Introduction. Clinical manifestations

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1 Pseudotumor cerebri syndrome Deborah I Friedman MD MPH (Dr. Friedman of the University of Texas Southwestern Medical Center has no relevant financial relationships to disclose.) Jonathan D Trobe MD, editor. (Dr. Trobe of the University of Michigan has no relevant financial relationships to disclose.) Originally released March 30, 1994; last updated February 15, 2016; expires February 15, 2019 Introduction This article includes discussion of pseudotumor cerebri syndrome, benign intracranial hypertension, pseudotumor cerebri. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations. Overview Pseudotumor cerebri syndrome continues to be a diagnostic and therapeutic challenge, and the incidence is rising as obesity becomes more prevalent. The author updates the clinical features of pseudotumor cerebri syndrome in adults and children, secondary causes, current therapies, and the role of cerebral venous sinus disease. Key points Headaches, transient obscurations of vision, and pulsatile tinnitus are the most frequent early manifestations of pseudotumor cerebri syndrome in adults. Obese women of childbearing age are most commonly affected by idiopathic intracranial hypertension, but the syndrome may occur from a secondary cause in children, nonobese patients, and those over 45 years of age. The manifestations of pseudotumor cerebri syndrome in children differ from those in adults and include prominent neck or back pain, diplopia, torticollis, other focal neurologic signs, headache, visual loss, and asymptomatic papilledema. Visual acuity reduction at presentation is an ominous sign, requiring aggressive intervention. A team approach to management is ideal, and a team leader (generally a neurologist or neuro-ophthalmologist) is critical. The Idiopathic Intracranial Hypertension Treatment Trial provides evidence-based therapy for patients who have mild visual loss. Historical note and terminology In 1897, Quincke described a syndrome of elevated intracranial pressure and bilateral papilledema due to impaired cerebrospinal fluid circulation. Seven years later, Nonne recognized that this group of conditions mimicked an intracranial tumor and named them "pseudotumor cerebri." In 1937, Dandy suggested that pseudotumor cerebri resulted from increased cerebral blood volume. In 1955, Foley popularized the term "benign intracranial hypertension." Recognition of the complication of visual loss by Corbett in the 1980s resulted in substitution of the descriptor "idiopathic" for "benign." The diagnostic criteria were updated in 2002 to reflect advances in neuroimaging techniques and to incorporate atypical presentations (Friedman and Jacobson 2002). Revised criteria in 2013 defined the diagnosis of pseudotumor cerebri syndrome in adults and children, including criteria for those in whom papilledema is absent (Friedman et al 2013). Idiopathic intracranial hypertension is the term applied when no secondary cause is found, generally in obese women of childbearing age. Clinical manifestations Presentation and course

2 Required for diagnosis of pseudotumor cerebri syndrome: (A) Papilledema. (B) Normal neurologic examination, except for cranial nerve abnormalities. (C) Neuroimaging. For obese women, normal brain parenchyma without evidence of hydrocephalus, mass, or structural lesion, and no abnormal meningeal enhancement on magnetic resonance imaging (MRI) with and without gadolinium; for other patients, MRI criteria listed for obese women, together with magnetic resonance venography (MRV). If MRI is unavailable or contraindicated, contrast-enhanced computed tomography may be substituted. (D) Normal cerebrospinal fluid (CSF) composition. (E) Elevated lumbar puncture opening pressure [>250 mm of CSF fluid in adults and >280 mm of CSF in children (250 mm of CSF if the child is not sedated and not obese)] in a properly performed lumbar puncture. Patients meeting criteria A through D above whose CSF pressure is below the limit specified in criterion E have probable pseudotumor cerebri syndrome. If papilledema is not present, the diagnosis of pseudotumor cerebri should not be made unless all imaging criteria listed above are met and the patient has sixth nerve palsy or at least 3 of the following features: (1) Empty sella. (2) Distention of the perioptic subarachnoid space with or without a tortuous optic nerve. (3) Flattening of the posterior sclerae. (4) Transverse venous sinus stenosis. Idiopathic intracranial hypertension should be differentiated from intracranial hypertension without ventriculomegaly from an identifiable cause. Causes of secondary intracranial hypertension include a variety of medications, cerebral venous sinus thrombosis, cerebral arteriovenous fistula, spinal cord tumors, gliomatosis cerebri, and other conditions. Clinical features of idiopathic and secondary intracranial hypertension may be identical. However, because the treatment of secondary forms may be different, it is extremely important to investigate for secondary causes before concluding that the intracranial hypertension is idiopathic. In this article, the term pseudotumor cerebri syndrome is used to describe aspects of both forms, unless otherwise specified. Most patients with idiopathic intracranial hypertension are obese females. Patients with pseudotumor cerebri syndrome and a normal body mass index (BMI) are likely to have a secondary cause (ie, medication-induced) of intracranial hypertension (Bruce 2010). Headache is present in 85% to 90% of patients and is the initial manifestation in most patients. The headache phenotype is variable but is usually characterized as severe, daily, and pulsatile, and it is often accompanied by migrainous associated features such as photophobia, phonophobia, and nausea (Mallery et al 2014). Visual signs and symptoms are frequent. Transient visual obscurities occur in three fourths of patients who describe blurring or complete loss of vision lasting from seconds to minutes. Papilledema is the hallmark of the disorder and is present in almost all patients with pseudotumor cerebri syndrome. In one fourth of patients, sixth nerve palsy is present as a nonlocalizing sign of increased intracranial pressure. Signs of optic disc swelling include elevation of the disc margins, a peripapillary halo, venous congestion and tortuosity, retinal exudates, nerve fiber layer hemorrhages, and retinal infarcts (also known as cotton wool spots ). Extension of the disc swelling into the retina may produce choroidal folds and macular edema. Nonvisual symptoms include back and shoulder pain, weakness, numbness, and pulsatile tinnitus; pulsatile tinnitus, when present, is highly suggestive of this disorder. Some patients are asymptomatic and are diagnosed when papilledema is discovered on a routine ophthalmic examination (Galvin and Van Stavern 2004). Idiopathic intracranial hypertension occurring after 44 years of age is uncommon. Obesity, female predominance, and headache are less common in this population (Bandyopadhyay and Jacobson 2002; Bruce et al 2010). Although papilledema at the time of diagnosis is typical of pseudotumor cerebri syndrome, the disc edema may be asymmetrical or, rarely, absent. A variant of idiopathic intracranial hypertension without papilledema may be considered in patients with a chronic daily headache that does not respond to standard headache therapy (Wang et al 1998). However, unless a sixth nerve palsy is present, neuroimaging evidence of increased intracranial pressure is required to suggest the diagnosis (Bono et al 2008; Friedman et al 2013). Medication overuse headache must be

3 excluded. Compartmentalization of the subarachnoid space of the optic nerves with impeding bidirectional CSF flow from the brain may explain this finding (Killer et al 2007). Alternatively, the patient may have had mild papilledema months to years prior that subsequently resolved. The entity of idiopathic intracranial hypertension without papilledema, manifested as chronic headache, is uncommon and not well defined. A prospective study in 62 patients with chronic migraine from a headache center found elevated CSF pressure in 6 patients, 5 of whom were obese (BMI over 25) (Vieira et al 2008). It is estimated to account for approximately 5% of patients with idiopathic intracranial hypertension seen in neuro-ophthalmologic practice (Digre et al 2009). Compared to patients with papilledema, patients tend to be diagnosed later in their course, have higher rates of nonorganic visual loss, and respond less favorably to medical therapy for idiopathic intracranial hypertension (Digre et al 2009). Pseudotumor cerebri syndrome in infants and young children produces a different constellation of signs and symptoms. Vomiting, lethargy, stiff neck, and focal neurologic deficits may be prominent. Strabismus from sixth nerve palsy is a common presenting sign (Ko and Liu 2010). An open fontanelle in infants may preclude the development of papilledema. In contrast to adults with idiopathic intracranial hypertension, the gender ratio in prepubescent children is nearly equal, and obesity is less likely to be present (Rangwala and Liu 2007). Behavioral changes, including disrupted attention and concentration, may be an early sign in school-age children and generally remit with treatment (Parness-Yossifon et al 2008). Prognosis and complications The most frequently reported complication of pseudotumor cerebri syndrome is visual loss. The incidence of visual loss in idiopathic intracranial hypertension cannot be estimated with any certainty due to the lack of prospective studies. Permanent visual field loss (excluding blind spot enlargement) occurs in approximately 25% to 30% of patients (Corbett et al 1982). Visual acuity loss occurs in approximately 10% of patients with severe or complete loss in 7% (Corbett et al 1982). However, with scanning laser polarimetry, retinal ganglion cell axon loss may be detected in patients after regression of their papilledema even in the absence of optic disc pallor (Laemmer et al 2010). Patients with the pseudotumor cerebri syndrome caused by cerebral venous thrombosis may deteriorate rapidly with a poor visual outcome. Systemic hypertension, renal failure, and increased intraocular pressure are associated with a poor visual prognosis (Digre and Corbett 2002). Functional visual loss in patients with pseudotumor cerebri syndrome presents an additional management challenge to avoid unnecessary surgical intervention (Ney et al 2009). Many patients will continue to have headaches despite optimal treatment of their intracranial pressure (Friedman and Rausch 2002). The Idiopathic Intracranial Hypertension Treatment Trial, which studied patients with mild visual loss, is discussed in detail in section 14. With a supervised weight loss diet, acetazolamide was superior to placebo in improving perimetric mean deviation, papilledema grade, vision-related quality of life, and a reduction in weight. Risk factors for the 7 participants who met criteria for treatment failure in the study were male sex, high-grade papilledema at baseline, and decreased visual acuity at baseline (Wall et al 2015). The Idiopathic Intracranial Hypertension Treatment Trial assessed vision-specific and general quality of life at study entry and at 6 months (Digre et al 2015). In this cohort of patients with mild visual loss, reductions in vision-specific quality of life at baseline were comparable to those of patients with multiple sclerosis and a history of optic neuritis. Quality of life was impaired even prior to the initiation of medical treatment. Headache was a significant contributor to reduced quality of life, in addition to visual acuity, perimetric mean deviation, diplopia, and transient visual obscurations. Greater improvements in quality of life assessments at 6 months occurred in the group receiving active treatment with acetazolamide. A small percentage of patients have a fulminant course of idiopathic intracranial hypertension (Thambisetty et al 2007). Symptoms develop rapidly with an early rapid decline in vision. Aggressive intervention is required to preserve vision, although some patients are refractory to treatment. Adolescent females with idiopathic intracranial hypertension may be at higher risk of permanent visual loss than adults and young children (Stiebel-Kalish et al 2006). A retrospective study of 450 patients in the United States found that African Americans were more likely than those of other ethnic groups to have severe visual loss in at least 1 eye (Bruce et al 2008). There are few long-term data regarding the prognosis of idiopathic intracranial pressure. One report of 20 patients followed for over 10 years at a neuroophthalmology clinic found that 11 patients had a stable course without worsening, and 9 patients had worsening after a stable course. Six of the 9 patients worsened between 28 and 135

4 months after their initial presentation and had recurrent papilledema 12 to 78 months after their initial remission (Shah et al 2008). Weight gain may provoke a recurrence (Ko 2011). Although idiopathic intracranial hypertension may be a chronic disorder in some patients, these findings are likely influenced by ascertainment and referral bias, as patients who are doing well are less apt to return for follow-up visits. Most children with idiopathic intracranial hypertension have a favorable clinical outcome, although one study showed an overall recurrence rate of 23.7% (Soiberman et al 2011). Most recurrences occurred within 18 months of diagnosis, and no specific risk factors for recurrence or predictors of outcome were identified in this cohort. Clinical vignette A 12-year-old girl developed headaches that were intermittent and periocular. They were throbbing and pressure-like with dizziness, phonophobia, nausea, and vomiting. There was no photophobia or osmophobia. The pain worsened with routine activity, and she missed 6 days of school. She heard intracranial noises like air rushing through my head that were pulse-synchronous. One week later, she had double vision. A CT scan of the brain was normal, and she was treated with amoxicillin and decongestants for a presumed sinus infection. When she developed a noticeable esotropia, she came to the emergency department where a lumbar puncture revealed a high CSF pressure and normal CSF contents. Examination showed normal visual acuity, bilateral blind spot enlargement, and bilateral grade 3 optic disc edema. The patient had taken minocycline for acne for 6 months, which was discontinued. Acetazolamide was prescribed. The diplopia resolved shortly after the lumbar puncture, and she was asymptomatic with normal optic nerves within 1 month. This case illustrates several important aspects of diagnosis and management. The patient had secondary pseudotumor cerebri syndrome, and her symptoms were identical to those of the idiopathic form. The patient was appropriately treated with acetazolamide in addition to stopping the minocycline. Biological basis Etiology and pathogenesis The cause of idiopathic intracranial hypertension is being investigated in the Idiopathic Intracranial Hypertension Treatment Trial. Case-controlled studies show that only obesity, female gender, and recent weight gain are significantly more common in adults with idiopathic intracranial hypertension than in controls. These studies found no association between the disorder and menstrual irregularity, pregnancy, endocrinopathies, oral contraceptives, corticosteroids, antibiotics, vitamins, and other medications (Ireland et al 1990). Nonetheless, case reports implicate a variety of medications, vitamin A, and diseases including renal failure, vitamin D-dependent rickets, and HIV infection (Digre and Corbett 2002; Noel et al 2012). Medications associated with pseudotumor cerebri syndrome are antibiotics (ofloxacin, tetracycline and related compounds, trimethoprim-sulfamethoxazole, nalidixic acid, nitrofurantoin), vitamins (retinoids, vitamin A, isotretinoin), psychotropics (lithium), miscellaneous medications (cyclosporine, benzene hexachloride, indomethacin), and endocrine medications (beta-human chorionic gonadotropin hormone, growth hormone, thyroid hormone, synthetic LH-RH, anabolic steroids, and corticosteroids) (Digre 2002; Friedman 2005). There is no compelling evidence implicating either implantable or oral contraceptives as a cause. Medication-induced intracranial hypertension is frequently identified in children (Ko and Liu 2010). Secondary intracranial hypertension in adults may result from impairment of cranial venous outflow and subsequent venous hypertension. Chronic ear disease, head injury, intracranial arteriovenous fistulas, meningeal tumors, surgical ligation of extracranial veins, cardiac failure, chronic respiratory disease, and jugular paragangliomas can all contribute to cranial venous outflow obstruction (Johnston et al 1991). Transverse sinus stenosis has been described and is most commonly a result of increased intracranial pressure rather than the cause of it. In most cases, the venous sinus stenosis resolves when the intracranial pressure is lowered by lumbar puncture or shunting procedure. However, direct retrograde cerebral venography and manometry occasionally demonstrate morphological and functional venous outflow obstruction. The presence of ophthalmoparesis, other than sixth nerve palsy, should prompt the search for venous sinus thrombosis or a hypercoagulable state (Friedman et al 1998). Case control studies have not been performed in the pediatric population to identify those conditions associated with secondary intracranial hypertension. Case reports suggest a link to parameningeal infections, endocrinopathies, Lyme disease, vitamin A usage, human growth hormone, Down syndrome, venous sinus thrombosis from mastoiditis, otitis

5 media, obesity in adolescents (but not in preadolescents), endocrine disorders (such as hypoparathyroidism), medications, and malnutrition (Digre and Corbett 2002; Ko and Liu 2010; Brara et al 2012). Nonetheless, even when a potential inciting exposure is identified, obesity should be considered in all children with pseudotumor cerebri syndrome. A study of 60 children with secondary pseudotumor cerebri found no difference in body mass index compared to children with primary (idiopathic) pseudotumor cerebri, with 79% being overweight or obese (Paley et al 2015). The pathophysiology of idiopathic intracranial hypertension is unknown (McGeeney and Friedman 2014). Pathological evidence of extracellular brain edema has been refuted (Wall et al 1995). Occult venous sinus thrombosis may be present in patients with otherwise typical idiopathic intracranial hypertension, suggesting a vascular etiology (Cremer et al 1996; Karahalios et al 1996). The lack of ventriculomegaly may be attributed to cerebral venous hypertension (King et al 2002). Any condition that decreases flow through the arachnoid granulations or obstructs the venous pathway from the arachnoid granulations to the right heart may elevate intracranial pressure without producing ventriculomegaly. Considerable attention has been focused on abnormalities in cerebrospinal fluid absorption at the level of the arachnoid villi, resulting from increased resistance to drainage across the arachnoid membrane. However, evidence suggests that the extracranial lymphatics, rather than the arachnoid villi, may be the primary site of CSF absorption (Johnston et al 2004). Changes in B cell-mediated immunity were identified in the spinal fluid in a small series of patients; the significance of these changes is uncertain (Da et al 2004). Cytokine antibody arrays and ELISA assessment showed significant elevations of CSF chemokine CCL2 in idiopathic intracranial hypertension patients compared to controls, but there was no difference in leptin levels between the groups (Dhungana et al 2009). Other investigators have found elevated CSF leptin levels in idiopathic intracranial hypertension patients, but serum leptin levels appear to be similar when controlled for body weight (Ball et al 2009). Natriuretic pro-peptide levels in the CSF of idiopathic intracranial hypertension patients are similar to those in control subjects although plasma pro-b-type natriuretic peptide (BNP) levels are lower in patients with idiopathic intracranial hypertension than in control subjects; plasma concentrations of BNP are inversely associated with body mass index and may increase during weight loss (Skau 2010). Aquaporin-4 gene variants do not appear to be associated with idiopathic intracranial hypertension (Kerty et al 2013). Obstructive sleep apnea and pseudotumor cerebri syndrome may coexist, and apneic episodes have been linked to a rise in intracranial pressure. A case- control study of men with idiopathic intracranial hypertension found that obstructive sleep apnea and symptoms associated with testosterone deficiency were more common in patients than in controls (Fraser et al 2010). Polycystic ovary syndrome, also associated with marked obesity and thrombophilia, may be associated with intracranial hypertension (Glueck et al 2003). Familial intracranial hypertension may occur in up to 10% of patients. It is most often associated with obesity and suggests a dominant inheritance, but no genetic defect has been identified (Corbett 2008). Epidemiology" Several epidemiologic studies found an average annual age-adjusted incidence rate of 0.9 per 100,000 for the total population, with a rate of 3.3 per 100,000 for females aged 15 to 44 years. Obesity (20% above ideal body weight) increased the incidence rate to approximately 19 per 100,000 in women ages 20 to 44 years. The female-to-male ratio was 8 to 1 (Durcan et al 1988; Kesler and Gadoth 2001). The mean age at time of diagnosis was 30 years. The incidence of idiopathic intracranial hypertension seems to reflect the prevalence of obesity in the population. There is evidence that the incidence of idiopathic intracranial hypertension in the United States has at least doubled since 1990, commensurate with the rising incidence of obesity (Jacobs et al 2004). Similarly, a study from Israel found an overall annual incidence of 2.02 per 100,000 (3.17 per 100,00 for women and 0.85 per 100,00 for men), among whom 83.4% of patients were obese. The incidence rate for women 18 to 45 years of age was 5.49 per 100,000 (Kesler 2014). However, routine screening of morbidly obese individuals for signs of idiopathic intracranial hypertension has an exceedingly low yield (Krispel 2011). Prevention At present, there is no method to prevent pseudotumor cerebri syndrome, although maintaining a normal weight is likely useful for the prevention of idiopathic intracranial hypertension.

6 Differential diagnosis Although the diagnosis of pseudotumor cerebri syndrome may seem apparent, particularly when it affects an obese female of childbearing age, it is a diagnosis of exclusion. Most importantly, a mass lesion causing intracranial hypertension must be ruled out. The initial manifestations of space-occupying lesions include headaches, other focal neurologic deficits, behavioral changes, cognitive decline, seizures, fatigue, and visual manifestations. Some of the signs and symptoms of brain tumors overlap with those of the pseudotumor cerebri syndrome. A study of children with brain tumors who were first evaluated by an ophthalmologist found that the most common visual findings were decreased vision with disc pallor or papilledema (Alswaina et al 2015). Less common presentations were strabisumus with either disc pallor or swelling, acquired esotropia or exotropia, nystagmus, and papilledema with headache. There is striking similarity between the headache phenotypes of brain tumors, migraine, and pseudotumor cerebri syndrome. Disorders that may be mistaken for idiopathic intracranial hypertension include cerebral venous sinus thrombosis, infection, and malignancy. Cerebral venous sinus thrombosis was detected in approximately 9% of idiopathic intracranial hypertension patients seen in tertiary referral centers (Lin et al 2006). Most of the patients were atypical, and an underlying cause for the venous sinus thrombosis was identified in all but 2 patients. Headache may precede the onset of focal deficits and seizures in patients with cerebral venous sinus thrombosis, and it is frequently refractory to common pain medications (Iurlaro et al 2015). Tension headache, migraine headache, medication overuse headache, and depression may coexist in patients with idiopathic intracranial hypertension (Friedman and Rausch 2002). Therefore, it is essential to perform a careful funduscopic examination in patients with long-standing headache, particularly in those who are female or obese. Infrequently, chronic increased intracranial pressure exists without papilledema (Digre et al 2009). Diagnostic workup Neuroimaging studies and a lumbar puncture are essential to the diagnosis of idiopathic intracranial hypertension. A careful measurement of the opening pressure in the lateral decubitus position reveals spinal fluid pressures above 250 mm water. Pressures between 200 to 250 mm water are nondiagnostic in adults. The upper limit of normal CSF pressure for diagnosing idiopathic intracranial hypertension in children is 280 mm CSF (Avery et al 2010). The spinal fluid contents are normal. Papilledema is expected at the time of diagnosis, although it may be absent with preexisting optic atrophy, recurrent disease, or very early in the course of the disease. Imaging studies are used to exclude a secondary cause of intracranial hypertension. CT and CTV exclude many secondary causes of intracranial hypertension, including dural venous sinus thrombosis, but are much less sensitive than MRI and MRV in detecting fistulas, gliomatosis cerebri, meningeal disorders, and the subtle signs of idiopathic intracranial hypertension. MRI and MRV are particularly applicable when evaluating atypical patients (eg, men or non-obese women who would be unlikely to have idiopathic intracranial hypertension, those with severe manifestations, and those with rapid worsening) (Kesler et al 2001; Said and Rosman 2004). In idiopathic intracranial hypertension, CT and MRI often show an empty sella, flattening of the posterior sclera, distention and/or tortuosity of the optic nerve complex, protrusion of the optic nerve head into the vitreous cavity (papilledema), and tortuosity of the optic nerve. The empty sella results from bony enlargement of the sella from chronically raised intracranial pressure (Kyung et al 2014). CTV and MRV often reveal smooth-walled transverse sinus stenosis or sinus flow gaps, often mistakenly interpreted as indicating thrombosis (Degnan and Levy 2011). Although MRI findings are helpful for diagnostic purposes, their presence or absence does not predict visual outcome (Saindane et al 2013). Ophthalmologic evaluation of visual acuity, the fundus, and the visual field is requisite. Serial perimetry is important to detect and prevent visual loss. Echography (A scan and B scan) and optical coherence tomography (Lee et al 2011) may be helpful in differentiating idiopathic intracranial hypertension from the pseudopapilledema of optic disc drusen. Spectral domain optical coherence tomography was studied prospectively in the Idiopathic Intracranial Hypertension Treatment Trial. It was more sensitive than fundus photography in detecting retinal and choroidal folds in study participants (Sibony et al 2015). Retinal nerve fiber layer thickness, total retinal thickness, and optic nerve head volume measurements showed greater improvement with acetazolamide and dietary management than with placebo and dietary management (Optical Cohenece Tomorgraphy Substudy Committee 2015). Optical coherence tomography measurements were more strongly correlated with papilledema grade at baseline than at 6 months.

7 Early visual acuity loss in patients with idiopathic intracranial hypertension arises from optic neuropathy and retinal changes, such as subretinal fluid, chorioretinal folds, and peripapillary choroidal neovascularization (Chen et al 2015). The outer retinal changes are mostly reversible, and the degree of optic neuropathy, as determined by an algorithm based on optic nerve and macular optical coherence tomography, best predicted the visual outcome. Management Medication and diet. The Idiopathic Intracranial Hypertension Treatment Trial, sponsored by the National Eye Institute, studied the effect of acetazolamide and a supervised diet compared to placebo and a supervised diet in patients with mild visual loss (Friedman et al 2014). Perimetric mean deviation as measured by the Humphrey Visual Field Analyzer ranged from -2 to -7 db at study entry, and the primary outcome measure was change in the perimetric mean deviation at 6 months. The starting dose of study medication was 500 mg twice daily and was gradually increased to 2 grams twice daily, or the maximum tolerated dose (Wall et al 2014). At 6 months, participants randomized to acetazolamide therapy had improved perimetric mean deviation, papilledema grade, vision-related quality of life, and a greater reduction in weight than patients randomized to placebo and weight loss. The overall treatment effect was an improvement of 0.71 db, with a more robust effect (2.27 db) in participants with more severe papilledema at baseline (Frisén papilledema grade of 3 to 5). Acetazolamide was not superior to placebo for reducing headache disability. Based on the study results, treatment with acetazolamide up to 4 grams daily combined with a weight loss regimen is recommended for patients with mild visual loss. There are no evidence-based guidelines for treating patients with more severe visual field loss at presentation (NORDIC Idiopathic Intracranial Hypertension Study Group Writing Committee et al 2014). Treatment of his condition is predicated, to some extent, on determining its cause. Medical therapy has included a supervised weight loss program, repeated lumbar punctures, salt and fluid restriction, carbonic anhydrase inhibitors, medical treatment of headaches, and diuretic therapy (Friedman and Streeten 1998; Johnson et al 1998; Kupersmith et al 1998; Sinclair et al 2010). Discontinuation of the causative agent is mandatory but may not be sufficient to treat the patient. Patients with intracranial hypertension from a secondary cause often need additional treatment to prevent visual loss (Friedman et al 2004). Treatment strategies are similar in adults and children. Corticosteroids are reserved for emergent management of impending visual loss; even this indication is controversial, as some experts contend that patients who receive perioperative corticosteroids worsen as the steroids are withdrawn, precipitated by a rebound rise in intracranial pressure. The side effects associated with long-term steroid usage are undesirable in these patients (ie, weight gain, fluid retention). For patients with infrequent flare-ups, a therapeutic lumbar puncture (withdrawing enough cerebrospinal fluid to decrease the pressure to 120 to 175 mm CSF) may temporarily reduce headache. Patients with pseudotumor cerebri syndrome may experience a low-pressure headache after a lumbar puncture that can produce visual symptoms and signs indistinguishable to those found with increased intracranial pressure (Horton and Fishman 1994). Surgery. Surgical options include optic nerve sheath decompression and cerebrospinal diverting procedures. No prospective trials have been conducted to compare one type of procedure to the other, and the choice of procedure often depends on available resources (Uretsky 2009). Sometimes more than one type of procedure is necessary. A retrospective study of 41 patients undergoing optic nerve sheath fenestration or shunting showed similar improvements in visual acuity but worse results in perimetric mean deviation in the group treated with optic nerve sheath fenestration (Fonseca et al 2014). However, the treatments were not randomized and the baseline visual function may have influenced the surgical procedure chosen. Optic nerve sheath fenestration relieves local cerebrospinal fluid pressure on the optic nerve and may improve visual function, but it may fail any time after surgery (Feldon 2007). This procedure appears to have similar efficacy in children and adults (Thuente and Buckley 2005). If the papilledema is chronic, this modality may be less successful. Shunting offers the theoretical benefit of treating the underlying problem of increased intracranial pressure. However, it is limited by a high failure rate, requiring one or more shunt revisions in most cases (Uretsky 2009; Sinclair et al 2011). Low pressure headaches, lumbar radiculopathies, and tonsillar herniation may occur following lumboperitoneal shunting. It is not an effective long-term treatment for idiopathic intracranial pressure-associated headaches (Sinclair et al 2011). Use of a programmable shunt valve may help diminish the complications of lumboperitoneal shunting (Zemack and Rommer 2000), particularly when used in conjunction with a ventricular access device. This device is inserted stereotactically into the frontal horn of the lateral ventricle and provides an access point for measuring CSF pressure in the setting of suspected shunt failure (Nadkarni et al 2008). Ventriculoperitoneal

8 shunting lessens the likelihood of over-shunting and radiculopathy. Stereoscopic surgical navigation is helpful to achieve cannulation of normal-sized ventricles when standard maneuvers are unsuccessful (Garton 2004). Stereotactic frameless procedures have been employed with good initial results but at a 50% failure rate of 1 year (Woodworth et al 2005). Direct comparison studies of the various surgical procedures have not been performed, although ventriculoperitoneal shunts may require revision less frequently than lumboperitoneal shunts (McGirt et al 2004). Bariatric surgery may be helpful in the long-term management of idiopathic intracranial hypertension in morbidly obese individuals. It is not useful in the setting of an acute presentation with visual loss. Venous sinus stenting. Based on the observation of venous sinus stenosis associated with a pressure gradient across the stenotic sinus in some patients, intravascular stenting has been performed in some patients with idiopathic intracranial hypertension, including those with a fulminant presentation (Elder et al 2015). A meta-analysis of optic nerve sheath fenestration, shunting, and stenting evaluated 30 studies containing class III evidence (Lai 2014). Visual acuity improved with all 3 modalities, and shunting and stenting demonstrated a modest improvement in headache. The authors concluded that there is insufficient evidence to recommend or reject any of the treatment modalities. The criteria for patient selection are undefined, although some centers require persistent stenosis following cerebrospinal fluid drainage to consider stenting. Life-threatening complications (ie, subdural hematoma, epidural hematoma, uncontrolled intracranial hypertension) have occurred from the procedure, and 1 death has been reported (Ahmed et al 2011; Subramanian and Haq 2014). Markedly, elevated lumbar puncture opening pressure (<50 cm CSF) prior to intervention and persistent papilledema after stenting were associated with a refractory course, requiring shunting after stent placement in 1 series (Goodwin et al 2014). At this time, stenting should only be considered for patients who are refractory to conventional medical and surgical treatments. Bariatric surgery may be helpful in the long-term management of idiopathic intracranial hypertension in morbidly obese individuals. It is not useful in the setting of an acute presentation with visual loss. Special considerations Pregnancy Although pregnancy is not a risk factor per se, pseudotumor cerebri syndrome may develop or worsen in pregnancy. Most patients can be successfully managed conservatively during pregnancy with serial lumbar punctures. If vision is threatened, acetazolamide, corticosteroids, optic nerve sheath decompression, and lumboperitoneal shunting are alternatives (Lee et al 2005). Vaginal delivery is not contraindicated in these patients. Venous sinus thrombosis must be considered when pseudotumor cerebri syndrome develops in the puerperium after a miscarriage or an ectopic pregnancy (Evans and Friedman 2000). Anesthesia Anesthesia is not contraindicated with pseudotumor cerebri syndrome. References cited Ahmed R, Friedman DI, Halmagyi GM. Stenting of the transverse sinuses in idiopathic intracranial hypertenstion. J Neuroophthalmol 2011;31(4); PMID Alswaina N, Elkhamary SM, Shammari MA, Khan AP. Ophthalmic features of outpatient children diagnosed with intracranial space-occupyting lesions by ophthalmologists. Middle East Afr J Ophthalmol 2015;22(3): PMID Avery RA, Shah SS, Licht DJ, et al. Reference range for cerebrospinal fluid opening pressure in children. N Engl J Med 2010;363: PMID Ball AK, Sinclair AJ, Curnow SJ, et al. Elevated cerebrospinal fluid (CSF) leptin in idiopathic intracranial hypertension (IIH): evidence for hypothalamic leptin resistance. Clin Endocrinol (Oxf) 2009;70(6): PMID Bandyopadhyay S, Jacobson DM. Clinical features of late-onset pseudotumor cerebri fulfilling the modified Dandy criteria. J Neuroophthalmol 2002;22:9-11. PMID

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11 Karahalios DG, Rekate HL, Khayata MH, Apostolides PJ. Elevated intracranial venous pressure as a universal mechanism in pseudotumor cerebri of varying etiologies. Neurology 1996;46: PMID Kerty E, Heuser K, Indahl UG, et al. Is the brain water channel aquaporin-4 a pathogenetic factor in idiopathic intracranial hypertension. Results from a combined clinical and genetic study in a Norwegian cohort. Acta Ophthalmol 2013;91(1): PMID Kesler A, Gadoth N. Epidemiology of idiopathic intracranial hypertension in Israel. J Neuroophthalmol 2001;21:12-4. PMID Kesler A, Goldmanner Y, Gadoth N. Do men with pseudotumor cerebri share the same characteristics as women. A retrospective review of 141 cases. J Neuroophthalmol 2001;21(1):15-7. PMID Kesler A, Stolovic N, Bluednikov Y, Shohat T. The incidence of idiopathic intracranial hypertension in Israel from : results of a nationwide survey. Eur J Neurol 2014;21(8): PMID Killer HE, Jaggi GP, Flammer J, Miller NR, Huber AR, Mironov A. Cerebrospinal dynamics between the intracranial and the subarachnoid space of the optic nerve. Is it always bidirectional. Brain 2007;130: PMID King JO, Mitchell PJ, Thomson KR, Tress BM. Manometry combined with cervical puncture in idiopathic intracranial hypertension. Neurology 2002;58: PMID Ko MW. Idiopathic intracranial hypertension. Curr Treat Options Neurol 2011;13(1): PMID Ko MW, Liu GT. Pediatric idiopathic intracranial hypertension (pseudotumor cerebri). Hormone. Res Pediatr 2010;74(6): PMID Krispel CM, Keltner JL, Smith W, Chu DG, Ali MR. Undiagnosed papilledema in a morbidly obese patient population: a prospective study. J Neuroophthalmol 2011;31(4): PMID Kupersmith MJ, Gamell L, Turbin R, Spiegel P, Wall M. Effects of weight loss on the course of idiopathic intracranial hypertension in women. Neurology 1998;50: PMID Kyung SE, Botelho JV, Horton JC. Enlargement of the sella turcica in pseudotumor cerebri. J Neurosurg 2014;120(2): PMID Laemmer R, Heckmann JG, Mardin CY, Schwab S, Laemmer AB. Detection of nerve fiber atrophy in apparently effectively treated papilledema in idiopathic intracranial hypertension. Grafes Arch Clin Exp Ophthalmol 2010;248(12): PMID Lai LT, Danesh-Meyer HV, Kaye AH. Visual outcomes and headache following interventions for idiopathic intracranial hypertension. J Clin Neurosci 2014;21(10): PMID Lee AG, Pless M, Falardeau J, Capozzoli T, Wall M, Kardon RH. The use of acetazolamide in idiopathic intracranial hypertension during pregnancy. Am J Ophthalmol 2005;139: PMID Lee KM, Woo SJ, Hwang JM. Differentiation of optic nerve head drusen and optic disc edema with spectral-domain optical coherence tomography. Ophthalmology 2011;118(5): PMID Lin A, Foroozan R, Danesh-Meyer HV, DeSalvo G, Savino PJ, Sergott RC. Occurrence of cerebral venous sinus thrombosis in patients with presumed idiopathic intracranial hypertension. Ophthalmology 2006;113: PMID Mallery RM, Friedman DI, Liu GT. Headache and the pseudotumor cerebri syndrome. Curr Pain Heaadche Rep 2014;18(9):446. PMID McGeeney BE, Friedman DI. Pseudotumor cerebri pathophysiology. Headache 2014;54(3): PMID McGirt MJ, Woodworth G, Thomas G, Miller N, Williams M, Rigamonti D. Cerebrospinal fluid shunt placement for pseudotumor cerebri-associated intractable headache: predictors of treatment response and an analysis of long-term

12 outcomes. J Neurosurg 2004;101: PMID Nadkarni TD, Rekate HL, Wallace D. Concurrent use of a lumboperitoneal shunt with programmable valve and ventricular access device in the treatment of pseudotumor cerebri: review of 40 cases. J Neurogsurg Pediatrics 2008;2(1): PMID Ney JJ, Volpe NJ, Liu GT, Balcer LJ, Moster ML, Galetta SL. Functional visual loss in idiopathic intracranial hypertension. Ophthalmology 2009;116(9): PMID Noel N, Hutie M, Wechsler B, et al. Pseudotumoural presentation of neuro-behcet's disease: case series and review of literature. Rheumatology (Oxford) 2012;51(7): PMID NORDIC Idiopathic Intracranial Hypertension Study Group Writing Committee, Wall M, McDermott MP, et al. Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss: the idiopathic intracranial hypertension treatment trial. JAMA 2014;311(16): PMID Optical Coherence Tomography Substudy Committee, NORDIC Idiopathic Intracranial Hypertension Study Group. Papilledema outcomes from the Optical Coherence Tomography Substudy of the Idiopathic Intracranial Hypertension Treatment Trial. Ophthalmology 2015;122(9): PMID Paley GL, Sheldon CA, Burrows EK, Chilutti MR, Liu GT, McCormack SE. Overweight and obesity in pediatric secondary pseudotumor cerebri syndrome. Am J Opthalmol 2015;159(2): PMID Parness-Yossifon R, Margalit D, Pollack A, Leiba H. Behavioral disorders in children with idiopathic intracranial hypertension. J Child Neurol 2008;23(4): PMID Rangwala LM, Liu GT. Pediatric idiopathic intracranial hypertension. Surv Ophthalmol 2007;52(6): PMID Said RR, Rosman NP. A negative cranial computed tomographic scan is not adequate to support a diagnosis of pseudotumor cerebri. J Child Neurol 2004;19: PMID Saindane AM, Bruce BB, Riggeal BD, Newman NJ, Biousse V. Association of MRI findings and visual outcome in idiopathic intracranial hypertension. AJR Am J Roentgenol 2013;201(2): PMID Sibony PA, Kupersmith MJ, Feldon SE, Wank JK, Garvin M, OCT Substudy Group for the NORDIC Idiopathic Intracranial Hypertension Trial. Retinal and choroidal folds and papilledema. Invest Ophthalmol Vis Sci 2015;56(10): PMID Sinclair AJ, Burdon MA, Nightingale PG, et al. Low energy diet and intracranial pressure in women with idiopathic intracranial hypertension: prospective cohort study. BMJ 2010;341:c2701. PMID Sinclair AJ, Kuruvath S, Sen D, Nightingale PG, Burdon MA, Flint G. Is cerebrospinal fluid shunting in idiopathic intracranial hypertension worthwhile. A 10-year review. Cephalalgia 2011;31(16): PMID Skau M, Boetze JP, Rehfeld, JF, Jensen R. Natriuretic pro-peptides in idiopathic intracranial hypertension. Reg Peptides 2010;264(2-3):71-7. PMID Shah VA, Kardon RH, Lee AG, Corbett JJ, Wall M. Long-term follow-up of idiopathic intracranial hypertension. The Iowa experience. Neurology 2008;70(8): PMID Soiberman U, Stolovitch C, Balcer LJ, Regenbogen M, Constantini S, Kesler A. Idiopathic intracranial hypertension in children: visual outcome and risk of recurrence. Childs Nerv Syst 2011;27(11): PMID Stiebel-Kalish H, Kalish Y, Lusky M, Gaton DD, Erlich R, Shuper A. Puberty as a risk factor for less favorable visual outcome in idiopathic intracranial hypertension. Am J Ophthalmol 2006;142: PMID Subramanian PS, Haq A. Cerebral venous sinus thrombosis and stenosis in pseudotumor cerebri syndrome. Int Ophthalmol Clin 2014;54(1): PMID