Idiopathic intracranial hypertension (IIH) is a disorder of unknown etiology that predominantly affects obese women of childbearing age.[1] The primary problem is chronically elevated intracranial pressure (ICP), and the most important neurologic manifestation is papilledema (see the image below), which may lead to secondary progressive optic atrophy, visual loss, and possible blindness. Although IIH, pseudotumor cerebri, and benign intracranial hypertension (BIH) are synonymous terms in the literature, IIH is the preferred term.
View Image
Left optic disc with moderate chronic papilledema in a patient with idiopathic intracranial hypertension (pseudotumor cerebri). Paton lines (arc-shape....
Signs and symptoms
Patients with IIH usually present with symptoms related to increased ICP and papilledema. Symptoms of increased ICP may include the following:
Headaches (typically nonspecific and varying in type, location, and frequency)
Visual loss (typically visual field but rarely visual acuity loss)
Transient visual obscurations (typically lasting seconds at a time)
Diplopia (typically horizontal due to nonlocalizing sixth nerve palsy but rarely vertical)
Pulsatile tinnitus
Radicular pain (typically in the arms, uncommon symptom)
Nonspecific symptoms such as nausea and vomiting may also be present.
Rarely, patients presenting with increased ICP with related optic nerve edema may be asymptomatic.
Visual symptoms of papilledema may include the following:
Transient visual obscurations, often predominantly or uniformly orthostatic
Progressive loss of peripheral vision in one or both eyes (nerve fiber layer defects, enlargement of the blind spot)
Blurring and distortion (ie, metamorphopsia) of central vision due to macular edema or optic neuropathy
Photopsia
Rapid development of visual loss (eg, fulminant IIH)
The most significant physical finding in IIH is papilledema (ie, bilateral disc edema due to increased ICP).
See Clinical Presentation for more detail.
Diagnosis
Typically, no laboratory testing is mandatory for typical IIH, but some authors have recommended blood tests (eg, CBC count) and special CSF studies depending on clinical circumstances, including the following:
Complete blood count
Electrolytes, bicarbonate
Full procoagulant profile (typically obtained only in patients with a previous history of thrombosis or magnetic resonance imaging [MRI] or MR venographic evidence of a dural venous sinus)
Neuroimaging studies (preferably cranial MRI with magnetic resonance venography [MRV] with and without gadolinium) are essential to rule out the possibility of an intracranial lesion prior to performing a lumbar puncture. In addition, it is necessary to rule out the potential associated diagnosis of a dural sinus thrombosis. As a result, a combined MRI/MRV of the brain with gadolinium is the preferred study. At the very least, initially, CT scanning of the brain to rule out an intracranial lesion can be performed if a MRI is not immediately available.
Once an intracranial mass lesion is ruled out, a lumbar puncture is usually indicated to measure the opening pressure, to confirm elevated ICP, and to evaluate the CSF contents.
See Workup for more detail.
Management
The goal is to preserve optic nerve function while managing increased ICP. Pharmacologic therapy may include the following:
Acetazolamide (the most effective agent for lowering ICP and the only agent shown to be effective in a randomized, controlled, clinical trial) is the first-line therapy.
Furosemide or, rarely, other diuretics, as well as topiramate, have been used with anecdotal success as second-line agents.
Primary headache prophylaxis (eg, amitriptyline, propranolol, other commonly prescribed migraine prophylaxis agents, or topiramate)
Corticosteroids (for lowering ICP in IIH of inflammatory etiology or for supplementing acetazolamide) (Typically, this should be considered only on a short-term basis and only in patients who present with marked loss of visual function because steroids can cause weight gain and withdrawal of steroids may worsen IIH)
If visual function deteriorates while on maximal medical therapy, surgical interventions should be strongly considered. Such interventions include the following:
Optic nerve sheath fenestration (a protective measure to decompress the fluid surrounding the optic nerve)
Cerebrospinal fluid diversion (ie, via a lumboperitoneal or ventriculoperitoneal shunt)
Intracranial venous sinus stenting (in the presence of an area of evident focal stenosis of the dural sinus venous system)
Treatment of IIH with repeated lumbar punctures is considered to be of historic interest only, as the CSF volume reforms rapidly. However, serial lumbar punctures have been considered in some patients who refuse or cannot undergo conventional medical or surgical therapy (eg, pregnant patients). Placement of a lumbar drain as a temporizing measure in hospitalized fulminant IIH cases can be considered while awaiting a definitive surgical procedure.
Weight loss is a cornerstone of long-term management of these patients. No activity restriction is required; in fact, exercise programs are strongly recommended in conjunction with the weight-reduction diet. Some patients with IIH have experienced dramatic improvement after bariatric surgery.
Idiopathic intracranial hypertension (IIH) is a disorder of unknown etiology that predominantly affects obese women of childbearing age.[1] The primary problem is chronically elevated ICP, and the most important neurologic manifestation is papilledema, which may lead to progressive optic atrophy and blindness.
The presentation of acute/subacute symptoms of increased ICP and papilledema should be considered a clinical urgency/emergency until a neuroimaging study results confirm the presence or absence of an intracranial mass. Patients with symptoms and signs of longer duration (months) may not require urgent evaluation, and the timing of such evaluation may be limited by patient choice, insurance approval/coverage, and neuroradiology scheduling availability. A significant number of patients presenting in this manner whose neuroimaging study results do not reveal a mass lesion are diagnosed with IIH. Although IIH, pseudotumor cerebri, and benign intracranial hypertension (BIH) are synonymous and refer to the same diagnosis, IIH is the preferred term.
The diagnostic criteria for IIH, including those of the Dandy criteria as described by Dandy in 1937 and later modified, are as follows:
There are only symptoms and signs of increased ICP
There are no other localizing neurologic signs other than those related to increased ICP (eg, unilateral or bilateral sixth nerve paresis, papilledema, or papilledema-related visual loss)
Cerebrospinal fluid (CSF) may show increased pressure, but there are no cytologic or chemical abnormalities
Neuroimaging reveals radiographic signs of increased ICP but no structural cause or hydrocephalus
No other causes of increased ICP found through workup
Subsequent additions to these criteria include the following[2, 3, 4] :
The diagnostic lumbar puncture should be performed with the patient in the lateral decubitus position.
MRI and MRV should be considered the ideal imaging studies to rule out intracranial venous sinus thrombosis. However, some patients cannot undergo MRI (eg, ferromagnetic foreign body, non-MRI compatible aneurysm clip or cardiac pacemaker), so CT scanning and CT venography (CTV) may be necessary as alternative neuroimaging studies.
The pathophysiology of IIH is unclear. A dominant early theory held that cerebral edema played a role in the pathogenesis of elevated ICP in these patients. Against this view was the observation that no altered levels of alertness, cognitive impairments, or focal neurologic findings were associated with the elevated ICP. In addition, no pathologic signs of cerebral edema were documented in these patients. Early reports describing edema were later considered to represent fixation artifact (ie, from tissue preparation) rather than in vivo edema.
Current hypotheses include the link between relatively obstructive segments in the distal transverse sinus and IIH and the presence of increased arterial inflow with an accompanying low-grade stenosis of the transverse sinus.[5, 6]
In a series reported by Farb et al, 29 patients with IIH showed demonstrable narrowing of the transverse dural venous sinus on magnetic resonance (MR) venography, whereas none of the 59 control subjects had this finding.[7] The authors suggested that the narrowing is a consequence of elevated ICP and that when the narrowing develops, it exacerbates the pressure elevation by increasing venous pressure in the superior sagittal sinus. Their findings underscored the following points:
The CSF production rate (mL/min) should be equal to the CSF reabsorption rate
If production exceeds absorption, ICP rises until it exceeds the mean arterial pressure (MAP); if this rise should be sustained, it would be fatal
In IIH, the CSF production rate equals the CSF reabsorption rate; however, a higher than normal pressure is required to achieve this balance, owing to the increased resistance at the arachnoid granulations lining the dural venous sinuses
Bateman showed that some IIH patients with normal dural venous drainage have increased arterial inflow, which suggests that collateral venous drainage occurs in addition to the drainage provided by the superior sagittal sinus and transverse sinuses.[8]
Bateman also used MR venography and MR flow quantification in cerebral arteries and veins in 40 IIH patients, 21 of whom had venous stenosis; arterial inflow was 21% higher than normal, and superior sagittal sinus outflow was normal, resulting in a reduced percentage of venous outflow as compared with inflow.[9] The remainder of arterial inflow volume was presumed to have drained via collateral venous channels. With clinical remission of symptoms, arterial inflow volumes returned to normal.
Subsequently, Bateman et al proposed a mathematical model to address the role of collapsible dural venous sinuses in the pathogenesis of IIH; the model included arterial inflow volume, venous outflow resistance, and CSF pressure.[5] The investigators used combined flow rates in the 2 carotid arteries and the basilar artery (as measured by MRI in individual patients) as the measure of inflow blood volume and used measured values from the literature for the pressure gradient from superior sagittal sinus to jugular bulb and venous outflow resistance.
The model predicts 2 CSF pressure equilibrium points for the collapsible dural sinus cases with greater than 40% stenosis (usually of the transverse sinus), one in the normal range and the other in the range encountered in IIH patients.[5] This may account for the prolonged remission of symptoms that follows removal of CSF through lumbar puncture, presumably because this step relieves the venous sinus stenosis.
Without dural sinus collapse and stenosis, as is encountered in some patients with IIH, the model required increased arterial inflow volume to account for the elevated ICP; however, it did not require increased resistance to outflow of CSF across the arachnoid villi.[5]
IIH commonly occurs in women who are overweight; however, the role obesity plays in this disorder is unclear. In some instances, obesity and IIH may be familial.[10] It has been proposed that obesity increases intra-abdominal pressure and thereby raises cardiac filling pressures. These rises in pressure lead to impeded venous return from the brain (due to the valveless venous system that exists from the brain to the heart) with a subsequent elevation in intracranial venous pressure.
A link between obesity and an elevated level of cytokines, interleukins, and leptin suggests a possible inflammatory component for IIH.[11] Leptin is a protein secreted by adipose tissue, and its level is in proportion with total body fat content. In one case control study, a significantly higher serum leptin level was found in patients with IIH than in controls (P< 0.0001), and this did not correlate with body mass index (BMI).[12] Levels of other adipokines and the gastric hormone ghrelin were not consistently found to have an association with IIH.[13]
A role for vitamin A in the pathogenesis of IIH was reported in early studies, which noted elevated levels of vitamin A and its metabolites in CSF compared to controls.[14, 15] However, more recently, results from the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) in patients with IIH versus obese controls over 6 months showed no difference in CSF vitamin A levels except in those treated with acetazolamide.[16]
Hormones in women of childbearing age have also been suggested to have a role in the pathogenesis of IIH. To date, however, there is no proven hormone profile in individuals with IIH, and hormone testing is not typically performed in such patients.[17]
Low-calorie diets that have resulted in weight loss and ICP reduction have also been shown to decrease 11beta-HSD1, an enzyme that controls the level of active cortisol.[18] Currently, a phase II trial is ongoing to assess safety and efficacy of an 11beta-HSD1 inhibitor.
Aquaporins (AQP) are CNS membrane channel proteins. AQP4 has been studied in transgenic mice; its deficiency was associated with IIH-like pathology.[11, 19] In other studies, acetazolamide was shown to decrease AQP1, while steroids and retinoid increase its expression.[20, 21]
Most cases of IIH occur in young women who are obese; a considerably smaller percentage occur in men who are otherwise healthy. Patients with higher body mass indexes (BMIs) and recent weight gain are at increased risk.[6, 22] If IIH presents in an individual who is not overweight, it is necessary to rule out associated risk factors, such as the following[4, 6] :
Exposure to or withdrawal from certain exogenous substances (eg, steroids, growth hormone)
Systemic diseases (eg, infectious and inflammatory etiologies)
In 1994, Radhakrishnan et al reviewed the literature on IIH associated with other diseases and with drugs. They argued that for these diseases and drugs to be included in the list of causally related associations, the following criteria should be met[23] :
At least 2 cases should have been described
The reported cases should have met all the criteria for the diagnosis of IIH
Intracranial dural sinus thrombosis should have been ruled out with reasonable certainty
Exogenous substances
The list of exogenous substances associated with IIH is extensive. Although the association between these substances and this disorder is generally considered well established, the exact causal relation has not been fully clarified in the literature.
Exogenous substances reportedly associated with IIH include amiodarone, antibiotics (eg, nalidixic acid, penicillin, and tetracycline), carbidopa, levodopa, chlordecone, corticosteroids (topical and systemic), cyclosporine, danazol, growth hormone, indomethacin, ketoprofen, lead, leuprolide acetate, levonorgestrel implants, lithium, oxytocin, perhexiline, phenytoin, and vitamin A (>100,000 U/day)/retinoic acid.[4, 6] However, the Idiopathic Intracranial Hypertension Treatment Trial compared serum and CSF levels of vitamin A metabolites in patients with IIH and controls. No differences were found in patients with IIH and controls prior to treatment, leading the study to conclude that vitamin A does not affect the development of IIH.[16] Although many potential associations have been reported, few have been proven to be causal using typical causation criteria (eg, World Health Organization criteria).
According to the 1994 review by Radhakrishnan et al and numerous subsequent reports,[24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40] medication risk factors that meet minimal criteria but have not been confirmed in case-controlled studies include the following:
All-trans-retinoic acid (ATRA) used in the treatment of promyelocytic leukemia, cyclosporine, levonorgestrel implant, pancreatin
Recombinant human growth hormone/natural growth hormone (somatotropin)
Vitamin A in infants
However, a case-control study[42] found that several of the conditions that were thought to be associated with IIH were not more common than in the control patients, including iron deficiency anemia, thyroid disease, pregnancy, antibiotic intake, and use of oral contraceptives.[42] No direct causation has ever been established in cases of contraceptives, including birth control pills and drug-eluting intrauterine devices. It is believed that rapid weight gain after starting the contraceptives, rather than direct hormonal influence, is probably the trigger.
In some instances, although a patient may present with IIH after exposure to a certain medication, the disorder can continue despite discontinuance of the presumed offending agent.
Withdrawal from corticosteroids may result in IIH.[4] If corticosteroids are used for the treatment of IIH, their withdrawal may lead to a rebound increase in ICP.[2]
Systemic diseases
A myriad of illnesses are associated with IIH. Some of these disorders are known to result in increased viscosity of the CSF. In most of them, however, the causal link with increased ICP is not clear. The following diseases have all been reportedly associated with IIH.[4] As with the supposed medication-induced cases of IIH, many of these reports may be coincidental and not necessarily causal.
Anemia[43]
Chronic respiratory insufficiency
Familial Mediterranean fever
Hypertension
Multiple sclerosis
Polyangiitis overlap syndrome
Psittacosis
Chronic renal disease
Reye syndrome
Sarcoidosis
Systemic lupus erythematosus
Thrombocytopenic purpura
Behcet syndrome[44, 45]
Hypervitaminosis A[46, 47, 48]
Coagulation disorders[49, 50, 51, 52]
Sleep apnea[53, 54]
Uremia[55]
Polycystic ovary syndrome (PCOS)[49]
Addison disease[56, 57]
Disorders of cerebral venous drainage
Compression of cerebral veins by extravascular tumors, secondary thrombosis due to coagulopathy, or relative stenosis due to a venous flow anomaly can result in impaired absorption of CSF and, thus, IIH.[5, 58] Restriction of venous drainage from the head may be impaired with radical neck dissection, even if it is completed only on the right (drainage from the head takes place mainly via the right jugular vein). Spontaneous recanalization usually occurs, but if it is delayed, chronic papilledema may result.
The diagnosis of cerebral sinus thrombosis may be missed if only computed tomography (CT) is performed. Therefore, in patients who present atypically or in cases where management dilemmas arise, it is worthwhile to perform MRI or MR venography to rule out cerebral venous thrombosis.
Endocrine disturbances
Pregnancy is occasionally associated with IIH.[2] The disorder can present at any stage of pregnancy. In view of the limitations of neuroimaging studies and the restrictions on medical treatment in pregnant patients, it is advisable that both diagnostic and therapeutic strategies be formulated on a case-by-case basis. Any neuroimaging studies or therapeutic interventions should be performed in conjunction with the patient’s obstetrician.
According to reports by Radhakrishnan and others,[24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40] endocrine risk factors that have been confirmed in epidemiologic studies include the following:
Female sex
Reproductive age group
Menstrual irregularity
Obesity
Recent weight gain
Endocrine risk factors that meet minimal criteria but have not been confirmed in case-controlled studies include the following:
Adrenal insufficiency
Cushing disease
Hypoparathyroidism
Hypothyroidism
Excessive thyroxine replacement in children (ie, low thyrotropin levels)
Other risk factors
Increased venous red blood cell (RBC) aggregation and relatively elevated fibrinogen concentrations have been demonstrated in patients with IIH as compared with matched control subjects.[59]
The ratio of retinol to retinol-binding protein is elevated in the CSF of patients with IIH as compared with non-IIH neurologic control subjects and with normal control subjects.[14]
Because IIH is concentrated in women between puberty and menopause, Fraser et al emphasized the potential role of sex hormones in the pathogenesis of IIH; they also pointed out that obstructive sleep apnea (OSA) has been proposed as a risk factor.[60] Because women taking exogenous estrogen and pregnant women are not at particular risk for IIH, the investigators suggested that low levels of testosterone might be the important hormonal link in women with IIH.
Fraser et al administered 2 standardized questionnaires embedded in a telephone interview of 24 men with IIH and 48 control subjects matched for gender, age, race, and World Health Organization (WHO) BMI category.[60] They found that the men with IIH were significantly more likely to have symptoms of testosterone deficiency and OSA than the control subjects were.
Studies of American-based populations have estimated that the incidence of IIH ranges from 0.9 to 1.0 per 100,000 in the general population, increasing to 1.6-3.5 per 100,000 in women and to 7.9-20 per 100,000 in women who are overweight.[2, 4, 6]
For example, annual figures for IIH in Iowa and Louisiana in the late 1980s were as follows[61] :
0.9 case per 100,000 population
13 cases per 100,000 (Iowa) and 14.85 per 100,000 (Louisiana) in women aged 20-44 years and 10% over their ideal weight
19.3 cases per 100,000 in women 20% over their ideal weight
An 8:1 female-to-male ratio for a mean weight 38% over the ideal weight for height
Annual incidence figures for the Mayo Clinic (Rochester, MN) between 1976 and 1990 were as follows[62] :
0.9 case per 100,000 population
1.6 cases per 100,000 women
3.3 cases per 100,000 females aged 15-44 years
7.9 cases per 100,000 obese women aged 15-44 years
International statistics
The incidence of IIH varies from country to country. Because of the disease’s relation to body habitus, its occurrence varies according to the incidence of obesity in the respective region.
In a study conducted between 1982 and 1989 that comprised 81 patients (76 females and 5 males) aged 8-55 years, the annual incidence of IIH in Benghazi, Libya, was as follows:[63]
2.2 cases per 100,000 population
4.3 cases per 100,000 women of all ages
12 cases per 100,000 women aged 15-44 years
21.4 cases per 100,000 obese women aged 15-44 years
Age-, sex-, and race-related demographics
Although IIH may affect individuals of any age, most patients with this disease present in the third decade of life.[6] IIH can occur in the pediatric population[64] ; these younger patients are often not obese.
IIH has a strong predilection for women. More than 90% of patients with IIH are women of childbearing age.[6] However, men with IIH are twice as likely as women to lose visual function as a result of papilledema. Thus, the visual function of men with IIH must be followed more closely to avoid irreversible damage.[65]
No evidence exists to suggest that IIH has a predilection for any particular racial or ethnic group over and above any variations in the prevalence of obesity that may be noted in the different groups.
A national prospective populated-based cohort study in the United Kingdom investigated the incidence of IIH in children aged 1-16 years and found a similar incidence in children of both sexes younger than 7 years, but the incidence in obese girls was double that of obese boys after age 7 years. Obesity remained a major risk factor for both sexes in childhood.[66]
IIH is not known to be associated with any specific mortality risk per se, but endovascular and surgical treatments (eg, venous sinus stenting or shunting) may cause morbidity and mortality. The increased mortality associated with morbid obesity has a selective expression in this group because of the strong predilection of the disease to affect obese females.
The morbidity of IIH is mainly related to the effects of papilledema on visual function.[67] If left untreated, long-standing disc edema results in an irreversible optic neuropathy with accompanying constriction of the visual field and loss of color vision.[68, 69, 70] In end-stage papilledema, central visual acuity is also involved. With timely and appropriate treatment of IIH, the visual prognosis can be encouraging.
The Idiopathic Intracranial Hypertension Treatment Trial examined quality of life (QOL) in 165 patients with IIH and mild vision loss using the National Eye Institute Visual Function Questionnaire. They found that the use of acetazolamide with a low-sodium weight-reduction diet resulted in improvement in visual field function compared with diet alone. When compared with published controls and obese controls, patients with IIH had lower QOL scores due to decreased visual loss and associated symptoms such as diplopia, headache, and neck pain.[71]
Unfortunately, the incidence of visual loss has been reported to be significant in some studies of this disease.
Since the increase in ICP tends to be chronic, all patients with IIH must be monitored for years after presentation. If necessary, medical treatment should be continued on a long-term basis.
Vision loss
The frequency and degree to which vision loss occurs in IIH is difficult to establish from the existing literature. Depending on the referral population and the rigor with which visual function is tested, the prognosis for vision loss in IIH has varied considerably in different series. Authors writing in the 1960s and 1970s indicated that fewer than 25% of these patients had functionally significant blindness; however, this figure has since been revised upward.
As outlined by Radhakrishnan et al in 1994,[23] the reported incidence of vision impairment is much higher in series from referral centers (as many as 96% of cases with some degree of visual field loss) than in population-based series (eg, 22% in Iowa[61] ). Two equally valid explanations for this discrepancy have been proposed:
The referral centers perform more extensive vision testing, including Goldmann and computerized automated threshold perimetry; thus, they discover visual deficits that are not tested for in the community-based studies
The worst cases are referred for tertiary care consultation; thus, the referral center series are biased toward more severe vision loss cases than the community-based studies are
In a major prospective study of visual function in IIH, Wall and George found that 96% of the 50 patients in a series had some degree of visual field loss on Goldmann-type perimetry, whereas 92% had abnormal findings on automated perimetry[72] ; 50% had abnormal contrast sensitivity, and 22% had abnormal Snellen visual acuity. During follow-up (2-39 months; average, 12.4 months), visual fields improved in 60% of patients and deteriorated in 10%.
The University of Iowa observed 20 IIH patients for more than 10 years and found that whereas 11 of the 20 had followed a stable course without visual-field changes or papilledema, 9 had experienced deterioration after initially following a stable course for a time.[73] In 6 of the 9, the deterioration occurred late (28-135 months after initial presentation), and in 3 of the 9, recurrences after resolution of papilledema developed 12-78 months after the initial resolution of IIH.
Informing patients who are overweight that weight control is a long-term factor in the management of IIH is important. Asking patients about their weight loss at the beginning of each visit reinforces this concept. In addition, it may be worthwhile to mention that the loss of as little as 6% of body weight may lead to the termination of this disorder and also may significantly diminish the risk of its recurrence. A recent clinical trial determined that acetazolamide and weight loss (compared with diet alone) was the preferred treatment in patients with mild visual loss (Idiopathic Intracranial Hypertension Treatment Trial at NORDIC Clinical Trials).
In particular, it is essential to educate patients regarding the potential for disabling blindness. The importance of weight loss as the only effective means of reducing the papilledema—and with it the threat of progressive blindness—cannot be overemphasized.[74, 75]
Patients should be urged to enroll in an aggressive weight-loss program, ideally one using a multidisciplinary approach that includes diet and exercise along with psychological and lifestyle counseling. Even when such a program is followed, many patients cannot sustain significant weight reduction and may require drastic steps such as gastric stapling or resection. These measures can be effective for patients who experience vision loss despite aggressive medical and surgical management.[76, 77]
Although IIH may appear to be self-limiting, it is considered to be a chronic disorder; therefore, once the medications given to treat it are tapered off, patients should be instructed to return to an ophthalmologist if symptoms of increased ICP recur. If a particular agent, such as tetracycline, is associated with the rise in ICP, the patient should be educated to avoid this agent.
Patients with idiopathic intracranial hypertension (IIH) usually present with symptoms related to increased ICP and papilledema, including headache, transient visual obscurations, and diplopia due to unilateral or bilateral abducens nerve (cranial nerve [CN] VI) palsy. Rarely, patients presenting with increased ICP with related optic nerve edema may be asymptomatic. Nonspecific symptoms may include dizziness, nausea, vomiting, photopsias, retrobulbar pain, and pulse-synchronous tinnitus.[6]
Symptoms of elevated intracranial pressure
Headaches are recorded in almost all IIH patients.[78] They are typically nonspecific and vary in type, location, and frequency. The pain is generally described as being diffuse, worsening in the morning and being exacerbated by the Valsalva maneuver. In a large case series, men were less likely than women to report headache (79% vs 89%; P = 0.01). In a 2016 UK pediatric cohort study, headaches were reported in 87% of cases but were less common in children younger than 7 years.[65, 66]
The pain is generally described as being diffuse, worsening in the morning and being exacerbated by the Valsalva maneuver. Retrobulbar pain, pain with eye movement or compression, or pain that follows a trigeminal or cervical nerve root distribution are specific to IIH to some extent.[79]
Associated nausea and vomiting is not infrequent. Some report exacerbation with posture and some relief with NSAID therapy and/or rest. The common refractory nature of headaches prompt patients to over-use analgesic medication, which may lead to or superimpose rebound headache.[80]
A randomized prospective trial that assessed headache-related disability found significant patient-reported quality-of-life implications in the physical, mental, and visual domains.[81]
Patients who present with double vision most frequently complain of horizontal displacement of the images. Horizontal diplopia is a symptom of a false-localizing CN VI palsy. Vertical diplopia is rare, but it has been reported.
Pulsatile tinnitus may be reported. This is a rhythmic sound, heard in one or both ears, with a pulsing synchronous rhythm that may be exacerbated by the supine or bending position. It is believed to represent vascular pulsation transmitted by CSF fluid under high pressure to the venous sinuses.[82]
Radicular pain (usually in the arms) is an uncommon symptom.
Symptoms of papilledema
Transient visual obscurations occur in 68% of patients.[42] The disturbance can last up to 30 seconds and is described as a dimming or blackout of vision in one or both of the eyes. These obscurations may be predominantly or uniformly orthostatic (ie, developing with standing up or bending over) and can be precipitated by bright light or eye movement. Visual obscurations are not predictive of visual loss or correlated with degree of elevated ICP.[68]
Progressive loss of peripheral vision in one or both of the eyes may be noted. Typically, the vision loss starts in the nasal inferior quadrant and is followed by loss of the central visual field (possibly affecting visual acuity) and, finally, loss of color vision.
Blurring and distortion (ie, metamorphopsia) of central vision is caused by macular wrinkling and subretinal fluid spreading from the swollen optic disc.
Sudden visual loss is due to intraocular hemorrhage secondary to peripapillary subretinal neovascularization related to chronic papilledema.
Visual function tests (visual field assessment, ocular motility examination) are the most important parts of the neurologic examination for diagnosing and monitoring patients with IIH.
Vision
Visual acuity is usually normal before development of significant peripheral visual field loss with progressive postpapilledema optic atrophy.
Color vision
Color vision is usually tested in the office with color-confusion–type plates, most commonly the Ishihara or Hardy-Rand-Rittler (HRR) plates. Unlike visual acuity testing, color vision testing is not sensitive for early postpapilledema optic atrophy, since color perception is concentrated in the central visual field.
Visual fields
Formal visual field testing should be conducted in patients with suspected IIH. Goldmann-type dynamic perimetry and computerized automated Humphrey-type static perimetry are both options for testing the visual field. While Goldmann-type dynamic perimetry provides reliable information concerning the most peripheral parts of the visual field, the results of the test are operator-dependent. Although Humphrey-type static perimetry usually does not test beyond 30° of eccentricity, it is less operator-dependent. Thus, Humphrey-type static perimetry is the recommended test for more reliable long-term follow-up.[83]
In the IIHTT, the most prominent baseline hemifield abnormality classification was a partial arcuate defect with an enlarged blind spot (about three-fourths of the hemifields in the study eye and about half of the hemifields in the fellow eye). If left untreated, chronic disc swelling eventually leads to clinically significant visual loss. Although all patients present with enlarged blind spots during their initial perimetry, uncontrolled papilledema results in progressive peripheral visual field constriction or nerve fiber bundle defects (eg, nasal depression, nasal steps, arcuate scotomas).
The first sign of incipient postpapilledema optic atrophy is constriction of the inferior nasal quadrant of the visual field with a border reflecting the nasal horizontal midline (nasal step). This starts in the most peripheral points in the visual field (ie, 50° from fixation) and progresses inward (see the image below).
View Image
Most common early visual field defect in papilledema as optic nerve develops optic atrophy is inferior nasal defect, as shown in left eye field chart ....
The central visual field is affected in end-stage chronic papilledema. Sudden loss of central vision may result from an associated anterior ischemic optic neuropathy, a vascular occlusion, or an associated subretinal neovascular membrane.
Ocular motility examination
Occasionally, limited abduction of one or both eyes results from increased ICP. This is termed false-localizing CN VI palsy. It is usually observed as the patient follows the examiner’s hand to the right and the left with both eyes.
Typically, the involved eye does not move as fully outward (ie, abduction), leaving some white sclera showing lateral to the cornea on the involved side compared with the other side. The speed of the abducting movement is also usually less in the paretic eye than in the normal eye. Some patients with full abduction still show some sclera; therefore, when using this sign, demonstrating asymmetry between the eyes in abduction is important. Measurements with a prism cover test to document the degree of esotropia in primary position and in the diagnostic positions of gaze may be useful for follow-up over time.
These CN palsies diminish with lowering ICP. Occasionally, patients with diplopia present with oculomotor or trochlear nerve palsy. In rare instances, vertical diplopia results from a skew deviation. The presence of any other ocular motor cranial neuropathy other than CN VI (a nonlocalizing sign of increased ICP) supports the diagnosis of idiopathic suspect.
Fundus examination
The most significant physical finding in patients with IIH is bilateral disc edema due to increased ICP.
This papilledema varies from patient to patient and is indistinguishable from optic nerve swelling caused by intracranial space-occupying lesions. In more pronounced cases of disc swelling, macular involvement with subsequent edema and diminished central vision may be present. High-grade and atrophic papilledema and subretinal hemorrhage are poor visual prognostic signs. In some cases, the disc swelling is asymmetric; in the IIHTT, 7% of papilledema cases were asymmetric.[84] In rare instances, the appearance of the optic nerve is relatively normal. Risk of permanent visual loss is higher with more severe papilledema.[85]
Peripapillary flame hemorrhages, venous engorgement, and hard exudates are features consistent with acute papilledema. Telangiectatic vessels on the disc surface, optociliary shunt veins (which exit the disc at its margin), and optic disc pallor are associated with chronic papilledema (see the images below). The severity of papilledema is assessed using the Frisen grade. The grading scale is 0 to 5, with 0 being no papilledema and 5 being severe edema with obscured vessels on the disc and leaving the disc. This grading scale correlates with optical coherence tomography (OCT) findings of retinal nerve fiber layer thickness.[86] In the IIHTT, grade 2 was the most common.[84]
View Image
Left optic disc with moderate chronic papilledema in a patient with idiopathic intracranial hypertension (pseudotumor cerebri). Paton lines (arc-shape....
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Right optic disc with postpapilledema optic atrophy in a patient with idiopathic intracranial hypertension (pseudotumor cerebri). Diffuse pallor of di....
The only severe and permanent complication of IIH is progressive blindness due to postpapilledema optic atrophy. As optic nerve axons die, the apparent degree of papilledema may diminish, giving a false sense of improvement. For this reason (and others), the patients must be monitored with frequent visual field examinations.
Visual acuity and color vision are not affected until late in the disease, when the peripheral visual field isopters are quite contracted.
Occasionally, a patient may develop an acute loss of vision due to ischemic optic neuropathy or a retinal vascular occlusion associated with the papilledema.
Blood tests are useful for ruling out systemic lupus erythematosus or other collagen-vascular diseases, which have been reported as underlying conditions in some patients with IIH.[87]
An increased incidence of anticardiolipin antibodies has been reported in patients with IIH. Accordingly, some authors advocate anticardiolipin antibody assessment in all patients with IIH, regardless of prior history of thrombosis.[51] Some authors advocate screening for anticardiolipin antibodies and other procoagulant states in all patients with IIH who are either male or nonobese.[52] A meta-analysis of thrombophilic factors in IIH revealed that antiphospholipid antibodies were significantly associated with IIH (odds ratio [OR] = 4.25 [1.68-12.60]), similar to the association with high factor VIII (OR = 16.17 [2.87-91.01]), higher plasminogen activator inhibitor-1 (PAI-1) levels (OR = 6.91 [2.28-20.91]), and high lipoprotein (a) (LP[a]) (OR = 3.54 [1.54-8.70]). Obesity, often observed in patients with IIH, is frequently linked with thrombophilic factors.[88]
Cases of IIH associated with Lyme disease have been reported.[89] Lyme disease screening via enzyme-linked immunosorbent assay (ELISA) should be considered in patients with a history of exposure to Lyme disease in endemic areas.
The most frequent abnormal laboratory findings included elevated C-reactive protein (CRP) levels (51%), thrombophilia (31%), increased plasma cortisol levels (29%), and elevated lactate dehydrogenase (LDH) levels (20%). Patients with elevated CRP and patients with thrombophilia had an unfavorable visual outcome. Increased cortisol levels and abnormal calcium correlated with a higher rate of recurrence. The visual outcome of patients with elevated LDH levels was better than those with normal LDH levels. Certain metabolic, inflammatory, and coagulation abnormalities may influence the course of IIH. If confirmed in further studies, these findings could contribute to elucidation of the etiology and prognosis of IIH.[90]
Most patients with typical history, gender, and body habitus need only routine CSF tests.
A patient with bilateral disc swelling should undergo urgent neuroimaging studies to rule out an intracranial mass or a dural sinus thrombosis.
Brain MRI with gadolinium enhancement and MRV is probably the study of choice in all patients with IIH, in that it provides sensitive screening for hydrocephalus, intracerebral masses, meningeal infiltrative or inflammatory disease, and dural venous sinus thrombosis. In a retrospective study of imaging features that have been suggested as typical in IIH, only flattening of the posterior globe was found to be a reliable indicator of IIH, with a specificity of 100% and a sensitivity of 43.5%.[91]
MRV can be useful in patients who are at greater risk for dural venous sinus thrombosis, such as those with suspected thrombosis on MRI, nonobese or male individuals, or those with a documented procoagulant state. Sagittal T1-weighted images often provide excellent views of the superior sagittal sinus, and these are typically included in routine MRI. Extraluminal narrowing of the transverse sinuses may be a typical feature of IIH, as reported by Farb et al.[7]
Brain CT scanning is less expensive than MRI and is usually adequate to rule out an intracranial lesion; however, MRI and MRV are more effective in ruling out a mass lesion and a dural sinus thrombosis, respectively. CT scanning with contrast enhancement may be necessary in patients with contraindications to MRI (ie, pacemakers, metallic clips/foreign bodies). Although MRV was once considered an elective imaging study for atypical cases, it is now increasingly accepted as a routine study in all patients with IIH.[92]
In the setting of IIH, neuroimaging findings include normal or small slitlike ventricles, flattening of posterior sclera (43%-80%), distension of perioptic subarachnoid space (45%-67%), enhancement of prelaminar optic nerve (3%-30%), vertical tortuosity of orbital optic nerve (40%), intraocular protrusion of the prelaminar optic nerve (3%-30%), and an empty sella (25%-80%).[93, 94, 95, 96, 97, 98, 99]
The accuracy of MRI in the diagnosis of IIH was studied by Maralani et al. In this study, 43 IIH cases and 43 controls were evaluated with MRI and MRV. Partially empty sella had a sensitivity of 65% for IIH with a specificity of 95.3%; flattening of the posterior globes, 54% and 100%, respectively; a combined stenosis score of less than 4, 63% and 100%, respectively. The presence of one sign or any combination significantly increased the likelihood a IIH diagnosis. Their absence, however, did not rule out IIH.[92]
Butros et al have shown that chronically elevated CSF pressure can lead to osseous erosions, including widening of the foramen ovale and other canals and ostia. This may serve as a novel imaging marker for IIH. Average foramen ovale sizes were increased in patients with IIH compared to controls, with a sensitivity of 50% and specificity of 81% in the detection of IIH.[100] Other rarely reported abnormalities have included tonsillar ectopia, narrowing of the Meckel cave and cavernous sinuses, and meningoceles.[101, 102, 103]
Bedside or clinical ultrasonography has been used to identify intracranial hypertension by precisely measuring the diameter of the optic nerve sheath.[104] If this diameter increases in primary gaze and diminishes by 25% in eccentric gaze (30° test), then increased subarachnoid fluid surrounding the optic nerve is presumably present. This finding is consistent with papilledema if it is bilateral.
The drawback of this noninvasive technique is that it requires a highly skilled clinician to obtain reproducible results.
Once an intracranial mass lesion is ruled out, lumbar puncture is indicated. The opening pressure should be measured with the patient relaxed in the decubitus position to prevent a falsely elevated pressure reading. If any specific difficulty is encountered that may have caused such as false elevation, the clinician performing the procedure must communicate this to the ophthalmologist. Unfortunately, some patients demonstrate a transiently normal pressure despite harboring IIH; confirming the disease in these patients is difficult.
Besides the value of the opening pressure, the clarity and color of the CSF should be noted. In addition, the CSF should be forwarded for cell count, cytology, culture, and measurement of glucose, protein, and electrolyte concentrations. All of these findings are normal in patients with IIH.
In obese patients, finding landmarks may be difficult; consequently, the tap is often performed with the patient seated. The normal CSF pressure at the foramen magnum in the seated position is nearly 500 mm water from the lumbar entry point in persons of average height. Thus, an opening pressure of 500 mm water is extremely high for the lateral decubitus position but normal for the sitting position. If possible, the patient should be moved to the lateral decubitus position before the pressure is measured.
Another approach to lumbar puncture in obese patients involves fluoroscopic guidance in the radiology department. Prone positioning on the x-ray table and increased abdominal pressure in this position may falsely elevate the CSF pressure. If the pressure is normal with the patient in the prone position, then the measurement is probably accurate. However, if it is high, the patient must be rolled into the lateral decubitus position and allowed to relax before a reliable pressure reading can be completed.
Obviously, such maneuvers carry a risk of displacing the needle from the thecal space. However, no alternative method exists for obtaining an accurate pressure reading.
The treatment goal in patients with idiopathic intracranial hypertension (IIH) is to preserve optic nerve function while managing increased ICP. Medical management is multifaceted. Optic nerve function should be carefully monitored with an assessment of visual acuity, color vision, optic nerve head appearance, and perimetry. Weight control is recommended for obese patients.[105] Exogenous agents related to increased ICP should be discontinued.
Patients without visual loss are most often treated with a carbonic anhydrase inhibitor (eg, acetazolamide) to lower the ICP. While, historically, this has been the mainstay of treatment, it has now been corroborated with an NIH-funded study (Idiopathic Intracranial Hypertension Treatment Trial). In patients with severe symptoms, early visual field loss, or poor response to standard medical therapy, some clinicians use a short course of high-dose oral corticosteroids to temporarily postpone the need for surgical intervention.
When new visual field loss is documented, medical management should be coupled with plans for emergency surgical intervention if the visual function continues to deteriorate or does not improve immediately with corticosteroid treatment.
Visual loss in one or both of the eyes can evolve rapidly despite best efforts to arrest the process.
The exact interval within which vision loss can be reversed after symptomatic decline is unknown. Opinions among experts vary as to how rapidly and aggressively any given patient should be treated.
One of the standard teachings regarding this condition has been that pregnancy exacerbates or triggers the onset of symptomatic IIH. At present, however, there is little statistical evidence of a causal association between pregnancy and IIH, beyond the fact that pregnancy is common in the age group and gender that is predominantly affected by IIH.[106, 42]
In a 2014 NIH-funded study of 165 patients with IIH and mild vision loss (the Idiopathic Intracranial Hypertension Treatment Trial), researchers found that acetazolamide treatment for 6 months in conjunction with a low-sodium weight-reduction diet modestly improved vision, reduced ICP, improved quality of life, and reduced papilledema. Average improvement in perimetric mean deviation (PMD) was 1.43 dB with acetazolamide and 0.71 dB with placebo. Data showed that the drug’s effect was independent of weight loss.[107, 108] Compared with the placebo group, patients on acetazolamide treatment had statistically significant improvement of retinal nerve fiber layer thickness, total retinal thickness, and optic nerve volume based on OCT measurements.[109]
Acetazolamide appears to be the most effective agent for lowering ICP. Most patients experience adequate relief of symptoms (typically, headache) with this first-line agent. The brand-name formulation Diamox appears to be better tolerated than generic acetazolamide.
Among patients who are able to tolerate acetazolamide, it has been successful in managing symptoms and stabilizing vision in 47%-60% of cases.[110, 111, 112]
A randomized prospective trial assessed headache response to study interventions in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). Using the Headache Impact Test-6 (HIT-6) questionnaire, the trial showed that a similar amount of improvement occurred in the acetazolamide versus placebo group at 6 months. The lack of correlation between headache disability and CSF pressure at baseline and at the end of the randomized phase of the study implies that headache in IIH may be related to factors other than intracranial hypertension and that specific headache treatment is needed in addition to therapies directed at lowering CSF pressure.[113]
In a long-term follow up study of 54 patients, recurrent episodes of IIH occurred in 38% of cases over a mean period of 6.2 years; no reoccurrences occurred in patients receiving ongoing acetazolamide treatment.[114]
The initial acetazolamide dosage should be 0.5-1 g/day. Although many physicians start patients on 250 mg twice daily, others consider this dosage too low. A 500-mg oral dose of Diamox Sequels twice daily is often preferred; however, some insurers cover only an oral dose of 250 mg 4 times per day. Most patients respond to a dosage of 1-2 g/day. This can be increased to 3-4 g/day, but some patients cannot tolerate the adverse effects (eg, extremity paresthesias, fatigue, metallic taste from carbonated beverages, and decreased libido) that occur at this high dosage.[6, 2] In the Idiopathic Intracranial Hypertension Treatment Trial, of the 86 patients in the acetazolamide treatment group, 38 patients (44.1%) tolerated the maximum dose of 4 g/day.[115] Seventy-seven (89.5%) of the 86 patients taking acetazolamide tolerated dosages of 1 g/day or more. Compared with the 79 patients from the placebo group, the 86 patients taking acetazolamide were more likely to experience paresthesia, dysgeusia (foul or metallic taste), vomiting and diarrhea, nausea, and fatigue.[115]
In the event of intolerance to acetazolamide, furosemide may be used as a replacement diuretic in this group. Unfortunately, it does not appear to be as effective as acetazolamide.
Headache prophylaxis
In patients with stable visual function but inadequate headache relief with first-line pressure-lowering drugs, primary headache prophylaxis should be considered. Patients with IIH may experience headaches that have many of the features of migraine. These headaches can often be controlled with amitriptyline, propranolol, or other commonly prescribed migraine prophylaxis agents. Topiramate is also an excellent choice, in that one of its side effects is weight loss (a common association in IIH), which can help put the disease in remission. One open-label study suggested that topiramate appears to have similar efficacy to acetazolamide in terms of visual field improvement and symptom relief.[116]
Corticosteroids
Corticosteroids are effective in lowering ICP in patients whose IIH has an inflammatory etiology. In addition, they may be used as a supplement to acetazolamide to hasten recovery in patients who present with severe papilledema. Because of their significant adverse effects, corticosteroids should not be considered as a long-term solution in patients with IIH. In addition, a rebound in the ICP may occur during the tapering of the corticosteroid dosage.[2]
Digoxin and furosemide have been advocated by some investigators, but these are on the same level of effectiveness as acetazolamide and are not appropriate as sole therapy in patients who are losing vision.
If a moderately severe new visual field loss is detected on a routine office visit and the patient is not experiencing progressive symptoms, outpatient management can continue.
If the patient presents with symptomatic vision deterioration and the examination documents worsening of visual field despite adequate standard medical therapy, the patient should be admitted to the hospital for consideration of emergency surgical decompression. Visual field examination should be performed daily, and surgical decompression should be performed if no improvement or further worsening is noted.
Serial lumbar puncture
Serial lumbar puncture has fallen out of favor as CSF reforms within 6 hours, it is uncomfortable for patients, it can have complications, and is technically difficult to perform in obese patients.[117]
Optic Nerve Sheath Fenestration, CSF Diversion, and Venous Sinus Stenting
Patients with IIH should be closely monitored while on medical treatment. The frequency of visits is determined by the initial state of the patient’s visual function and the response to medical treatment. Despite close follow-up care and maximum medical treatment, some patients experience deterioration of visual function. Others fail to respond, are noncompliant, are intolerant to medication, or have intractable headache or progressive visual loss. In this situation, surgical intervention may be considered. Such intervention most often takes 1 of the following 2 general approaches:
Optic nerve sheath fenestration (decompression)
Cerebrospinal fluid (CSF) diversion (ie, via a lumboperitoneal or ventriculoperitoneal shunt)
Intracranial venous sinus stenting has also been investigated (see below).
Optic nerve sheath fenestration
The ophthalmic surgical approach to managing progressive vision loss and papilledema involves cutting slits or rectangular patches in the dura surrounding the optic nerve immediately behind the globe.[118] This allows direct egress of CSF into the orbital fat, where it is absorbed into the venous circulation.
Optic nerve sheath fenestration (ONSF) has been demonstrated to reverse optic nerve edema and to bring about some recovery of optic nerve function. In addition, it may decrease headache in many patients. The approach to the optic nerve may be from either the medial or the lateral aspect of the orbit; each approach has its benefits and drawbacks.[119] . ONSF has also been shown to be safe and effective in children.[120, 121]
Although ICP typically remains elevated in these patients postoperatively, the local filtering effect of the fenestration acts as a safety valve and keeps the pressure from being transmitted to the optic nerve. Despite the general lack of an ICP-lowering effect, unilateral surgery occasionally has a bilateral curative effect on the papilledema. However, if this is not the case, the opposite nerve must undergo the same procedure.
Complications (not life-threatening) related to optic nerve sheath fenestration occur in 40%-45% of cases and include diplopia (29%-35%); optic nerve injury; vision loss (1.5%-2.6%), typically due to vascular occlusion; direct operative traction and trauma; orbital hematoma; sheath hematoma; tonic pupil (11%); and hemorrhage and infection (risks inherent to intraconal surgery).[122, 121, 123, 124, 125, 126, 127]
Unfortunately, ONSF may not have lasting benefits. In most cases, visual function stabilizes or improves postoperatively,[128] but, in at least one third of cases, secondary visual decline may occur within 3-5 years and may necessitate repeat surgery or an alternative treatment; Spoor and McHenry found the long-term success rate of this operation to be only 16%.[129]
A study of ONSF performed in 41 eyes among 21 patients with vision loss due to either IIH or intracranial hypertension caused by cerebral venous thrombosis found best-corrected visual acuity and visual field to be stabilized or improved in 32 of 34 eyes (94%) over a 3-month follow-up interval.[130] Transient benign complications were apparent in 4 eyes. Only marginal improvement was shown in 4 eyes with no light perception vision; these were not analyzed with the remainder of the group.
CSF diversion procedures
CSF diversion procedures are highly effective in lowering ICP.[131] In some facilities, they remain the procedures of choice for treating patients with IIH who do not respond to maximum medical treatment.[2, 4, 119] Shunts are also indicated in patients with intractable headaches, patients in regions where there is no access to a surgeon comfortable with optic nerve sheath fenestration, and patients in whom optic nerve sheath fenestration has failed.
Lumboperitoneal shunting is the traditional method for providing prompt reduction of ICP in patients with IIH.[132] However, this procedure has a high one-year failure rate. Some neurosurgeons currently prefer ventriculoperitoneal or ventriculoatrial shunting over lumboperitoneal shunting. The main reason why these neurosurgeons prefer ventricular shunts is that such shunts can be monitored for function by using an extracranial subcutaneous compressible bulb and a one-way valve (permitting intracranial-to-abdominal flow) in series with the intracranial and abdominal ends of the shunt. The bulb resists digital compression if the distal (abdominal or atrial) end is obstructed. It collapses under digital pressure but fails to reinflate if the intracranial end is obstructed.
However, Woodworth et al reported that, with a frameless stereotactic approach, they were able to place ventricular shunts in a single pass in all patients, even into slit ventricles, with good long-term viability.[133]
Sinclair et al found that, although CSF diversion minimizes visual decline and improves visual acuity, 68% of patients continued to have headaches and 28% had low-pressure headaches that complicated surgery. Shunt revision was required in 51% of patients, with most requiring multiple revisions. In patients with otherwise untreatable rapidly declining vision, CSF diversion shunting should be conducted as a last resort. Other treatments, such as weight reduction, may be more effective and may have less associated morbidity.[134]
Uncontrolled studies report shunting causes alleviation of headache, diplopia, papilledema, and visual loss. Stabilization and remission of visual remission was reported up to 95%-100% in some studies, while one study showed up to 32% reported worsen vision.[132, 135, 136, 137, 138, 139] One case series reported that headache relief was not sustained, with nearly 50% of patients experiencing recurring severe headaches despite a working shunt.[140]
Intracranial venous sinus stenting
Venous stenting is a relatively new intervention and remains somewhat controversial.
A literature review of 143 patients treated with venous stenting showed that 88% of patients experienced improved headache and 87% reported improved visual symptoms. Follow-up was limited, effects on vision were not consistent, and complications were reported in 6% of cases.[141]
Comparison of visual outcomes
In a meta-analysis of the literature comparing visual outcomes after optic nerve sheath decompression, ventriculoperitoneal and lumboperitoneal shunting, and intracranial venous sinus stenting, Feldon reported the following findings[142] :
Optic nerve sheath decompression: Visual defects were improved or resolved in 80% of 252 cases.
Ventriculoperitoneal (VP) shunt placement: Visual defects were improved or resolved in 38.7% of 31 cases.
Lumboperitoneal (LP) shunt placements: Visual defects were improved or resolved in 44.6% of 44 cases.
Intracranial venous sinus stent placement: Visual defects were improved or resolved in 47% of 17 cases.
Visual worsening was rare for all procedures. The author concluded that visual outcome was best documented for optic nerve sheath fenestration, which appeared to be the best surgical procedure for vision loss in IIH. While optic nerve sheath decompression improves visual defects, many patients continue to have significant headaches that require CSF shunt placement.[121]
Reduction of body weight by 5%-10% was found to be effective hastening improvement of papilledema and visual fields.[74]
In a literature review of bariatric surgery for obese patients with IIH, Fridley et al found a total of 62 patients, of whom 52 (92%) experienced resolution of the presenting symptoms.[143] Of 35 patients who underwent postoperative funduscopy, 34 had resolution of papilledema. Of 12 patients who underwent preoperative and postoperative visual field examinations, 11 showed resolution of visual field defects.
Among 13 patients in whom CSF pressures were measured preoperatively and postoperatively, there was an average postoperative decrease of 254 mm water.[143] The authors called for prospective controlled studies to confirm the effectiveness of this surgical approach for patients with IIH in long-term follow-up.
Even for initial diagnosis, most patients do not require inpatient care, because lumbar puncture is usually performed in the ambulatory care setting. An occasional patient may develop an intractable low-tension headache after lumbar puncture and may require a short hospital stay for intravenous (IV) hydration and analgesic management. A blood patch (by an anesthesiologist) is sometimes indicated if the post–lumbar puncture headache does not subside spontaneously within a few days.
Admission for surgical management of increased intracranial pressure
Patients who report progressive visual loss (typically, constriction of peripheral vision or dimming of vision in one or both eyes) and have documented new visual field loss may respond to high-dose corticosteroid therapy. They should be considered for hospital admission and should undergo daily monitoring of visual function. Patients with fulminant IIH should also be considered for admission and rapid surgical intervention.
If the visual field worsens or does not recover promptly (ie, within 24-48 hours) with corticosteroid therapy, emergency CSF shunting (lumboperitoneal, ventriculoperitoneal, or ventriculoatrial) or optic nerve sheath fenestration should be performed.
If any delay in implementing surgical decompression of the failing optic nerve is anticipated, the patient should be moved to the ICU or a stepdown unit for lumbar CSF drainage until the definitive procedure can be performed. Another short-term treatment option is intravenous mannitol, but definitive pressure-lowering surgery must still be performed within 2-3 days.
A very small number of patients with normal visual fields may require surgical relief of CSF pressure because of intractable headache. Optic nerve sheath fenestration does not provide reliable CSF pressure normalization or headache relief; thus, these patients require a shunting procedure. Because patients with IIH frequently have other types of headaches, the decision to choose ventriculoperitoneal shunting over optic nerve sheath fenestration should not be made based on headache alone.
Most patients with IIH are females who are overweight. Weight loss is a cornerstone in the long-term management of these patients. As little as a 5%-10% weight loss has been demonstrated to yield a reduction in ICP with accompanying resolution of papilledema.[75, 74, 6] Unfortunately, weight reduction generally proves to be a difficult task for these patients.[144] To formalize the process of weight reduction, referral to a dietitian is appropriate.
On initial diagnosis, a weight-reduction diet should be strongly recommended to all patients with IIH. Often, a formal weight-loss program is required. No activity restriction is required in managing IIH. In fact, exercise programs are strongly recommended in conjunction with the weight-reduction diet.
Diagnosis and long-term management of IIH requires lumbar puncture, which is typically performed by neurologists or internists, and careful monitoring of visual status (in particular, peripheral visual field and fundus photography). Vision examination and fundus photography are the domain of ophthalmologists, and neuro-ophthalmologists are especially expert in examining visual fields. A team approach is therefore needed for most, if not all, patients with IIH.
Neurosurgical consultation is required for ventriculoperitoneal shunting when patients are losing visual field and medical management does not arrest or reverse the process promptly (ie, within hours to days). Consultation with an orbital plastic surgeon is required for optic nerve sheath fenestration for the same clinical indications.
The frequency of the follow-up visits is determined by a number of factors, to include the following:
Initial visual function of the patient
Underlying disease causing increased ICP
Perceived compliance of the patient with medical therapy
Once the initial diagnosis has been established, investigations have been performed, and therapy has been initiated, the patient can be observed every 3-4 weeks.
If, however, the patient presents with a significant visual function deficit or marked papilledema, daily monitoring for 1 week is appropriate until some improvement and subsequent stability in visual function can be demonstrated. The clinician should be prepared to titrate the patient’s treatment to the status of visual function and should not hesitate to refer the patient for surgical treatment (optic nerve sheath fenestration or CSF diversion) if visual function does not stabilize.
During follow-up visits, the best-corrected visual acuity for distant and near vision, color vision (with pseudoisochromatic plates), static perimetry, and optic nerve appearance (including the status of spontaneous venous pulsations) should be recorded. Patients who do not perform well on static perimetry testing may be better monitored with kinetic perimetry testing.
Spontaneous pulsation of large retinal veins generally indicates a normal ICP. If the patient continues to remark on the persistence of a significant headache despite the presence of spontaneous venous pulsations, a source other than IIH for the headache should be considered.
In a clinical trial of acetazolamide as treatment for IIH (Idiopathic Intracranial Hypertension Treatment Trial at NORDIC Clinical Trials), risk factors for treatment failure included male sex, high-grade papilledema, low baseline visual acuity, and increased number of transient visual obscuration episodes per month. Among patients with these risk factors, the study group recommends closer monitoring while considering more aggressive treatment options.[145]
When a patient appears to have stabilized with respect to visual function and treatment, the frequency of follow-up visits can be extended to once every 2-4 months.
IIH has no known cause and no known methods of prevention. Among patients who have been diagnosed with IIH, the goal is to prevent further visual loss and comorbid symptoms, including headache. Progression of IIH is prevented through medical and surgical treatment, as well as diet and lifestyle modifications.
Management guidelines are based on symptoms and extent of visual impairment at presentation. If there is no immediate threat to vision, medical therapy is recommended. In case of immediate threat to vision, a temporary CSF draining procedure (ie, placement of a lumbar drain) is immediately performed, and a definitive surgical plan is made, either a ventriculoperitoneal shunt or optic nerve sheath fenestration.[146]
Specific therapy for idiopathic intracranial hypertension (IIH) is aimed at lowering ICP pharmacologically. Carbonic anhydrase inhibitors (eg, acetazolamide) and loop diuretics (eg, furosemide) are thought to exert their effect on ICP by reducing cerebrospinal fluid (CSF) production at the choroid plexus. Cardiac glycosides have a similar effect.
Corticosteroids are indicated on a short-term basis in patients who present with severe papilledema and compromised visual function. They are effective in reducing ICP, but the mechanism of action is unknown. Corticosteroids are often used as maximum medical management when rapid lowering of ICP is required.
Patients with IIH may experience headaches that have many of the features of migraine. These headaches can often be controlled with amitriptyline, propranolol, or other commonly prescribed migraine prophylaxis agents. Topiramate is also an excellent choice, in that one of its side effects is weight loss (a common association in IIH), which can help put the disease in remission.
Clinical Context:
Acetazolamide is a nonbacteriostatic sulfonamide and a potent CA inhibitor that is effective in diminishing fluid secretion. It lowers ICP by decreasing production of CSF. Inhibition of CA results in a drop in sodium ion transport across the choroidal epithelium. Reduction of CSF production occurs within hours.
Acetazolamide commonly achieves long-lasting control of transient visual obscurations, headache, and diplopia, all of which are manifestations of intracranial hypertension, even though papilledema does not resolve completely. The effect on ICP is not sustained, and many patients develop adverse effects severe enough to hinder compliance.
Few patients tolerate dosages higher than 2 g/day, but 4 g/day may be required to produce a measurable pressure-lowering effect. Treatment is usually initiated at 1 g/day and increased to 2 g/day if symptoms are not controlled and adverse effects are not severe. Treatment with acetazolamide alone is not appropriate for patients who are experiencing progressive visual field loss.
Carbonic anhydrase (CA) is an enzyme found in many tissues. It catalyzes a reversible reaction whereby carbon dioxide becomes hydrated and carbonic acid becomes dehydrated. These changes may result in a decrease in CSF production by the choroid plexus.
Clinical Context:
Furosemide inhibits CSF production, but the precise mechanism by which it does so is unclear. A combination of CA inhibition and an effect on sodium absorption across the choroid plexus may result in the decreased CSF production.
Clinical Context:
Digoxin is present in high concentrations in the choroid plexuses of patients taking standard cardiac doses. It has been shown to reduce CSF production by as much as 78% in humans, probably by inhibiting the Na-K-ATPase pump. There has been only 1 report in which a patient with IIH was treated with digoxin, but the patient was asymptomatic, and thus, it is not known whether symptoms would have been controlled.
Clinical Context:
The mechanism of action by which corticosteroids lower CSF pressure has not been established. Some believe that they may facilitate outflow at arachnoid granulations.
Clinical Context:
The mechanism of action by which corticosteroids lower CSF pressure has not been established. Some believe that they may facilitate outflow at arachnoid granulations.
Beta-blockers may prevent migraines by blocking vasodilators, decreasing platelet adhesiveness and aggregation, stabilizing the membrane, and increasing the release of oxygen to tissues. Significant to their activity as migraine prophylactic agents is the lack of partial agonistic activity. Latency from initial treatment to therapeutic results may be as long as 2 months.
Clinical Context:
Amitriptyline has efficacy for migraine prophylaxis that is independent of its antidepressant effect. Its mechanism of action is unknown, but it inhibits activity of such diverse agents as histamine, 5-HT, and acetylcholine.
Amitriptyline, nortriptyline, doxepin, and protriptyline have been used for migraine prophylaxis, but only amitriptyline has proven efficacy and appears to exert its antimigraine effect independent of its effect on depression.
Clinical Context:
Topiramate is indicated for migraine headache prophylaxis. Its precise mechanism of action is unknown, but the following properties may contribute to its efficacy: (1) blockage of voltage-dependent sodium channels, (2) augmentation of activity of the neurotransmitter GABA at some GABA-A receptor subtypes, (3) antagonization of the AMPA/kainate subtype of the glutamate receptor, and (4) inhibition of the carbonic anhydrase enzyme, particularly isozymes II and IV. Topiramate is also an excellent choice, in that one of its side effects is weight loss (a common association in IIH), which can help put the disease in remission.
Clinical Context:
Divalproex is now considered first-line preventive medication for migraine. This agent is believed to enhance GABA neurotransmission, which may suppress events related to migraine that occur in cortex, perivascular sympathetics, or trigeminal nucleus caudalis. Divalproex has been shown to reduce migraine frequency by 50%.
How is idiopathic intracranial hypertension (IIH) characterized?What are the signs and symptoms of increased ICP in idiopathic intracranial hypertension (IIH)?What are the signs and symptoms of papilledema in idiopathic intracranial hypertension (IIH)?How is idiopathic intracranial hypertension (IIH) diagnosed?Which medications are used in the treatment of idiopathic intracranial hypertension (IIH)?When is surgery indicated in the treatment of idiopathic intracranial hypertension (IIH)?What is the role of repeated lumbar puncture (LP) in the treatment of idiopathic intracranial hypertension (IIH)?What is the role of weight loss in the treatment of idiopathic intracranial hypertension (IIH)?What is idiopathic intracranial hypertension (IIH)?What are the diagnostic criteria for idiopathic intracranial hypertension (IIH)?What is the pathophysiology of idiopathic intracranial hypertension (IIH)?What is the role of the transverse dural venous sinus in the pathophysiology of idiopathic intracranial hypertension (IIH)?What is the role of arterial inflow in the pathophysiology of idiopathic intracranial hypertension (IIH)?What is the Bateman mathematical model for the pathogenesis of idiopathic intracranial hypertension (IIH)?What is the role of obesity in the pathogenesis of idiopathic intracranial hypertension (IIH)?What is the role of vitamin A in the pathogenesis of idiopathic intracranial hypertension (IIH)?What is the role of hormones in the pathogenesis of idiopathic intracranial hypertension (IIH)?What is the role of AQPs in the pathogenesis of idiopathic intracranial hypertension (IIH)?What causes idiopathic intracranial hypertension (IIH)?What is the role of exogenous substances in the etiology of idiopathic intracranial hypertension (IIH)?Which systemic diseases are associated with idiopathic intracranial hypertension (IIH)?Which disorders of cerebral venous drainage may cause idiopathic intracranial hypertension (IIH)?What is the role of pregnancy in the etiology of idiopathic intracranial hypertension (IIH)?What are the endocrine risk factors of idiopathic intracranial hypertension (IIH)?What are the risk factors for idiopathic intracranial hypertension (IIH)?What is the prevalence of idiopathic intracranial hypertension (IIH) in the US?What is the global prevalence of idiopathic intracranial hypertension (IIH)?Which patient groups have the highest prevalence of idiopathic intracranial hypertension (IIH)?What is the prognosis of idiopathic intracranial hypertension (IIH)?What is the prevalence of vision loss in idiopathic intracranial hypertension (IIH)?What is the reported incidence of vision impairment in idiopathic intracranial hypertension (IIH)?What is included in patient education about idiopathic intracranial hypertension (IIH)?Which clinical history findings are characteristic of idiopathic intracranial hypertension (IIH)?Which clinical history findings are characteristic of elevated ICP in idiopathic intracranial hypertension (IIH)?Which clinical history findings are characteristic of papilledema in idiopathic intracranial hypertension (IIH)?What is included in the neurologic exam to evaluate idiopathic intracranial hypertension (IIH)?Which visual acuity findings are characteristic of idiopathic intracranial hypertension (IIH)?How is color vision assessed in idiopathic intracranial hypertension (IIH)?What is the role of formal visual field testing in the workup of idiopathic intracranial hypertension (IIH)?Which visual findings are characteristic of CN palsies in idiopathic intracranial hypertension (IIH)?Which fundus exam findings are characteristic of idiopathic intracranial hypertension (IIH)?What are the possible complications of idiopathic intracranial hypertension (IIH)?Which conditions are included in the differential diagnoses of idiopathic intracranial hypertension (IIH)?What are the differential diagnoses for Idiopathic Intracranial Hypertension (IIH)?What is the role of blood tests in the workup of idiopathic intracranial hypertension (IIH)?What is the role of MRI and CT scanning in the workup of idiopathic intracranial hypertension (IIH)?What is the role of ultrasonography in the workup of idiopathic intracranial hypertension (IIH)?What is the role of lumbar puncture (LP) in the workup of idiopathic intracranial hypertension (IIH)?What are the treatment goals for idiopathic intracranial hypertension (IIH)?How is vision loss treated in idiopathic intracranial hypertension (IIH)?How does pregnancy affect idiopathic intracranial hypertension (IIH)?What is the role of acetazolamide and furosemide in the treatment of idiopathic intracranial hypertension (IIH)?What is the role of headache prophylaxis in the treatment of idiopathic intracranial hypertension (IIH)?What is the role of corticosteroids in the treatment of idiopathic intracranial hypertension (IIH)?What is the role of serial lumbar puncture in the treatment of idiopathic intracranial hypertension (IIH)?What is the role of surgery in the treatment of idiopathic intracranial hypertension (IIH)?What is the role of optic nerve sheath fenestration in the treatment of idiopathic intracranial hypertension (IIH)?What is the role of CSF diversion in the treatment of idiopathic intracranial hypertension (IIH)?What is the role of venous sinus stenting in the treatment of idiopathic intracranial hypertension (IIH)?What is the efficacy of surgical interventions in the treatment of idiopathic intracranial hypertension (IIH)?What is the role of bariatric surgery in the treatment of idiopathic intracranial hypertension (IIH)?When is inpatient care indicated for the treatment of idiopathic intracranial hypertension (IIH)?Which dietary and activity modifications are used in the treatment of idiopathic intracranial hypertension (IIH)?Which specialist consultations are beneficial to patients with idiopathic intracranial hypertension (IIH)?How is the frequency of follow-up visits to monitor idiopathic intracranial hypertension (IIH) determined?What is included in the long-term monitoring of idiopathic intracranial hypertension (IIH)?How is idiopathic intracranial hypertension (IIH) prevented?What are the treatment guidelines for idiopathic intracranial hypertension (IIH)?Which medications are used in the treatment of idiopathic intracranial hypertension (IIH)?Which medications in the drug class Antiepileptics are used in the treatment of Idiopathic Intracranial Hypertension (IIH)?Which medications in the drug class Tricyclic Antidepressants are used in the treatment of Idiopathic Intracranial Hypertension (IIH)?Which medications in the drug class Beta-Blockers are used in the treatment of Idiopathic Intracranial Hypertension (IIH)?Which medications in the drug class Corticosteroids are used in the treatment of Idiopathic Intracranial Hypertension (IIH)?Which medications in the drug class Cardiovascular, Other are used in the treatment of Idiopathic Intracranial Hypertension (IIH)?Which medications in the drug class Loop diuretics are used in the treatment of Idiopathic Intracranial Hypertension (IIH)?Which medications in the drug class Antiglaucoma, Carbonic Anhydrase Inhibitors are used in the treatment of Idiopathic Intracranial Hypertension (IIH)?
Mark S Gans, MD, Associate Professor, Director of Neuro-Ophthalmology, Interim Chair, Department of Ophthalmology, McGill University Faculty of Medicine; Clinical Director, Department of Ophthalmology, Adult Sites, McGill University Hospital Center, Canada
Disclosure: Nothing to disclose.
Chief Editor
Andrew G Lee, MD, Chair, Department of Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital; Clinical Professor, Associate Program Director, Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch School of Medicine; Clinical Professor, Department of Surgery, Division of Head and Neck Surgery, University of Texas MD Anderson Cancer Center; Professor of Ophthalmology, Neurology, and Neurological Surgery, Weill Medical College of Cornell University; Clinical Associate Professor, University of Buffalo, State University of New York School of Medicine
Disclosure: Received ownership interest from Credential Protection for other.
Additional Contributors
Ariel Chen, Baylor College of Medicine
Disclosure: Nothing to disclose.
Ashwini Kini, MD, FRCS, Clinical Fellow in Neuro-Ophthalmology, Department of Ophthalmology, Houston Methodist Hospital
Disclosure: Nothing to disclose.
Acknowledgements
Robert A Egan, MD Director of Neuro-Ophthalmology, St Helena Hospital
Robert A Egan, MD is a member of the following medical societies: American Academy of Neurology, American Heart Association, North American Neuro-Ophthalmology Society, and Oregon Medical Association
Disclosure: Nothing to disclose.
Eric R Eggenberger, DO, MS, FAAN Professor, Vice-Chairman, Department of Neurology and Ophthalmology, Colleges of Osteopathic Medicine and Human Medicine, Michigan State University; Director of Michigan State University Ocular Motility Laboratory; Director of National Multiple Sclerosis Society Clinic, Michigan State University
Eric R Eggenberger, DO, MS, FAAN is a member of the following medical societies: American Academy of Neurology, American Academy of Ophthalmology, American Osteopathic Association, and North American Neuro-Ophthalmology Society
Disclosure: Nothing to disclose.
James Goodwin, MD Associate Professor, Departments of Neurology and Ophthalmology, University of Illinois College of Medicine; Director, Neuro-Ophthalmology Service, University of Illinois Eye and Ear Infirmary
James Goodwin, MD is a member of the following medical societies: American Academy of Neurology, Illinois State Medical Society, North American Neuro-Ophthalmology Society, and Royal Society of Medicine
Disclosure: Nothing to disclose.
Edsel Ing, MD, FRCSC Associate Professor, Department of Ophthalmology and Vision Sciences, University of Toronto Faculty of Medicine; Consulting Staff, Toronto East General Hospital, Canada
Edsel Ing, MD, FRCSC is a member of the following medical societies: American Academy of Ophthalmology, American Association for Pediatric Ophthalmology and Strabismus, American Society of Ophthalmic Plastic and Reconstructive Surgery, Canadian Ophthalmological Society, North American Neuro-Ophthalmology Society, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
Brian R Younge, MD Professor of Ophthalmology, Mayo Clinic School of Medicine
Brian R Younge, MD is a member of the following medical societies: American Medical Association, American Ophthalmological Society, and North American Neuro-Ophthalmology Society
Hughes S. Drug Improves Vision in Idiopathic Intracranial Hypertension. Medscape Medical News. Available at http://www.medscape.com/viewarticle/824073. Accessed: April 29, 2014.
Left optic disc with moderate chronic papilledema in a patient with idiopathic intracranial hypertension (pseudotumor cerebri). Paton lines (arc-shaped retinal wrinkles concentric with the disc margin) are seen along the temporal side of the optic nerve head.
Most common early visual field defect in papilledema as optic nerve develops optic atrophy is inferior nasal defect, as shown in left eye field chart (left side of figure). Shaded area indicates defective portion of field. Note sharp line of demarcation between defective lower nasal quadrant and normal upper nasal quadrant along horizontal midline. This is characteristic of early papilledema optic atrophy and is referred to as nasal step or inferonasal step.
Left optic disc with moderate chronic papilledema in a patient with idiopathic intracranial hypertension (pseudotumor cerebri). Paton lines (arc-shaped retinal wrinkles concentric with the disc margin) are seen along the temporal side of the optic nerve head.
Right optic disc with postpapilledema optic atrophy in a patient with idiopathic intracranial hypertension (pseudotumor cerebri). Diffuse pallor of disc and absence of small arterial vessels on surface are noted, with very little disc elevation. Disc margin at upper and lower poles and nasally is obscured by some residual edema in nerve fiber layer and gliosis that often persists even after all edema has resolved.
Left optic disc with moderate chronic papilledema in a patient with idiopathic intracranial hypertension (pseudotumor cerebri). Paton lines (arc-shaped retinal wrinkles concentric with the disc margin) are seen along the temporal side of the optic nerve head.
Right optic disc with postpapilledema optic atrophy in a patient with idiopathic intracranial hypertension (pseudotumor cerebri). Diffuse pallor of disc and absence of small arterial vessels on surface are noted, with very little disc elevation. Disc margin at upper and lower poles and nasally is obscured by some residual edema in nerve fiber layer and gliosis that often persists even after all edema has resolved.
Most common early visual field defect in papilledema as optic nerve develops optic atrophy is inferior nasal defect, as shown in left eye field chart (left side of figure). Shaded area indicates defective portion of field. Note sharp line of demarcation between defective lower nasal quadrant and normal upper nasal quadrant along horizontal midline. This is characteristic of early papilledema optic atrophy and is referred to as nasal step or inferonasal step.
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