Idiopathic intracranial hypertension: An old disease getting new attention

Idiopathic intracranial hypertension (IIH)^1,2 has come under increased clinical scrutiny in the last 2 decades. This neurologic disorder is characterized by increased intracranial pressure of unknown origin, and while it was once considered rare, the opposite now may indeed be true, based on the increasing numbers of IIH cases being diagnosed.

Two experts in IIH delved deeply into the most current knowledge about IIH to assist eye care, primary care, and emergency department clinicians in establishing a correct diagnosis.

Marc Bouffard, MD, an Assistant Professor of Neurology at Harvard Medical School and neuro-ophthalmologist at Mass General Brigham in Boston, described his team’s focus on a potentially new diagnostic imaging technique that is under development, and Rudrani Banik, MD, an Associate Professor of Ophthalmology and neuro-ophthalmologist at the Icahn School of Medicine at Mount Sinai and Co-Director of the Neuro-Ophthalmology Service, New York Eye and Ear Infirmary of Mount Sinai, New York, reported on the nuances involved in diagnosing and treating patients with IIH.

Demographics

Gender is the outstanding risk factor of the disease, with the vast majority of patients being overweight or obese women (body mass index [BMI] over 30) of childbearing age.³ In addition to those risks, the following “highly likely risk factors” although extremely rare risks, also have been reported: endocrine disorders, ie, Addison’s disease, hypoparathyroidism, steroid withdrawal, and growth hormone use in children; and nutritional disorders such as hypervitaminosis A, and hyperalimentation in deprivation dwarfism.³

One explanation for the preponderance of women affected by IIH is a hormonal component in these patients who are of childbearing age between ages 18 to 55 years. However, as Banik explained, “when hormonal changes are coupled with being overweight or obese or recent weight gain, the combination can trigger elevated intracranial pressure,” she said.

This is borne out in the literature. IIH has been reported to be increasing in incidence in parallel with the current obesity epidemic. A large population study reported the IIH incidence to be 19/100,000 among obese women aged 20 to 44 years who were 20% or more over their ideal weight, compared to 0.9/100,000 in the general population.³ Other population studies also have confirmed these data.^3,4 The World Health Organization reported a twofold increase in IIH in the UK between 1997 and 2002 and a threefold increase in the US between 1990 and 2006. A recent epidemiology study reported an incidence of IIH occurring in 28/100,000/year.⁴

Typical and atypical disease presentations

Banik explained that headache is the most common symptom. “The typical patients with IIH report headaches that are holocranial, a pressure-like sensation, and possibly co-morbid migraine,” she said.

Another symptom, she noted, is pulsatile tinnitus in the ear that patients may not recognize as part of this syndrome. “This is a specific type of tinnitus, ie, pulse synchronous low-frequency tinnitus that is synced with the heartbeat, resulting from turbulence in the veins that is associated with IIH, and patients may be more aware of it at night, while lying in bed on a particular side,” she explained.

In addition to those common symptoms, other manifestations include transient blindness with positional changes seen in about half of patients; diplopia; scotoma; neck and shoulder pain; loss of peripheral vision; feelings of sleepiness, sickness, and irritability; photophobia; and mental confusion.⁵ Bouffard added that brain fog reported by patients is just beginning to be studied.

An important less-known factor is that some patients with IIH are asymptomatic. “In this scenario, a patient may undergo a regular annual eye examination and the optometrist or ophthalmologist recognizes swollen optic nerves indicating potential papilledema,” Banik pointed out.

Men, who represent only 9% of the cases, tend to have a more aggressive course of IIH with headache, tinnitus, and vision loss, she said. They may have more sudden symptom onset in contrast to women in whom the symptoms can develop gradually and more rapidly progressively disease that occurs over several weeks in her practice.

Men are more likely to present with severe visual acuity and visual field defects and worse visual outcomes compared with women.^6,7

In addition, men tend to experience a shorter time between the onset of the first symptom to the time of diagnosis compared to women, which may be related to the more severe vision loss experienced by men. Another difference is that men are more likely than women to require surgical intervention for visual impairment.⁷

Affected men also are typically obese and more likely to have sleep apnea. The worse visual prognosis in men may be because they less frequently experience or report other symptoms of raised intracranial pressure, which may lead to more advanced disease on presentation.⁶

Bruce et al.⁶ also found that men with IIH tended to be morbidly obese (BMI, 35 and over).

Although rare, IIH also can occur in children and elderly patients.³ In children, a study⁸ that looked at the differences between pre- and post-pubertal IIH reported that pre-pubescent patients had a more variable presentation and did “not display the same predilection towards the female sex and obesity as post-pubertal children, who have a similar phenotype to the adult cohort.” The authors advised that the study methodology may have muddied the conclusions by including secondary causes of raised intracranial pressure.

Differential diagnosis

“Intracranial hypertension caused by medications or another medical condition is a consideration in patients who present with papilledema. Patients with an identifiable etiology for intracranial hypertension have secondary intracranial hypertension or secondary pseudotumor cerebri syndrome. Several medications have been associated with intracranial hypertension including tetracyclines, corticosteroids (administration or withdrawal), growth hormone, oral contraceptives, and vitamin A derivatives. Intracranial tumors and dural venous sinus thromboses can also cause intracranial hypertension, and both can present similarly to IIH,” according to Hernandez et al,⁹ although central venous thrombosis are characterized by a much faster evolution, Bouffard pointed out.

They also noted that ocular diseases such as optic neuritis, optic disc drusen, and anterior ischemic optic neuropathy can manifest with optic nerve elevation and visual disturbances, as can systemic disorders, notably infectious meningitis, hypertensive retinopathy, diabetic papillitis, and infiltrative optic neuropathies, that may present with similar ophthalmic findings.⁹

The why of IIH

The precise pathophysiologic mechanisms underlying the development of IIH remains incompletely understood. Dysregulation of cerebrospinal fluid (CSF) dynamics are candidate mechanisms. While venous sinus stenosis is considered to be unlikely as the origin of IIH, it is frequently caused by elevated ICP and may contribute to decreased venous drainage, with increased venous sinus pressures, decreased CSF absorption, and higher ICP leading to worsened extrinsic compression of the venous sinuses and a vicious cycle of increasing ICP.¹⁰

Diagnosing IIH

The current standard is a combination of tests to establish the IIH diagnosis with lumbar puncture being one of the components. The modified Dandy criteria,¹¹ ie, the diagnostic requirements that confirm the presence of IIH, include the following:

• Signs and symptoms of increased intracranial pressure (ICP) (headaches, nausea, vomiting, transient visual obscurations, papilledema)
• No localizing neurologic signs, except for unilateral or bilateral sixth cranial nerve palsy
• CSF opening pressure >25 cm H₂O with normal CSF composition
• No evidence of hydrocephalus, mass, structural, or vascular lesion (including venous sinus thrombosis) on imaging
• No other cause of increased ICP identified

Analysis looks at the white cell count and the protein and glucose count in the CSF to rule out infectious, inflammatory, or neoplastic causes such as CNS lymphoma, which can mimic IIH, Banik explained.

While in many patients, the diagnosis is unambiguous and the presentation is typical, in others it is not so straightforward. “There are opportunities for IIH to present real diagnostic difficulties. That may be the case if there is something atypical about any combination of the presenting features or if the demographic is atypical. A combination of nonspecific symptoms, borderline exam findings, and borderline opening pressures can occur, making mild IIH sometimes difficult to establish clearly. Opening pressures between 20 to 25 cm H₂O are generally considered compatible with a diagnosis of IIH, but only if additional criteria are met. Furthermore, a small percentage of healthy individuals may have opening pressures >25 cm H₂O and they can both fluctuate normally and can be influenced by patient positioning and relaxation, leading to false positives and false negatives. The criteria require binary cut-offs, but in reality, it’s not always so simple,” Bouffard said.

“Establishing or excluding the diagnosis with the modified Dandy criteria (or others, such as Friedman’s 2013 criteria) can be difficult in some cases, heightened by the fact that there is no gold-standard blood test or imaging biomarker that is definitively diagnostic of IIH,” according to Bouffard. “A swollen optic nerve is a typical manifestation of IIH,” he noted, but “it is thought that some patients may have IIH without papilledema. Separate diagnostic criteria have been advanced for this condition, but we need to advance our scientific understanding of this condition to avoid both underdiagnosis and overdiagnosis.”

Ancillary testing can be crucial in distinguishing IIH from other optic neuropathies and neuro-ophthalmic conditions. Visual field testing, optical coherence tomography (OCT), and neuroimaging studies can provide valuable information to aid in the differential diagnosis and guide appropriate management strategies. Neuro-ophthalmologists sometimes require collaboration with neurologists, neurosurgeons, and other specialists to ensure comprehensive evaluation and treatment of patients presenting with signs and symptoms suggestive of IIH.⁹

OCT is performed to measure the retinal nerve fiber layer and analyze the ganglion cells followed by fundus photography. Loss of ganglion cells on OCT is irreversible.

A caveat is that identification of papilledema is a common source of error in the diagnosis of IIH, in that it is both under- and over-diagnosed. Therefore, where doubt exists, a specialist physician should confirm its presence.²

A potential new diagnostic method via the glymphatic system

The fact that IIH can be difficult to diagnose yet carry serious ramifications emphasizes the need for better noninvasive diagnostic methods that mitigate the ambiguity that can be present. In light of that, Bouffard and his collaborators elected to conduct research into the workings of glymphatic transit in IIH, the brain’s version of the lymphatic system, he clarified. The hope is that gaining an understanding of the fluid transit in the glymphatic system in the brain in patients with IIH compared with those without could lead to a new noninvasive way to diagnose the disease.

Their latest research published in the Journal of Neuro-Ophthalmology and funded by the Mass General Brigham Idiopathic Intracranial Hypertension Research and Treatment Initiative, looked at how the activity of the glymphatic system changed in individuals with IIH.¹²

The glymphatic system, a fairly new entity that was only recognized in mammals in 2012,¹³

according to Bouffard, comprises the brain’s network of perivascular channels and serves as the brain’s system of clearing interstitial fluid and waste products – analogous to but anatomically distinct from the body’s lymphatic system.

“There had been some clues in the literature that there was probably some system to drain interstitial fluid and brain waste other than the dural venous sinuses. Before 2012, however, it wasn’t clear exactly what type of system was mediating the transit that was suspected to exist,” he said. Using two-photon microscopy, Iliff et al.¹³ and others¹⁴ showed that the CSF passed into channels around arteries formed by astrocytes and then into brain tissue; fluid and waste products then moved into perivenous astrocyte-walled channels and were drained into the lymphatic system,” Bouffard explained.

The big question remains about what causes IIH, considering that only blood, CSF, and brain tissue are in the head. Could abnormal glymphatic transit provide the missing key in understanding of how IIH causes elevated pressure in the head?

Bouffard and colleagues theorized that “Improved characterization of glymphatic transit in IIH may offer insights into pathophysiologic or adaptive changes in CSF and interstitial fluid transit, which in turn may have beneficial diagnostic or therapeutic ramifications. Decreased glymphatic transit in the setting of acute secondary intracranial hypertension has been observed in murine models.¹²

In their study, Bouffard and colleagues at Mass General Brigham and Beth Israel Deaconess Medical, Boston, used a magnetic resonance imaging (MRI) technique called diffusion tensor imaging along the perivascular space (ALPS) to measure perivascular diffusivity and generate indices of glymphatic transit (ALPS-indices) in the brain. Healthy patients and those with IIH underwent imaging. The patients with IIH had either untreated or treated IIH or had been cured. The untreated IIH was classified as acute if patients had undergone imaging within 6 months of symptoms onset; the treated IIH was classified as chronic if the patients underwent imaging 6 months or longer after onset. The imaging measured how easily fluid was able to transit through the spaces surrounding veins in one area of the brain.

The authors reported results from 40 study participants. “We identified a positive, nonlinear correlation between ALPS-indices and disease duration in patients with untreated IIH, reaching what looks like a ceiling value after around a year. The ALPS-indices differed among participants with chronic, treated, and acute IIH, in descending order,” they reported.

The patients with acute IIH had lower ALPS-indices compared with the healthy controls, and those with chronic IIH had higher ALPS-indices than the controls. The ALPS-indices were the same in the healthy controls and those who still had IIH but were treated to achieve a normal or near-normal pressure.

“This research is promising, exciting, fascinating, and a work in progress. Our work has suggested that our original hypothesis, ie, that glymphatic dysfunction might cause IIH, is less likely. If the glymphatic system is mechanistically involved in IIH, our results suggest that it is probably not a simple, causal mechanism wherein glymphatic dysfunction results in intracranial hypertension,” he commented.

The investigators continue their work, they explained, “to integrate these findings with other indices of glymphatic transit and to clarify the extent to which ALPS-indices might be leveraged as a diagnostic aid for IIH.”

Treatment

Banik’s treatment strategy is based on two factors, patient symptoms and the ophthalmologic and test findings.

Weight loss is integral to the treatment plan, according to Banik. Even modest weight loss, ie, 5% to 10% of body weight, can cause disease remission.

An eye examination is performed to grade the papilledema using the Frisén scale¹⁵ from 0 to 5. She relies heavily on visual field testing, which indicates if progressive vision loss is imminent. If only mild deficits are seen, treatment can be less aggressive. However, if the visual field shows substantial vision loss or central loss or scotoma, an aggressive approach is warranted with medication and close monitoring to determine the need for optic nerve sheath fenestration or ventricular peritoneal shunting, she explained.

Oral acetazolamide is the first-line medical treatment based on the Idiopathic Intracranial Hypertension Treatment Trial¹⁶ reference generally is started at 500 mg twice daily; the dose can be increased as needed for symptom control up to 2,500 mg daily to resolve the papilledema; the maximum dose is 4,000 mg daily. If side effects such as paresthesia occur, magnesium can offset that.

Alternatives are topiramate (Topamax, Janssen Pharmaceuticals), a migraine treatment that can suppress appetite, or furosemide (Lasix, Sanofi-Aventis US) for patients who cannot tolerate acetazolamide. Both drugs interfere with the production of CSF at the level of the choroid plexus epithelium. She reserves steroids for patients at risk of vision loss and awaiting surgery.

Surgery to implant a shunt to divert CSF flow is an option in the presence of progressive vision loss and refractoriness to maximal medical therapy. Dr. Banik pointed out that less than 5% of her patients required surgical intervention.

Typical case report

Banik described the case of a 33-year-old woman who presented to the Emergency Department with a 3-month history of progressively worsening daily headaches. She described the headaches as diffuse, pressure-like, and worse in the morning, and they were exacerbated by bending over or coughing. She also reported transient episodes of blurred vision lasting several seconds, particularly when standing up quickly, along with pulsatile tinnitus described as a “whooshing” sound in both ears.

The past medical history was notable for recent weight gain of approximately 25 pounds over the past year, for a current weight of 275 lbs. Her BMI was 34 kg/m². She was otherwise healthy and not taking vitamin A derivatives, tetracyclines, or hormonal therapy. An ophthalmology consult was requested because of the blurry vision.

The visual acuity was 20/20 in both eyes. There was no afferent pupillary defect. The color vision and intraocular pressure were normal. A dilated fundus examination showed bilateral optic disc edema consistent with papilledema (grade IV in both eyes defined as total obscuration of some but not all major vessels on the disc). Humphrey visual field testing showed enlarged blind spots and mild inferior arcuate defects. A neurologic examination was otherwise nonfocal.

MRI of the brain with MR venography showed partially empty sella, flattening of the posterior globes, distention of the perioptic subarachnoid space, bilateral transverse sinus stenosis, and the absence of a mass lesion or hydrocephalus.

Lumbar puncture results showed an opening pressure of 32 cm H₂O (normal, <25 cm H₂O) and normal cerebral spinal fluid composition.

Based on the modified Dandy criteria,¹¹ the patient was diagnosed with IIH.

Treatment includedacetazolamide (Diamox) 500 mg twice daily, titrated up to 1,000 mg twice daily.

A structured weight reduction program targeting 6% to 10% weight loss was started accompanied by nutritional counseling and lifestyle modification.

At the 6-month follow-up, the patient achieved an 8% reduction in body weight, the headaches had improved significantly, the pulsatile tinnitus resolved, the visual fields were measurably improved, and the papilledema grade decreased to Frisen grade I in both eyes.

The acetazolamide was weaned down to 500 mg twice daily, Banik reported.

Message to eye care clinicians

“Ophthalmologists should be aware the IIH is much more common than we think. It should be on the radar for any patient in this demographic between the ages of 18 and 55 years, especially women who are overweight. Don’t skip the dilated eye exam to evaluate the optic nerve,” Banik said.

Bouffard emphasized the importance of lowering the barrier for referring patients to neuro-ophthalmologists. “So much is changing in our understanding of IIH and its management. Establishing an unambiguous diagnosis and confidently treating patients can be a challenge and neuro-ophthalmologists can help. Fostering a relationship between ophthalmologists, optometrists, and neuro-ophthalmologists and keeping communication open is important,” he said.

References

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15. Frisén L.Swelling of the optic nerve head: A staging scheme.J Neurol Neurosurg Psychiatry. 1982;45:13–8.

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