Idiopathic Intracranial Hypertension (IIH): Practice Essentials, Background, Pathophysiology

Idiopathic intracranial hypertension (IIH) is a disorder of unknown etiology characterized by chronically elevated intracranial pressure (ICP), and the most important neurologic manifestation is papilledema. The presentation of acute/subacute symptoms of increased ICP and papilledema should be considered a clinical emergency until a neuroimaging study confirms the absence of an intracranial mass. If left untreated, chronic papilledema may lead to secondary progressive optic atrophy, visual field loss, and ultimately blindness. In the event that the increased intracranial pressure is determined to be related to a dural sinus thrombosis or the administration of an exogenous substance, the raised ICP is no longer considered idiopathic and falls under the broader disease category of pseudotumor cerebri.

Thus, although IIH, pseudotumor cerebri, and benign intracranial hypertension (BIH) may be considered to be used interchangeably, IIH is the more precise term for the disease entity that is not linked to a secondary disorder.

Signs and symptoms

Patients with IIH usually present with symptoms related to increased ICP which may include the following ^[1] :

• Headaches - 84% (nonspecific and varying in type, location, and frequency)

• Transient visual obscurations - 68% (a "graying out of vision" lasting seconds at a time, usually related to orthostatic movements)

• Pulse synchronous tinnitus - 52%

• Subjective visual loss - 32% 

• Horizontal diplopia - 18% (due to a nonlocalizing sixth nerve palsy)

The most significant physical finding in IIH is papilledema (ie, bilateral disc edema due to increased ICP).

There are rare patients with classic symptoms of increased ICP who present with asymmetric papilledema (one optic nerve edematous and the other one less so or not at all) or with no papilledema at all.

See Presentation for more detail.

Diagnosis

It is essential to perform urgent neuroimaging studies on any patient presenting with bilateral optic nerve edema in order to rule out an intracranial mass. Once a mass lesion is ruled out, a lumbar puncture (LP) is performed to confirm an elevated opening pressure and to evaluate the cerebrospinal fluid (CSF) contents (description of the fluid,analysis of the protein, glucose, blood cell type/count, culture). An LP should never be performed prior to neuroimaging.

The preferred neuroimaging procedure is a combination of a magnetic resonance image (MRI) of the brain and magnetic resonance venography (MRV) to rule out both an intracranial mass lesion and a dural sinus thrombosis or stenosis. If MRI is not available on the initial presentation, at the very least a computed axial tomography (CAT scan) of the brain can be performed.

See Workup for more detail.

Management

The goal of management in IIH is to preserve optic nerve function while managing increased ICP. During active treatment, serial eye exams including assessment of the optic nerve appearance and static perimetry are essential to follow the visual function of these patients.

Pharmacologic therapy includes the following:

• Acetazolamide is the first-line therapy. It is an effective agent for lowering ICP, and it was shown to improve the visual function of patients with IIH in a randomized, controlled, clinical trial. ^[2]

• Furosemide or, rarely, other diuretics, as well as topiramate, have been used as second-line agents.

• Primary headache prophylaxis (eg, topiramate) may also be given.

• Corticosteroids should only be considered on a very short-term basis in patients who present with marked loss of visual function.

If visual function deteriorates while on maximal medical therapy, surgical intervention should be strongly considered. Such intervention includes the following ^[3] :

• Optic nerve sheath fenestration (decompression of the fluid surrounding the optic nerve)

• Cerebrospinal fluid (CSF) 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. 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 along with a low sodium diet are the cornerstones of long-term management of these patients. Some patients with IIH have experienced dramatic improvement after bariatric surgery due to the resulting weight loss that follows.

See Treatment and Medication for more detail.

The Dandy criteria (described by Dandy in 1937 and later modified) were the original criteria used to diagnose IIH and are as follows ^[4] : 

• Symptoms and signs of increased ICP.

• 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 are found through workup.

A subsequent article further refined the diagnostic criteria by adding the following two criteria ^[5] :

• 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. An initial theory thought that cerebral edema played a role in the pathogenesis of elevated ICP in these patients, but later reports described the edema to represent fixation artifact (ie, from tissue preparation) rather than in vivo edema. ^[6]

Although the precise mechanism is not understood, IIH is likely due to a dysregulation of CSF dynamics involving a blend of hypersecretion of CSF at the choroidal plexus, reduced reabsorption at the arachnoid granulations and abnormal venous pressure gradients. ^[7]

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. 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.ref11} Although not accepted as a method of primary surgical treatment for IIH, stenting of stenotic dural sinuses has been demonstrated to decrease ICP in patients with IIH. ^[8]  

Another pathway of CSF drainage that is under study, the glymphatics, may prove to have an important role in the pathophysiology of IIH.  Several recent studies show that the CSF glymphatic function is congested in IIH, resulting in elevated intracranial pressure. ^{[9, 10]}

IIH commonly occurs in women who are overweight; however, the role obesity plays in this disorder is unclear. While it has been proposed that obesity increases intra-abdominal pressure and thereby raises cardiac filling pressures, this is likely not the sole underlying link between obesity and IIH. Some researchers are moving towards linking obesity, related neuroendocrine imbalances and IIH. ^{[7, 11]}  However, obesity appears to have no association with IIH in the pediatric population. An autoimmune component may play a role in pediatric IIH, given the high rate of atopy observed in this pediatric IIH patient cohort.  ^[12]

Although a role for vitamin A in the pathogenesis of IIH was initially suspected, the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) demonstrated no difference in CSF vitamin A levels in patients with IIH versus obese controls over a 6 month period except in those treated with acetazolamide. ^[13]

Other medications that have been implicated for resulting in IIH include tetracycline, amiodarone, oral contraceptives such as levonorgestrel (Norplant), cyclosporine, cytarabine, growth hormone, isotretinoin, levothyroxine (children), lithium carbonate and acute change of steroid use.  ^[14]

United States statistics

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 3.5 per 100,000 in women and to 19 per 100,000 in women aged20 to 44 years who exceed ideal body weight by 20%. ^[7]  

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. As an example, a far lower incidence has been noted in Asian countries (0.03/100,000), which is interpreted as the result of the markedly lower rate of obesity in these countries as compared to the United States. ^[7]

Age and race-related demographics

Although IIH may affect individuals of any age, most patients with this disease present in the third decade of life.

No evidence exists to suggest that IIH has a predilection for any particular racial or ethnic group.

IIH is not known to be associated with any specific mortality risk, 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 mainly is related to the effects of papilledema on visual function. 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. In end-stage papilledema, central visual acuity also is involved. With timely and appropriate treatment of IIH, the visual prognosis can be encouraging.

Since IIH tends to be chronic, visual function (visual acuity, visual fields, optic nerve appearance) must be monitored for years after presentation. If necessary, medical treatment should be continued on a long-term basis.

Loss of visual function

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, 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). ^{[15, 16]}  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 ^[17] ; 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 patients with IIH for more than 10 years and found that whereas 11 of the 20 had followed a stable course without visual-field changes or papilledema, nine had experienced deterioration after initially following a stable course for a time. ^[18]  In 6 of the 9, the deterioration occurred late (28-135 months after initial presentation), and in 3 of the nine, recurrences after resolution of papilledema developed 12 to 78 months after the initial resolution of IIH.

In the IIHTT the 3 most important negative risk factors for poor prognosis related to progressive visual field loss were male gender, high-grade papilledema and decreased visual acuity at baseline. ^[19]

It is important to inform patients with IIH that weight control along with a low sodium diet are key long-term factors in the management of their disease. Asking patients about their weight loss at the beginning of each visit reinforces this concept. In addition, it is worthwhile to stress that the loss of as little as 6% of body weight may lead to the termination of this disorder and significantly diminishes the risk of its recurrence. ^[20]

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.

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. 

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.