Clinical manifestations

Presentation and course

Because papilledema is a manifestation of elevated intracranial pressure, its presence requires immediate diagnostic evaluation for potential neurologic emergencies.

Symptoms. Symptoms of elevated intracranial pressure that accompany papilledema include headache, pulsatile tinnitus, transient visual obscurations, nausea, vomiting, and diplopia. Although headache is one of the most common symptoms of raised intracranial pressure, many features of headache do not reliably identify the presence or absence of elevated intracranial pressure (33; 54). Worrisome features include an increase in headache severity with Valsalva maneuvers, early morning headaches, or headaches that awaken the patient from sleep. Pulsatile tinnitus may be unilateral or bilateral, constant or intermittent, and occasionally pronounced enough to be audible to auscultation (06). Binocular horizontal diplopia may occur as a symptom of impaired abduction secondary to unilateral or bilateral sixth nerve palsies. Focal neurologic symptoms such as weakness or numbness may accompany papilledema due to a focal intracranial lesion.

Patients with papilledema may complain of visual loss, may have evidence of visual dysfunction but be unaware of it, or may have no visual complaints and normal visual function. A common visual symptom in the setting of papilledema is transient visual obscurations. This symptom consists of monocular or binocular fleeting (lasting only seconds), painless blackouts of vision that resolve spontaneously and completely. The visual blackouts are frequently induced by postural changes. The pathophysiologic mechanism of these visual obscurations may be transient optic nerve ischemia resulting from hypoperfusion in the small low-pressure vasculature of the optic nerve head as a consequence of increased intraneural tissue pressure (36; 68).

Ophthalmoscopic appearance. The different stages of papilledema have characteristic features that can be observed during an ophthalmoscopic examination. It is important to note the degree of optic disc edema, color of the optic disc, presence or absence of venous engorgement, obscuration of the vasculature, hemorrhage, nerve fiber layer infarction, choroidal folds, and spontaneous venous pulsations. However, these optic disc signs are not unique to papilledema and often also apply to causes of acquired optic disc edema where the intracranial pressure is normal, including inflammatory and ischemic processes (65).

The earliest sign of papilledema is obscuration of the optic disc margins. As optic disc edema evolves, it progresses in a predictable manner, affecting first the inferior and superior poles of the nerve, then the nasal portion of the nerve, and lastly the temporal portion (35; 31). Frisen grading of disc edema has widely been used in research and clinical settings (31).

Modified Frisen Scale for Papilledema Grading

As an alternative to the Frisen scale, a simpler grading of mild, moderate, and severe disc edema is also commonly used in clinical practice. In order to identify mild disc edema, the inferior and superior portions of the optic nerve must be carefully examined.

In contrast, the entire disc margin is swollen in moderate and severe papilledema.

Papilledema can be mimicked by congenitally anomalous optic disc elevation with or without optic disc drusen and by juxtapapillary myelinated nerve fibers. Measurement of visual acuity does not serve to distinguish these conditions from papilledema because it can be normal or reduced in either case.

The following features of papilledema are helpful in distinguishing it from congenital abnormalities that produce optic disc elevation (pseudopapilledema).

(1) In papilledema, the disc is typically hyperemic, possessing a deep reddish color due to hypervascularity and capillary engorgement. In addition to obscuration of the optic disc margin from swelling, hyperemia is often present in mild or early papilledema.

(2) As papilledema progresses, decreased venous outflow causes engorgement of the veins. These vessels often become partially obscured by the swollen, edematous nerve fiber layer.

(3) Hemorrhage around the optic nerve head can also be seen, particularly in the form of radially oriented, small, flame-shaped splinter hemorrhages that track between the nerve fibers. Focal peripapillary congestion may result in ischemia of the nerve fiber layer and retinal infarction, visible as white cotton wool spots near the optic nerve head. In severe papilledema, hard exudates in the perimacular retina may lead to the formation of a macular star or hemi-star figure.

(4) Choroidal folds, known as Paton lines, resulting from pressure-related choroidal distortion may appear as parallel or circumferential striae in the retina surrounding the optic nerve (34; 64).

Ophthalmoscopic features of congenitally anomalous elevated optic discs include (1) normal (rather than hyperemic) disc color; (2) absence of opacification of the peripapillary nerve fiber layer; (3) absence of engorgement of the vascular structures; (4) absence of obscuration of the vasculature at the disc margin despite moderate obscuration/blurring of the optic disc margins; and (5) absence of hemorrhage, cotton wool spots, or choroidal folds around the optic nerve. Anomalous optic discs are frequently accompanied by tortuous, anomalous vasculature.

Optic nerve head drusen are important to recognize as a unique cause of optic disc elevation with characteristic features on ophthalmoscopic examination. Optic nerve head drusen are calcifications that often appear as refractile masses on or beneath the surface of the optic disc, causing an elevated nerve appearance. Optic nerve drusen can be invisible on ophthalmoscopic examination, but they are easily detected with the enhanced depth imaging of OCT.

The presence or absence of spontaneous venous pulsations can help to determine whether an abnormal-appearing optic disc represents papilledema. Spontaneous retinal venous pulsations synchronous with the arterial pulse are a useful indicator of normal intracranial pressure. The best location to observe them is in the venous segment that traverses the optic nerve head. One explanation for spontaneous retinal venous pulsation is that increased intraocular pressure during systole leads to transient collapse of the proximal intraocular retinal veins. At this location, there is a pressure gradient between the intraocular venous system and the retrolaminar central retinal vein, and that gradient depends upon the intracranial pressure (51; 48). Normal spontaneous venous pulsations may arise because changes in intraocular venous pressure during the cardiac cycle exceed the variation of the CSF pulse pressure transmitted to the retrolaminar central retinal vein. When the intracranial pressure is elevated, however, the CSF pulse pressure is increased, thus, matching the intraocular retinal venous pulse pressure and causing cessation of spontaneous retinal venous pulsations.

Although the presence of venous pulsations provides good evidence that intracranial pressure is normal at that moment (50), absence of venous pulsations does not necessarily indicate increased intracranial pressure, as venous pulsations are absent in approximately 10% of the normal population (53). Furthermore, spontaneous venous pulsations may be absent in the setting of optic disc edema, drusen, a small optic cup, or other disc anomalies without elevated intracranial pressure (57; 48). A final caveat is that the detection of spontaneous venous pulsations is a subjective judgment and interobserver reliability is not high. Some studies show that spontaneous venous pulsations can be detected even in patients with elevated intracranial pressure (83). Overreliance on this examination finding could, therefore, lead to important diagnostic errors.

Additional diagnostic tests can be beneficial in cases in which it is difficult to clinically differentiate between true papilledema and pseudopapilledema. Some studies propose that fluorescein angiography can reveal optic disc dye leakage at the optic nerve head in cases of acquired disc elevation but not in congenital optic disc elevation. However, its accuracy is uncertain, especially in children. A study found that oral fluorescence angiography has a limited reliability of 62% to 69% in distinguishing between true papilledema and pseudopapilledema in children under 18 years of age (21).

With ocular ultrasound, a “30° test” can be performed by obtaining measurements of the optic nerve diameter in primary gaze and in eccentric gaze. A reduction in diameter during this maneuver indicates fluid in the optic nerve sheath, as occurs with true papilledema.

OCT can provide ultra-high-resolution measurements of the peripapillary retinal nerve fiber layer thickness, total retinal thickness, and optic nerve head volume. OCT with enhanced depth imaging of the optic nerve head has high sensitivity and specificity for the diagnosis of optic nerve head drusen (55). It is also important to be aware that pseudopapilledema due to congenital optic disc elevation or optic disc drusen may coexist with papilledema.

The appearance of the optic nerve head may change as papilledema becomes chronic. Hyperemia, peripapillary hemorrhages, and cotton wool spots typically resolve, and the disc becomes a gliotic gray dotted with yellow, refractile flecks called pseudodrusen. At this point, it may be difficult to tell that papilledema had been present, as optic disc pallor is a nonspecific sign of axon loss but surrounding “high water marks” in the peripapillary retina may delineate the extent of prior elevation and swelling. If papilledema gives rise to secondary optic atrophy, the nerve flattens out and assumes a white color.

Although papilledema is typically bilateral, in rare instances unilateral cases also occur. The development of unilateral papilledema is complex and involves several anatomic differences in optic nerve sheath or lamina cribrosa, including the diameter of the optic canal, variations in microscopic nerve sheath structures, changes in the compliance of the lamina cribrosa, and variations in the perioptic subarachnoid space compartments (41; 03; 75).

These anatomic variances lead to asymmetric transmission of the elevated intracranial pressure to the optic nerve heads. Unilateral optic disc swelling together with symptoms of elevated intracranial pressure and examination features of papilledema, such as spared visual acuity and enlargement of the blind spot, should alert the examiner to the possibility of unilateral papilledema.

Ophthalmic examination. In addition to a fundus examination, the evaluation of a patient with suspected papilledema should include an assessment of visual acuity, color vision, pupillary examination, ocular motility and alignment, and visual fields. Visual acuity is usually normal in the presence of papilledema unless it is extremely severe or atrophic. In mild to moderate papilledema, preservation of visual acuity is a critical feature that distinguishes it from other causes of acquired optic disc edema. Visual acuity is retained because visual loss from papilledema develops first in the visual field remote from the point of fixation. Therefore, visual acuity, which represents visual function at the point of fixation (the fovea), is retained unless optic nerve damage is severe or peripapillary retinal swelling has extended to the macula itself (40; 14). Color vision may also be relatively preserved. Another feature of papilledema is that there is no relative afferent pupillary defect.

Patients may complain of diplopia owing to ocular misalignment caused by increased intracranial pressure. Unilateral or bilateral impaired abduction of the eyes may occur secondary to traction on the sixth cranial nerves within Dorello’s canal from the increased intracranial pressure. In other cases, the eye movements may be full, yet the patient has double vision owing to esotropia from loss of fusional ability. Patients with raised intracranial pressure may have skew deviation or rarely have palsies of the third, fourth, or seventh cranial nerves (66).

Precise visual field assessment, such as Humphrey visual field analysis, is essential to management. The visual field appearance provides support for a suspected impression of papilledema and is often the most important parameter on which decisions regarding treatment of the papilledema depend. Although confrontation visual fields should be carefully performed, such visual field examinations are insensitive to the early visual field loss in patients with papilledema (44).

Visual field defects in the setting of papilledema have been most extensively studied in idiopathic intracranial hypertension (80). Enlargement of the blind spots is typical and may be caused by elevation of the retina around the swollen optic nerve (15). Permanent visual field defects associated with prolonged papilledema often show a slow progression, beginning as inferior arcuate defects that progress to generalized constriction and, eventually, total loss (79). Rapid progression of peripheral visual field or even central vision loss suggests a fulminant type of idiopathic intracranial hypertension (76). Although papilledema may occur without visual field loss, severe optic disc edema is correlated with more extensive visual field deficits (81).

Portable digital fundus cameras and OCT are becoming increasingly available and can assist in the early detection of papilledema in primary care clinics and emergency departments (09; 69).

In addition, there have been significant advances in automated analysis of the mydriatic fundus photo, classifying the presence and severity of papilledema based on features, such as optic disc blurring, discontinuity of major vessels, and textural properties of the peripapillary nerve fiber layer (20). The Brain and Optic Nerve Study with Artificial Intelligence (BONSAI) group reported using a deep-learning system to classify optic discs as normal, showing papilledema, or presenting other abnormalities using fundus photographs (60). The system was trained, validated, and externally tested on a dataset of 15,846 ocular fundus photographs collected from individuals of various ethnic backgrounds. The system demonstrated high performance in distinguishing normal discs from those with papilledema and other abnormalities, with an area under the receiver-operating-characteristic curve (AUC) of 0.99 in the validation set. In the external testing dataset, the system achieved an AUC of 0.96 for detecting papilledema, with a sensitivity of 96.4% and specificity of 84.7%. This approach offers promising potential for non-ophthalmologist physicians to accurately diagnose optic-disc abnormalities using artificial intelligence.

Prognosis and complications

The initial visual changes, including transient visual obscuration and enlarged blind spots, are often reversible with timely treatment. However, irreversible visual field loss may develop if the underlying disease is unattended or when high-grade papilledema occurs due to rapid and severe intracranial pressure elevation. In fulminant idiopathic intracranial hypertension, severe visual field loss is often permanent despite aggressive intervention. A study showed that 4.7% of patients referred to a tertiary center for idiopathic intracranial hypertension had decreased visual acuity (14). Among them, 46% had associated outer retinal changes in the macula, including subretinal fluid and chorioretinal folds. The visual deficit associated with subretinal fluid was reversible, but the deficit associated with outerretinal changes, such as creases and photoreceptor disruption, as well as chorioretinal folds, was not. Optic neuropathy accounted for 21% to 33% of irreversible visual loss, which can be predicted by thinning of the retinal ganglion cell-inner plexiform layer complex (GCL-IPL) thickness on optical coherence tomography.

African-American and morbidly obese patients appear to be at greater risk of severe vision loss (10). Severe vision loss due to idiopathic intracranial hypertension is more frequent in men than in women. This could result from the difference in underlying mechanisms in each gender or the difference in how symptoms are presented or reported, which might contribute to delays in diagnosis and treatment. Patients of either gender with normal body mass index and aged 50 years or more are likely to have relatively good visual outcomes (10; 08). In idiopathic intracranial hypertension, recurrences of papilledema may occur after a long period of stability and are associated with weight gain (46).

Clinical vignette

A 13-year-old nonobese girl presented with headaches and bilateral blurred vision. The headaches were severe, throbbing, and worse with lying down. She reported pulsatile tinnitus in the right ear and transient visual obscurations. Initial visual acuity was 20/40 in each eye. Color vision was normal. Fundus exam revealed severe bilateral disc edema with peripapillary hemorrhages, cotton wool spots, and bilateral macular star figures. Automated Humphrey visual fields showed extensive bilateral blind spot enlargement. The symptoms and signs were highly suggestive of elevated intracranial pressure.

MRI with gadolinium and MR venogram was normal. Lumbar puncture showed an elevated opening pressure (54 cm H2O) and normal CSF contents. She had been prescribed minocycline for acne. As minocycline has been linked to intracranial hypertension, it was discontinued immediately, and acetazolamide treatment was initiated. Within 2 weeks, vision and papilledema improved significantly. At a 3-month follow-up visit, visual acuity was normal, the papilledema had completely resolved, and visual fields showed a minor residual enlargement of the blind spots.

Biological basis

Impaired axoplasmic transport is believed to be the central pathogenetic mechanism of papilledema (37). Increased pressure within the subarachnoid space results in increased pressure in the optic nerve sheaths. This intrasheath pressure subsequently leads to increased tissue pressure within optic nerve axons, impairment of axoplasmic transport, and axonal swelling (61; 37). Impaired axoplasmic transport may also be the result of compromised perfusion of retrobulbar optic nerve axons due to the perturbed pressure gradient (78). Although obscuration of the optic disc margin may be observed within 24 hours of an experimental elevation in intracranial pressure, it may take days to develop clinically (35; 71).

Etiology and pathogenesis

Although the differential diagnosis for the underlying etiologies of papilledema is extensive, it can be simplified by considering categories of disease that may elevate intracranial pressure: (1) an intracranial or intraspinal mass lesion or vascular malformation; (2) cerebral venous sinus diseases; (3) meningeal disorders; (4) subarachnoid hemorrhage, (5) traumatic brain injury, (6) intracranial hypertension secondary to medication or systemic medical conditions; and (7) idiopathic intracranial hypertension.

Intracranial or intraspinal mass lesion or vascular malformation. Common intracranial mass lesions include primary or metastatic brain tumors, intracranial hemorrhage, and intracranial abscesses. An under-recognized cause is an arteriovenous malformation or fistula that produces increased dural sinus venous pressure (01; 11). Intracranial mass lesions may occur with or without obstructive hydrocephalus and ventriculomegaly.

Cerebral venous sinus diseases. Intracranial hypertension is the presenting manifestation of cerebral venous thrombosis in 10% to 25% of patients (18; 32). Venous outflow obstruction secondary to focal venous sinus stenosis can cause clinical symptoms indistinguishable from idiopathic intracranial hypertension (05).

Meningeal disorders. Meningitis, meningiomas, and other meningeal tumors are common causes of papilledema. Acute or chronic bacterial, viral, or fungal meningitis, autoimmune inflammatory meningitis (such as sarcoidosis, lupus erythematosus, or Behçet disease), neoplastic meningitis, and chemical meningitis are potential etiologies of elevated intracranial pressure. Meningiomas are likely to cause papilledema if they involve the sagittal sinus, torcular herophili, or transverse-sigmoid sinus region (74). Primary and secondary leptomeningeal tumors of many kinds can also cause papilledema (84).

Subarachnoid hemorrhage. A meta-analysis study showed that over 70% of patients with aneurysmal subarachnoid hemorrhage developed secondary intracranial hypertension (26). In one study, papilledema was present in almost one half of patients with subarachnoid hemorrhage (22). However, papilledema is a delayed sign of subarachnoid hemorrhage, so its absence is expected during the acute presentation.

Traumatic brain injury. Swelling associated with traumatic brain injury may cause massive elevation in intracranial pressure that is closely correlated with poor neurologic outcome.

Intracranial hypertension secondary to medication or systemic medical conditions. The following medications are strongly associated with elevated intracranial pressure: tetracyclines (including doxycycline and minocycline), high doses of vitamin A or vitamin A derivatives (such as retinoids), corticosteroids (typically when being withdrawn), and lithium (27). Although many other medications have been associated with elevated intracranial pressure, the data are weak and prospective controlled trials are lacking. Systemic medical conditions associated with intracranial hypertension include leukemia, sleep apnea, systemic lupus erythematosus, and Addison disease.

Idiopathic intracranial hypertension. Idiopathic intracranial hypertension is a diagnosis of exclusion established following a complete evaluation, including normal neurologic exam except for cranial nerve palsy, normal neuroimaging, and spinal fluid formula, that yields no other explanation for elevated intracranial pressure (30; 28).

Epidemiology

Papilledema may occur in any age group without gender or racial predilection. The most common causative condition, idiopathic intracranial hypertension, is primarily a disease affecting obese women in the childbearing age range (20 to 44 years old), with an incidence of approximately 19 per 100,000 in women who are 20% overweight, compared to 0.9 per 100,000 in the general population (19; 13). The fact that female sex, childbearing age, and obesity are all strongly associated with idiopathic intracranial hypertension suggests that sexual hormones play a role. Male patients account for approximately 9% of all definite idiopathic intracranial hypertension cases, and the majority of them are obese (77). With increasing rates of obesity across the Unites States, it is likely that the incidence of idiopathic intracranial hypertension will rise (25; 13).

Prevention

Maintenance of a moderate weight is likely to reduce the likelihood of developing idiopathic intracranial hypertension. Age-appropriate cancer screening may reduce the likelihood of metastatic disease as a cause of elevated intracranial pressure. The other causes of papilledema do not have obvious preventative strategies.

Differential diagnosis

The principal diagnostic challenge is to distinguish papilledema from congenital optic disc elevation and from other acquired causes of optic disc elevation, such as anterior ischemic optic neuropathy, some forms of toxic optic neuropathy, inflammatory optic neuropathy, and infiltration of the meninges by carcinomatosis or lymphomatosis.

Differentiating papilledema from congenital anomalous elevated optic discs is typically accomplished by examining ophthalmoscopic features. Distinguishing papilledema from other acquired optic disc elevation solely through ophthalmoscopy might not be straightforward. However, these alternative conditions can be identified by their tendency to cause early visual impairment and by their non-ophthalmic symptoms.

Anterior ischemic optic neuropathy rarely affects both eyes at the same time. This condition is characterized by sudden painless vision loss and, often, altitudinal visual field defects. Among the toxic optic neuropathies, methanol toxicity may present with pronounced bilateral disc swelling. The toxins that produce minimal or mild bilateral disc edema include drugs, such as antimicrobials, immunomodulators, and chemotherapeutic agents, as well as heavy metals, such as lead. Neuroretinitis, an inflammatory (possibly bacterial, viral, or postviral) condition, may infrequently affect both eyes simultaneously and can easily be mistaken for papilledema. Within days to weeks of onset, a distinctive macular star or hemi-star often develops. Cat-scratch disease, which is caused by Bartonella henselae, is considered a common cause of neuroretinitis. Optic nerve inflammation (eg, due to myelin oligodendrocyte glycoprotein antibody disease, neuromyelitis optica spectrum disorders, sarcoidosis, or lupus) may result in bilateral optic disc edema. Acute and frequently profound loss in vision and visual field should help to differentiate these entities from papilledema, although sometimes they may spare the central visual acuity. MRI should reveal enhancement of inflamed or infiltrated optic nerves or nerve sheath. Discovery of a normal opening pressure on lumbar puncture is another important differentiating feature (except in the case of concurrent meningitis that also produces elevated intracranial pressure).

Diagnostic workup

Although papilledema seems to be a straightforward diagnosis by funduscopic examination in some patients, standard perimetry for visual field assessment and ophthalmic imaging modalities, such as OCT, fundus photo, autofluorescence, and fundus fluorescence angiography, are frequently required to rule out congenital or other acquired optic nerve anomalies that mimic the appearance of papilledema.

Once papilledema is identified, the next critical step is neuroimaging studies, such as CT, MRI, and contrast-enhanced CT venography or MR venography. Evidence of an intracranial mass lesion or hydrocephalus should be sought. Imaging findings that are supportive (but not diagnostic) of a diagnosis of idiopathic intracranial hypertension include empty (or partially empty) sella, flattening of the posterior globes, distention of the optic nerve sheaths, dilation of Meckel cave, cerebellar tonsillar herniation, meningoceles, and transverse venous sinus stenosis (04; 12). Bilateral transverse venous sinus stenosis in contrasted magnetic resonance venogram (MRV) is highly sensitive (97%) for the diagnosis of idiopathic intracranial hypertension (04). However, it can also be an incidental finding in normal subjects (43). The true relationship between increased intracranial pressure and transverse sinus stenosis remains unclear. Some studies demonstrated resolution of stenosis after lowering of the intracranial pressure through treatment (39), whereas others have shown persistent stenosis even after reduction of intracranial pressure and resolution of symptoms (07). Awareness of this diagnostic challenge with MRV is essential to avoid overdiagnosis of idiopathic intracranial hypertension.

Optic nerve head protrusion, posterior scleral flattening, optic nerve tortuosity, and distension of the optic nerve sheath are highly specific for idiopathic intracranial hypertension (with pooled specificities of 99%, 98%, 90%, and 89%, respectively) but less sensitive (with pooled sensitivities of 36%, 66%, 43%, and 58%, respectively) than transverse venous sinus stenosis (04). On the other hand, although these MRI signs of intracranial hypertension are common findings, a study showed that they occurred in only 1.7% of all patients undergoing brain MRI (12). The presence of papilledema correlated with the number of MRI signs of intracranial hypertension. Papilledema was found in 2.8% of patients showing at least one MRI sign of intracranial hypertension and 40.0% of those with at least four MRI signs of intracranial hypertension. It should be noted that relying solely on MRI signs of intracranial hypertension is not advisable for making decisions about invasive procedures for intracranial hypertension.

Lumbar puncture is usually performed with three goals in mind: (1) evaluation of the cerebrospinal fluid contents, including cytology and flow cytometry; (2) measurement of the opening pressure in the lateral decubitus position; and (3) determination of headache improvement in the 24 to 48 hours following the lumbar puncture. If imaging and cerebrospinal fluid contents are normal and opening pressure is elevated (greater than 20 cm H2O in a thin patient, 25 cm H2O in an obese patient, or 28 cm H2O in a pediatric patient), a diagnosis of elevated intracranial pressure is established (82; 02).

Management

With successful treatment of an underlying disorder, intracranial pressure may return to normal, and papilledema may subside. In idiopathic intracranial hypertension, the most common cause of papilledema in clinical practice, the goals of therapy are to alleviate symptoms and to preserve visual function. An indirect result of these goals is often resolution of papilledema, but such resolution is not a primary objective. Treatment options for idiopathic intracranial hypertension fall into three primary categories: (1) weight loss; (2) medical treatment; and (3) surgical treatment.

Weight loss. Weight loss in the range of 6% to 10% often leads to reversal of papilledema due to idiopathic intracranial hypertension (73). Among patients with idiopathic intracranial hypertension in whom CSF opening pressure was measured at diagnosis and 3 months later, a significant reduction in intracranial pressure was seen in those patients who had weight loss greater than 3.5% of BMI but was not seen in patients who did not lose weight during that interval (70). Lifestyle modification programs and selected commercial weight loss programs may be helpful to support the long-term maintenance of weight loss (73). Surgical weight loss via bariatric procedures can provide significant therapeutic effects, but complications such as nutritional deficiency and long-term success rates have yet to be fully documented (56). Because weight loss typically does not occur rapidly enough, additional medical or surgical treatments are frequently necessary in the short term.

Medical treatment. Acetazolamide is a potent carbonic anhydrase inhibitor that decreases cerebrospinal fluid production. A typical initial acetazolamide dose is 500 mg twice per day.

In the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT), the first multicenter, double-blind, randomized, placebo-controlled study to assess the clinical efficacy of acetazolamide (62), the maximum acetazolamide dose was 4 g per day. At that level, perioral and extremity paresthesias were a frequent side effect. If prescribed at a dose of greater than 2 g per day, the potassium level should be checked regularly. The IIHTT showed that acetazolamide plus diet was associated with greater improvement in the visual field than placebo plus diet. Topiramate provided moderate carbonic anhydrase inhibition and may be considered as an adjunct or an alternative to acetazolamide. A typical starting dose is 25 mg twice per day, followed by a slow titration to 100 mg to 150 mg twice per day. Potential additive benefits from topiramate include chronic migraine prevention and weight loss. Cognitive slowing is a common side effect, however. The diuretic furosemide may provide mild clinical benefit. Intravenous corticosteroids have been reported to emergently lower intracranial pressure in severe cases (52) but are commonly associated with side effects, including weight gain, fluid retention, and hyperglycemia. Moreover, the withdrawal of corticosteroids induces idiopathic intracranial hypertension in some cases. For these reasons, their use as a treatment for idiopathic intracranial hypertension should be avoided (29).

Surgical treatment. In cases of rapidly declining vision (such as in fulminant idiopathic intracranial hypertension) or progressive visual loss despite maximum medical intervention for papilledema, surgical treatments are often warranted. Options include optic nerve sheath fenestration, cerebrospinal shunting, and dural venous sinus stenting. Clinical or randomized trials experience and many uncontrolled studies support their efficacy, but rigorous studies directly comparing these surgical procedures are lacking, and data regarding visual outcomes are limited.

Optic nerve sheath fenestration can be an effective surgical treatment for patients with high-grade papilledema and progressive visual loss from intracranial hypertension, particularly when significant headaches are not present. Two proposed mechanisms of action for optic nerve sheath fenestration are decompression of cerebrospinal fluid from the optic nerve sheath and compartmentalization of the subarachnoid space, investing the optic nerve head with fibrous scar (24).

An analysis of a nationwide database demonstrates a rapid increase in the utilization of cerebrospinal fluid shunting procedures for idiopathic intracranial hypertension between 1988 and 2002 (16). A chart review study using the Nationwide Inpatient Sample from 2002 to 2009 reported data in favor of ventriculoperitoneal shunts over lumboperitoneal shunts (59). Ventriculoperitoneal shunts had lower revision rates (3.9% vs. 7.0%), shorter hospital stays (3 vs. 4 days), and less summed charges than lumboperitoneal shunts.

Compression of the transverse sinus appearing as venous stenosis is frequently found in patients with idiopathic intracranial hypertension (72). Venous sinus stenting was first used to treat idiopathic intracranial hypertension in 2022 and has been increasing in popularity due to good responses in many patients (38). A study examined adult patients with idiopathic intracranial hypertension who underwent surgical treatments using data from the 2016 to 2020 National Inpatient Sample databases (45). The findings showed a significant 80% annual increase in venous sinus stenting procedures (p < 0.001), whereas the numbers of cerebrospinal fluid shunts and optic nerve sheath fenestration procedures decreased by 19% and 54% per year, respectively (both p < 0.001).

The largest systematic review of the efficacy, complication profile, and failure rate of surgical options for idiopathic intracranial hypertension was reported in 2021 (42). A total of 109 controlled or observational studies were analyzed, including venous stenting surgery, shunting, and optic nerve sheath fenestration. Venous stenting surgery provided the best results in terms of improvement in papilledema (87.1%), visual fields (72.7%), and headache (72.1%), with a low rate of severe complications (2.3%) and failure (11.3%). Optic nerve sheath fenestration and venous stenting surgery had comparable efficacy in improving visual field (65.2% vs. 66.8%). Although optic nerve sheath fenestration ameliorated papilledema more than venous stenting surgery (90.5% vs. 78.9%), with a lesser rate of severe complications (2.2% vs. 9.4%) and failure (9.4% vs. 43.4%), it had an inferior headache response compared to shunting (49.3% vs. 69.8%). The author recommended venous stenting surgery as the first-line surgical modality for the treatment of medically refractory idiopathic intracranial hypertension. However, venous stenting surgery required longer follow-up periods and may not be available in some locations.

The pressure gradient across the venous sinus stenosis is typically measured prior to proposed venous stenting surgery. A review of 32 studies (186 patients) suggested that patients with a mean pressure gradient greater than 21 were more likely to benefit from venous stenting surgery than those with gradients of 21 or less (94.2% vs. 82.0%, p = 0.022) (58). The change in pressure gradient following stent placement was found to be an independent predictor of favorable outcome. Significantly higher chances of a positive outcome were observed when the change in gradient after venous stenting surgery was 18 mmHg or greater (97.5% vs. 83.3%, p = 0.0023). Factors associated with a poor prognosis for stenting in venous stenting surgery include younger age (mean age 30 years) and a high opening pressure on lumbar puncture (> 46 mm H2O) (47). Whether or not body mass index can be used as a prognostic factor is controversial. Serious complications of venous stenting surgery include subarachnoid hemorrhage, subdural hematoma, epidural hematoma, venous sinus thrombosis, herniation, and death (67).

Special considerations

Pregnancy

Management of papilledema during pregnancy depends on the underlying cause of the elevation in intracranial pressure. For idiopathic intracranial hypertension, therapeutic lumbar punctures may be used intermittently for exacerbations. Although teratogenic effects have been reported in rodents and rats taking acetazolamide, a study of 101 women in 158 pregnancies who were taking acetazolamide (including 50 women taking the drug within the first trimester) found no adverse pregnancy or fetal outcomes associated with the treatment (49; 23). Hence, acetazolamide has been considered safe for prescription, even in the first trimester, if there is a high risk of vision loss from papilledema.