implants. Additionally, lesions of the skull base in the sella and parasellar region can cause optic neuropathy; these include primary brain tumors (e.g., pituitary adenoma, meningioma, craniopharyngioma, germinoma), tumors arising from adjacent areas (e.g., head and neck tumors such as squamous cell carcinoma, esthesioneuroblastoma), and tumors metastatic to the skull base region (breast). Optic neuropathy due to leptomeningeal disease (LMD) can occur in patients with hematogenous tumors (e.g., leukemias), solid tumors (e.g., breast, lung, melanoma), and primary brain tumors (glioma, germinoma etc.). Paraneoplastic syndromes affecting vision usually involve the retina, but may also affect the optic nerve (e.g., CRMP 5). Optic neuropathy can also result from orbital cellulitis, a serious infection in immune-suppressed patients. Optic neuropathies in cancer patients may also be the result of infectious meningeal diseases (e.g., cryptococcal meningitis). In this chapter, we will concentrate on optic neuropathies that do not have an obvious direct compressive component and in which imaging, therefore, may not be helpful. We discuss optic neuropathies related to raised intracranial pressure (ICP), nutritional deficiencies, drugs, and radiation injury.

35.2 Optic Neuropathies Related to Elevated ICP

Optic neuropathies related to elevated ICP are not rare in cancer patients. Elevated ICP leads to papilledema, and chronic papilledema can lead to vision loss.

Optic neuropathy associated with elevated ICP does not initially affect vision; therefore, early recognition of its presence is important for visual preservation. Optic neuropathy associated with long-standing papilledema initially affects the peripheral visual field (inferonasal); central vision is affected late in the process, most commonly within 6 months but as soon as 2 weeks in cases of severe and acute ICP elevation. Also, papilledema may be present for months to years without affecting visual function. Patients may not note vision impairment until central vision becomes affected; therefore, patients may have significant visual field loss before they are found to have papilledema. The optic neuropathy of papilledema may be asymmetric, i.e., one eye may have significant visual field loss while the other eye is not symptomatic.

35.2.1 Causes of Elevated ICP

Large volume brain lesions: Intracranial masses (primary brain tumors or brain metastases from a primary tumor at another site) can cause elevated ICP as a result of displacement of space in the cranium, cerebral edema, and/or obstruction of cerebrospinal fluid (CSF) flow. Supratentorial tumors may compress the falx or vein of Galen. Infratentorial tumors often obstruct the aqueduct and/or fourth ventricle and lead to hydrocephalus.

treatment is aimed to symptoms, such as headaches. However, when elevated ICP is associated with visual field loss with or without visual acuity loss, elevated ICP must be treated to avoid continued damage to the optic nerve.

The treatment modality for elevated ICP depends on the cause. The goal must be reduction of ICP and/or reduction of pressure in the perioptic nerve sheath. The severity of the visual acuity loss and visual field loss determines the rapidity with which interventions need to be implemented. Specific treatment options include the following: tumor removal (for tumor-induced elevated ICP); treatment of underlying hydrocephalus or leptomeningeal disease; discontinuation of drugs (in the case of drug-induced elevated ICP); utilization of diuretics with or without steroids; shunting by means of a lumboperitoneal or ventriculoperitoneal shunt; optic nerve sheath fenestration; and chemotherapy or radiation therapy (if elevated ICP is related to a tumor or leptomeningeal disease).

Patients with severe visual field loss and involvement or fixation before initiation of treatment usually have irreversible damage. Routinely sending patients with any of the above potential causes of elevated ICP for ophthalmic examination is a way to identify the condition early and potentially stall vision loss.

35.3 Optic Neuropathies Caused by Nutritional Deficiencies

The nutritional deficiencies that most commonly affect the optic nerve are deficiencies of vitamin B12 (cobalamin), folate, and thiamine (B1).

The symptoms and signs of an optic neuropathy related to nutritional deficiency are progressive symmetric painless visual loss affecting the central and the color vision early on with initially normal findings on pupil examination and central or cecocentral scotomas on visual field testing and late development of temporal disc pallor.

35.3.1 Vitamin B12 Deficiency Optic Neuropathy

Vitamin B12 deficiency optic neuropathy can occur in seemingly healthy individuals and is more common in males (80% of affected patients) than in females [3]. The risk of vitamin B12 deficiency and associated optic neuropathy is seen with partial or complete removal of the stomach, as in patients needing gastrectomy to remove malignant tumors, and patients who have undergone bariatric surgery, up to 40% of whom suffer from B12 deficiencies [4]. Vitamin B12 deficiency is also present in patients with pernicious anemia, an autoimmune condition that impairs the absorption of vitamin B12 in the ileum due to lack of intrinsic factor. Sometimes optic neuropathy is the first sign of pernicious anemia. The neurologic manifestations of this deficiency can be the earliest manifestations and include myelopathy affecting the posterior columns and cortical spinal tract, referred to as subacute combined degeneration, involving the cervical and upper thoracic posterior columns [4].

These patients can present with paresthesias and weakness [5]; rarely, sensory and autonomic disturbances [6] and neuropsychiatric manifestations such as memory problems, personality changes, and psychosis [4] can be seen as well as a megaloblastic anemia that develops slowly and can be severe.

Adenosine triphosphate (ATP) is thought to play a key role in optic neuropathy related to vitamin B12 deficiency [3]. The postulated mechanism is as follows: vitamin B12 deficiency increases the level of methyltetrahydrofolate, which in turn causes excessive depolarization and depletion of ATP. This ATP deficiency could be the explanation for the cecocentral scotoma characteristically seen in vitamin B12 deficiency optic neuropathy, because the parvoretinal ganglion cells of the papillomacular bundle require more energy than the magnoganglion cells [3].

In patients in whom vitamin B12 deficiency optic neuropathy is suspected, serum cobalamin, serum methylmalonate, and serum homocysteine levels should be checked [3]. Methylmalonate and homocysteine are metabolites of cobalamin, and if the serum cobalamin level is at low-normal or normal levels, these other metabolites can help establish a diagnosis of cobalamin deficiency. Once vitamin B12 deficiency has been established, a Schilling test should be done to determine the degree of cobalamin malabsorption.

Patients with vitamin B12 deficiency optic neuropathy are generally treated with cyanocobalamin 100 μg intramuscularly three times weekly for the first 2 weeks and then 500–1000 μg intramuscularly monthly [3]. Most patients must continue this therapy forever. Stopping maintenance therapy can result in the return of neurological symptoms. The earlier the therapy is instituted, the higher the likelihood that symptoms and signs will resolve.

35.3.2 Folate Deficiency Optic Neuropathy

Like B12, folate is involved in methionine metabolism. Folate, in the form of methyltetrahydrofolate, donates a methyl group to homocysteine to form methionine and tetrahydrofolate. Tetrahydrofolate helps metabolize formate. Folate deficiency leads to the accumulation of formate, a toxic metabolite from methanol, causing optic neuropathy [4]. Folate deficiency also causes other neurological manifestations, such as polyneuropathy and even subacute combined degeneration of the spinal cord, that are many times indistinguishable from those caused by cobalamine deficiency.

In women of childbearing age who have epilepsy and are on anticonvulsant treatment, a daily dose of folate 0.4 mg is suggested to avoid future neural tube defects when these women have children [4].

Although folate deficiency often occurs with other nutrient deficiencies, isolated folate deficiency has been shown to cause optic neuropathy [7]. In the study by Hsu et al. [8], six patients with low folate levels but normal B12 levels developed bilateral visual loss, color defects, and central or cecocentral scotomas with optic discs that were normal or had temporal disc pallor. Measurement of erythrocyte folate was found to be more sensitive than measurement of serum folate in the early diagnosis