Overview and differential diagnosis of papilledema

INTRODUCTION — While the term "papilledema" is often used broadly to denote a swollen optic nerve head, the term "papilledema" should be reserved for optic disc swelling that is due to raised intracranial pressure.

This topic will provide an overview and differential diagnosis of papilledema. The entity of increased intracranial pressure and specific causes of papilledema are discussed elsewhere. (See "Evaluation and management of elevated intracranial pressure in adults".)

ETIOLOGIES AND PATHOGENESIS — Papilledema occurs when raised intracranial pressure is transmitted to the optic nerve sheath. The raised pressure mechanically disrupts axoplasmic flow within the nerve. Obstipation of intra-axonal fluid results in swelling of the axons and leakage of water, protein, and other cellular contents into the extracellular space of the optic disc giving rise to optic disc edema [1,2]. Venous obstruction and dilation, nerve fiber ischemia, and vascular telangiectasias are secondary phenomena.

Any entity that increases intracranial pressure may lead to papilledema. These include:

●Intracranial mass lesions (eg, tumor, hematoma)

●Cerebral edema (such as in acute hypoxic-ischemic encephalopathy, large cerebral infarction, severe traumatic brain injury)

●Increased cerebrospinal fluid (CSF) production (eg, choroid plexus papilloma)

●Decreased CSF absorption (eg, arachnoid granulation adhesions after bacterial meningitis)

●Obstructive hydrocephalus

●Obstruction of venous outflow (eg, venous sinus thrombosis, jugular vein compression, neck surgery)

●Idiopathic intracranial hypertension (pseudotumor cerebri)

Rarer entities causing increased intracranial pressure include increased arterial inflow as from an arteriovenous fistula [3,4], intraspinal lesions [5,6], chronic respiratory illness [7,8], and other toxic metabolic conditions that cause diffuse cerebral edema [9]. Reported cases of papilledema in acute or chronic inflammatory demyelinating neuropathy may represent a consequence of elevated CSF protein, which may impair resorption or circulation of CSF [10-13].

Idiopathic intracranial hypertension (pseudotumor cerebri) is discussed in detail separately. (See "Idiopathic intracranial hypertension (pseudotumor cerebri): Epidemiology and pathogenesis" and "Idiopathic intracranial hypertension (pseudotumor cerebri): Clinical features and diagnosis" and "Idiopathic intracranial hypertension (pseudotumor cerebri): Prognosis and treatment".)

CLINICAL MANIFESTATIONS — Papilledema is usually discovered when a patient is evaluated for other symptoms of increased intracranial pressure, rather than for symptoms directly resulting from optic nerve pathology.

Because the causes of intracranial hypertension are generalized phenomena, papilledema is almost universally bilateral, although it may be asymmetric. If there is underlying optic nerve injury or disease, then the appearance of papilledema may be unilateral, since the damaged nerve does not swell. The classic example is the Foster-Kennedy syndrome, in which a frontal lobe tumor compresses and destroys the optic nerve on one side before causing increased intracranial pressure. This gives rise to optic atrophy in one eye and disc edema in the other.

Symptoms of increased intracranial pressure — Headache is a cardinal symptom of increased intracranial pressure. However, few features of the headache specifically point to intracranial hypertension as a cause. Nausea and vomiting are frequent in this setting, but they are also a manifestation of migraine. Worrisome features include a positional quality to the headache, usually worsening with recumbency, as well as a diurnal pattern; headaches associated with intracranial hypertension are classically worse in early morning. (See "Evaluation and management of elevated intracranial pressure in adults".)

Another classic symptom of increased intracranial pressure is binocular horizontal diplopia resulting from unilateral or bilateral lateral rectus paresis. Cranial nerve six, the abducens nerve, is believed to be peculiarly vulnerable to the effects of increased intracranial pressure because of its long course in the subarachnoid space and its bend to enter the cavernous sinus.

A pulsatile machinery-like sound in the ear, probably due to venous sinus obstruction, is also common and often persistent even after the raised intracranial pressure is relieved.

Visual symptoms — While rarely the presenting symptom, visual symptoms are common in patients with papilledema. These are typically visual obscurations that clear completely, are often unilateral, and are typically very brief (just seconds) [14]. They may occur spontaneously or with changes in position, and they are believed to represent transient fluctuations in nerve head perfusion. Their presence correlates with the degree of intracranial pressure elevation. Increasing intensity, frequency, and duration of these symptoms can be a prognostic sign for permanent visual loss, but this symptom is not reliably predictive.

It is unusual for patients to have persistent deficits of visual acuity or field loss until quite late in the course. Untreated, chronic papilledema can lead to progressive visual field loss in the form of peripheral field contraction, nerve fiber bundle defects, and even blindness [15,16]. The field loss often mimics the field loss of glaucoma.

Funduscopic findings — Because the findings in papilledema evolve over time, ophthalmologists often characterize papilledema into stages: early, fully developed, and chronic or late.

Clinicians often photograph patients' fundi in order to follow changes in the examination and monitor response to treatment. Another approach might be to use a grading scheme, but some of these have not been well validated or universally accepted [17].

Early — One of the earliest findings in papilledema is loss of spontaneous venous pulsations, occurring with pressure elevations of only 200 mm [18-28]. This is a sensitive rather than specific sign, as 20 percent of normal individuals do not have detectable venous pulsations. These pulsations are best seen in the section of the central retinal vein that is going into the optic nerve cup.

The optic cup is retained when the papilledema is mild. However, splinter hemorrhages in the nerve fiber layer, at or beyond the disc margin, may be seen early (picture 1). This is also a nonspecific sign, especially in older patients [28].

Fully developed — As the edema progress, the optic disc becomes elevated, the cup is obliterated, and the disc margins become obscured. Blood vessels are buried as they course the disc. Serpentine engorgement of retinal veins is evident, and the disc appears hyperemic. The edema extends into the retina, giving the appearance of an enlarged optic nerve head. Multiple flame hemorrhages and cotton wool spots, resulting from nerve fiber infarction, appear. Retinal microfolds form around the swollen disc. At this stage, the blind spot will be increased (picture 2) [28].

Chronic — The central cup remains obliterated. Hemorrhagic and exudative components resolve. The appearance of hard exudates in the nerve fiber layer indicate a process of some months' duration. The nerve now appears flat with irregular margins; nerve fiber attrition leads to disc pallor (picture 3). One usually can detect some loss of visual field at this stage.

DIFFERENTIAL DIAGNOSIS — There are many causes of an elevated optic nerve head. While the term "papilledema" is sometimes used to describe the findings in these conditions, it should be reserved for patients who have elevated disc heads as a consequence of increased intracranial pressure. The causes of papilledema (ie, increased intracranial pressure) are listed above. (See 'Etiologies and pathogenesis' above.)

While there is overlap between the two categories, it is useful to consider those conditions that cause bilateral abnormalities versus those that are more usually unilateral (table 1).

Bilateral disc abnormalities — Funduscopic findings, the clinical setting, and the presence of associated visual loss may help distinguish the following entities from true papilledema.

●Pseudopapilledema – Congenital anomalies of the disc, including drusen and myelinated nerve fibers, and even farsightedness or hyperopia, may cause the appearance of disc swelling or pseudopapilledema. This term is reserved for conditions that are not due to disease states.

Drusen are hyaline bodies thought to be remnants of calcific axonal degeneration. Drusen tend to be buried in children (sometimes raising concern for increased intracranial pressure) and become more exposed in adults. Most, 75 to 85 percent, are bilateral [29,30]. Present in approximately 2 percent of the population, they may be inherited as an autosomal dominant condition. Usually asymptomatic, some will have measurable visual field abnormalities, including enlarged blind spot, field constriction, and inferior nasal visual field loss. An afferent pupillary defect may be present if the condition is unilateral or asymmetric.

Disc drusen appear as a lumpy mass with refractile bodies within (picture 4). Another anomaly, myelinated nerve fibers are white, cover the underlying retina, and have scalloped edges. In contrast to papilledema, the appearance of the nerve fiber layer in pseudopapilledema appears normal, not hazy. The absence of spontaneous venous pulsations is not useful here, as they are often absent in pseudopapilledema. Other clues to the presence of a congenital anomaly are an absent portion (often nasal) of the nerve head and unusual patterns of the blood vessels as they emerge from the nerve head [31]. Other signs of true papilledema, cotton wool spots, hemorrhages, hyperemia, and venous congestion are absent [29]. Computed tomography (CT) scanning, ultrasonography, and optical coherence tomography clarify the diagnosis of drusen by revealing calcium deposits not visible on ophthalmoscopic examination.

●Malignant hypertension – Severe systemic hypertension can cause a change in the optic nerve head that resembles papilledema. However, the swelling of the nerve head is usually mild. Recognizable hypertensive changes are seen in the vessels away from the nerve head in the posterior pole. These include hemorrhages, exudates, cotton wool spots, and even a "star" figure pointing to the fovea (picture 5 and picture 6) [32,33]. The optic nerve functions well, but damage to the retina can compromise vision and produce scotomata, dimming in vision, diplopia, and photopsia [34]. (See "Moderate to severe hypertensive retinopathy and hypertensive encephalopathy in adults" and "Ocular effects of hypertension".)

●Diabetic papillopathy – While relatively benign, this is a troublesome entity to diagnose because it mimics both papilledema from raised intracranial pressure and anterior ischemic optic neuropathy (AION). Optic edema may vary from minimal to extensive with telangiectasias, hemorrhages, and macular star (picture 7) [35].

When diabetic papillopathy is bilateral or occurs in a young juvenile diabetic as traditionally described, it is not likely to be mistaken for AION [35,36]. However, many cases are described in the literature in which the pathology is unilateral and the patient older. The prognosis is good, but during the acute phase there may be loss of central vision, enlarged blind spots, or field defects. These usually resolve. Impaired visual acuity is rare. Ischemia of the optic nerve is considered to be the probable mechanism; this process is independent of the diabetic retinopathy [37]. The prognosis might be worse in older patients with type II diabetes [38]. (See "Diabetic papillopathy".)

●Others – Hyperviscosity, hypotension, and blood loss have been reported to cause bilateral disc edema [39]. Toxic optic neuropathies producing papilledema early in their course have been described with methanol, ethambutol, ethylene glycol, and other toxins [9]. Optic atrophy emerges more rapidly in these conditions, while it tends to appear later in chronic papilledema. Bilateral disc edema may result from optic nerve compression by infiltrated extraocular muscles in severe thyroid ophthalmopathy.

Unilateral disc abnormalities — Most of the entities that cause unilateral disc elevation can be broadly classified into ischemic, inflammatory, and infiltrative lesions. Because they are usually unilateral, they are not confused with true papilledema. However, in some situations, as noted below, these can be bilateral and raise concern for papilledema. Similarly, in some patients papilledema may be sufficiently asymmetric as to seem unilateral.

●Anterior ischemic optic neuropathy – AION may be arteritic (eg, giant cell arteritis) or nonarteritic [28]. The latter occurs in older individuals and has been associated with atherosclerotic risk factors, particularly hypertension and diabetes. Nonarteritic AION has also been described in patients treated with phosphodiesterase-5 inhibitors such as sildenafil. (See "Nonarteritic anterior ischemic optic neuropathy: Clinical features and diagnosis" and "Nonarteritic anterior ischemic optic neuropathy: Epidemiology, pathogenesis, and etiologies" and "Clinical manifestations of giant cell arteritis" and "Treatment of male sexual dysfunction", section on 'Visual effects'.)

AION is almost always unilateral except in giant cell arteritis. There is always immediate loss of some or all of the vision; altitudinal defects are classic. An afferent pupillary defect is common. Prognosis for vision recovery is poor.

The swelling is not congested as it is with raised intracranial pressure but is usually pallid; if there are hemorrhages, they are small, splinter shaped on the edge of the disk [40].

●Papillitis, neuroretinitis – Papillitis is optic neuritis of the anterior portion of the optic nerve. It does not have the same implications as retrobulbar neuritis to the underlying etiology. For papillitis, the underlying causes are much broader, while retrobulbar neuritis is usually due to demyelinating disease or multiple sclerosis [41] (see "Manifestations of multiple sclerosis in adults", section on 'Visual symptoms'). When there is associated inflammation in the retina, as manifest by macular exudates, it is called neuroretinitis, and it is virtually never demyelinating in origin. Causes include viral syndromes, toxoplasmosis, cat scratch disease, sarcoidosis, syphilis, Lyme disease, and other vasculitides including systemic lupus erythematosus and granulomatosis with polyangiitis [42-46].

Papillitis is almost always unilateral. There is loss of vision, and the pupillary light reflex is abnormal in the affected eye. Pain, especially with eye movement, is common.

On funduscopic examination, the nerve is diffusely swollen and congested. There are few hemorrhages, but there may be some cells in the vitreous just in front of the nerve and, in some cases, a group of yellow-white linear deposits pointing like the spokes of a wheel around the fovea of the retina (picture 8).

●Sarcoidosis – Optic nerve involvement is rarely the initial presentation of sarcoidosis [47]. Sarcoidosis can affect the meninges and cause true papilledema. Some patients may present with a solitary sarcoid nodule of the nerve head. A yellowish mass is seen often with other typical lesions of sarcoid in the retina, conjunctiva, or anterior chamber. This is almost always unilateral. There may be loss of vision associated with this mass; occasionally, patients will be asymptomatic [48]. Other patients with sarcoid can develop disc swelling from vasculitis, uveitis, or more subtle infiltration of the optic nerve head. (See "Neurologic sarcoidosis".)

●Central retinal vein occlusion – Occlusion or thrombosis of the central retinal vein is associated with chronic glaucoma, atherosclerotic risk factors (age, diabetes, hypertension), hyperviscosity, and coagulopathy [49]. The cause is often unknown. (See "Retinal vein occlusion: Epidemiology, clinical manifestations, and diagnosis".)

The disc is typically mildly congested. Hemorrhages are prominent and extend far beyond the posterior pole of the eye into the retinal periphery; these are much more extensive than in papilledema. Vision loss corresponds to the hemorrhages and any superimposed retinal ischemia (picture 9) [50].

●Papillophlebitis – This presumed inflammatory condition occurs in young people and has a good prognosis [51]. The nerve is swollen. Funduscopic examination suggests a mild central retinal vein occlusion. Enlargement of the blind spot correlates with the amount of retinal hemorrhage in the macula [52]. Spontaneous improvement is common.

●Malignancy – Metastatic tumors rarely invade the nerve head. Breast and lung cancers are the most common culprits; others include meningioma, glioma, hamartoma, dermoid tumors, lymphoma, and leukemia [53,54]. The nerve head appears to be destroyed by the invading tissue (picture 10). Little of the normal architecture remains. When invasion or compression of the optic nerve occurs more posteriorly, it can appear similar to raised intracranial pressure. There is progressive loss of vision in all cases [55]. (See "Optic pathway glioma".)

●Leber hereditary optic neuropathy – At the onset of the expression of this hereditary condition, the optic nerve head appears to be modestly elevated [56]. It usually starts out in only one eye but eventually affects both. The blood vessels around the nerve have a telangiectatic appearance; however, this finding needs to be looked for carefully to be seen. There are no hemorrhages. Vision loss is always present. Profound optic atrophy then develops. In most cases, there is a history of this condition in the family. Genetic testing can confirm the diagnosis. (See "Neuropathies associated with hereditary disorders", section on 'Leber hereditary optic neuropathy'.)

●Other causes – Disc swelling from low intraocular pressure or chronic intraocular inflammation may be seen after eye surgery (cataract surgery or glaucoma) or after injuries (often iatrogenic) to the globe [57]. They are always unilateral and easily confirmed by measuring the eye pressure and the slit lamp examination.

An optic neuropathy occurring 6 to 24 months after radiation therapy is often associated with disc edema at onset [58,59]. (See "Delayed complications of cranial irradiation", section on 'Optic neuropathy'.)

DIAGNOSTIC TESTING — Diagnostic testing can help differentiate papilledema from other causes of disc edema, follow the course of papilledema, and determine the underlying etiology.

Neuroimaging — When a patient presents with findings suggestive of papilledema, diagnostic evaluation should proceed expeditiously. The first step is neuroimaging of the brain. Magnetic resonance imaging (MRI) with gadolinium contrast is generally preferred, but computed tomography (CT) scan can be ordered initially if access to MRI is delayed. MRI will detect intracranial mass lesions and hydrocephalus. Additional sequences, magnetic resonance venography (MRV), can be used to detect venous obstruction in the dural sinuses and in the neck. Rarely, increased intracranial pressure may arise from spinal lesions; therefore, if this diagnosis is suggested by clinical signs or symptoms (back or neck pain, myelopathic signs, abnormal spinal fluid) an MRI of the spine should be ordered as well.

Lumbar puncture — If neuroimaging is normal, lumbar puncture should be done for opening pressure and analysis. The technique of measuring the opening pressure is described elsewhere. (See "Lumbar puncture: Technique, indications, contraindications, and complications in adults".)

Using correct technique, elevated pressure is defined as greater than 250 mmH₂0; measurements between 200 and 250 mmH₂O are considered equivocal. Normal pressure levels in children are still a matter of debate. Intracranial hypertension in the absence of other cause defines the entity of idiopathic intracranial hypertension or pseudotumor cerebri. (See "Idiopathic intracranial hypertension (pseudotumor cerebri): Clinical features and diagnosis", section on 'Lumbar puncture'.)

Visual field testing — Formal visual field testing with perimetry is very useful in the detection of subclinical visual field abnormalities and quantifying changes over time. Visual field testing is mandatory in following the progress of the visual sequelae of papilledema and monitoring response to treatment. The size of the blind spot is an indirect measure of the degree of disc edema. Measurement in an individual patient must be done under exactly the same refractive conditions each time, as blind spot size is sensitive to refractive error. Constrictions in field perimetry and development of sector field defects are signs of impending serious visual loss. This finding is more valuable for prognosis than either symptoms or fundus appearance. The clinician should choose a perimetric technique that reliably measures the patient's visual field. Automated perimetry may not be ideal for all patients.

Fluorescein angiography — Fluorescein angiography may be helpful in the detection of early papilledema, showing dye leakage, disc vascularity, and excess early and late disc fluorescence. Ophthalmologists, however, find it incompletely reliable, especially in equivocal situations, and usually unnecessary in this clinical setting.

Optical coherence tomography — Where available, optical coherence tomography may be useful to monitor the swelling of the nerve and also to clarify the effect upon and changes within the surrounding retina. This technique is very dependent upon the skills of the person performing the test and thus is prone to error. Modern technology (spectral rather than time based) has improved reliability.

TREATMENT — The treatment of increased intracranial pressure is specific to the underlying etiology and is discussed separately. (See "Evaluation and management of elevated intracranial pressure in adults" and "Idiopathic intracranial hypertension (pseudotumor cerebri): Prognosis and treatment".)

VISUAL PROGNOSIS — Permanent loss of vision is a common consequence of papilledema that is untreated or unresponsive to treatment. Clinical findings predictive of visual loss are high-grade disc edema, peripapillary subretinal hemorrhages, opticociliary shunt vessels, abnormal vision at presentation, and the development of visual field loss. Anemia, old age, myopia, glaucoma, and systemic hypertension have been found to be risk factors for a poor prognosis in some studies [60]. Progressive changes in the visual field or acuity are useful to predict patients at risk; however, vision loss sometimes occurs abruptly. Visual field loss attributed to hemorrhage can be expected to resolve.

SUMMARY AND RECOMMENDATIONS — The term "papilledema" is most properly applied to optic disc edema occurring as a consequence of intracranial hypertension.

●The causes of papilledema often have serious consequences for impending morbidity and mortality; hence, diagnostic evaluation is urgent. (See 'Etiologies and pathogenesis' above.)

●Unilateral disc edema and abnormal visual acuity at presentation suggest alternative diagnoses. (See 'Clinical manifestations' above.)

●The first step in the evaluation for the cause of papilledema should be a neuroimaging study; brain magnetic resonance imaging (MRI) is preferred, but a computed tomography (CT) scan should be done if an MRI is not immediately available. (See 'Neuroimaging' above.)

●Lumbar puncture with measurement of opening pressure and analysis of cerebrospinal fluid (CSF) should follow a normal neuroimaging study. (See 'Lumbar puncture' above.)

●Serial clinical evaluations including measurements of visual acuity, funduscopic examination, and visual field testing with perimetry are invaluable in following the course of papilledema and response to treatment. (See 'Visual field testing' above.)