Grant T. Liu, MD; Nicholas J. Volpe, MD; and Steven. L. Galetta, MD

From the Division of Neuro-ophthalmology, Departments of Neurology and Ophthalmology, Hospital of the University of Pennsylvania, The Children's Hospital of Philadelphia, and Scheie Eye Institute; University of Pennsylvania School of Medicine; Philadelphia, PA

Introduction
Demographics
Associated Conditions
Mechanism
Clinical Features
Neuroimaging
Cerebrospinal Fluid
Management
Treatment: No Visual Loss
Treatment: Mild to Moderate Visual Loss
Treatment: Severe or Progressive Visual Loss Despite Medical Management
Pregnancy
Outcome

Pseudotumor cerebri is an idiopathic disorder characterized by papilledema and elevated intracranial pressure without a mass lesion. Most patients are female and young and are either overweight or have a history of recent weight gain. Other disease states, such as systemic lupus erythematosus, and drugs, such as tetracycline, have also been associated with the development of pseudotumor cerebri. The mechanism is unclear, but is likely related to decreased cerebrospinal fluid resorption.

Almost all patients have headache, but the greatest morbidity of the disorder is visual loss related to optic disc swelling. Common radiographic findings in pseudotumor cerebri include an empty sella, dilation of the optic nerve sheaths, and elevation of the optic disc. The cerebrospinal fluid, aside from elevated opening pressure, is normal without evidence of infection or inflammation.

Treatment of patients with no or mild to moderate visual loss is primarily medical, with acetazolamide as the first line agent. Acetazolamide decreases CSF production. Furosemide and corticosteroids are secondary choices. Optic nerve surgery is reserved for patients with severe visual loss or progression in visual deficits despite medical management.

The treatment of pseudotumor cerebri has evolved from the systematic use of corticosteroids with repeated lumbar punctures to a modern approach based upon the patient's level of visual loss. Patients with no, mild, or moderate visual loss receive medical management, while optic nerve surgery is reserved for those with severe or progressive visual deficits. This review will first discuss the demographic and clinical aspects of this disorder, review its possible mechanisms, then describe the management of patients with pseudotumor cerebri, with an emphasis on the medical options.

Features common to all patients with pseudotumor cerebri are elevated intracranial pressure measured during a lumbar puncture, normal spinal fluid constituents, and neuroimaging which excludes a mass lesion. The diagnosis is formally established when the modified Dandy criteria (1,2) are satisfied (Table 1). The greatest morbidity of the disorder is visual loss related to optic disc swelling.

Table 1. Modified Dandy criteria (1,2) for the diagnosis of pseudotumor cerebri.

1. Signs and symptoms of increased intracranial pressure (headache nausea, vomiting, transient obscurations of vision, papilledema)
2. Normal neurological exam, except for a 6th nerve paresis
3. Elevated cerebrospinal fluid pressure (>250 mm H2O) with normal constituents
4. Modern neuroimaging (computerized tomography (CT), with and without contrast, or magnetic resonance imaging (MRI), demonstrating normal to small symmetrical ventricles and excluding a mass lesion or other cause of raised intracranial pressure

Historically, another term used for this disorder included "otitic hydrocephalus," because many cases in the pre-antibiotic era were associated with mastoiditis and venous thrombosis. Foley (3) coined the term "benign intracranial hypertension," which was also advocated by Weisberg (4) and even used by more recent authors (5-7). This designation should be eschewed, however, because the condition may be associated with severe debilitating visual loss in as many as 25% of patients (8,9), and therefore it is not always "benign." Instead, experts today advocate the use of the more accurate term "idiopathic intracranial hypertension" (2,10). However we have found "pseudotumor cerebri" or "pseudotumor" more descriptive and easier for patients (and many physicians) to remember. Furthermore, the term "pseudotumor cerebri" is applicable in situations in which a cause is identified (i.e. not idiopathic).

In cases which are idiopathic, the patients are almost uniformly females in early adulthood and are overweight or have a history of recent weight gain. In three large series, approximately 90% were women and the mean age was 27.8-32.9 years (2,8,11). The approximate annual incidence of pseudotumor cerebri is 0.9-1.7/100,000 in the general population (12-14). However, among females 15-44 years of age, the incidence is 3.3-12.0/100,000, and among obese females in this age group, the incidence climbs to 7.9-21.4/100,000 (12-14). Case control studies (11,15) confirm that obesity and recent weight gain are more common among patients with pseudotumor cerebri than among controls. It is uncertain whether there is a racial predilection for this disorder, as the racial distribution in each reported series reflects the makeup of the local population. When men develop pseudotumor cerebri, they tend to be in a similar age distribution as affected women, they are also usually obese, and their signs and symptoms are no different than in women (16).

Although pseudotumor cerebri occurs more frequently in adults, its occurence in pediatric patients, even infants and young children, is not uncommon (16). Several large series have been reported (17-23), and in contrast to the female predominance among adults, males comprise 39-53% of pediatric patients with pseudotumor cerebri. Affected adolescents tend to be overweight, but obesity and weight gain do no appear to be risk factors in patients under 10 years of age (24). Unfortunately, children are not immune from the severe visual loss which may affect adults (9,18).

The literature is replete with several disease and drug associations, but many cases must be reviewed skeptically because they fail to satisfy the modified Dandy criteria. For instance, steroid withdrawal (not steroid use) is a well-recognized, but infrequently well-documented, risk factor (25), most commonly occuring in children on chronic corticosteroids for respiratory, renal or dermatologic disorders (9,21,26). Several authors incorrectly diagnosed pseudotumor cerebri, as their patients had abnormal neurologic findings including decreased mental status, ataxia, hemiparesis, third-nerve palsy, asymmetric reflexes, and extensor plantar responses (19,27-29). Other reported patients lacked either CSF examinations or adequate neuroradiologic studies (22,30-32).

Pregnancy, menstrual irregularities, antibiotic and oral contraceptive use, and iron deficiency anemia (33-36) have been purported risk factors, but case control studies found their incidences to be similar among patients with pseudotumor cerebri compared with controls (11,15). Digre et al. (37) compared pregnant patients with pseudotumor cerebri and those without, and they found that those with pseudotumor tended to be obese. Gardner et al. (38) reviewed the literature regarding the relationship between pseudotumor and tetracycline, and its synthetic relative, minocycline. A true association was suggested in many affected patients who improved following removal of the drug and recurrence in some who then restarted the medication. The authors also suggested a combination of other factors, including genetic susceptibility. Patients with acne often use tetracycline and vitamin A or an analog, isotretinoin, and this combination may increase the risk for pseudotumor cerebri (39).

The cause of pseudotumor cerebri is unclear, but any explanation must account for elevated intracranial pressure with normal neuroimaging (without hydrocephalus), CSF constituents, and neurological examinations. Decreased CSF absorption by the arachnoid villi is the most likely explanation suggested by radioisotope cisternography and other observations (40-43). However, it is possible that decreased CSF absorption is a secondary phenomena, resulting from compression of the arachnoid villi by elevated intracranial pressure from any cause (44).

Abnormal CSF pressure gradients caused by increased intracranial venous pressure may also account for decreased absorption (5). King et al. (45) performed cerebral venography and manometry in patients with pseudotumor cerebri, and they found consistently elevated venous pressures due in many cases to mural thrombi within the lateral transverse sinuses. Karahalios et al. (46), also using venography in patients with pseudotumor cerebri, discovered that in those with normal dural venous anatomy, right atrial pressures were elevated and transmitted up to the intracranial venous sinuses. They suggested elevated venous pressure as a universal mechanism for pseudotumor cerebri, even in patients without demonstrable venous outflow obstruction.

Elevated brain volume secondary to cerebral edema or increased cerebral blood volume also has been proposed (47-49), but the histologic evidence is less supportive. Sahs and Joynt (50) reported on brain biopsy results following subtemporal decompression, and they found intracellular and extracellular edema in several patients. Studies using MR-imaging of brain water self-diffusion also suggested increased water mobility caused interstitial and intracellular fluid accumulation (51,52). However Greer found one autopsied brain and two brain biopsies to be normal (53). Recent pathologic studies by Wall et al. (54) failed to reveal cerebral edema in two patients, although the autopsies were performed 1-2.5 years after presentation. Wall et al. (54) also reviewed three of the biopsies reported by Sahs and Joynt (50) and the authors found no convincing evidence of cerebral edema. Increased rate of CSF formation is also unlikely (55,56), as choroid plexus papillomas tend to cause hydrocephalus

The association between pseudotumor cerebri and female gender and obesity suggests an endocrine basis for the disorder (53). Reports of pseudotumor cerebri occurring in corticosteroid-deficient states such as Addison's disease (57,58), adrenocorticotropic hormone (ACTH) deficiency (59), and following removal of an ACTH-secreting pituitary adenoma (60,61), implies an abnormality in the adrenal-pituitary axis. Furthermore, corticosteroids in many instances effectively treat pseudotumor cerebri (2), and corticosteroid withdrawal is associated with pseudotumor cerebri (25), suggesting that corticosteroids have an effect on CSF dynamics. However, Soelberg Sørensen et al. (62) screened a series of patients with pseudotumor cerebri and found no consistent abnormality in pituitary, gonadal, thyroid, or adrenal function.

In summary, the mechanism is likely to be decreased CSF absorption due either to dysfunction at the level of the arachnoid villi or to elevated intracranial venous pressures. The association of pseudotumor cerebri and so many other conditions suggests that these purported mechanisms may be the final common pathway, but the inciting factors may be multiple.

The frequency of presenting symptoms is likely underestimated in the various retrospective series (3,4,8,63-65), and the best data comes from a prospective study by Wall and George (66). Headache was the most common complaint, occurring in 94% of patients in their study. Many had related neck stiffness or retrobulbar pain, the latter sometimes exacerbated by eye movements. Seventy-two percent reported transient visual obscurations (TVO's). Photopsias (54%), diplopia (38%) and visual loss (26%) were less frequent ophthalmic complaints. Sixty percent of patients complained of a pulsatile intracranial noise, characterized either by a "whooshing" noise (internal auditory bruit) or tinnitus. The cause is likely increased turbulent blood flow through the venous sinuses. Mentation and level of alertness was normal in all patients.

When it occurs, visual loss is typically insidious, and most patients are unaware of minor deficits because central vision is usually spared. Severe loss of visual acuity in pseudotumor cerebri is unusual. Visual field testing (67) is the most sensitive method for detecting visual loss in these patients, and the most common abnormalities are blind spot enlargement, generalized constriction of isopters, and inferior nasal field loss (2). Visual acuity, color vision, and pupillary reactivity are typically normal in these patients. Sixth nerve palsies occur in just a minority (approximately one-fifth) (66). Most patients have papilledema, which can be asymmetric and rarely unilateral.

Although either is acceptable, MRI of the brain without gadolinium is preferred over CT scanning with contrast to exclude hydrocephalus or any cause of elevated intracranial pressure such as a mass lesion, venous sinus thrombosis, or dural arteriovenous malformation. Common radiographic findings in pseudotumor cerebri include an empty sella, dilation of the optic nerve sheaths (68), and elevation of the optic disc (69). The empty sella is thought to result from chronically elevated intracranial pressure associated with a congentally incompetent diaphragma sella (70,71). Many patients will have "slit-like" ventricles (72), but in at least two more recent studies (69,73), age-matched controls had similar ventricular sizes. Some studies (74) have suggested sulci effacement on CT scanning is a helpful radiologic sign, but we have found this to be an inconsistent feature.

Following normal neuroimaging, a lumbar puncture (LP) is necessary to rule out meningitis, e.g., and to document the CSF opening pressure. To establish the diagnosis of pseudotumor cerebri, the CSF opening pressure should exceed 250 mm H20, the upper limit of normal for most obese and non-obese adults (75). The cell count and glucose should be normal, and the protein normal or low. Many patients will enjoy relief of their headache after the first LP. Serial LP's, either to withdraw more fluid or follow the CSF pressures, have limited role in the management of this disorder (see below) (76).

While the diagnosis requires a neurologist, the management of patient with pseudotumor cerebri also requires the skills of an ophthalmologist or neuro-ophthalmologist (10). The initial evaluation of a patient with suspected pseudotumor cerebri should include complete ophthalmic and neurologic examinations and computerized visual field testing. The MRI and LP, in that order, should then be performed. All non-pregnant obese patients are strongly encouraged to lose weight, and often they are referred to a nutritionist. Improvement in pseudotumor cerebri has been documented anectodally following a rice/reduction diet (77) and gastric bypass surgery (78). Potentially inciting risk factors, such as systemic lupus erythematosus or Addison's disease, should be treated, and offending medications such as tetracycline or vitamin A should be discontinued.

Immediate treatment of the elevated intracranial pressure per se is unneccessary. In contrast to patients with large cerebral neoplasms, hydrocephalus, and intracranial hemorrhages, patients with pseudotumor cerebri do not have alteration in consciousness and in general are not at risk for uncal or downward herniation. There is no need for emergent intraventricular, subarachnoid, or epidural monitoring or catheterization. Hyperventilation or urgent therapy with hyperosmolar agents are also unneccessary.

Treatment modalities which are no longer routinely recommended include subtemporal decompression, chronic corticosteroids, and serial lumbar punctures. The role of subtemporal or suboccipital cranial decompression (removing part of the skull to relieve elevated intracranial pressure), because of severe side effects such as subdural hematomas and seizures, is now of historical interest only (79). Chronic steroid treatment is complicated by elevated intraocular pressures, weight gain, and difficulty weaning off the medication (8).

In addition, following intracranial pressures with repeated lumbar punctures is unnecessary, impractical, invasive, and punitive (10). They are poorly tolerated, and serial lumbar punctures are ineffective as a long-term treatment (76). It is impossible for serial LP's alone to removed enough fluid to relieve elevated intracranial pressure, as CSF is produced at a rate of 0.35mL/min, allowing the entire CSF circulation to be replenished in just 2 hours (44). In fact, we believe most cases require just one (the first) spinal tap, which is both diagnostic and sometimes therapeutic, without the need of repeating the procedure. Its longlasting effects are likely due to a persistent CSF leak at the LP site, or decompression of the arachnoid villi, allowing improved CSF absorption (44).

Corbett and Thompson have emphasized that the modern management of pseudotumor cerebri should be based upon the level of visual loss, as additional therapeutic strategies should be guided by visual fields and visual acuity. Most treatment regimens have been advocated based upon the results of retrospective chart reviews, and unfortunately to date none has been studied prospectively in a controlled fashion.

Treatment - no visual loss. Patients with no visual loss, headache, or other symptoms can be observed. Those with headache may be treated with medications commonly used for vascular headaches such as acetaminophen, nonsteroidal anti-inflammatory agents, tricyclic antidepressants, or beta-blockers, for instance (but not steroids). Acetazolamide (Diamox, see below) may be used in these instances as well but may not be necessary.

Treatment - mild to moderate visual loss. Most patients with pseudotumor cerebri fall into this group, and for the most part they are treated medically. Visual deficits include enlarged blind spots, arcuate defects, mild peripheral constriction, and visual acuity is 20/30 or better.

Acetazolamide is the first line medication in these instances. Active CSF secretion in the choroid plexus is mediated by a Na+-K+-ATPase pump, which depends upon the presence of hydrogen ions supplied by the carbonic anhydrase mediated reaction:

H2O + CO2 <-> H2CO3- + H+

Acetazolamide is a carbonic anhydrase inhibitor with a proven ability to decreases CSF production (80). The diuretic effect is only mild. The drug has a half life of 6-9 hours and is excreted by the kidneys (81).

Its efficacy in pseudotumor cerebri has been documented anecdotally (82-85) but has not been proven in any prospective trial. We prefer acetazolamide 500 mg sequels, orally two or three times per day, as a starting dose, and will increase the total dosage to 3 grams if necessary. Sequels are better tolerated than tablets (86). Acetazolamide's major side effects include paresthesias of the lips, fingers, and toes (which most patients tolerate), nausea, vomiting, malaise, sedation, renal calculi, metabolic acidosis, and rarely, aplastic anemia (44). The dose can be lowered in individuals not tolerating the drug (86). The drug should not be given to those with sulfa allergies because of cross reactivity. Most individuals with mild to moderate visual loss will do extremely well with acetazolamide, with resolution of the field defects and papilledema within three to six months, after which the medication can be tapered.

When acetazolamide is not tolerated, we switch the patient to furosemide (orally, 20-100 mg) and monitor the potassium carefully. Although a potent loop diuretic, furosemide likely lowers intracranial pressure by decreasing CSF production (80). Major side effects of furosemide include hyponatremia, hypokalemia, hypomagnesemia, hypocalcemia, and ototoxicity (81).

Other diuretics, such as thiazides and ethacrynic acid, have been used by others (87), but are not as popular as furosemide. There is little clinical experience with methazolamide, another carbonic anhydrase inhibitor used commonly in the treatment of glaucoma, in pseudotumor cerebri.

We rarely use digoxin or glycerol in these cases, but they have been reported alternatives (87). Digoxin likely decreases CSF production by inhibiting the Na+-K+-ATPase pump mentioned previously (88). However, the use of digoxin has not been widely studied in patients with pseudotumor. Several anecdotal reports have described the effectiveness of glycerol, a hyperosmolar agent, in pseudotumor cerebri (89). Disadvantages to the use of glycerol include a four to six times per day regimen and the production of nausea.

Treatment - severe or progressive visual loss despite medical management. Optic nerve sheath fenestration surgery is the primary option for these patients, which fortunately make up only a minority of those with pseudotumor cerebri. Other indications for optic nerve surgery are severe visual loss at presentation, inability to comply with medications, poor followup, or inability to cooperate with visual field testing (10). During this procedure, windows or slits are created through the dura and arachnoid surrounding the optic nerve, allowing CSF egress, local relief of CSF pressure, and improvement in papilledema.

Optic nerve sheath decompression is more effective in reversing visual loss due to acute papilledema, in contrast to that due to chronic disc swelling (88). In the long term, vision stabilizes or improves in the majority, but as many as 32% of operated eyes may experience deterioration following initially successful surgery (90). A reoperation can be performed (91), but we prefer lumboperitoneal shunting in these instances.

If the severe visual loss is sudden, if central visual loss is caused by macular edema, or if optic nerve sheath fenestration is not immediately available, then high-dose IV steroids combined with acetazolamide is another treatment option (92). Intravenous methylprednisolone, 250 mg four times per day for 5 days can be given in combination with acetazolamide sequels 500 mg three times per day and ranitadine. Lack of immediate improvement is an indication for optic nerve sheath decompression. The IV steroids are followed by 80 mg prednisone orally, tapered over four to eight weeks in order to avoid the side effects of chronic use, and the acetazolamide is continued until the disc swelling resolves. How steroids lower intracranial pressure is unclear, but increasing CSF outflow at the arachnoid granulations is one proposed mechanism, and decreasing cerebral edema, although less likely, is another (93).

We reserve lumboperitoneal shunting for patients in whom headache is the major problem or in whom visual loss progresses despite optic nerve sheath fenestration (94). Although lumboperitoneal shunting is effective in treating visual loss (95), shunt failure and low pressure headaches are common enough in our opinion not to make it a first-line therapy (93). Sometimes within the same patient, shunts fail several times, requiring multiple shunt revisions. Relatively small or normal ventricle sizes make ventriculoperitoneal shunting difficult.

Women who are pregnant and develop pseudotumor cerebri can be treated similarly to non-pregnant patients except for the following three caveats: 1) because of a single case report of a sacrococcygeal teratoma in an infant following the mother's use of acetazolamide in the first trimester, the drug should be reserved for use only in the last two trimesters; 2) stronger diuretics should not be used; and 3) weight reduction should not be recommended (37,44). Therapeutic abortions are unnecessary.

In our experience, most patients with mild to moderate visual loss tend to recover vision following medical therapy. Papilledema usually resolves completely over weeks or months, but many patients are left with some residual disc elevation, especially nasally. Some patients exhibit macular pigment epithelial changes if lipid deposition or edema had been present, while others have circumferential "high-water" marks delineating the prior extent of peripapillary retinal elevation associated with disc swelling.

Among those with severe visual loss requiring surgery, residual acuity and field deficits are not uncommon and are occasionally debilitating (8,9). In Wall and George's series (66), approximately 3% of eyes had visual acuity worse than 20/100. Rarely cases act in a malignant fashion and seem recalcitrant to medications, optic nerve sheath fenestration, and lumboperitoneal shunting. In one series (8), 8% of patients had return of symptoms, while in another (64), 37% experienced recurrence. In addition to the aforementioned residual fundus changes, most patients in this group are left with some degree of optic atrophy.

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