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Update on the Diagnosis and Treatment of Idiopathic Intracranial Hypertension Samuel Bidot, MD1,2

Beau B. Bruce, MD, PhD3,4,5

1 Department of Ophthalmology, Fondation Ophtalmologique

Adolphe de Rothschild, Paris, France 2 Department of Ophthalmology, Centre Hospitalier National des Quinze-Vingts, Paris, France 3 Department of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia 4 Department of Neurology, Emory University School of Medicine, Atlanta, Georgia 5 Department of Epidemiology, Rollins School of Public Health and Laney Graduate School, Emory University, Atlanta, Georgia

Address for correspondence Beau B. Bruce, MD, PhD, NeuroOphthalmology Unit, Emory Eye Center, The Emory Clinic, 1365-B Clifton Road NE, Atlanta, GA 30322 (e-mail: [email protected]).

Abstract

Keywords

► idiopathic intracranial hypertension ► modified Dandy criteria ► cerebrospinal fluid ► papilledema ► acetazolamide

Idiopathic intracranial hypertension (IIH) is a rare disorder occurring more frequently in obese women of childbearing age, resulting in increased intracranial pressure (ICP) from an unknown cause. Recent advances in epidemiology, imaging, and treatment have provided a better understanding of IIH in recent years, with better identification of visual risk factors and atypical forms of IIH, including fulminant IIH and spontaneous cerebrospinal fluid leaks, and a randomized clinical trial providing the rationale for the use of acetazolamide. In addition, a revised version of the modified Dandy criteria for the diagnosis of IIH was suggested in 2013, with better definition of IIH in adults and children; however, controversy regarding nomenclature has precluded its acceptance among IIH experts. Finally, questions regarding the best surgical strategy, the indications for venous sinus stenting, and the diagnostic role of the radiologic findings commonly seen in IIH have remained unanswered.

Idiopathic intracranial hypertension (IIH) is a syndrome occurring most frequently in obese women of childbearing age. It is characterized by elevated intracranial pressure (ICP) from an unknown cause, after excluding conditions such as a space-occupying lesion, hydrocephalus, a meningeal process, or venous sinus thrombosis, according to the revised modified Dandy criteria (►Table 1).1 The naming of IIH has been under debate since Walter Dandy’s early description in 1937.2 Initially, IIH was defined by what it appeared to be, but was not (“pseudotumor cerebri;” i.e., having the appearance of a brain tumor when none was present). Later, it was named by its prognosis in comparison to other causes of increased ICP (“benign intracranial hypertension”). However, this descriptive name was inaccurate because a substantial proportion of patients have poor visual outcomes, so ultimately it was

Issue Theme Neuro-Ophthalmology; Guest Editor: Beau B. Bruce, MD, PhD

renamed by what it is (“idiopathic intracranial hypertension;” i.e., increased ICP without an identifiable cause). Although IIH is the preferred modern term for the condition, the name remains imperfect because it also refers to situations in which the patient is taking a medication associated with the disorder (e.g., vitamin A or a cycline antibiotic). To avoid ambiguity, some authors have advocated for labeling such forms of intracranial hypertension by what they are (e.g., steroid withdrawal-induced intracranial hypertension), and for reserving the term of IIH for only those cases in which no precipitating factor is identified.3 To add further confusion, “pseudotumor cerebri” has reappeared as an umbrella term of “pseudotumor cerebri syndrome” in the most recently suggested diagnostic criteria.4 This reintroduction remains controversial, and has not been widely accepted by IIH experts.3

Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

DOI http://dx.doi.org/ 10.1055/s-0035-1563569. ISSN 0271-8235.

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Semin Neurol 2015;35:527–538.

Update on the Diagnosis and Treatment of Idiopathic Intracranial Hypertension

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Table 1 Modified Dandy criteria for diagnosing idiopathic intracranial hypertension1 1. If symptoms present, they may only reflect those of generalized intracranial hypertension or papilledema. 2. If signs present, they may only reflect those of generalized intracranial hypertension or papilledema. 3. Elevated intracranial pressure  25 cm H2O measured in the lateral decubitus position 4. Normal CSF composition. 5. No evidence of hydrocephalus, mass, structural, or vascular lesion on MRI or contrast-enhanced CT for typical patients, and MRI and MR venography for all others. 6. No other cause of intracranial hypertension identified. Abbreviations: CSF, cerebrospinal fluid; CT, computed tomography; MRI, magnetic resonance imaging. Note: Criteria 1–6 must be fulfilled for definite diagnosis of idiopathic intracranial hypertension.

New epidemiologic studies, imaging innovations, and the IIH Treatment Trial (IIHTT) have provided a better understanding of IIH in recent years. This review provides an update on the diagnosis and the treatment of IIH, with a focus on recent developments.

Clinical Features Symptoms Headaches are experienced by the vast majority (90%) of IIH patients; this is often the presenting symptom.5,6 Although “high pressure” headaches in the setting of IIH have been classically reported as fronto-orbital, throbbing, severe, and slowly worsening,7 their profile lacks specificity and no description was listed in the most recent International Classification of Headaches Disorder (3rd version; ICHD-3) (►Table 2).8 As “high pressure” headaches may mimic a wide range of headache disorders, the ICHD-3 recommends demonstrating causation between raised ICP and headaches. Therefore, an alternate mechanism explaining the headaches should be considered if headaches persist after CSF pressure lowering. Transient visual obscurations correspond to transient episodes of monocular or binocular visual loss lasting seconds with full recovery. They usually occur with standing, bending, or Valsalva maneuver. They are reported by most IIH patients (70%).7

Pulsatile tinnitus is often described as a heartbeat or a whooshing sound, which might be unilateral or bilateral, intermittent or constant. Tinnitus occurs in 60% of IIH patients. Diplopia occurs in 30% of IIH patients. It typically results from a unilateral or bilateral sixth nerve palsy without localizing value.9 Other ocular motor disturbances have been reported in anecdotal cases,10 but their presence should raise concern for an alternate diagnosis. Occasionally, monocular diplopia occurs in the setting of macular involvement associated with severe papilledema. Spontaneous CSF leaks (i.e., without history of head trauma, congenital bone defect, brain tumor, or hydrocephalus) have been recently associated with IIH,11 and arise from dehiscence of thin bones at the level of the skull base. Unlike spontaneous spinal CSF leaks in which low-pressure headache is the most prominent symptom,12 patients with spontaneous skull base CSF leaks often present with isolated clear rhinorrhea, or less often, otorrhea.13 The fluid is collected and tested for β2-transferrin activity, which confirms the fluid is CSF when positive.13

A Major Clinical Sign: Papilledema Papilledema refers to optic disc edema resulting from increased ICP.14 It is the hallmark of intracranial hypertension and a major criteria for definite IIH in the most recently suggested diagnostic criteria.4 It is so prevalent that clinicians

Table 2 Characteristics of idiopathic intracranial hypertension (IIH) headaches according to International Classification of Headaches Disorder8 (ICHD-3) A. Any headache fulfilling criterion C B. IIH has been diagnosed, with CSF pressure > 250 mm H2O (measured by lumbar puncture performed in the lateral decubitus position, without sedative medications, or by epidural or intraventricular monitoring). C. Evidence of causation demonstrated by at least two of the following: 1. Headache has developed in temporal relation to IIH, or led to its discovery. 2. Headache is relieved by reducing intracranial hypertension. 3. Headache is aggravated in temporal relation to increase in intracranial pressure. D. Not better accounted for by another ICHD-3 diagnosis Abbreviations: CSF, cerebrospinal fluid. Note: Criteria A–D must be fulfilled. Seminars in Neurology

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Ancillary Tests Visual Fields Visual field testing, along with the evaluation of papilledema severity, remains the mainstay of IIH monitoring. The technique of choice is standard automated perimetry testing of the central 24 to 30 degrees of the visual field.19 Goldmann perimetry lacks sensitivity and should be reserved for IIH patients unable to perform automated perimetry because of poor vision or cognitive deficits. An enlarged blind spot is almost universal and secondary to mechanical deformation of the peripapillary retina induced by papilledema (►Fig. 2A, black arrows). The vast majority of the other patterns of visual field defects are related to irreversible optic fiber loss (►Fig. 2B). The earliest defect is the loss of the inferonasal portion of the visual field (nasal step, ►Fig. 2A , gray arrows) followed by progressive constriction of the visual field with late visual acuity sparing, explaining why visual acuity is not reliable to monitor IIH over time.9,19

Optical Coherence Tomography Optical coherence tomography (OCT) is a noncontact tool that quickly and noninvasively obtains pseudohistologic crosssections of the retina and the optic nerve during routine care. In IIH, the use of OCT has been essentially limited to

Fig. 1 Modified Frisén scale. (A) Grade 0: Normal optic disc. Prominence of the retinal nerve fiber layer at the nasal, superior, and inferior poles in inverse proportion to disc diameter. Radial nerve fiber layer striations without tortuosity. (B) Grade 1: Minimal degree of edema. C-shaped halo that is subtle and grayish with a temporal gap obscuring underlying retinal details. a Disruption of normal radial nerve fiber layer arrangement striations. Temporal disc margin normal. (C) Grade 2: Low degree of edema. Circumferential halo. a Elevation of the nasal border. No major vessel obscuration. (D) Grade 3: Moderate degree of edema. Obscuration of  1 segment of major blood vessels leaving disc. a Circumferential halo with an irregular outer fringe and finger-like extensions. Elevation of all borders. (E) Grade 4: Marked degree of edema. Total obscuration on the disc of a segment of a major blood vessel on the disc. a Elevation of whole nerve head, including the cup. Complete border obscuration. (F) Grade 5: Severe degree of edema. Obscuration of all vessels on the disc and leaving the disc. aKey feature (major finding) for each grade. Seminars in Neurology

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should consider an alternate diagnosis when the optic discs appear normal. It is most often bilateral and symmetric, although asymmetric or unilateral papilledema has been reported in approximately 5% of cases.15,16 Proper appreciation of the severity of papilledema remains critical to guide case management. The modified Frisén scale is a standardized grading system categorizing papilledema into five grades of increasing severity (►Fig. 1).17 Although this tool is widely used for routine care and research, clinicians must be aware of its limitations. Because atrophy is a well-known factor preventing the optic disc from swelling,18 confusion can arise over the severity of papilledema when optic fiber loss has occurred. Therefore, the modified Frisén scale remains valid only when the optic disc does not show pallor and there is not severe visual loss. Elevated optic discs are not synonymous with papilledema, and might result from buried drusen, congenital abnormalities, or myelinated optic nerve fiber layer (“pseudopapilledema”). Differentiating pseudopapilledema from papilledema can be challenging, even for experienced neuro-ophthalmologists, but is a crucial step to obviate the need for invasive procedures and potentially harmful treatments. Generally, this dilemma can be solved by a thorough examination of the optic discs with the assistance of ancillary tests.

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Update on the Diagnosis and Treatment of Idiopathic Intracranial Hypertension

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Fig. 2 Examples of papilledema with corresponding Humphrey visual fields. The right optic disc is on the left side and the visual field of the right eye is on the right side. (A) Papilledema grade 4 with numerous peripapillary hemorrhages in both eyes. The visual fields show enlarged blind spots (black arrows). The visual field of the right eye shows a nasal step (gray arrows). (B) Papilledema grade 4 with optic disc pallor and numerous peripapillary cotton wool spots in both eyes. The visual fields show severe visual loss in both eyes, worse in the left. This indicates severe optic fiber loss that might underestimate the grade of papilledema.

macular edema screening in the setting of severe papilledema,20 but several studies have attempted to better define its role in the diagnosis and monitoring of papilledema. Diagnosing early papilledema remains challenging. Thickening of the peripapillary retinal nerve fiber layer (RNFL) on OCT has been proposed to help clinicians in such cases,17 but this finding is not specific to papilledema and has been reported in other causes of optic disc edema and pseudopapilledema.21,22 Other studies23,24 have addressed indirect

signs of papilledema on OCT and have showed inward deflection (pointing toward the vitreous cavity, ►Fig. 3B) of the retinal pigmentary epithelium (RPE) layer in the majority (67%) of eyes with papilledema. The RPE deflection is analogous to flattening of the posterior pole on magnetic resonance imaging (MRI),25 and has been uncommonly seen in other causes of optic disc edema.23,24 Optical coherence tomography has also been suggested to monitor papilledema resolution by measuring the course of

Fig. 3 Optical coherence tomography of the optic disc showing the position of the retinal pigmentary epithelium (RPE; arrows) according to the gradient between the intraocular pressure and the cerebrospinal fluid (CSF) pressure. (A) Optic disc drusen: The RPE is flat or bends outward reflecting the normal anteroposterior gradient (intraocular pressure > CSF pressure). (B) Papilledema: The RPR bends inward reflecting the inverted pressure gradient (CSF pressure > intraocular pressure). Seminars in Neurology

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the RNFL thickness during treatment.26,27 However, OCT is unable to differentiate resolving papilledema from optic disc atrophy, and a potential pitfall is false reassurance from decreasing of the RNFL thickness that instead represents optic disc atrophy. As mentioned above, differentiating true papilledema from pseudopapilledema remains critical to avoid misdiagnosis. Several studies28–31 have attempted to differentiate mild papilledema from buried optic disc drusen on OCT with inconsistent results. The wide variety of shapes, reflectivity, size, and location of drusen on OCT28–33 and the poor interreviewer agreement in differentiating papilledema from drusen28 have slowed attempts to distinguish these diagnoses by OCT. The role of OCT in the diagnosis and monitoring of papilledema remains unclear. Fundus examination with automated perimetry remains the gold standard in routine care, whereas OCT interpretation requires clinical correlation to avoid making errors.

exclude other pathologies causing increased ICP.4 Although the diagnosis of IIH remains a diagnosis of exclusion, specific findings on brain and venous imaging may suggest intracranial hypertension (►Fig. 4).34 Radiologic findings include empty sella, CSF leaks, widening of the foramen ovale, meningoceles, meningoencephaloceles, flattening of the globes, optic nerve head protrusion, tortuosity of the optic nerve, dilatation of the optic nerve sheath, transverse venous sinus stenosis, enhancement of the optic disc, and tonsillar herniation.35–38 The most recently suggested diagnostic criteria have included some of these radiologic findings to suggest the possibility of IIH in patients without papilledema or sixth nerve palsy.4 However, their presence is not required to diagnose definite IIH. Additionally, the incidental report of one of these findings on routine brain imaging should not prompt invasive and costly procedures, unless papilledema or other signs or symptoms consistent with increased ICP is present.

Brain and Cerebral Venous System Imaging

Lumbar Puncture

Brain imaging (ideally brain MRI with and without contrast) and venous imaging (MR venography or computerized tomographic venography) is necessary for the diagnosis of IIH to

A lumbar puncture (LP) is required in suspected IIH to confirm elevated cerebrospinal fluid opening pressure (CSF OP) and normal CSF contents.4 The upper range of normal CSF OP has

Fig. 4 Examples of classic radiologic findings suggesting longstanding intracranial hypertension. (A) Brain magnetic resonance image (MRI), midsagittal T1 image, precontrast. Empty sella. (B) Brain MRI, axial fluid-attenuated inversion recovery (FLAIR) image, precontrast. Flattening of the posterior globe (large arrow) and optic nerve head protrusion (thin arrow) (C) Orbit MRI, coronal T2 image, fat saturation, precontrast. Dilation of the optic nerve sheaths. (D) Magnetic resonance venography. Venous stenoses at the distal portion of the transverse sinuses. Seminars in Neurology

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Update on the Diagnosis and Treatment of Idiopathic Intracranial Hypertension

Update on the Diagnosis and Treatment of Idiopathic Intracranial Hypertension been set at 25 cm H2O in adults4,39 and 28 cm H2O in children.4,40 Several precautions must be taken to obtain a valid measurement, including positioning the patient in lateral decubitus with legs extended without sedation (if possible).4 As LPs are sometimes difficult in obese patients, radiologists have increasingly performed fluoroscopically guided LPs in the prone position, which may result in incorrect CSF OP measurements.39 When properly performed (i.e., rolling the patient from the prone position to the lateral decubitus position with proper placement of the zero mark of the manometer), CSF OP obtained under imaging guidance is equivalent to that of LP performed based on anatomical landmarks alone.41 Other means to zero the manometer include adding the length of the needle to the measurement obtained from the manometer or interposing a rubber tube between the needle and the manometer to adjust its position at the level of the spine.39 A recent survey found that 15% of radiologists do not zero the manometer during CSF OP measurements (therefore underestimating CSF pressure), so one may need to ensure the conditions under which the fluoroscopically guided LP was performed to interpret the results properly.41 The cutoff of 25 cm H2O in adults is not strict and only constitutes the upper limit of the 95% confidence interval of the CSF OP, indicating that 2.5% of normal adults have CSF OP above 25 cm H2O.39 Cerebrospinal fluid opening pressure is only a snapshot of the CSF pressure and does not capture its variation throughout the day. Therefore, CSF OP must be interpreted cautiously in conjunction with other symptoms and signs of intracranial hypertension.

Bidot, Bruce

Diagnosis According to the revised modified Dandy criteria from 2002 (►Table 1), IIH is a syndrome of intracranial hypertension with normal brain imaging, normal CSF contents, and no focal neurologic signs (other than a sixth nerve palsy).1 Confusion regarding terminology and recent advances in CSF physiology and brain imaging prompted a controversial revision of the 2002 criteria in 2013 (►Table 3).4 Because the term IIH usually encompasses IIH from an unknown cause and those precipitated by an identifiable factor, the authors have suggested reintroducing the old term of “pseudotumor cerebri” under which all IIHs would be lumped together along with other identifiable causes of increased ICP. The term of IIH would be reserved exclusively for IIH from an unknown cause, and the term of “secondary pseudotumor cerebri” for the others (including, e.g., venous sinus thrombosis). Substantial controversy has arisen about the 2013 criteria, and several authors do not agree with the new proposed terminology.3,42 In addition to the changes with respect to “pseudotumor cerebri syndrome,” the 2013 diagnostic criteria proposed the following: 1. The entity of “IIH without papilledema” is considered separately and three levels of diagnostic certainty with respect to IIH itself have been introduced: definite, probable, and “suggested.” In the absence of papilledema, a definitive diagnosis of IIH can be made only in patients with a sixth nerve palsy.

Table 3 Most recent proposed diagnostic criteria for idiopathic intracranial hypertension4 1. Required for the diagnosis of idiopathic intracranial hypertension A diagnosis of idiopathic intracranial hypertension is definite if the patient fulfills criteria A–E. The diagnosis is considered probable if criteria A–D are met, but the measured CSF pressure is lower than specified for a definite diagnosis. A. Papilledema B. Normal neurologic examination except for cranial nerve abnormalities C. Neuroimaging: Normal brain parenchyma without evidence of hydrocephalus, mass, or structural lesion and no abnormal meningeal enhancement on MRI, with and without gadolinium, for typical patients (obese women), and MRI, with and without contrast, and MRV for others; if MRI is unavailable or contraindicated, contrast-enhanced CT may be used D. Normal CSF composition E. Elevated lumbar puncture CSF opening pressure ( 250 mm H2O in adults and  280 mm H2O in children [250 mm H2O if the child is not sedated and not obese]) in a properly performed lumbar puncture 2. Diagnosis of idiopathic intracranial hypertension without papilledema In the absence of papilledema, a diagnosis of idiopathic intracranial hypertension can be made if B–E from above are satisfied, and in addition the patient has a unilateral or bilateral abducens nerve palsy In the absence of papilledema or sixth nerve palsy, a diagnosis of idiopathic intracranial hypertension can be suggested, but not made, if B–E from above are satisfied, and in addition at least 3 of the following neuroimaging criteria are satisfied: i. Empty sella ii. Flattening of the posterior aspect of the globe iii. Distention of the perioptic subarachnoid space with or without a tortuous optic nerve iv. Transverse venous sinus stenosis Abbreviations: CT, computed tomography; CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; MRV, magnetic resonance venography.

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Update on the Diagnosis and Treatment of Idiopathic Intracranial Hypertension 2. Brain MRI is the first-line imaging in all patients with presumed intracranial hypertension. 3. The cutoff for elevated CSF pressure in children has been set at 28 cm H2O. 4. Radiologic findings associated with increased ICP have been introduced to suggest IIH in patients without papilledema or sixth nerve palsy.

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aches, reported as different from their “high pressure” headaches, most often including migraine, chronic or episodic tension headaches, and analgesic overuse headaches.57 Proper identification of the underlying mechanism(s) of headaches associated with IIH is critical to providing appropriate long-term management.

Complications Permanent Visual Loss Although most IIH patients have satisfactory visual outcomes with appropriate medical management, approximately 10% experience severe, irreversible visual loss in at least one eye.43 Most significant visual loss in IIH (i.e., other than related to transient visual obscurations and enlarged blind spots) is irreversible and due to progressive optic neuropathies related to disruption of the axonal flow in the setting of chronic papilledema (►Fig. 5).9 Uncommonly, visual loss may arise from an ischemic event44 or a retinopathy related to choroidal folds or macular extension of findings associated with papilledema, including edema, exudates, and hemorrhages.45 Proper identification of risk factors for visual loss remains paramount at initial presentation, and patients at high risk should be carefully monitored. Demographic risk factors include male gender46 (risk 2), African American ethnicity47 (risk 3), severe obesity48 (risk 2 per 20 kg/m2 body mass index [BMI]), and recent weight gain.7 The major clinical risk factors are the severity of papilledema,15 fulminant IIH (see below),49 and visual field loss at presentation,9 but other factors, such as lack of headaches,46 sleep apnea,47 iron deficiency-related anemia,47 and the magnitude of the CSF OP elevation47,50 have also been put forward.

Cerebrospinal Fluid Leaks Although IIH is a recognized etiology of spontaneous skull base CSF leaks in the otolaryngology and neurosurgery literature,11,51,52 it has only been recently appreciated in the neuro-ophthalmology community.53,54 It has been put forward that spontaneous skull base CSF leaks might represent a variant of IIH in patients who do not develop typical symptoms of IIH with the leak acting as a “natural” CSF diversion.11 Meningoceles or meningoencephaloceles are often associated with CSF leaks in 50 to 100% of cases.55,56

Chronic Headaches Despite apparently satisfactory ICP control, the majority (70%) of IIH patients continue to experience chronic head-

Although reduced quality of life (QOL) is a major morbidity of IIH, few studies have addressed its psychosocial burden.58–60 Patients with IIH have a lower health-related QOL compared with normal, obese, and other neuro-ophthalmic disorder controls, and increased rates of depression and anxiety compared with normal controls.58,59 Poorer health-related QOL has even been found at initial presentation in IIH patients with mild visual loss,60 suggesting that IIH symptoms rather than medication side effects were the main contributors to reduced QOL. Among these symptoms, one study60 has shown that headaches and transient visual obscurations were the two major symptoms contributing to reduced QOL, but other signs and symptoms, including neck pain, diplopia, and visual loss have also been associated with poorer QOL.

Management Suppression of Risk Factors Weight loss in obese patients, discontinuation of precipitating medications when present, and treatment of associated conditions (e.g., anemia61 or sleep apnea62) are paramount to prevent visual loss and recurrence. Weight loss of as little as 5 to 10%63,64 has been associated with sustained improvements in headache, papilledema, and ICP,65,66 but can be difficult to maintain.64 Bariatric surgery can be a reasonable consideration for extremely (BMI  40) obese patients, but its substantial morbidity rate needs to be considered in the balance.67 Weight loss remains critical and constitutes the mainstay of IIH management. However, its efficacy over the short term is limited and must be initiated in conjunction with other treatment.68

Lumbar Puncture The initial LP, important for diagnostic purposes, is also the first step for IIH management. Indeed, bilateral transverse sinus stenoses are commonly seen in IIH.69 Although their pathophysiology is still poorly understood, they might contribute to a cycle involving decreased venous outflow drainage, cerebral venous hypertension, CSF passive resorption impairment, and further raising of the CSF pressure, resulting in external compression of the distal portion of the transverse venous sinus, leading to worsening of the venous stenosis and perpetuation of the situation.68 It has been suggested that LP might break this vicious circle, as most patients report immediate relief and sustained remission has been reported after one or two procedures.70 Therefore, the use of serial LP remains controversial. It is also limited because of patient tolerance issues, but might Seminars in Neurology

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Psychosocial Impact Finally, the authors have underscored the need to rule out pseudopapilledema and other causes of optic disc edema and the lack of diagnostic value of the response to LP on headaches. Although not necessarily obvious from a reading of the title and abstract only, these revised criteria were intended only as a proposal, and in fact they have not been widely accepted among experts in the field. Therefore, additional study is needed to address the validity of these criteria.

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Fig. 5 Severe visual loss in both eyes with severe optic disc atrophy secondary to “burnt-out” papilledema.

be considered in pregnant women and as a temporizing measure while awaiting surgery.49,71

Medical Treatment: The Idiopathic Intracranial Hypertension Treatment Trial Diuretics have been the traditional treatment of IIH despite the lack of large controlled trials. Among diuretics, acetazolamide has remained widely accepted as the first-line medication in IIH since it was found to be effective in lowering CSF pressure in children with hydrocephalus.72 It inhibits the carbonic anhydrase present in the choroid plexus, which has a major role in CSF secretion. However, the lack of evidenceSeminars in Neurology

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based guidelines on the management of IIH have prompted the NORDIC (Neuro-Ophthalmology Research Disease Investigator Consortium) to conduct a multicenter, double-masked placebo-controlled randomized trial (Idiopathic Intracranial Hypertension Treatment Trial [IIHTT]) to determine the efficacy of high-dose (up to 4 g) acetazolamide compared with placebo.73 The study included 165 IIH patients with mild visual loss. All patients were placed on a low-sodium weightreduction program. The primary outcome was the change in the Humphrey visual field perimetric mean deviation (a way to quantify overall visual field loss) at 6 months. The IIHTT showed efficacy of acetazolamide in visual loss, severity of

Update on the Diagnosis and Treatment of Idiopathic Intracranial Hypertension

Surgery The most common indication for surgery is deterioration of visual function attributable to papilledema despite maximal medical management.71,76 Surgery can be considered for intractable headaches, but their direct relation to increased ICP must be demonstrated because chronic headaches are common after IIH even with ICP control.8 The primary surgical options are CSF diversion procedures in which the CSF is diverted from the ventricles or the lumbar subarachnoid spaces to the peritoneal cavity (lumbo- or ventriculoperitoneal shunts) and optic nerve sheath fenestration, in which a “window” is opened through the orbital optic nerve sheath. Classically, a shunting procedure is indicated when visual loss is associated with severe headaches, whereas an optic nerve sheath fenestration is preferred when headaches remain under control. However, the preferred procedure remains controversial, and the indication depends on the availability and the expertise of the local team.

Transverse Venous Sinus Stenting The high prevalence of bilateral transverse venous sinus stenosis in IIH has prompted the use of transverse venous sinus stenting as a promising alternative to conventional surgery.77 Several small and uncontrolled studies78–80 have shown interesting results, but initial enthusiasm has been tempered by substantial morbidity, including stent migration, venous sinus perforation, stent thrombosis, subdural hemorrhage, and recurrent stenosis.71 Until a properly

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designed randomized trial is conducted, transverse venous sinus stenting should be reserved for patients with a demonstrated pressure gradient across bilateral venous stenoses in whom other conventional procedures have failed.68,71,76

Specific Situations Fulminant Idiopathic Intracranial Hypertension Although visual loss is typically insidious in IIH, some authors have reported IIH patients with a fulminant course, characterized by rapid and devastating visual loss in the setting of severe papilledema and very high CSF OP.49 Fulminant IIH is uncommon, and accounted for less than 3% of IIH patients in two tertiary centers.49 Because of its rarity, one should have increased concern that a secondary cause of increased ICP may be present, such as venous sinus thrombosis or a meningeal process. Prevention of further visual loss requires prompt recognition of the disorder and an emergent CSF diversion procedure with a short course of intravenous steroids combined with serial LPs or lumbar drain while awaiting the definitive surgery.

Idiopathic Intracranial Hypertension and Pregnancy The discovery of papilledema during pregnancy remains challenging, prompting an emergent workup to exclude venous sinus thrombosis or eclampsia.81 In patients carrying the diagnosis of IIH prior to pregnancy, no specific changes in the management of pregnancy or the delivery are required. However, caution may be needed with labor anesthesia for patients with a lumboperitoneal shunt because the anesthetic may flow from the subarachnoid spaces into the peritoneal cavity, leading to insufficient analgesia. 82 Regarding the treatment of IIH during pregnancy, acetazolamide appears safe in humans83 and we continue it if the patient has any degree of significant visual loss with permission of the patient’s obstetrician. If the patient has only mild or no visual loss, we will frequently stop the acetazolamide during the first trimester and follow the patient closely.84 Serial LPs can also be used as needed until delivery.

Pediatric Idiopathic Intracranial Hypertension Idiopathic intracranial hypertension might occur at any age, and clinicians must be aware of the possibility of IIH in children. However, pediatric IIH has several distinctive features that one must keep in mind.85 Although adolescents with IIH share the same demographics as adults with IIH, the sex ratio is closer to 1:1 and the association with obesity is weaker in prepubertal children with IIH. Regarding the diagnosis, the cutoff for elevated CSF pressure has been set at 28 cm H2O in the 2013 criteria4 based on a recent evaluation of CSF OPs in children.40 Other distinctive features include a higher proportion of secondary intracranial hypertension, the frequent absence of papilledema in children with open sutures, and slowly resolving papilledema over months despite satisfactory ICP control. The treatment is not different from that of adults, except that repeat LPs are often not as well-tolerated in children.85 Seminars in Neurology

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papilledema, and quality of life, but failed to show efficacy for headache control, although the headaches in both groups improved. Although the IIHTT has shown efficacy of acetazolamide to prevent visual loss in IIH, the effect was modest with an average dosage higher than what had generally been used in practice before the trial (2.5 g on average [up to 4 g] per day vs. 1–2 g per day).74 A subgroup analysis found higher efficacy of acetazolamide in patients with severe papilledema. This study confirms acetazolamide combined with weight loss as the treatment of choice in IIH patients with mild visual loss, but further studies are required to better refine the management of IIH patients with more severe visual loss. Apart from acetazolamide, few other drugs have been used in IIH. Corticosteroids have been found to be effective, but they are not recommended for long-term use because of the high rate of rebound of IIH upon withdrawal and the possibility of causing weight gain. High-dose intravenous corticosteroids may be useful in fulminant IIH with severe visual loss as a bridge to an emergent CSF shunting procedure.49 Patients with chronic headaches despite satisfactory control of ICP may benefit from a neurologist’s assistance. Most antimigraine drugs can be used in IIH, but topiramate is routinely used because it causes weight loss and has carbonic anhydrase activity; however, caution is warranted if patients are simultaneously taking topiramate and acetazolamide given their similar mechanism of action and the most notable risk for metabolic acidosis.75

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Conclusion Over the past few years, our understanding of IIH has increased substantially, with better identification of visual risk factors allowing tailored monitoring based on patients’ risk profiles, better description of atypical forms of IIH, including fulminant IIH and CSF leaks, improved brain imaging technology revealing findings specific to increased ICP, and a randomized controlled trial (i.e., the IIHTT) providing a solid basis for the use of acetazolamide in IIH. Other advances are more controversial, such as the most recent revision of the diagnostic criteria that has better defined IIH, but which has added confusion in terms of nomenclature. Finally, many questions remain unanswered. Clinical trials regarding patients with more severe visual loss and the efficacy of surgical procedures are required, and the role of venous sinus stenting has to be better defined. Finally, determining whether the new findings revealed by brain imaging and OCT truly assist clinicians in diagnosing and monitoring IIH remains unclear.

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Disclosures Supported in part by an unrestricted departmental grant (Department of Ophthalmology) from Research to Prevent Blindness, Inc., New York, and by NIH/NEI core grant P30EY006360 (Department of Ophthalmology). Dr. Bidot receives research support from Berthe Fouassier Foundation (Paris, France) and Philippe Foundation (New York, New York, USA). Dr. Bruce receives research support from the NIH/NEI (K23-EY019341).

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