Subject Review. Idìopathic Intracranial Hypertension

Transcription

1 Subject Review Idìopathic Intracranial Hypertension KURUPATH RADHAKRISHNAN, M.D., J. ERIC AHLSKOG, PH.D., M.D., JAMES A. GARRITY, M.D., AND LEONARD T. KURLAND, M.D., DR.P.H. Objective: This review was undertaken to summarize the significant progress that has been made in the epidemiology of idiopathic intracranial hypertension (IIH), the changing nosology, and the diagnostic criteria and therapeutic strategy. Design: We reviewed the pertinent literature on IIH published in major English-language journals for the last 20 years. Material and Methods: The diagnosis, epidemiology, pathophysiology, complications, and treatment of IIH are described. Results: IIH occurs at an average annual incidence rate per 100,000 persons of 1 to 2 for the total population and 19 to 21 in obese females of the reproductive age-group. IIH is a recognized cause of reversible vision loss in adult obese women. The diagnosis of IIH requires a documented elevation of intracranial pressure, normal cerebrospinal fluid (CSF) composition, and normal findings on neuroimaging studies. At least two primary mechanisms for the development of increased CSF pressure in IIH have been postulated and supported by experimental data: vasogenic extracellular brain edema and a low conductance of CSF outflow at the arachnoid villi. This condition may be secondarily exacerbated by compression of intracranial venous sinuses by the increased intracranial pressure, resulting in a further reduction of flow across the arachnoid villi. The therapeutic strategy is determined by visual status, which needs close monitoring. Conclusion: Although medical measures to lower the intracranial hypertension are successful in the majority of patients, surgical therapy should not be delayed in those with significant or progressive vision loss. Based on recent advances, a practical approach has been described for the diagnosis, early detection of visual impairment, and targeting therapy to preserve the vision or to reverse recent loss of vision in patients with IIH. (Mayo Clin Proc 1994; 69: ) CSF = cerebrospinal fluid; CT = computed tomography; IIH = idiopathic intracranial hypertension; MRI = magnetic resonance imaging The distinctive syndrome of intracranial hypertension and papilledema with no focal localizing neurologic signs, together with a normal cerebrospinal fluid (CSF) composition and normal or small ventricles, was recognized nearly a century ago.1 The majority of patients with this syndrome manifest no apparent cause for the intracranial hypertension; hence, it is currently known as idiopathic intracranial hypertension (IIH).2"4 Today, the confirmed diagnosis of IIH requires (1) a documented elevation of intracranial pressure, (2) normal findings on a neurologic examination except for papilledema and an occasional abducens nerve paresis, (3) the absence of a space-occupying lesion or ventricular enlargement on computed tomography (CT) or magnetic reso- From the Department of Neurology (K.R., J.E.A.), Department of Ophthalmology (J.A.G.), and Section of Clinical Epidemiology (L.T.K.), Mayo Clinic Rochester, Rochester, Minnesota. This study was supported in part by Grants AR and NS from the National Institutes of Health, Public Health Service. Address reprint requests to Dr. J. E. Ahlskog, Department of Neurology, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN nance imaging (MRI), and (4) a normal CSF composition.36 The typical patient with IIH is a young obese female. Although IIH is usually a self-limited condition, in some patients it may be a chronic process.7 8 Some degree of vision loss is reported in over 50% of referral groups of patients with IIH; however, the frequency of vision loss is much less in population-based samples."13 The hospital incidence reported in several large series suggested that IIH was a rare disorder However, recent studies, which evaluated the disease in the population, have documented annual incidence rates of 1 to 2 per 100,000 persons.1113 In the high-risk group of obese women in the reproductive age-group, the annual incidence climbs to 19 to 21 per 100,000 persons.1113 In the past decade, significant progress has been made in the epidemiology of this disease; the nosology is changing, and the diagnostic criteria and therapeutic strategy are becoming well established. However, the pathogenesis of IIH is still an enigma, and the natural history of the disease is largely unknown. In view of these developments and their Mayo Clin Proc 1994; 69: Mayo Foundation for Medical Education and Research

2 170 IDIOPATHIC INTRACRANIAL HYPERTENSION Mayo Clin Proc, February 1994, Vol 69 implications, we believe it is appropriate to review this subject. NOSOLOGY Although the syndrome of IIH is well recognized, the terminology has varied and has been a source of confusion. Quincke 1 is attributed with the first clear description of the disease, which in 1897 he named "serous meningitis." Before Foley introduced the term "benign intracranial hypertension," 7 the syndrome was variously described by a score of names such as otitic hydrocephalus, toxic hydrocephalus, sinus thrombosis causing intracranial hypertension, hypertensive meningeal hydrops, pseudoabscess, intracranial pressure without brain tumor, brain swelling of unknown cause, papilledema of indeterminant etiology, and pseudotumor cerebri For patients with ΠΗ who exhibit very rapid loss of vision, the term "malignant pseudotumor cerebri" was suggested. 18 Fortunately, only three of these names, pseudotumor cerebri, benign intracranial hypertension, and IIH, are in use today. The syndrome is not "benign" in view of its potential visual sequelae. In this era of advanced neuroimaging techniques, confusion with tumor is much less likely than in the past; therefore, the term "pseudotumor" has less meaning now than in years past. The term that most accurately describes the syndrome is "idiopathic intracranial hypertension," which is emerging as the favored terminology. 2A We prefer IIH, which will be used throughout this article. DIAGNOSIS The modified diagnostic criteria of Dandy for IIH 36 are illustrated in Table 1. By strictly adhering to the diagnostic criteria, the perceived benefits are twofold: (1) to facilitate epidemiologie, clinical, and experimental investigation of this syndrome in as uniform a sample as possible and (2) to allow a more rational approach to therapy through a unified concept of the pathophysiologic process. Symptoms. The classic case of IIH is characterized by new onset headache and visual obscurations in the setting of papilledema in a conscious adult obese woman. Weisberg, 8 in a retrospective review of 120 patients, noted that headaches occurred in 99% of patients as a presenting symptom and visual changes in 35%. In a case-control study of questionnaire-interview design that compared symptoms of 50 referral patients with IIH with those of 100 age-matched control subjects," the symptoms most commonly reported by patients with IIH were headache (94%), transient visual obscurations (68%), pulsatile intracranial noises (58%), photopsia (54%), diplopia (38%), visual loss (30%), and retrobulbar pain on eye movements (22%). Signs. The signs of IIH are papilledema with its resultant vision loss and sixth cranial nerve palsies as a false Table 1. Modified Dandy's Criteria for the Diagnosis of Idiopathic Intracranial Hypertension Signs and symptoms of increased intracranial pressure No localizing neurologic signs, in an awake and alert patient, other than abducens nerve paresis Normal neuroimaging studies except for small ventricles or empty sella Documented increased pressure (250 mm of water or more) but a normal composition of the cerebrospinal fluid Primary structural or systemic causes of elevated intracranial venous sinus pressure excluded (for example, sinovenous thrombosis, hyperviscosity syndromes, and right heart failure) localizing sign of elevated intracranial pressure. The diagnosis of IIH should be viewed with suspicion in patients with ocular motility disturbances other than sixth nerve palsies. Other focal neurologic signs such as seventh nerve palsy and long tract involvement have been attributed to IIH, 20 but these are distinctly atypical and raise suspicions of another diagnosis. Although papilledema is usually bilateral, unilateral and highly asymmetric papilledema is frequently found in IIH. Lepore 21 noted that IIH patients with unilateral papilledema were significantly older than those with bilateral papilledema; however, there was no difference between the two groups with respect to disease duration, presence of headaches or transient visual obscurations, CSF opening pressure, or visual impairment. Anomalous elevation of the optic nerve head that is, pseudopapilledema can occur in cases of hyperopia and drusen and, if associated with obesity and headache, can cause a mistaken diagnosis of IIH. 22 Chronic papilledema can result in the development of pseudodrusen, which can also be confusing. 23 Transient visual obscurations may occur in patients with optic nerve drusen; 24 furthermore, drusen may occasionally cause a progressive optic neuropathy, 25 and drusen may also rarely coexist with IIH. 26 As discussed subsequently, study of CSF pressure should establish the diagnosis in cases of equivocal papilledema. Fluorescein angiography may help to clarify the diagnosis when there is further uncertainty; fluorescein usually leaks diffusely with papilledema but leaves discrete spots of late focal fluorescence with drusen. 22 There are reports of patients with increased intracranial pressure of unknown cause without papilledema. 27 However, it should be emphasized that it may be difficult to appreciate early disc elevation with direct ophthalmoscopy; stereoscopic fundus photography or stereoscopic biomicroscopy with a fundus contact lens or a Hruby lens may be necessary. Neuroradiology. Findings on CT or MRI are normal in patients with IIH. Although the term "slitlike" is commonly

3 Mayo Clin Proc, February 1994, Vol 69 IDIOPATHIC INTRACRANIAL HYPERTENSION 171 used to describe the CT appearance of small ventricles in IIH, 28 a recent study that compared linear indices of CT ventricular size in patients with IIH and age-matched control subjects 29 found no difference between these groups. Other nonspecific CT findings in IIH include empty sella, prominent cisterna magna, and dilated optic nerve sheaths. 28 In a series of 29 men with IIH, an empty sella was noted on 55% of CT scans. 30 Gibby and colleagues 31 compared the CT findings of 17 patients with IIH with 20 age- and sexmatched control subjects. An empty sella was noted more frequently in patients with IIH than in control subjects (16 versus 7). Cerebrospinal Fluid. The diagnosis of IIH should not be made without examination of the CSF and measurement of the opening pressure. A carefully performed lumbar puncture should show an elevated CSF pressure, a normal or low CSF protein level, a normal CSF glucose level, and a normal cell count. Previous conventional wisdom has accepted 200 mm of water as the upper limit of normal CSF opening pressure. However, Corbett and Mehta 32 have reported CSF opening pressures up to 250 mm of water in both obese and nonobese normal subjects. Hence, confirmation of intracranial hypertension requires opening pressure values greater than 250 mm of water. A single elevated measurement of the CSF pressure at lumbar puncture is almost always sufficient for the diagnosis. However, in the rare patient whose opening pressure is normal but whose clinical and radiologie signs are otherwise highly suggestive of IIH, repeated measurement and perhaps monitoring for a period of at least 30 to 60 minutes by an epidural transducer or via a lumbar cannula may be necessary to document elevated pressure. 17 More than a single hour of monitoring may occasionally be needed, and both subarachnoid bolt and intraventricular monitoring techniques are also reported as safe methods. 33 Many previous reports have emphasized low CSF protein levels in about two-thirds of patients with IIH One study even documented an inverse relationship between CSF opening pressure and CSF protein. 35 Johnston and associates 36 found CSF protein of less than 20 mg/dl in only 26% of their 177 patients with IIH and could find no linear correlation between the CSF protein and opening pressure. An algorithm for the diagnosis of IIH is shown in Figure 1. DIFFERENTIAL DIAGNOSIS Intracranial Hypertension Associated With Sinovenous Thrombosis. Patients with clinical and radiologie evidence of cranial venous outflow impairment, such as raised intracranial pressure in heart failure, superior vena cava syndrome, bilateral or unilateral jugular obstruction, or lat- Papitledema in a conscious, alert patient with no neurologic signs other than abducens nerve paralysis Space-occupying lesion or hydrocephalus CT/MRI I 1 Normal Lumbar puncture i Abnormal CSF I Normal CSF ( t protein or cells) Normal pressure Repeat lumbar puncture/ continuous Intracranial pressure monitoring f Sino-venous thrombosis Suspected intracranial sino-venous thrombosis MRI/digital subtraction angiography Increased pressure Normal ' Unknown/ uncertain Exclude pseudopapllledema Mlcpattile intracranial hypertension Fig. 1. Algorithm for diagnosis of patients with idiopathic intracranial hypertension. CSF = cerebrospinal fluid; CT = computed tomography; MR! = magnetic resonance imaging. eral or superior sagittal sinus thrombosis, have often been included in the category of those with IIH Despite some clinical similarities, this group should be considered a distinctive diagnostic category. The pathogenesis, clinical and radiologie features, management, and outcome of these patients are different from those with IIH. Perhaps a nomenclature that does not overlap with IIH would be preferable, such as "sinovenous occlusion-related intracranial hypertension," to describe this entity. Intracranial hypertension, without localizing neurologic signs, is the most common mode of presentation of limited intracranial sinovenous thrombosis, typically the transverse sinus. Usually the CT scan and CSF are normal, although conventional MRI sometimes reveals the abnormality. 38 Sinovenous thrombosis has been associated with head injury, otitis media, and a variety of hypercoagulopathy and hyperviscosity syndromes. 39 A high degree of clinical suspicion is required to diagnose intracranial venous sinus thrombosis, because the presentation is nonspecific, and its confirmation often requires digital subtraction or magnetic resonance angiography. Intracranial Hypertension Associated With Abnormal CSF Composition. Patients with abnormalities of CSF composition would not qualify for the diagnosis of IIH.

4 172 IDIOPATHIC INTRACRANIAL HYPERTENSION Mayo Clin Proc, February 1994, Vol 69 Patients with papilledema, normal results of neuroimaging studies, and abnormal CSF composition have been reported to have a variety of infections and inflammatory conditions, such as poliomyelitis, Guillain-Barré syndrome, chronic brucellosis, cysticercosis, chronic cryptococcal meningitis, and neurosarcoidosis. 39 It is generally presumed that the abnormality of CSF composition in these cases in some way impedes the absorption of CSF either by cellular or macromolecular obstruction of the arachnoid villi or by involvement of the narrow subarachnoid space over the cerebral convexities. It is still uncertain why this phenomenon occurs in relatively few patients with such CSF abnormalities. Occult Mass Lesion. There are very rare reports of patients with autopsy-proven gliomatosis cerebri (widely disseminated glioma) with severe papilledema, but with otherwise normal findings on neurologic examination, CT scan, and CSF analysis, diagnosed with and treated for IIH with a lumboperitoneal shunt. 39 DISEASES AND CONDITIONS ASSOCIATED WITH IIH Numerous retrospective studies and reviews have emphasized the association of IIH with a vast array of other medical conditions. For example, a 1984 edition of an outstanding neurology textbook 40 listed more than 35 etiologic entities in 10 subgroups under the heading of benign intracranial hypertension, most of which are now believed to be coincidental associations. Conditions that we would accept as probably causally linked to IIH should conform to the following criteria: 5 ( 1 ) at least two cases have been described; (2) the individual case satisfies the diagnostic criteria for IIH (Table 1), including normal findings on CT or MRI, normal CSF composition, and elevated opening pressure; and (3) head trauma and conditions that result in intracranial sinovenous thrombosis and hyperviscosity syndrome have been excluded. Conditions fulfilling these criteria are shown in Table 2. In most cases, when it is possible, withdrawal of the putative causative agents listed in Table 2 leads to resolution of intracranial hypertension, while reexposure will characteristically result in a recrudescence. It is possible that, of the many patients exposed to the factors known to precipitate IIH, those few patients in whom it develops also have an underlying obscure abnormality insufficient to manifest itself without the addition of the precipitating factor. Many had additional well-established risk factors for IIH, namely, female gender and obesity. It should be emphasized that epidemiologie studies (vide infra) have provided proof of a significant association with IIH for only female gender, reproductive age-group, obesity, recent weight gain, and menstrual irregularities. Pregnancy and oral contraceptive use were previously identified as Table 2. Conditions and Diseases Associated With Idiopathic Intracranial Hypertension Confirmed in epidemiologie studies nnnm Female sex Reproductive age-group Menstrual irregularity Obesity Recent weight gain Meet minimal criteria but unconfirmed in case-control studies Endocrine Adrenal insufficiency 42,43 Cushing's disease Hypoparathyroidism ' ' 46 Hypothyroidism"' 47 Medication 48 Minocycline Isotretinoin Nalidixic acid Tetracycline Trimethoprim-sulfarnethoxazole Cimetidine Corticosteroids Tamoxifen Lithium Danazol Nitrofurantoin Levothyroxine Miscellaneous Chronic renal failure 49 Systemic lupus erythematosus 50 related factors; however, these are common events of women in childbearing years and appear to be chance associations Because of the very frequent use of corticosteroids and antibiotics, the provocation of IIH by these drugs is rare indeed. EPIDEMIOLOGY OF IIH Descriptive Studies. In their initial observation in Benghazi, Libya, Radhakrishnan and coworkers" reported annual incidence rates per 100,000 persons of 1.7 for the total population and 3.6 for females of all ages. Durcan and colleagues 12 surveyed all neurologists, ophthalmologists, and neurosurgeons in Iowa, eastern Nebraska, and Louisiana over a 1-year period and determined an incidence rate per 100,000 persons of 0.9 in the general population, 3.5 in females 15 to 44 years of age, and 19 in obese women aged 20 to 44 years. A recently completed study that utilized the medical records-linkage system of the Mayo Clinic to identify cases of IIH in a 15-year period among the population of Rochester, Minnesota, 13 computed an average annual ageadjusted incidence rate per 100,000 of 0.9 for the total population, 1.6 for the female population of all ages, and 3.3 for the females aged 15 to 44 years. Table 3 summarizes the descriptive epidemiology of IIH. The female:male ratio was

5 Mayo Clin Proc, February 1994, Vol 69 IDIOPATHIC INTRACRANIAL HYPERTENSION 173 Duration of study (yr) Population base No. of patients Female:male ratio Obesity (%) Visual deficit Frequency (%) Extent Crude annual incidence rate per Total population Female population Females age yr Obese* females age yr Obese* females age yr Table 3. Comparison of Data From Population-Based Studies of Idiopathic Intracranial Hypertension Benghazi, Libya , : Moderate/severe 100,000 persons t Adjusted annual incidence rate per 100,000 persons/ Total population Female population State of Iowa ,914, : Unspecified t State of Louisiana ,481, : Rochester, Minnesota , : Mild * *Accurate data are unavailable on the prevalence of obesity for any of the populations studied; hence, these figures are arbitrary. toverweight >20%. $Body mass index >26. Obesity, not defined. /Adjusted to 1980 US population :1 in two population-based series from the United States. IIH tends to be a disease of early female adulthood, with annual rates per 100,000 of 3.3 to 10.3 in females between the ages of 15 and 44 years and of 7.9 to 20.2 in females of the same age-group with obesity (overweight >20% or body mass index >26). It should be admitted that the data described in these epidemiologie studies are derived from symptomatic patients with IIH ascertained through all the available medical resources in the community. However, IIH is known to occur without headache 16 and without papilledema. 27 Patients with IIH who have no headache and those who do not have papilledema constitute a subgroup of unknown size, since they may never come to neurologic attention unless they become symptomatic for some other reason. Case-Control Studies. Two recent case-control studies examined the risk factors associated with IIH Both studies found a strong association of IIH with obesity and recent weight gain. In one study, patients more frequently reported a change in menstrual pattern in the year prior to reference time. 41 A significant association of arterial hypertension and IIH was noted in these case-control studies However, arterial hypertension might have been overreported among obese patients with IIH because of the use of standard size rather than wide sphygmomanometer cuffs. Several conditions previously documented to be associated with IIH were no more common in patients than in control subjects. It should be emphasized that lack of statistical association does not prove that no association exists. Both studies indicated wide confidence intervals for the odds ratio, reflecting inadequate sample size and low statistical power for most of the variables investigated. PATHOGENESIS The pathogenesis of pseudotumor cerebri has yet to be fully understood. The ambient CSF pressure depends on the following: the venous pressure in the superior sagittal sinus, the inherent resistance of the arachnoid villi to the egress of CSF, the rate of formation of CSF, the intracranial volume of blood and brain, the elastic properties of the brain and blood vessels, and the capacity of the cranial and spinal subarachnoid space to expand. 33 Evidence in favor of and against the dysfunction of each of these factors in IIH can be found in the literature These contradictory results are perhaps due in part to the poor homogeneity of the different series, plus the extent to which these factors interact and influence one another. Any theory regarding the pathogenesis of IIH must be consonant with (1) raised intracranial pressure, (2) absence of ventricular dilation, (3) rapid therapeutic response to drainage of CSF, and (4) normal brain function.

6 174 IDIOPATHIC INTRACRANIAL HYPERTENSION Mayo Clin Proc, February 1994, Vol 69 Increased CSF Outflow Resistance as a Primary Cause ofhh. A threefold to fivefold decrease in CSF absorption in IIH has been documented by using the technique of radioisotope cisternography in several patients Bulk flow of CSF across the arachnoid villi appears to proceed by vacuolar transport rather than by a system of open channels. 54 How this function is altered in different conditions characterized by a decreased arachnoidal CSF conductance is unknown. Delayed maturation or congenitally fewer arachnoid villi would increase resistance to CSF flow. However, increased resistance to CSF egress across the arachnoid granulations can be a secondary phenomenon induced by compression of the arachnoid villi and the intracranial venous sinuses due to raised intracranial pressure from any cause. 55 Vasogenic Brain Edema: Increase in Brain Water as a Primary Cause of IIH. Sahs and Joynt 56 provided the first histologie evidence of extracellular edema in brain biopsy specimens taken at the time of subtemporal decompression for IIH. S0rensen and associates 57 recently documented increased volume of brain free water in IIH using MRI techniques. The increased cerebral interstitial fluid in IIH has been ascribed to transependymal migration of CSF 34,51 but could alternatively be due to primary vasogenic edema developing throughout the brain parenchyma. In a recent study of CSF dynamics, Malm and coworkers 55 reported decreased CSF arachnoid conductance in almost all their patients with chronic IIH; however, the conductance was not sufficiently low to explain the rise in CSF pressure. They also noted elevated sagittal sinus pressure in slightly more than half of their patients, which was thought to be related to compression of venous compartments that made some arachnoid villi-nonfunctional. Thus, they postulated two mechanisms, each of primary importance in different subsets of patients with IIH: (1) an increase in brain water content (vasogenic edema) and (2) impaired CSF conductance across the arachnoid villi. The results of this study, 55 which consisted of a small group of selected patients destined to have had an unusually chronic course, may not be representative of the majority of patients with IIH with a self-limited disease course. Elevated Intracranial Blood Volume. Increased intracranial blood volume has been documented in IIH but may not be a primary cause of the condition. Mathew and colleagues 58 found markedly elevated regional cerebral blood volume in two patients with IIH. Using positron emission tomography, Raichle and associates 59 provided further evidence for an increase in brain blood volume in IIH. The cause of this phenomenon is believed to be an obstruction of the venous outflow secondary to raised pressure in the subarachnoid space. Grubb and coworkers 60 demonstrated an increase in cerebral blood volume in adult rhesus monkeys following induced increase in CSF pressure. In summary, IIH has been associated with two fundamental defects of obscure origin: a defect in CSF absorption and an increase in brain intraparenchymal water. The latter produces a swollen noncompliant brain parenchyma, which probably counteracts the dilation of the ventricular system. The relative importance of these two factors in the pathogenesis of the majority of cases of IIH seen in young obese females is at present unknown. Lessons Learned From Related Syndromes. Familial IIH. Although a large kindred study is lacking, familial clustering of IIH has been reported. In four families, IIH occurred in successive generations in a pattern suggesting an autosomal dominant mode of inheritance There are four reports of intracranial hypertension occurring in siblings, suggesting an autosomal recessive inheritance All the reported familial cases have been associated with obesity. A recent report in which the mother and three of four daughters had a diagnosis of IIH and one son developed communicating hydrocephalus adds some weight to the concept that there exists a genetic defect of CSF absorption common to some cases of IIH and communicating hydrocephalus. 68 Infantile IIH. This group of patients encompasses those infants who present with an abnormal rate of head growth without neurologic or developmental abnormalities and who have a normal CT scan. 39 Characteristically, the condition is self-limiting, with a return to a normal rate of head growth and continuing normal development. Few progress to distention of the subarachnoid space and mild ventricular dilation necessitating shunting of CSF. A maturational defect in CSF dynamics or cranial volume reserve (or both) has been considered to explain the pathogenesis. 69 Slit-Ventricle Syndrome. Slit-ventricle syndrome is characterized by chronic or recurring headaches associated with subnormal ventricular volume in shunted hydrocéphalie patients. 70 The slitlike appearance of the ventricle on CT scans resembles that seen in some patients with IIH. A small group of these patients have been shown to have paroxysms of increased intracranial pressure in the presence of normal shunt function, 71 thought to be the result of increased cerebral blood volume, which has some pathogenetic similarity to IIH. Rarity of IIH Beyond Middle Age. ΠΗ rarely manifests beyond middle age; perhaps this relates to the presence of increased spatial reserve due to age-related brain atrophy. Conversely, a mismatch between brain and intraskull volume could be a contributory factor in younger patients with IIH; this spatial relationship has not been systematically studied. COMPLICATIONS Vision Loss. It is not always recognized that vision loss, which is the only serious complication of IIH, may occur

7 Mayo Clin Proc, February 1994, Vol 69 IDIOPATHIC INTRACRANIAL HYPERTENSION 175 either early or late in the course of the disease, may be sudden or gradually progressive, and is often avoidable with appropriate therapeutic intervention. The rate of vision loss is variable, symptoms may be minimal, and, in many patients, the vision loss may be undetected until profound. Multiple pathophysiologic mechanisms involving dysfunction of the retina, optic disc, and optic nerve have been incriminated in the vision loss in IIH. 4 9 The most likely mechanism of reversible vision loss in IIH is a nerve conduction defect related to the status of axoplasmic flow found in papilledema. 72 Other mechanisms ascribed to vision loss are extension of edema from the disc to the macula, macular hemorrhages, macular pigment epithelial changes, retinal neovascular membrane formation, elevation and detachment of peripapillary retina and choroidal folds, central retinal venous stasis, and ischemie papillopathy Frequency of Vision Loss. Referral Center-Based Studies. Nearly 50% of referral patients with IIH have been reported to suffer some deficit of visual function, and severe deficits in visual acuity have been reported in up to 25% of them. 910 In a recent prospective study, vision loss, as determined by Goldmann perimetry, occurred in 96% of 50 patients with IIH at initial evaluation. 4 Population-Based Studies. Vision loss is less frequently reported and less profound in population-based studies. Twenty-two percent of the patients described in the epidemiologie study from Iowa 12 had loss of vision, although the authors did not report the severity and the course of the visual deficit in detail. In the Rochester, Minnesota, series, 13 two of nine patients had mild visual deficits, but these did not impair their normal functioning. Table 3 summarizes the frequency of visual deficit in population-based series. Tertiary referral center-based studies depict IIH as a chronic disease complicated by a high frequency of vision loss Studies based on symptomatic patients ascertained from the population describe a more benign disease with a self-limiting course. 13 Furthermore, those who are asymptomatic and unaffected visually will remain undetected except by accident. Thus, the natural history of the disease as it is currently understood, based mostly on referral center studies, probably does not represent a true picture. Risk Factors for Vision Loss. Several investigators have evaluated the factors affecting vision loss among referral groups of patients with IIH. In a retrospective survey of referred patients, Corbett and colleagues 9 found systemic hypertension to be the only statistically significant risk factor for poor vision outcome; systemic corticosteroid administration and raised intraocular pressure were presumed to be additional risk factors. In a case-control comparison, the frequency of vision loss was found to be the same in pregnant and nonpregnant patients. 74 Orcutt and associates 75 observed transient visual obscurations, anemia, older age, and high myopia as significant risk factors for vision loss. Another group at risk for severe visual impairment was black males. 30 A prospective study showed recent weight gain as the only factor significantly associated with worsening of vision. 4 Small sample size and its selected nature may explain the variable results. The only factor shown to be related to poor vision outcome in population-based studies is the duration of IIHrelated symptoms prior to the diagnosis. Whereas the Rochester patients, 13 with a median duration of prediagnosis symptoms of 1 month, had a benign vision outcome, 20% of the Libyan patients, 76 with a mean symptom duration of 2.7 months, had disabling visual sequelae. However, it is often difficult to know how long elevated intracranial pressure has been present when a patient initially presents with symptoms. Future epidemiologie studies on IIH should attempt to define the characteristics contributing to vision loss. Visual Monitoring. It is generally accepted that Snellen visual acuity testing is an insensitive index of incipient vision loss Contrast sensitivity testing reveals deficits in 50% to 75% of the eyes of referral IIH cases Color vision loss and afferent pupillary defects occur in about onethird of referral patients Many recent studies have established that perimetry is the best test to detect and follow the course of vision loss in IIH Perimetry. Currently, visual field examinations are best performed with either a Goldmann manual perimeter or a computed automated perimeter. The Goldmann method is a kinetic technique that can effectively examine both the central 30 degrees and the periphery. A skilled technician is essential for an accurate examination, however. When an Armaly-Drance strategy was employed, the detection rate of visual loss was shown to be better than routine screening strategies by the Goldmann perimeter Computerized automated fields, on the other hand, are threshold examinations. As a result, they are more sensitive but require a more attentive, motivated, and alert patient. One does not need the same level of technical skill to administer the examination; however, the results can be more difficult to interpret. The detection rate of field loss in a group of patients with IIH with an automated perimeter was 77.5% versus 75% with a Goldmann perimeter and Armaly- Drance testing strategy. 79 On a practical note, the number of automated visual field machines in everyday usage is probably greater than that of Goldmann perimeters. It is also likely that future trends will emphasize more automated fields because of software improvements, ease of test administration, and cost. The common field defects found in IIH are related to the optic disc, such as enlargement of the physiologic blind spot, concentric constrictions, inferior nasal defects, arcuate defects, and cecocentral scotomas. 4 9,80 In a recent prospective

8 176 IDIOPATHICINTRACRANIAL HYPERTENSION Mayo Clin Proc, February 1994, Vol 69 study, the most common field defects identified at initial examination were constriction (30%) and inferonasal loss (15%). 4 Visual Evoked Response. The majority of visual evoked response values found in patients with IIH are within normal limits In one study, which included only a small number of patients, a linear relationship was demonstrated between the intracranial pressure and the visual evoked response latency. 81 In patients in whom severe vision loss developed, a progressive increase in the latency in visual evoked response preceded the effect on the visual fields and acuity. 81 Since alteration in visual evoked response is infrequent and insignificant and usually does not appear until late, this test should not be relied on to detect or to follow vision loss in IIH. Grading of Vision Loss. Elaborate grading criteria based on a best corrected visual acuity and manual and automated perimetry defects have been developed to evaluate vision loss in IIH. 4 Blind spot enlargement is ubiquitous in IIH and is not considered significant in visual assessment. A simplified grading system may be useful in selecting patients who need a more thorough ophthalmic evaluation and referral for surgical intervention (Table 4). Unfortunately, because of the variable sensitivity of different test methods in the determination of early changes in the visual field and the absence of reliable information about the predictive factors and course of vision loss in IIH, these grading systems are arbitrary. Patients with IIH should be followed up with serial perimetry and stereoscopic fundus photographs or indirect ophthalmoscopy Contrast sensitivity loss has also been found to be a sensitive indicator of vision loss in IIH. 4 The frequency of follow-up should be individualized and dictated by the initial visual involvement and its course. Snellen acuity, confrontational visual fields, direct ophthalmoscopic assessment of the degree of papilledema, and visual evoked response are insensitive and are much less useful in the follow-up. Vision Loss in Childhood IIH. Contrary to statements in the literature, children do not seem to be protected from vision loss in IIH. A recent study on pediatrie IIH found no difference in the frequency or extent of the vision loss in children when compared with adults Children should be kept under the same close ophthalmic surveillance advocated for adults with this disease. Sedation may be required to examine the fundus adequately, and fundus photographs may prove to be invaluable in follow-up assessment. Older children can be tested like adults, but young children are often unable to cooperate adequately for testing visual fields. Empty Sella and Endocrine Dysfunction. Chronically increased intracranial pressure in patients with IIH may produce an empty sella if the diaphragma sella is incompetent and the subarachnoid space herniates into the sella turcica. 84 CT scans may show evidence of an empty sella in a high proportion of patients with ΠΗ It has been suggested that herniation of optic nerves and chiasm into the empty sella may contribute to vision loss in these patients. 84 However, in careful studies, an empty sella conferred no statistically significant risk of vision loss when compared with a normal sella. 911 Endocrine dysfunction, including hyperprolactinemia ascribed to an empty sella, 85 is reported in IIH anecdotally; however, detailed endocrinologie investigations in patients with IIH are usually normal TREATMENT Since the only permanent morbidity from IIH is loss of vision, therapy for IIH is dictated by the presence and pro- Grade* Normal Mild Moderate Severe Table 4. A Simplified Grading System for Visual Impairment in Idiopathic Intracranial Hypertension Visual symptoms None May or may not be aware of defects Aware of defects Disabled by defects Best corrected visual acuity 20/20 or better 20/30 or better 20/40 to 20/100 Worse than 20/100 *The maximum defect determines the grade for an eye. Visual fields Goldmann Automated Normal field, other than Same enlarged blind spot Constriction up to 20 with I4e target Constriction >20 with any target but V4e isopter at least 50 Only one quadrant with absolute field loss <20 field with V4e target No point loss >10dB Point loss > 10 db Same <20 field with brightest target

9 Mayo Clin Proc, February 1994, Vol 69 IDIOPATHIC INTRACRANIAL HYPERTENSION 177 gression of vision loss. Hence, follow-up of patients with IIH often requires the clinical skills of an ophthalmologist. In the event of vision loss, the help of an ophthalmic surgeon or neurosurgeon may be needed. Treatment of the disorder, therefore, focuses on the early detection and prevention of vision loss. However, in certain cases, treatment may have to be directed at the disturbing symptom of headache. Although many different modes of treatment, including repeated lumbar punctures, corticosteroids * diuretics, cardiac glycosides, oral glycerol, subtemporal decompression, lumboperitoneal shunt, and optic nerve fenestration, have been tried in patients with IIH, none of these methods has been studied by a prospective randomized trial. Subtemporal or suboccipital decompression that was used from the 1940s to the 1960s has been abandoned because of the many complications and is only of historical interest. Because IIH is an infrequent diagnosis, a multicenter collaborative study would be required to obtain a sufficient number of subjects to randomize different modes of therapy. Correction of the Predisposing Factors. In the event of a presumed or overt precipitating factor (as listed in Table 2), withdrawal of the offending medication or correction of the condition, when possible, may result in the resolution of the syndrome. The role of weight reduction in the treatment of symptomatic patients with IIH is unclear; uncontrolled experience suggests this may be an effective treatment. 88 Lack of sustained patient compliance often limits this therapeutic approach. Recent weight gain was associated with visual deterioration in one study. 4 Weight loss should be recommended as a treatment for IIH in those who are obese. Serial Lumbar Punctures. If the patient's symptoms resolve after the initial diagnostic lumbar puncture, no further therapy is necessary. In those patients who continue to be symptomatic, repeated lumbar punctures have been recommended as a way of lowering intracranial pressure. This is appropriate and practical on a limited basis perhaps up to three to four lumbar punctures within the first 2 to 4 weeks. Sometimes complete resolution occurs after the first one to four lumbar punctures. Even in the absence of sustained resolution, the procedure may result in symptomatic remission for up to several days. This is somewhat paradoxical since, with a CSF production rate of 0.35 ml/min, the CSF removed by lumbar puncture is replenished in less than 2 hours. Two explanations have been offered ( 1 ) a persistent CSF leak may be present at the site of the lumbar puncture(s); (2) relief of elevated intracranial pressure by lumbar puncture alleviates compression of arachnoid villi (thereby improving CSF egress), which may be a secondary factor in some patients. Although previously advocated, serial lumbar punctures beyond two to four are unlikely to be productive in most patients. Lumbar puncture can be difficult to perform in an obese patient; serial taps become progressively difficult to perform and may contribute to chronic low-back pain and, very rarely, intraspinal epidermoid tumors. 89 Acetazolamide. Acetazolamide (Diamox), a carbonic - anhydrate inhibitor, is perhaps the most frequently used drug in cases of IIH. Its benefits have been attributed to a reduction in CSF production; however, it is unclear if the reduction in CSF production by acetazolamide is clinically substantial. In one study in humans, the reduction in CSF production abated approximately 30 minutes following a large intravenous injection. 90 However, in a study involving patients with IIH undergoing long-term intracranial pressure monitoring, an oral dose of 4 g/day of acetazolamide was shown to decrease CSF pressure. 17 Tomsak and coworkers, 91 in an uncontrolled study, have documented resolution of papilledema in patients with IIH treated with oral acetazolamide, 1 g/day. Its use in high doses is often limited by the well-known side effects of paresthesias, drowsiness, nausea, general malaise, metabolic acidosis, altered taste, and renal calculi. We start treatment at an oral dose of 250 mg four times a day, increased by 250 mg/day until a daily dose of 500 mg four times a day is reached or side effects develop. Use of the long-acting form of the drug (Diamox Sequels) may be associated with fewer side effects. 92 Diuretics other than acetazolamide, such as chlorthalidone, furosemide, and ethacrynic acid, are frequently used in IIH to reduce intracranial pressure. 22 In general, the reports of resolution of IIH associated with acetazolamide, other diuretics, and other medications are often difficult to interpret since spontaneous resolution, especially following lumbar puncture, is frequent. Corticosteroids. An occasional patient with IIH, whose symptoms do not respond to acetazolamide or who develops intolerable side effects to this drug, may benefit from a short course of oral corticosteroids. One acceptable treatment approach is to prescribe 40 to 60 mg/day of prednisone or a comparable amount of dexamethasone. At these doses, a decrease in symptoms can be expected in 10 to 14 days, which should be followed by a tapering of the medication over the next 2 weeks. Although acute administration of a systemic corticosteroid can rapidly lower the intracranial pressure, 93 prolonged corticosteroid use may result in a recurrence or a chronic course of intracranial hypertension and papilledema. 94 However, clinical experience suggests that the benefit of a short course of corticosteroid therapy under close supervision probably outweighs its theoretical harmful effects. 35 Surgery. Indications for Surgical Therapy. If the vision loss progresses in spite of medjcal treatment or if the vision loss is severe initially, surgical intervention should be contemplated without delay. Another possible situation in which surgery may be the initial option is when a patient is

10 178 IDIOPATHIC INTRACRANIAL HYPERTENSION Mayo Clin Proc, February 1994, Vol 69 unreliable at formal visual field testing due to age or other factors and shows an increased delay in the major positive peak of visual evoked response. 81 Surgical Options. When surgical treatment of IIH becomes necessary, the neurologic and neurosurgical literature suggest lumboperitoneal shunting of CSF as the treatment of choice, 95 while recent ophthalmology literature advocates optic nerve decompression as the preferred treatment. 96 Optic Nerve Sheath Decompression. Fenestration of optic nerve sheaths from a transconjunctival medial approach or by a lateral approach is becoming established as the surgical treatment of choice for vision loss in IIH. 96 In addition to immediate decompression of the optic nerve, the fenestration may result in a long-term filtration of CSF. Many patients have shown improvement in headache and bilateral vision after unilateral surgery. 97 Others frequently need secondary or tertiary optic nerve sheath decompression Surgical complications include pupillary dysfunction, peripapillary hemorrhage, chemosis, and chorioretinal scarring; 98 however, in experienced hands, the operation seems to be a very safe procedure with negligible intraoperative and postoperative complications Kelman and colleagues 97 performed optic nerve fenestration in 12 patients with functioning lumboperitoneal shunts and progressive vision loss; all of them demonstrated improvement in visual function. Spoor and associates 98 found that 69 eyes with acute papilledema uniformly had improvement in visual function after optic nerve fenestration; of 32 eyes with chronic papilledema, only 10 had improved visual function after optic nerve fenestration, and 11 of 13 eyes had improved vision after repeated optic nerve fenestration. Thus, patients with IIH and vision loss should be offered optic nerve fenestration without delay, and if symptoms recur, repeated optic nerve fenestration should be considered. However, more data are needed to determine the optimal operative technique, the mechanism of the therapeutic benefit, the frequency of complications, and the success rate of optic nerve sheath fenestration. Lumboperitoneal Shunting. Until recently, lumboperitoneal shunting was generally considered the surgical treatment of choice in IIH. 95 This approach does carry a risk of complications and the occasional need for shunt revision. 100 In addition, lumboperitoneal shunting has failed to halt the progressive vision loss in several well-documented cases For an occasional patient whose headache continues to be severe following optic nerve fenestration or who fails to respond to this treatment approach, a lumboperitoneal shunt may still be appropriate. IIH in Pregnancy. Since IIH is much more prevalent in young obese women of childbearing age, an association of IIH and pregnancy is expected. It was believed that IIH was provoked or exacerbated by pregnancy Recent studies have failed to confirm an association between IIH and pregnancy In a case-control comparison, 74 vision loss occurred with the same frequency in pregnant and nonpregnant patients; obstetric complications occurred more frequently in the control subjects. Treatment of IIH in pregnant women should be the same as for nonpregnant women with IIH except that caution should be exercised in the use of diuretics and caloric restriction for weight reduction. Obstetric management of patients with IIH is no different from that of normal pregnancy. 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