INTRODUCTION — Idiopathic intracranial hypertension (IIH), also called pseudotumor cerebri, is a disorder defined by clinical criteria that include symptoms and signs isolated to those produced by increased intracranial pressure (ICP; eg, headache, papilledema, vision loss), elevated ICP with normal cerebrospinal fluid (CSF) composition, and no other cause of intracranial hypertension evident on neuroimaging or other evaluations [1].
While once called benign intracranial hypertension, to distinguish it from secondary intracranial hypertension produced by a neoplastic malignancy, it is not a benign disorder. Many patients with IIH suffer from headaches, which may be disabling, and there is a risk of severe, permanent vision loss.
While the pathogenesis of IIH is unknown, risk factors have been identified and many theories advanced as to its cause. The epidemiology and pathogenesis of IIH will be reviewed here. The clinical features, diagnosis, prognosis, and treatment of this disorder are discussed separately. (See "Idiopathic intracranial hypertension (pseudotumor cerebri): Clinical features and diagnosis" and "Idiopathic intracranial hypertension (pseudotumor cerebri): Prognosis and treatment".)
EPIDEMIOLOGY
Incidence — The annual incidence of IIH is 1 to 2 per 100,000 population [2,3]. There is a higher incidence in females with obesity between the ages of 15 and 44 years (4 to 21 per 100,000) [3,4]. The highest incidence, 28 per 100,000 per year, was reported in Ireland [5].
The incidence and prevalence of IIH are rising [6]; whether this is related to the obesity epidemic or other reasons is uncertain.
Risk factors — IIH is a disorder that primarily affects females of childbearing age who are overweight [3,4,7-11]. In a prospective study of 50 consecutively diagnosed IIH patients, 92 percent were females with a mean age of 31 years (range 11 to 58 years), and 94 percent were obese [10]. Other case series in different geographic areas and ethnic groups report similar findings [4,11-16].
IIH can also occur in males and in patients who are not overweight; it is also reported in children as young as four months and in older patients (up to 88 years) [15,17-20]. However, when symptoms occur in one of the less typical patient groups, the evaluation for secondary causes of intracranial hypertension is particularly important. (See "Idiopathic intracranial hypertension (pseudotumor cerebri): Clinical features and diagnosis", section on 'Differential diagnosis'.)
The annual incidence of IIH in children younger than 17 years old has been estimated as 0.63 per 100,000 children in the United States [21]. Risk factors are different in prepubertal children compared with adults. There is no female preponderance in young patients [17,22-30]. Also, prepubertal children with IIH are not more likely to be obese than the general age-matched population [22,23,26,27,29,30].
In one report, older patients (greater than 44 years) with IIH were also more often male and less often obese than patients with IIH in the more typical age range [31]. Males with IIH have a similar age distribution as females, and obesity remains a risk factor but may be less prevalent in males than in females with IIH [12,18].
Recent weight gain may be a risk factor for IIH, according to case-control studies [8,10,11,32]. In one series, there was an average reported weight gain of 1.8 kg over the two months preceding symptom onset [10]; in another series, there was an average 20 pound weight gain over the preceding year compared with an average weight loss of 1.2 pounds in controls [11].
In the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT), 5 percent of patients reported a family history of IIH [16]. As this frequency is higher than the prevalence of IIH in persons with obesity, a genetic component for IIH is suggested.
Associated conditions — Several systemic diseases, drugs, vitamin deficiencies and excesses, anemia [33,34], and hereditary conditions have been reported to be associated with IIH, but that association is uncommon.
The true link between these conditions and IIH is uncertain in many cases. In case-control studies, the prevalence of menstrual irregularities, pregnancy, antibiotic use, iron deficiency anemia, thyroid dysfunction, and oral contraceptive use was no different among cases versus controls [8,11]. However, these studies were small (40 to 50 patients), which may have limited their ability to detect true associations.
Medications — A number of medications and other exogenous substances have been linked to IIH. In some cases, the connection may be anecdotal. In other cases, evidence that supports a true association includes temporal proximity between drug initiation and IIH in a substantial number of patients, resolution with drug cessation or dose lowering, lack of recurrence off medication, and/or reemergence of IIH with drug rechallenge. Such evidence appears to exist for growth hormone, tetracyclines, and retinoids.
●Growth hormone appears to be associated with IIH in a dose-related manner [35-41]. One 2007 study estimated the incidence of IIH in children treated with growth hormone to be 27.7 per 100,000 treatment years. This complication usually develops within one year of initiation of therapy but may appear after several years [42]. IIH generally subsides with stopping growth hormone therapy; resuming therapy at a lower dose is often successful. Other specific treatments for IIH may also be required [39]. (See "Treatment of growth hormone deficiency in children".)
●Tetracyclines, including minocycline and doxycycline, have been linked in a number of cases to IIH, but other risk factors are often present [43-52]. When it occurs, IIH often appears shortly after onset of treatment (within a few weeks to months), but a more delayed onset has been described. Drug withdrawal appears to be sufficient for treatment in some patients.
●Hypervitaminosis A from excessive dietary intake has been a long-known cause of IIH [43,53]. Other retinoids used in the treatment of dermatologic conditions and cancer therapy, all-trans retinoic acid, retinol, isotretinoin, etretinate, and tretinoin have also been reported to be associated with IIH [43,44,48,54-58].
More limited, possibly anecdotal evidence links other medications with IIH:
●Thyroid replacement [25,59-61]
●Corticosteroid withdrawal [31,62,63]
●Nalidixic acid [26,68]
Systemic illnesses — In addition to obesity, systemic illnesses reportedly associated with IIH include:
●Addison disease [71,72]
●Hypoparathyroidism [73]
●Anemia, usually severe [15,33,74,75]
●Sleep apnea [15,16,19,76,77]
●Systemic lupus erythematosus (SLE) [78-80]
●Behçet syndrome [81,82]
●Polycystic ovary syndrome [83]
●Coagulation disorders [83-86]
●Uremia [87]
●Hypovitaminosis A [88-91]
The pathogenic mechanisms associating these conditions with IIH are uncertain, and in some cases, the apparent association may be indirect or spurious. As an example, sleep apnea is associated with obesity and therefore may be secondarily associated with IIH. In SLE, cases of apparent IIH may be due to occult cerebral venous thrombosis (related to inflammation of the venous sinus or hypercoagulability) or to corticosteroid withdrawal [78]. Other hypercoagulable syndromes, sarcoidosis, and Behçet syndrome may also be associated with IIH by causing secondary intracranial hypertension via occult venous sinus thrombosis. (See "Idiopathic intracranial hypertension (pseudotumor cerebri): Clinical features and diagnosis", section on 'Differential diagnosis'.)
PATHOGENESIS — Although many theories for IIH have been proposed, the precise pathogenesis of IIH remains unknown. Any theory must account for the high incidence of IIH in obese females of childbearing years. Proposed etiologies include cerebral venous outflow abnormalities (eg, venous stenoses and venous hypertension); increased cerebrospinal fluid (CSF) outflow resistance at the level of either the arachnoid granulations or CSF lymphatic drainage sites; obesity-related increased abdominal and intracranial venous pressure; altered sodium and water retention mechanisms; and abnormalities of vitamin A metabolism [92].
Intracranial venous hypertension — Elevated intracranial venous pressure is postulated both as a primary mechanism and as a "final common pathway" for IIH. This theory is supported by the similar clinical appearances of IIH and secondary intracranial hypertension due to cerebral venous thrombosis and other causes of obstructed venous outflow. Some patients thought to have IIH have been later discovered to have one of these conditions [81,93-95]. (See "Idiopathic intracranial hypertension (pseudotumor cerebri): Clinical features and diagnosis", section on 'Differential diagnosis'.)
Although several authors have reported cerebral venous outflow abnormalities on magnetic resonance imaging (MRI) and magnetic resonance venography (MRV) in patients with IIH, there is some disagreement as to the frequency or the significance of these findings [20,96,97]. Clear venous sinus thrombosis has definite clinicopathologic significance, but apparent bilateral venous sinus narrowing or stenosis is now known to be a biomarker of increased intracranial pressure (ICP) [98]. Differentiation of venous stenosis from flow-related abnormalities, especially on noncontrast MRV, can be difficult, as flow-related artifacts can mimic venous sinus stenoses or even be mistaken for sinus thrombosis. These issues can sometimes be resolved with postcontrast MRV. Literature that suggests a high frequency of venous sinus abnormalities in patients with IIH must be viewed with caution.
Cerebral venous sinus structural abnormalities were systematically identified in a series of 29 patients with IIH using a specialized MRV technique, auto-triggered elliptic-centric-ordered three-dimensional gadolinium-enhanced MRV (ATECO MRV) [99]. Masked readers detected substantial bilateral sinovenous stenoses in 27 of 29 patients compared with 4 of 59 controls, corresponding to a sensitivity and specificity of 93 percent. The investigators speculated that congenital narrowing of the venous sinus might be a primary cause of IIH or alternatively a secondary, but potentially contributing, factor. In the latter scenario, increased CSF pressure compresses the transverse sinuses leading to the stenoses, which in turn would exacerbate the increased ICP, potentially bringing the patient to clinical presentation.
Other evidence leaves open the question of whether these apparent venous abnormalities are a secondary or a primary (causative) phenomenon. One study documented high intracranial venous sinus pressures in patients with IIH that were reduced by removal of CSF [100]. This finding implies that increased cerebral venous sinus pressure and apparent stenosis in IIH is caused by the elevated ICP and is not its cause. Other reports have also documented reversal of apparent transverse sinus stenosis after CSF shunting [101-106]. By contrast, other case series have documented persistent transverse sinus stenosis in patients with IIH whose CSF pressure has normalized and an overall poor correlation between the severity of the venous abnormalities and the degree of pressure elevation or severity of clinical findings [107,108].
Other theories — There is evidence that obesity increases intraabdominal pressure, pleural pressure, cardiac filling pressure, and central venous pressure and may lead to increased intracranial venous pressure and IIH [109]. Limited support for this theory comes from a report of seven obese females with IIH who reported subjective symptom relief with the use of an externally applied device that lowered abdominal pressure [110]. However, this mechanism does not account for the sex difference in IIH, the lack of increased incidence in pregnancy, and the cases of IIH in thin patients [111,112].
Cerebral edema was one of the earliest proposed mechanisms for IIH and had pathologic support in one case series [113]. However, subsequent pathologic and MRI studies have not found evidence of cerebral edema in patients with IIH [114-117]. A link between IIH and altered sodium and water retention was suggested by another report in which 77 percent of patients with IIH had evidence of peripheral edema and 80 percent had orthostatic retention of sodium and water [118]. Impaired excretion after water or saline load in the upright posture was noted in patients with IIH with orthostatic edema compared with lean patients with IIH and obese controls without IIH. However, the precise mechanisms linking orthostatic changes and IIH were not defined, and many patients with IIH do not have these sodium and water abnormalities.
Case reports of IIH occurring in association with vitamin A intoxication have suggested a role for vitamin A in the pathogenesis of IIH [43,53]. Elevated serum vitamin A, retinol, and retinol-binding protein levels have been reported in some patients with IIH [119,120]. In other studies, higher CSF vitamin A, retinol, and retinol-binding protein levels have been found in patients with IIH compared with controls [121-123]. One case-control study concluded vitamin A toxicity was an unlikely cause of IIH [124].
Other causes of impaired CSF absorption or increased CSF production have also been postulated as an etiology of IIH. As an example, one hypothesis proposes that microthrombosis in the sagittal sinus may block CSF absorption in the arachnoid granulations there, even in the absence of a thrombosis of sufficient size to be seen on neuroimaging studies [83,125]. Conditions that obstruct venous outflow (venous sinus thrombosis), impair CSF absorption (subarachnoid hemorrhage or infectious meningitis), and are associated with CSF overproduction (choroid plexus papilloma) can produce a syndrome similar to IIH. (See "Idiopathic intracranial hypertension (pseudotumor cerebri): Clinical features and diagnosis", section on 'Differential diagnosis'.)
Sleep apnea can be a complication of obesity and may play a role in IIH, perhaps in males in particular [19,126]. Hypercarbia may produce elevated ICP through vasodilation. Papilledema occurs in approximately 1 percent of patients with sleep apnea [127,128]. One study found that 14 of 37 patients with IIH had a sleep disturbance, and of these, 13 had evidence of sleep apnea or upper airway resistance syndrome [77]. In another report, a patient with IIH underwent ICP monitoring with pulse oximetry to reveal that apneic episodes were associated with marked elevations of ICP [129].
Several studies have looked at the pathophysiology of obesity and its complications as a basis for IIH. Leptin is a protein secreted by adipose cells in proportion to total body fat content. Higher serum leptin levels were found in 15 obese patients with IIH compared with 16 obese and 15 nonobese controls [130]. The pathophysiologic consequences of this finding are not known. Other studies of other adipokines, leptin, and the gastric hormone, ghrelin, have not consistently found an association with IIH [125,131].
Few studies have examined the potential role of sex hormones in IIH. In one study of eight males with IIH, two had abnormal estradiol levels, four had abnormal follicle-stimulating and luteinizing hormone levels, and seven had low testosterone levels [132].
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●Basics topics (see "Patient education: Idiopathic intracranial hypertension (pseudotumor cerebri) (The Basics)")
SUMMARY
●Incidence and risk factors – The incidence of idiopathic intracranial hypertension (IIH) in the general population is 1 to 2 per 100,000 population and is 2 to 20 times higher in the primary risk group: overweight females of childbearing years. (See 'Epidemiology' above and 'Risk factors' above.)
●Associated medications and medical illnesses – A long list of medications has been reported to be associated with IIH. The evidence linking growth hormone treatment, retinoids, and tetracycline antibiotics is strongest; however, the mechanisms by which these might produce IIH is not known. (See 'Medications' above.)
Other than obesity, the association between other medical conditions and IIH is not proven. (See 'Systemic illnesses' above.)
●Theories of pathogenesis – The pathogenesis of IIH is unknown. Much attention has been placed on the association of IIH with venous sinus stenosis. However, most of the evidence at present suggests that apparent venous sinus narrowing is secondary to increased intracranial pressure (ICP) and is not the primary cause in most cases. (See 'Intracranial venous hypertension' above.)
Other theories include increased cerebrospinal fluid (CSF) outflow resistance, obesity-related increased abdominal and intracranial venous pressure, altered sodium and water retention mechanisms, and abnormalities of vitamin A metabolism. (See 'Other theories' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Claudia Prospero Ponce, MD, and Aroucha Vickers, MD, who contributed to an earlier version of this topic review.
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