Table 3.3  Potential causes of papilledema with spinal cord tumors

Protein molecules released into the CSF by the tumor may mechanically block the arachnoidal pores and prevent CSF absorption.

An aseptic arachnoiditis may develop secondary to protein leakage.

CSF hyperviscosity may follow release of products of protein disintegration, which slows CSF circulation from the cranial circulation to the spinal spaces.

Spinal cord tumors may hemorrhage into the subarachnoid space.

The spinal cord normally acts as an “elastic reservoir” for cerebrospinal fluid. Spinal cord tumors may reduce the capacitance of this reservoir by mechanical blockage and thereby cause papilledema.

cysts can be associated with either intracranial hypertension or hypotension.505 Mechanistically, it is very unlikely that the tumor itself has any direct blocking effect on the absorption of the CSF.454

Subacute Sclerosing Panencephalitis

Subacute sclerosing panencephalitis (SSPE) is a fatal neurological disease caused by the measles virus. It is more common in males than females and is usually associated with infection before 4 years of age.479 Neurovisual symptoms first become apparent in late childhood or early adolescence. The diagnosis is suggested by the clinical picture of mental deterioration, myoclonus and seizures, often with a characteristic maculopathy (see Chap. 10).479 Cortical visual loss, hemianopia, impaired visual spatial abilities, and visual hallucinations develop.503 The diagnosis is confirmed by elevated CSF and serum titers, measles titers, and immunoglobulin elevation. However, there is no evidence that the viral strains used for immunization cause SSPE.267 The classic electroencephalogram (EEG) changes are sharp wave complexes every 5–15 s in a “burst-suppression pattern.” MR imaging shows atrophy and high-signal T2 lesions scattered in the periventricular and subcortical white matter, as well as inflammatory changes in the splenium of the corpus callosum.16 These lesions asymmetrically involve parieto-occipital regions in the early stages, then involve the periventricular white matter symmetrically.420

Optic disc swelling has been reported frequently in SSPE and is generally ascribed to elevated intracranial pressure,136 though Hiatt et al239 found optic neuritis in 6% of patients. Although it is often described as a chorioretinitis, SSPE appears to preferentially affect the retina, with secondary involvement of the retinal pigment epithelium and the choroid.423 A ground-glass whitening of the macula with mottling of the underlying pigment epithelium is commonly found. Associated findings may include macular degeneration, which begins as chorioretinitis with macular edema, hemorrhages and white infiltrates, and leads to macular scarring, retinal

pigment epithelial atrophy, and epiretinal membrane formation.44 Over time, a gliotic retinal scar with contracture of the inner limiting membrane may develop. Although SSPE is uniformly fatal, intraventricular administration of interferonalpha, combined with oral inosine pranobex, appears to be the most effective regimen at present, producing remission or stabilization in approximately half of cases.187,591

Optic Disc Swelling Secondary to Systemic Disease

Diabetic Papillopathy

In 1971, Lubow and Makley360 reported on three young patients with juvenile-onset diabetes and bilateral optic disc edema, with an intricate capillary network on the surface of the disc. Visual disturbances were minimal (in two patients, the disc swelling was discovered on routine examination), and the disc edema resolved spontaneously in approximately 6 months. Twelve cases reported by Barr et al28 exhibited a similar picture: bilateral superior disc swelling that may be segmental, minimal reduction in visual acuity, mild visual field abnormalities (e.g., inferior arcuate scotomas, blind spot enlargement, inferior depression with involvement of fixation), excellent recovery, predominant occurrence in the second or third decades of life, no clear correlation with background diabetic retinopathy, and variable presence of dilated superficial radial capillaries on the surface of the disc (Fig. 3.7).28,425

Patients with diabetic papillopathy tend to have small, cupless discs, as seen in most adults with ischemic optic neuropathy. Some authors have hypothesized that optic disc edema in young patients with juvenile-onset diabetes represents a form of ischemic optic neuropathy.69,274,520 Slavin520 has suggested that younger patients may have sufficient collateral circulation to spare the axons from irreversible injury that would impair vision. According to this hypothesis, the dilation of the superficial peripapillary capillary network would represent a compensatory mechanism to ameliorate the ischemic process.69 Hayreh’s finding of asymptomatic optic disc swelling in the contralateral eye of adults with typical nonarteritic ischemic optic neuropathy lends support to the hypothesis that this self-limited form of disc edema is secondary to axonal stasis from low-grade ischemia, which is insufficient to produce visual dysfunction.229,281,520 Alternatively, disc swelling in young diabetics could result from a primary microangiopathy affecting the vascular bed subserving the distal optic nerve head, which would be influenced by local anatomic factors, such as axonal crowding due to the size of the surrounding scleral canal.281,425,557

Recently, it has been proposed that venous insufficiency and venous congestion underlies the chronic low-grade disc

swelling that characterizes this condition.346 Although diabetes is associated with both arterial and venous disease, it also is associated with capillary endothelial leakage and would be expected to produce more vasogenic edema for a given level of venous pressure elevation.346 One report suggests that intravitreal triamcinolone may hold promise in the treatment of diabetic papillopathy.8

Malignant Hypertension

Malignant hypertension in children is seen in several settings, including severe glomerulonephritis, vasculitis (lupus, polyarteritis), and renal artery stenosis, and in transplant patients with severe rejection. In the most widely used classification of hypertensive fundus changes, the presence of optic disc edema separates grades III and IV, with grade IV hypertension associated with a grave systemic prognosis. Disc swelling in malignant hypertension has been attributed to elevated CSF pressure due to cerebral edema, particularly in patients with hypertensive encephalopathy. Accordingly, optic disc swelling in this setting has been equated with papilledema.233

However, Hayreh et al231 have demonstrated that the optic disc swelling in hypertensive retinopathy is caused by local ischemia rather than by elevated intracranial pressure. The swollen optic disc characteristically shows either hyperemia or pallor. It is believed that leakage of high levels of angiotensin II from the choriocapillaris produces vasoconstriction in the choroid and choroidal occlusion. Additionally, diffusion of angiotensin through the border tissue of Elschnig and into the optic nerve head causes ischemia in the axons that reduces axoplasmic transport proximal to the ischemic site. This process causes disc swelling and, secondarily, more ischemia and occlusion, with resultant swelling of the disc. In addition to the well-recognized signs of hypertensive

retinopathy and choroidopathy, a pathognomonic finding – focal intraretinal periarteriolar transudates (FIPTs) – has been identified by Hayreh et al.230 Blindness due to optic disc ischemia (AION) may occur if there is a precipitous reduction in blood pressure in patients with malignant hypertension.231,353 The finding of bilateral neuroretinitis with a macular star but without vitreous cells should also raise suspicion for this condition.331

Sarcoidosis

The evaluation of optic disc swelling in a child with sarcoidosis requires a detailed ocular and systemic evaluation. Optic disc edema in sarcoidosis may be due to infiltration of the disc (i.e., granulomatous optic neuritis), a local reaction to contiguous intraocular inflammation, or an indirect effect of neurosarcoidosis (hydrocephalus or mass effect) (Table 3.4). The characteristic irregular, cauliflower appearance of the infiltrated optic disc is a clue to the diagnosis of neurosarcoidosis (Fig. 3.8).34 However, neurosarcoidosis can present with bilateral optic disc edema and normal visual acuity, mimicking IIH.426

The protean systemic manifestations of sarcoidosis present differently in children than in adults.275,426 Among children younger than 4 years of age, a triad of maculopapular rash, uveitis, and arthritis predominates.238,468 Because the initial chest X-ray is abnormal in only 22%, children with sarcoidosis must be differentiated from those with juvenile rheumatoid arthritis.468 Children in the 8- to 15-year-old age range with sarcoidosis are often black and have symptoms of malaise, cough, and fever.293 Ocular lesions occur in 24%, manifesting primarily as uveitis.293 The initial chest radiograph is abnormal, displaying hilar adenopathy or, less commonly, a parenchymal infiltrate.293 Eighty percent of children have increased angiotensin-converting enzyme (ACE) levels

at the time of diagnosis, whereas adults with sarcoidosis have increased ACE levels less often.463 Children with sarcoidosis also have higher ACE concentrations and less CNS involvement than adults. Relative to Caucasians, African-American patients with sarcoidosis tend to be younger when they first present to the ophthalmologist and to present with uveitis and/or adnexal granuloma.149 Radiological evidence of bilateral hilar adenopathy, with or without parenchymal involvement, is a hallmark of the disease. Serum ACE is elevated in approximately 80% of children aged 8–15 with sarcoidosis, but this figure may be lower for children younger than 5 years of age.248 Biopsy confirmation may be obtained from nodular areas of skin, conjunctiva, and lacrimal gland. Conjunctival biopsies yield positive results in only 10–28% of eyes without visible granulomas.248

Sarcoid optic neuropathy is a very nasty and unforgiving problem. While systemic corticosteroids are the mainstay of therapy for neurosarcoidosis, other immunosuppressive agents such as cyclosporine, azathioprine, cyclophosphamide, chlorambucil, and methotrexate provide useful alternative treatments.180 The acute form of meningitis responds favorably to corticosteroids, whereas chronic meningitis may go through a cycle of remissions and exacerbations that require

Table 3.4  Causes of optic disc swelling in sarcoidosis

Granulomatous infiltration of the optic nerve head

Postlaminar granulomatous involvement of the optic nerve or surrounding meninges (retrobulbar neuritis)

Papilledema secondary to intracerebral masses, hydrocephalus, or granulomatous meningitis

Ischemic optic nerve infarction associated with perivascular inflammation Idiopathic intracranial hypertension associated with steroid withdrawal Disc swelling secondary to ocular hypotony

Disc swelling secondary to contiguous intraocular inflammation

long-term corticosteroid therapy.506 Surgical therapy is indicated in cases of hydrocephalus, expanding mass lesions, or mass lesions causing increased intracranial pressure.506 Seizure activity with neurosarcoidosis is a bad prognostic sign.194,318 Most patients with neurosarcoidosis achieve favorable outcomes with corticosteroids plus alternative corticosteroid therapy.493 Low-dose methotrexate therapy has been used as a corticosteroid-sparing therapy in childhood sarcoidosis.358 For neurosarcoidosis, agents other than corticosteroids show increased efficacy with lower morbidity.

MR imaging and lumbar puncture combined with the evaluation of the anterior and posterior chambers of the eye are useful in determining which mechanisms are primarily responsible for the optic disc edema.146 Gadolinium increases the sensitivity of MR imaging if corticosteroids have not been given, permitting detection of meningeal, parenchymal, optic nerve, and ependymal sarcoid lesions not visible on unenhanced scans.133,502,602 Lumbar puncture serves to rule out elevated intracranial pressure and other infectious and granulomatous disorders (tuberculosis, coccidioidomycosis, parasites, and lymphoma). Diagnostic tests with the highest yield and common clinical usage include chest X-ray, ACE level, serum lysozyme levels, limited gallium scan, and tissue biopsy.42 The combination of a positive Gallium scan and an elevated ACE level carries a 73% sensitivity and a 100% specificity for the diagnosis of sarcoidosis.435

Neurological complications of sarcoidosis are said to occur in 5% of sarcoidosis patients, and autopsy studies have identified unrecognized CNS disease in 15%.42,318 Neurosarcoidosis has a predilection for the base of the brain.506 Granulomatous meningitis at the skull base with infiltration or compression of adjacent nerves is the most common intracranial manifestation.281,592 Neurological manifestations include cranial nerve palsies, meningitis, hypothalamic and pituitary lesions, granulomatous basal meningitis,

space-occupying masses (mimicking gliomas and meningiomas), peripheral neuropathy, spinal cord involvement, and progressive multifocal leukoencephalopathy.339,490,506,602 Facial nerve palsy is the most common neurological manifestation of sarcoidosis, followed by involvement of the optic nerves and chiasm and, in descending order of frequency, the glossopharyngeal, vagus, and auditory nerves.426,506 Localized granulomatous lesions have been found in practically every part of the CNS, including the meninges, the floor of the third ventricle, the lateral ventricle, the occipital, frontal, and temporal lobes, the optic chiasm, the optic nerves, the basal ganglia, the cerebellum, and the spinal cord.490

The epidemiology of sarcoidosis gives strong evidence for a potential transmissible factor.433 Increasing evidence has implicated a hypersensitivity response to an endemic mycobacteria in the development of sarcoidosis.115 With the use of polymerase chain reaction techniques, mycobacterial and propionobacterial DNA and RNA have been recovered from sarcoidal tissue.257 The histopathology of sarcoidosis reveals the classic noncaseating granuloma, consisting of multinucleated epitheliod cells typically surrounding a noncaseating core of debris. This pattern is reminiscent of granulomas caused by certain infections. Tuberculosis forms granulomas that typically caseate. Foreign bodies can also form noncaseating granulomas. All of these conditions have in common the presence of a localized antigen inciting this type of immune response from the innate immune system. It is likely that a combination of a normally benign trigger, and an altered, hyperreactive system, results in the observed disease.180

Leukemia

The diverse spectrum of ocular involvement in childhood leukemia can be divided into three groups: neuro-ophthal- mologic features associated with CNS involvement, vascular abnormalities reflecting changes in hematological status, and direct infiltration of ocular tissues.452 The acute forms of leukemia are responsible for most of these ocular and CNS complications. Since modern chemotherapy has prolonged survival and provided a possibility of cure in leukemic children, it has also increased the incidence of leukemic cell infiltration, especially of the CNS.415 While optic nerve infiltration is usually related to CNS involvement, anterior segment infiltration frequently occurs in the absence of CNS disease.411,452 Optic nerve infiltration occurs mainly in children with acute leukemia, with a proclivity for acute myelocytic leukemia.469

Several mechanisms have been defined by which leukemia can produce swelling of the optic nerve head (Table 3.5).144 The differentiation between leukemic infiltration of the optic nerve and disc swelling due to increased CSF pressure

Table 3.5  Causes of optic disc swelling with leukemia

Leukemic infiltration of the optic nerve head

Papilledema secondary to leukemic CNS infiltrate, intracranial hemorrhage, steroid withdrawal following prolonged treatment, or opportunistic CNS infection

Papilledema related to leukemic infiltrates in the CNS

Ischemic optic neuropathy secondary to local vascular compromise from tumor infiltration of the optic nerve or orbit, to sludging of blood flow secondary to hyperviscosity, or to small vessel thrombosis in the microcirculation of the optic nerve in patients with thrombocytosis

Optic neuropathy secondary to opportunistic infections of the CNS that are more common in patients with leukemia

Intracranial hypertension secondary to treatment with all-trans retinoic acid

remains the fundamental clinical distinction to be made, as early cases of leukemic infiltration can be reversed with local irradiation.116,144,250,457 Optic nerve infiltration may be predominantly prelaminar or retrolaminar.469 Prelaminar leukemic infiltration of the optic nerve head appears as an elevated, fluffy, whitish swelling of the disc that progressively obscures the retinal vessels and is associated with edema and varying degrees of hemorrhage (Fig. 3.9).469 Larger infiltrates may extend into the peripapillary retina and produce sheathing of the contiguous retinal vessels. The leukemic cells are characteristically most numerous in the perioptic meninges and peripheral portions of the nerve, and then they extend along the optic septa to accumulate about the blood vessels within the optic nerve.116,250 Direct leukemic invasion of the optic nerve head usually causes slowly progressive visual loss that occurs late in the course of the infiltration, although it can occasionally proceed rapidly.116 When leukemic infiltration is primarily posterior to the lamina cribrosa, a profound decrease in vision is usually accompanied by swelling of the disc without visible infiltrate.469 Leukemic infiltration of the optic nerve is a visual emergency requiring immediate local irradiation (approximately 2,000 rads over a 1- to 2-week period), usually combined with intrathecal injection of cytotoxic drugs.408 Optic atrophy is a frequent sequel of irradiation therapy, whether or not it is used in conjunction with chemotherapy.

Following bone marrow transplantation, leukemic patients may develop optic disc edema.21 This condition is generally attributed to cyclosporine toxicity since it usually resolves without consequence, following a decrease or discontinuation of cyclosporine.21 Nevertheless, lumbar puncture is essential, because irradiation therapy would not improve papilledema due to increased CSF pressure; orbital irradiation is the treatment of choice for direct optic nerve infiltration.469 Monoclonal typing of CSF lymphocytes may aid in the difficult clinical task of differentiating insidious optic nerve infiltration from infectious optic nerve damage.116

MR imaging can delineate leukemic optic nerve infiltration. Perineural enhancement within the subarachnoid space and leptomeninges has been accomplished with gadolinium and orbital fat suppression in a patient with leukemic invasion of the optic nerve.250

As mentioned earlier, there have been reports on the development of IIH in patients with APML treated with alltransretinoicacid(ATRA),avitaminAderivative.170,215,363,482,558 Children under 8 years of age seem particularly sensitive to this drug.363,521 ATRA is used in the treatment of acute promyelocytic leukemia in children.119 Immunosuppression may give rise to opportunistic infections. Bhatt et al47 described a 16-year-old boy with acute lymphoblastic leukemia in whom

unilateral optic disc swelling was the presenting sign of cytomegalovirus retinitis. The major forms of leukemic optic disc swelling are summarized in Table 3.5.

The prognostic implications of ophthalmic involvement in childhood leukemia are ominous.415 In a 15-year study, 28 of 131 children with leukemia developed ocular complications. Twenty-seven of these patients died within 28 months from the onset of the ophthalmic involvement. All patients with ophthalmic manifestations had either bone marrow relapse or CNS involvement. Ocular involvement would appear, then, to be the harbinger of a relapse.452 Newer investigational chemotherapeutic regimens may improve the morbid prognosis in this subgroup.