthalmologist (e.g., every few months) is important because of risk of recurrence or CNS involvement. Despite various treatment options, survival time remains poor, ranging from 12 to 35 months (86). SECONDARY INTRACRANIAL MALIGNANCIES (E.G., CENTRAL NERVOUS SYSTEM METASTASES) Although the most common PIM is GBM, SIM from brain metastases are the most common intracranial tumor seen in adults. Roughly 10 times more common than primary malignant brain tumors, intracranial malignancies are found in roughly 10%-35% of patients with cancer elsewhere in the body (31). Although the primary tumor is usually known, around 15% of cases of intracranial metastases have no known primary lesion (102). e42 The most common primary cancers to metastasize to the brain as SIM include lung (40%-50%), breast (15%- 30%), melanoma (5%-20%), colorectal cancer (3%-8%), renal cell cancer (2%-4%), and ovarian cancer (1%) (58). Moreover, autopsy studies have shown that 20%-25% of patients with systemic malignancy also have SIM brain metastasis at death (103). Several theories on SIM have been attributed to the metastatic potential of the cells. One theory proposed by Paget is the "seed and soil theory," which suggests that there are particular tumor characteristics that are attracted to "fertile environment" in the brain. Brain tissue is a suitable microenvironment for such growth, given its local expression of micronutrients, epidermal growth factors, and vascular endothelial growth factors that support angiogenesis and tumor growth (104-106). The blood-brain barrier, which is made up of continuous, nonfenestrated endothelium lined by astrocytes, may also limit the effectiveness of certain chemotherapy agents because of its relative impermeability. As a result, adjuvant chemotherapy may suppress systemic disease, but may be less effective in controlling disease within the brain parenchyma, particularly metastases (107). It is therefore unsurprising that intracranial metastases may be the first sign of recurrence and that CNS metastases have become a cause for morbidity and mortality in this patient group. Metastases to the brain from SIM largely occur from hematogenous spread from the primary tumor site, because the brain lacks a lymphatic system (which is otherwise a more common mechanism of spread to other organs). Metastasis are usually seen either at the gray-white junction in the distribution of the middle cerebral artery or the watershed areas of the arterial circulation between the middle and posterior cerebral arteries, where the tumor cells get entrapped in terminal arterioles and capillaries (31,104,105). Lesions are commonly found in the frontal lobe (19%-21%), followed by the parietal (13%-19%), occipital (5%-6%) and temporal (5%-10%) lobes, the cerebellum (10%-15%), and the brainstem (1%) (58). Metastasis could be solitary or multiple lesions. For most patients, presenting symptoms of SIM are related to the expanding tumor mass, its associated cerebral edema and hydrocephalus due to obstruction of CSF flow through the ventricles. Neurological signs or deficits are therefore largely dependent on tumor location and the compression it has on surrounding structures (58). Given how variable their location may be, intracranial metastases can affect both the afferent and efferent visual pathways. Tumors such as breast cancer and melanoma can metastasize perivascularly, using pre-existing vessels, which can serve as a conduit for tumor proliferation. These vessels are also a source of micronutrients required for tumor growth and sustenance. Other mechanism of spread to intracranial cavity is via perineural spread or skip lesions from the primary tumor. Perineural spread is typically described as a direct extension of the tumor rather than metastasis, but it can be Dermarkarian et al: J Neuro-Ophthalmol 2020; 40: e31-e48 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees' Corner visual or life-threatening complication of certain tumors such as adenoid cystic carcinoma, lymphoma, or squamous cell carcinoma of the head and neck. Cranial nerves commonly involved include the trigeminal nerve and the facial nerve (108). The tumor can spread along the course of the nerve and gain access into the cranial fossa through the nerve exiting the foramina. A clinician should have a high suspicion for perineural spread of tumor in patients with history of previously resected cutaneous or head and neck tumors who present with severe intractable pain or hypoesthesia in distribution of the V1 branches of the fifth cranial nerve or in presence of radiologic evidence of thickened nerves. Involvement of facial nerve can cause lagophthalmos and difficulty with eyelid closure. Involvement of the lacrimal or vidian nerve could present with dry eye symptoms. Suspicion of perineural spread should be raised especially when a patient with a prior cutaneous or head/neck tumor presents with unilateral unexplained dry eye. Ophthalmoplegia with cranial motor neuropathies could also be a presenting sign depending on the degree of spread because of tumors invading into the middle cranial fossa and gaining access to the cavernous sinus or orbit (90,109,110). Failure to recognize these findings early could lead progressive involvement of other adjacent nerves and may end up with complete ophthalmoplegia (111). Some tumors such as leukemia, lymphoma, and breast cancer can metastasize via leptomeningeal spread. These tumor types commonly present as malignant cells blocking the CSF outflow, creating a clinical picture of raised intracranial pressure (112,113). They are diagnosed by leptomeningeal enhancement on MRI brain with contrast and CSF fluid analysis demonstrating malignant cells. In addition to treating the underlying disease, patients may require additional therapeutic measures to reduce intracranial pressure either medically or by shunt to bypass the clogged CSF outflow pathways (112,113). Metastasis to the pituitary gland is quite rare and has a predilection to involve posterior lobe because of preferential blood supply and proximity to the dura. Rare cases are described in the literature, where metastasis can occur in a pre-existing pituitary adenoma (60). In addition to the hormonal variations, pituitary metastasis can present with visual field deficits from chiasmal compression with bitemporal hemianopia being the most common visual field deficit reported. Metastases here can also involve the third and sixth cranial nerves, causing diplopia (61-65). Metastasis and infiltration of cavernous sinus can present with ophthalmoplegia that is usually unilateral. Although unilateral or bilateral partial or complete ophthalmoplegia can occur, metastases to this anatomical location usually affects the third, fourth, and sixth cranial nerves (66,67). Infiltration of optic canal and sphenoid wing by metastatic tumors can lead to optic nerve compression and blindness (114). Dermarkarian et al: J Neuro-Ophthalmol 2020; 40: e31-e48 Metastasis to the brainstem is less common as the posterior circulation accounts for less than 25% of the total cerebral circulation. However, when present, it can cause efferent pathway deficits depending on location. Metastasis to cranial nerve nuclei can cause motility deficits. Involvement of sixth nerve nucleus in the pons will cause a gaze palsy ipsilateral to the lesion and could be associated with concomitant involvement of facial nucleus because of its proximity (115). Likewise, metastasis to the median longitudinal fasciculus can cause an INO with an adduction deficit ipsilateral to the side of the lesion and a contralateral abducting nystagmus. However, the overall incidence of INO secondary to metastasis is rare and accounts for less than 1% of all cases (68-70). Metastatic involvement of orbital apex can cause involvement of multiple cranial nerves and lead to various presentations such as pupillary mydriasis or mitosis and ptosis with metastatic involvement of sympathetic input. A patient with suspected metastases who presents with unilateral loss of vision with associated cranial neuropathy warrants immediate evaluation of the orbit to determine possible tumor involvement. Nystagmus may be present if a metastasis occurs in the brainstem or cerebellum. Changes in ICP secondary to mass effect can displace the brainstem and stretch the abducens nerve, leading to a nonlocalizing sixth nerve palsy (116). Likewise, if a patient with a known malignancy presents with multiple cranial nerve palsies or various neurological deficits, a provider should be wary of leptomeningeal spread of a malignancy (117-119). A summary of these presentations is listed in Table 7. Management and overall prognosis secondary to SIM is variable and largely dependent on the type of disease, the location of the tumor itself, and various other prognostic factors. The medial survival rate in patients with an intracranial metastasis is 25% at 1 year and 4% at 3 years, whether the patient has either a known or occult primary tumor (120). Patients with solitary metastasis have an overall better survival time when treated aggressively with surgery or radiotherapy (103). As discussed above, the role of the ophthalmologist/neuro-ophthalmologist is to communicate both the findings and define the possible causes for the visual loss to help the primary treating services to decide on best treatment and monitor treatment effects after surgery, chemotherapy, or surgery. CARCINOMATOUS MENINGITIS Carcinomatous meningitis (CM) is a disease process characterized by diffuse infiltration of the meninges and the CSF by metastatic tumor cells. CM is seen in about 5%-15% of patients with systemic malignancies (32). The most frequent causes of CM are hematologic tumors, particularly acute lymphoblastic leukemia, and non-Hodgkin lymphoma (32,71,121,122). CM can also be seen with any e43 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees' Corner solid tumor, including breast cancer (12%-35%), lung cancer (10%-26%), melanoma (5%-25%), gastrointestinal cancer (4%-14%), and cancers of unknown primary origin (1%-7%) (32,71,123-127). The mean time between primary tumor diagnosis and the diagnosis of CM is roughly 20 months, whereas the mean time between symptom onset and diagnosis of CM is roughly 4 months (72). Diagnosis and Management of Carcinomatous Meningitis Up to 90% of patients with CM can present with ocular findings; usually, patients have both afferent and efferent visual symptoms and signs (e.g., visual loss, diplopia and ocular motility deficits, pupillary abnormalities, papilledema, and optic atrophy) on initial presentation (32,71). Lanfranconi et al reviewed 41 patients with CM and ocular symptoms/signs were the presenting clinical feature in 83% of patients and were the only manifestation in 7% of patients (72). A formal ophthalmology examination should therefore be performed in any patient with suspicion of CM. In addition, up to 30% of patients with CM have ocular disturbances that may go undetected or be delayed in diagnosis (128). Visual loss was the presenting clinical manifestation in 50% of patients with CM and was the most common ocular symptom (70%). Afferent visual findings included papilledema (10%), scotomas (5%), and hemianopic visual field loss (2%) (72). Perhaps the most striking afferent symptom associated with CM is the acute/subacute onset of unilateral or bilateral blindness and is seen in up to 30%-40% of reported cases. The onset of blindness typically starts in one eye, but can quickly progress to the second eye within 24 hours (73). The cause of vision loss is unclear, but is hypothesized to be secondary to compression of the optic nerve by tumor cells or from chronic papilledema (129). Patients with CM can also present with efferent visual symptoms. In 20%-50% of patients with CM, there is diplopia typically secondary to cranial nerve palsies of the third, fourth, and sixth cranial nerves. Ptosis (19%), anisocoria (7%), exophthalmos (5%), and nystagmus (2%) have also been documented in CM (72). In cases, cranial nerves II, V, and VIII may also be affected by this disease process (74). A summary of these presentations is listed in Table 7. The preferred method for initial evaluation of this patient population is MRI of the brain and spine with and without gadolinium (130,131). If a patient presents with clinical features of CM, an abnormal MRI finding demonstrating subarachnoid tumor nodules or contrast enhancement of the leptomeninges or cranial nerves may be enough to make a diagnosis (131,132). However, lumbar puncture should be performed in any suspected cases of CM, because the hallmark of diagnosis is the presence of malignant cells in the CSF (72,123). A large volume parae44 centesis of around 10ml is beneficial for diagnostic purposes for cytologic analysis (131). Samples should be processed as soon as they are collected as the false-negative error rate can be as high as 36% in stored samples (131). Lumbar puncture is especially important when other imaging (e.g., brain MRI) or laboratory testing are unrevealing. Serial repeated high-volume lumbar punctures may be necessary however to make the diagnosis of CM. Increased opening pressure, CSF pleocytosis, elevated CSF proteins, and decreased glucose levels are suggestive of a positive diagnosis of MC (72). However, these abnormalities cannot prove the presence of CM, because these findings are also seen with other nonmalignant neurological diseases (132). Given this uncertainty, flow cytometry and CSF cytology are recommended. Epithelial cell adhesion molecule-based flow cytometry has been shown to have higher sensitivity and equal specificity for diagnosing CM when compared with CSF cytology and is currently being studied as a possible tool for treatment monitoring (132). If neuroimaging, CSF cytology, and flow cytometry are inconclusive, meningeal biopsy may be useful to confirm the diagnosis of CM, because it allows the direct visualization of malignant infiltration (133). Treatment for CM is typically directed at the primary tumor type and may be palliative to extend survival and improve neurological symptoms (32,74). Treatment involves either the placement of a ventriculoperitoneal shunt in patients with symptomatic hydrocephalus or radiation and intrathecal chemotherapy (32,134,135). Methotrexate, cytosine arabinoside, and thiotepa are commonly used in treatment regimens (136). Without treatment, median survival team is only 4-6 weeks (32). MALIGNANT INTRACRANIAL GERM CELL TUMORS Intracranial germ cell tumors (GCT) arise from abnormally migrated germ cells during embryogenesis and are an uncommon PIM usually seen in the second decade of life (78). GCT are seen disproportionately in persons of Asian/ Pacific islander origin, but can occur globally. GCT can be broadly classified as germinomatous (GGCT) and nongerminomatous (NGGCT) with germinomas being the most common (73%-86%) (78). Germinomas overall represents 0.1%-3.4% of all intracranial tumors and carry a better prognosis than NGGCT (137,138). The most common location of midline GCTs is the suprasellar cistern or the pineal gland; however, in 6% of reported cases, the tumor can occur in both locations simultaneously. Interestingly, GCTs account for 50%-75% of all pineal gland lesions and should be suspected in any case of a pineal gland lesion (78,139). Rarely, this tumor type can arise from basal ganglia, thalamus, hypothalamus, and third ventricle. Dermarkarian et al: J Neuro-Ophthalmol 2020; 40: e31-e48 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees' Corner Diagnosis and Management of Intracranial Malignant Germ Cell Tumors The initial presentation of a GCT can vary and is dependent on its location in either the suprasellar cistern or the pineal gland. GCTs that arise in the suprasellar region are known to present with visual acuity or visual field changes secondary to chiasmal (e.g., junctional, bitemporal, or homonymous hemianopsia) or optic nerve compression (33%), diabetes insipidus (41%), hypothalamic-pituitary dysfunction, including delay or regression of sexual development, hypopituitarism and rarely, precocious puberty (76,140). Conversely, GCT arising from the pineal gland are likely to present with hydrocephalus and various symptoms and signs of the dorsal midbrain syndrome including headache, nausea, vomiting, altered mental status, and a sixth nerve palsy secondary to elevated intracranial pressures. In many cases, pineal-based GCT can present with the dorsal midbrain syndrome. This syndrome is characterized by a constellation of clinical findings including upgaze palsy, convergence retraction nystagmus, Collier lid retraction, and pupillary light near dissociation. All of the findings are because of the mass effect in the pretectal dorsal midbrain region. Although the clinical features of the dorsal midbrain syndrome are characteristic, all the signs of the syndrome need not be present (76,77,141). Limitation of upgaze is usually the initial and most common feature, with pupillary abnormalities (light near dissociation) being the next common feature (79,142). NGCTs have a predilection for pineal gland (68%), but can occur in the lateral ventricle, fourth ventricle, or cerebellum. GCTs frequently cause compression of the cerebral aqueduct and produce secondary obstructive hydrocephalus. The increased intracranial pressure can lead to papilledema and optic atrophy (77). Occasionally, these tumors can lead to metastasis or leptomeningeal spread with rapid deterioration in clinical status of the patients (143). GCT are extremely radiosensitive and the neuroophthalmic findings may improve or resolve after radiotherapy. Some cases require surgery and gross resection of residual tumor after chemo-radiation has shown benefit (140,144). Treatment of hydrocephalus and increased ICP are also recommended in GCT. CONCLUSION Both PIM and SIM tumors can affect the afferent and/or efferent visual pathways and produce localizing neuroophthalmic signs. The topographical location of the tumor determines the presenting clinical symptoms and signs, but some tumors have a predilection for specific areas of the brain. In addition, even if the diagnosis of a specific PIM or SIM is made, visual loss can still occur from residual or secondary papilledema or hydrocephalus. Clinicians should be able to communicate the risk and Dermarkarian et al: J Neuro-Ophthalmol 2020; 40: e31-e48 deploy appropriate countermeasures to mitigate the visual sequelae of PIM and SIM. Neuro-ophthalmic signs may be the presenting or only finding of a PIM or SIM and timely recognition and workup could aid in earlier diagnosis and treatment. The roles of the ophthalmologist/neuro-ophthalmologist are: to diagnose the PIM/SIM in patients presenting with neuro-ophthalmic complaints; to recognize, image, diagnose, and then triage the patient to appropriate multidisciplinary care; to define the pathogenic mechanism for the neuro-ophthalmic findings; to define the patient's baseline findings including automated visual field testing and OCT as indicated; to monitor for neuro-ophthalmic findings during and after treatment and to monitor for afferent or efferent visual pathway treatment-related side effects; to follow patients for visual stability or progression; and to communicate the findings to the treating primary and multidisciplinary physicians. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: C. R. Dermarkarian, A. T. Kini, B. A. Al Othman, and A. G. Lee; b. Acquisition of data: C. R. Dermarkarian, A. T. Kini, B. A. Al Othman, and A. G. Lee; c. Analysis and interpretation of data: C. R. Dermarkarian, A. T. 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