Purpose
To provide an update on various features of idiopathic intracranial hypertension.
Design
Perspective.
Methods
Selected articles on the epidemiology, clinical and imaging features, natural history, pathophysiology, and treatment of idiopathic intracranial hypertension were reviewed and interpreted in the context of the authors’ clinical and research experience.
Results
Idiopathic intracranial hypertension primarily is a disease of obese women of childbearing age, but it can affect patients of any weight, sex, and age. Although a relatively rare disorder, idiopathic intracranial hypertension’s associated costs in the United States entail hundreds of millions of dollars. Even after treatment, headaches frequently are persistent and may require the continued involvement of a neurologist. Quality-of-life reductions and depression are common among idiopathic intracranial hypertension patients. However, visual dysfunction, especially visual field abnormalities, represents the major morbidity of this disorder, and serial automated perimetry remains the primary method of patient monitoring. Patients who are men, black, very obese, or anemic are at higher risk of visual loss. Vitamin A metabolism, adipose tissue as an actively secreting endocrine tissue, and cerebral venous abnormalities are areas of active study regarding the pathophysiology of idiopathic intracranial hypertension. Treatment studies show that lumbar puncture is a valuable treatment (in addition to its crucial diagnostic role), and that weight management is critical. However, open questions remain regarding the efficacy of acetazolamide, cerebrospinal fluid diversion procedures, and cerebral venous stenting.
Conclusions
Many questions remain unanswered about idiopathic intracranial hypertension. Ongoing studies, especially an ongoing National Institutes of Health-funded clinical trial of acetazolamide, should provide more insight into this important, yet poorly understood, syndrome of isolated intracranial hypertension.
Idiopathic intracranial hypertension is a syndrome characterized by increased intracranial pressure of unknown cause ( Table ). By definition, idiopathic intracranial hypertension encompasses patients with isolated raised intracranial pressure that is not related to an intracranial process, cerebral venous thrombosis, or a meningeal process. Additionally, patients in whom a syndrome develops of raised intracranial pressure secondary to certain medications or who are found to have cerebral venous sinus stenoses (not thrombosis) still are classified conventionally as having idiopathic intracranial hypertension. Therefore, although not always literal, the term idiopathic intracranial hypertension currently is the preferred designation for this disorder in the English literature, rather than pseudotumor cerebri (often including patients with other causes of raised intracranial pressure) or benign intracranial hypertension (erroneously reassuring, considering that a substantial proportion of idiopathic intracranial hypertension patients irreversibly lose vision). Many questions remain open in the field of idiopathic intracranial hypertension, and this perspective emphasizes recent studies regarding the epidemiology, clinical and imaging features, pathophysiology, and treatment of idiopathic intracranial hypertension.
| 1 | Signs and symptoms of increased intracranial pressure (headaches, nausea, vomiting, transient obscurations of vision, papilledema). |
| 2 | No localizing, focal neurologic signs, except unilateral or bilateral VIth nerve paresis. |
| 3 | Cerebrospinal fluid opening pressure ≥ 25 cm, but without cytologic or chemical abnormalities. |
| 4 | Normal neuroimaging results adequate to exclude cerebral venous thrombosis, i.e., magnetic resonance imaging of the brain, often with additional sequences (computed tomography or magnetic resonance venography). |
Epidemiology
Idiopathic intracranial hypertension occurs most frequently among obese women of childbearing age. A recent multicenter case-control study of newly diagnosed women with idiopathic intracranial hypertension compared with women with other neuro-ophthalmologic disorders showed a dose relationship of higher body mass index associated with a greater risk of idiopathic intracranial hypertension. Interestingly, this study also showed that even nonobese patients were at greater risk for idiopathic intracranial hypertension if they had a recent moderate weight gain (5% to 15%).
Despite a high predilection for obese young women, idiopathic intracranial hypertension can occur in children, older adults, and nonobese persons of either sex. This disorder is rare in prepubertal children, with characteristics distinct from the adult form, including no apparent predilection for obese girls. After puberty, however, the rate of obesity and the gender predilection is similar to that in the adult idiopathic intracranial hypertension population. A recent large series confirmed that only approximately 10% of idiopathic intracranial hypertension patients are men. Although affected men have a similar body mass index when compared with affected women, they are, on average, approximately 1 decade older than women at the time of presentation. Although race does not seem to influence the incidence of idiopathic intracranial hypertension, a recent study questioned whether the association between obesity and development of idiopathic intracranial hypertension among Asians is as robust as in other populations.
Idiopathic intracranial hypertension also has been associated with other factors, such as a certain medications, anemia, and untreated obstructive sleep apnea. However, most of the evidence is anecdotal, and studies evaluating the relationship between obstructive sleep apnea and idiopathic intracranial hypertension are ongoing.
It was suggested recently that the economic costs of idiopathic intracranial hypertension in the United States exceed $444 million per year, mostly because of frequent hospital admissions, unsatisfactory treatment options, and lost productivity of young patients. The rising incidence of obesity in the world likely will increase the prevalence of idiopathic intracranial hypertension, resulting in further idiopathic intracranial hypertension-related expenses.
Clinical Features
Idiopathic intracranial hypertension typically presents with symptoms and signs of raised intracranial pressure. Headache, the most common symptom at presentation, is less likely to be reported by men than by women. Many idiopathic intracranial hypertension patients have persistent headaches, even after normalization of the intracranial pressure, and frequently require the continued involvement of a neurologist for adequate treatment. Patients with idiopathic intracranial hypertension also experience depression, anxiety, and reduced quality of life. These reductions in quality of life are more than would be expected based on the patients’ persistent headaches and comorbid obesity. Ophthalmologists should be attuned to these issues and should seek appropriate consultations in idiopathic intracranial hypertension patients who report chronic symptoms.
Papilledema is the most common sign of idiopathic intracranial hypertension. It indeed is not uncommon to diagnose idiopathic intracranial hypertension after papilledema is detected on a routine eye examination on asymptomatic patients, which explains why ophthalmologists often diagnose this disease first. This is particularly common in men, who often do not report headaches. Papilledema can result in insidious and slowly progressive visual loss, which is usually reversible with appropriate treatment. However, in up to 25% of idiopathic intracranial hypertension patients, secondary optic atrophy and associated permanent visual loss develop.
Visual loss usually is relatively mild at presentation, but progresses insidiously. In fact, most patients have visual field defects on automated perimetry at presentation, but are unaware of their visual dysfunction. Visual field abnormalities typically progress from enlargement of the physiologic blind spot, to nasal and arcuate defects, and ultimately to severe visual field constriction. All idiopathic intracranial hypertension patients must be monitored carefully with formal automated perimetry, with more aggressive intervention taken whenever deterioration of visual fields is documented.
Several demographic risk factors for visual loss in idiopathic intracranial hypertension have been identified. In one recent study, black patients with idiopathic intracranial hypertension were 3 times more likely than nonblack patients to have severe visual loss in at least 1 eye and were nearly 5 times more likely to be blind in both eyes. This difference in visual prognosis was likely unrelated to racial differences in diagnosis, treatment, or access to care. Black patients with idiopathic intracranial hypertension seem to have a more aggressive disease, and therefore need closer follow-up and a lower threshold for early aggressive intervention. A second study from the same patient database showed that men were more likely to have worse visual acuity and visual fields at presentation and follow-up and were less likely to report headaches than women, with the odds of severe visual loss for men at least double those of women. Thus, men also likely need more aggressive intervention when visual loss ensues and closer follow-up given their lower propensity for headache. The same investigators also found that increasing degrees of obesity are associated with an increasing risk of severe visual loss (Szewka AJ, personal communication, 2011), but that although idiopathic intracranial hypertension patients with a normal body mass index or who are older than 50 years are only a small proportion of patients with idiopathic intracranial hypertension (< 5% each of all idiopathic intracranial hypertension patients at the study’s tertiary referral centers), these patients tend to have better visual outcomes than the more typical idiopathic intracranial hypertension patient.
Rarely, patients with idiopathic intracranial hypertension may have an acute onset of symptoms and signs of raised intracranial pressure (so-called fulminant or malignant idiopathic intracranial hypertension), with rapid worsening of visual loss over a few days, but meet the criteria for idiopathic intracranial hypertension with normal brain magnetic resonance imaging and venography results. In a study of 16 such fulminant idiopathic intracranial hypertension cases, immediate surgical treatment was required because of ongoing severe visual loss in all patients; 50% remained legally blind, and the visual fields remained severely impaired in all cases. Prompt recognition and early aggressive treatment of patients with fulminant idiopathic intracranial hypertension therefore is essential.
Occasionally, nonphysiologic visual field constriction occurs in patients who have coexisting organic visual loss from papilledema, making management decisions difficult. Additionally, it is common to observe nonspecific visual field depression and constriction related to poor test reliability on automated perimetry obtained in idiopathic intracranial hypertension patients who have headaches and feel poorly. Patients with visual loss from raised intracranial pressure should have obvious papilledema, unless severe secondary optic atrophy already has developed. In patients with raised intracranial pressure without papilledema, another cause of visual loss or nonorganic visual loss should be considered. Visual loss secondary to raised intracranial pressure in the setting of no visible papilledema has been reported, but remains exceedingly rare, and its existence hotly debated.
The role of optical coherence tomography in the evaluation of papilledema remains unclear. A few studies have proposed an adjunctive usefulness for optic nerve imaging by optical coherence tomography in differentiating pseudopapilledema from papilledema and in monitoring the thickness of the peripapillary retinal nerve fiber layer during the course of idiopathic intracranial hypertension. However, the reductions in the retinal nerve fiber layer observed as disc edema resolves may not be differentiated easily from axonal loss reflecting disease progression, rather than improvement. At this time, quantification of visual function by ophthalmic examination and automated perimetry remains much more helpful than anatomic characterization of the optic nerve with optical coherence tomography in the monitoring of patients with idiopathic intracranial hypertension.
Although brain imaging demonstrate normal results to diagnose idiopathic intracranial hypertension, imaging changes associated with raised intracranial pressure commonly are observed in idiopathic intracranial hypertension patients ( Figure ). These include an empty sella or flattening of the pituitary gland, tight subarachnoid spaces, flattening of the posterior globes, protrusion of the optic nerve heads, enhancement of the prelaminar portion of the optic nerve heads, distension of the optic nerve sheaths, and vertical tortuosity of the optic nerves. Although cerebral venous thrombosis must be ruled out in patients with suspected idiopathic intracranial hypertension, numerous studies from the last decade have shown that unilateral stenosis of the dominant transverse sinus or bilateral stenoses of the transverse sinuses, often with measurable hemodynamic gradients, are common in typical idiopathic intracranial hypertension patients (see below).
Clinical Features
Idiopathic intracranial hypertension typically presents with symptoms and signs of raised intracranial pressure. Headache, the most common symptom at presentation, is less likely to be reported by men than by women. Many idiopathic intracranial hypertension patients have persistent headaches, even after normalization of the intracranial pressure, and frequently require the continued involvement of a neurologist for adequate treatment. Patients with idiopathic intracranial hypertension also experience depression, anxiety, and reduced quality of life. These reductions in quality of life are more than would be expected based on the patients’ persistent headaches and comorbid obesity. Ophthalmologists should be attuned to these issues and should seek appropriate consultations in idiopathic intracranial hypertension patients who report chronic symptoms.
Papilledema is the most common sign of idiopathic intracranial hypertension. It indeed is not uncommon to diagnose idiopathic intracranial hypertension after papilledema is detected on a routine eye examination on asymptomatic patients, which explains why ophthalmologists often diagnose this disease first. This is particularly common in men, who often do not report headaches. Papilledema can result in insidious and slowly progressive visual loss, which is usually reversible with appropriate treatment. However, in up to 25% of idiopathic intracranial hypertension patients, secondary optic atrophy and associated permanent visual loss develop.
Visual loss usually is relatively mild at presentation, but progresses insidiously. In fact, most patients have visual field defects on automated perimetry at presentation, but are unaware of their visual dysfunction. Visual field abnormalities typically progress from enlargement of the physiologic blind spot, to nasal and arcuate defects, and ultimately to severe visual field constriction. All idiopathic intracranial hypertension patients must be monitored carefully with formal automated perimetry, with more aggressive intervention taken whenever deterioration of visual fields is documented.
Several demographic risk factors for visual loss in idiopathic intracranial hypertension have been identified. In one recent study, black patients with idiopathic intracranial hypertension were 3 times more likely than nonblack patients to have severe visual loss in at least 1 eye and were nearly 5 times more likely to be blind in both eyes. This difference in visual prognosis was likely unrelated to racial differences in diagnosis, treatment, or access to care. Black patients with idiopathic intracranial hypertension seem to have a more aggressive disease, and therefore need closer follow-up and a lower threshold for early aggressive intervention. A second study from the same patient database showed that men were more likely to have worse visual acuity and visual fields at presentation and follow-up and were less likely to report headaches than women, with the odds of severe visual loss for men at least double those of women. Thus, men also likely need more aggressive intervention when visual loss ensues and closer follow-up given their lower propensity for headache. The same investigators also found that increasing degrees of obesity are associated with an increasing risk of severe visual loss (Szewka AJ, personal communication, 2011), but that although idiopathic intracranial hypertension patients with a normal body mass index or who are older than 50 years are only a small proportion of patients with idiopathic intracranial hypertension (< 5% each of all idiopathic intracranial hypertension patients at the study’s tertiary referral centers), these patients tend to have better visual outcomes than the more typical idiopathic intracranial hypertension patient.
Rarely, patients with idiopathic intracranial hypertension may have an acute onset of symptoms and signs of raised intracranial pressure (so-called fulminant or malignant idiopathic intracranial hypertension), with rapid worsening of visual loss over a few days, but meet the criteria for idiopathic intracranial hypertension with normal brain magnetic resonance imaging and venography results. In a study of 16 such fulminant idiopathic intracranial hypertension cases, immediate surgical treatment was required because of ongoing severe visual loss in all patients; 50% remained legally blind, and the visual fields remained severely impaired in all cases. Prompt recognition and early aggressive treatment of patients with fulminant idiopathic intracranial hypertension therefore is essential.
Occasionally, nonphysiologic visual field constriction occurs in patients who have coexisting organic visual loss from papilledema, making management decisions difficult. Additionally, it is common to observe nonspecific visual field depression and constriction related to poor test reliability on automated perimetry obtained in idiopathic intracranial hypertension patients who have headaches and feel poorly. Patients with visual loss from raised intracranial pressure should have obvious papilledema, unless severe secondary optic atrophy already has developed. In patients with raised intracranial pressure without papilledema, another cause of visual loss or nonorganic visual loss should be considered. Visual loss secondary to raised intracranial pressure in the setting of no visible papilledema has been reported, but remains exceedingly rare, and its existence hotly debated.
The role of optical coherence tomography in the evaluation of papilledema remains unclear. A few studies have proposed an adjunctive usefulness for optic nerve imaging by optical coherence tomography in differentiating pseudopapilledema from papilledema and in monitoring the thickness of the peripapillary retinal nerve fiber layer during the course of idiopathic intracranial hypertension. However, the reductions in the retinal nerve fiber layer observed as disc edema resolves may not be differentiated easily from axonal loss reflecting disease progression, rather than improvement. At this time, quantification of visual function by ophthalmic examination and automated perimetry remains much more helpful than anatomic characterization of the optic nerve with optical coherence tomography in the monitoring of patients with idiopathic intracranial hypertension.
Although brain imaging demonstrate normal results to diagnose idiopathic intracranial hypertension, imaging changes associated with raised intracranial pressure commonly are observed in idiopathic intracranial hypertension patients ( Figure ). These include an empty sella or flattening of the pituitary gland, tight subarachnoid spaces, flattening of the posterior globes, protrusion of the optic nerve heads, enhancement of the prelaminar portion of the optic nerve heads, distension of the optic nerve sheaths, and vertical tortuosity of the optic nerves. Although cerebral venous thrombosis must be ruled out in patients with suspected idiopathic intracranial hypertension, numerous studies from the last decade have shown that unilateral stenosis of the dominant transverse sinus or bilateral stenoses of the transverse sinuses, often with measurable hemodynamic gradients, are common in typical idiopathic intracranial hypertension patients (see below).
