A High-Pressure Situation: Idiopathic Intracranial Hypertension Diagnosis and Treatments

Idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri, is a disorder of increased intracranial pressure (ICP), defined as more than 250 mm H₂O opening pressure, in the presence of normal neuroimaging and normal cerebral spinal fluid (CSF) content.¹ This condition typically affects women of child-bearing age with obesity, and its most common initial symptoms are headache, transient visual obscurations, back pain, and pulse synchronous tinnitus.^1,2 From 1997 to 2016, the annual incidence of IIH was 1.15 per 100,000 in the United States general population. However, for the group most likely to develop IIH, women of child-bearing age with obesity, the prevalence increases to 12 to 19 per 100,000.^3,4 This incidence is expected to rise in concert with the increasing incidence of obesity.  

Idiopathic Intracranial Hypertension’s Threat to Vision

The goals of treatment with IIH are to limit visual morbidity from persistent optic nerve edema and to relieve symptoms, which is most commonly headache. One prospective study of 50 patients with IIH that found visual field defects at initial presentation in at least 1 eye for 96% of patients assessed with the Goldmann perimeter and for 92% of patients assessed with the Humphrey perimeter.⁵ In addition, up to 30% of cases are discovered incidentally, which highlights the importance of comprehensive eye exams.⁶

Rapid weight gain in addition to use of tetracycline antibiotics, lithium, renal failure, anemia vitamin A derivatives such as isotretinoin, and exogenous testosterone are well-established associations with IIH, but the pathophysiology of the disease remains elusive.⁷ Researchers have proposed several possible pathophysiologic mechanisms, including vasogenic extracellular brain edema, low conductance of CSF outflow at the level of the arachnoid villi, and increased intra-abdominal pressure from central obesity resulting in impeded venous return from the intracranial circulation.^8,9 The potential role of sex hormones in the pathogenesis of IIH has also been explored, as pregnancy, polycystic ovarian syndrome (PCOS), and exogenous estrogens have been observed to promote or worsen IIH symptoms. Obesity combined with female sex and child-bearing age, nonetheless, remains the most significant known risk factor.^10,11 

Diagnosing IIH

The Modified Dandy Criteria used to diagnose IIH was reviewed and updated in 2013 to account for neuroimaging technologies, the potential for IIH without papilledema, and further delineate primary IIH from secondary causes.¹²

A careful medical history should be elicited, including symptomatology, recent weight gain, and use of potential offending medications. Next, a complete ocular evaluation is indicated, as fundus photography or optical coherence tomography (OCT) alone should not be relied upon to screen for the presence of papilledema. The exam should include dilated fundus examination, extraocular motility testing, and formal visual field testing to accurately assess for stigmata of elevated intracranial pressure such as papilledema and unilateral or bilateral, non-localizing sixth nerve palsies. Subsequently, when 1 or more of these findings is present, MRI is needed to exclude secondary causes of increased intracranial pressure. It is crucial to remember IIH, although common, is a diagnosis of exclusion, and all diagnostic steps must be taken to ensure that a secondary cause of intracranial hypertension or optic disc edema from a mechanism other than elevated intracranial pressure is not missed. This differential may include mass lesion, hydrocephalus, venous sinus thrombosis, hypertensive optic neuropathy, and infectious or inflammatory meningitis. 

Remember, papilledema is an optic neuropathy that generally spares central visual acuity and color vision until the later stages of the disease. As such, clinicians should consider an alternative diagnosis if there is significant acute or subacute visual acuity loss or color vision loss on presentation. The presence of vitreous cells may suggest an infectious cause of optic disc edema; such as syphilitic optic neuropathy, for example. Clinicians should have heightened concern for secondary causes of IIH in men, as patients with body habitus that is atypical for IIH, or patients in the fifth decade of life and older. 

IIH Imaging and Other Testing

In addition, although MRI and MRV in IIH is negative for mass lesions, hydrocephalus, leptomeningeal inflammation, and venous sinus thrombosis respectively, there are important but subtle stigmata of elevated intracranial pressure to look for. These include flattening of the posterior globes (most common), empty sella, prominent and/or tortuous optic nerve sheaths, and optic nerve head protrusion.¹³ MRV can show narrowing of the transverse sinuses and focal stenosis. While highly suggestive of elevated ICP when present, the absence of these signs does not rule out IIH. 

If the patient is unable to undergo MRI imaging due to claustrophobia, weight limitations of the scanner, contraindication due to metallic implant, or difficulty with scheduling, computed tomography (CT) scan of the head with contrast and CT venography of the head may be obtained as a more expeditious alternative. Ultimately, however, MRI is the imaging modality of choice for soft tissue characterization of the brain and is preferable to CT whenever possible. 

The presence of subtle findings on MRI suggestive of elevated ICP in isolation does not sufficiently take the place of accurate opening pressure measurement and CSF analysis. As such, after negative imaging, lumbar puncture must be performed, ideally in the left lateral decubitus position. Opening pressure and basic spinal fluid composition studies (cell count, protein, glucose, culture, and in select cases, cytology) should be collected. Normal opening pressure in adult patients is lower than  25 cm H₂O, and lower than 28 cm H₂O in pediatric patients. 

Baseline visual field testing and OCT of the retinal nerve fiber layer (RNFL) are important tools for determining frequency of surveillance and possible need to escalate therapy in the setting of advanced atrophy or visual field loss at the time of presentation. The severity of visual field loss may also help determine the urgency of referral to a neuro-ophthalmologist, ranging from obtaining consultation within 1 to 2 weeks to even same-day or next-day consultation depending on regional expertise. Referral to the emergency department for expedited work-up may be indicated in cases of high grade optic disc edema, rapid onset and progression of symptoms, and areas where urgent outpatient work-up or neuro-ophthalmology consultation may not be feasible to obtain.  

Preferred IIH Management

Weight loss and treatment with carbonic anhydrase inhibitors (CAI) such as acetazolamide are the mainstays of managing IIH. A small retrospective 2021 study of 39 patients shows that a 11.5% weight loss achieved clinical remission in 70% of patients, while a prospective study of 66 patients shows that 24% weight loss is required for ICP normalization.^14,15 This study also suggests that the degree of weight loss required to achieve disease remission was most likely achievable through bariatric surgery as opposed to weight management programs.¹⁵ 

The Idiopathic Intracranial Hypertension Treatment Trial was a multicenter, double-blind, randomized, placebo-controlled study of acetazolamide in 165 IIH participants with mild visual loss that found subjects taking acetazolamide along with a low-sodium diet program had significantly better visual outcomes than those taking placebo along with the diet.¹⁶ Typical dosing regimens begin at 500 mg twice daily and can be titrated up to 4 grams daily. Physicians should discuss common side effects with patients, including paresthesias, dysgeusia, nausea, diarrhea, kidney stones, and fatigue. 

An important consideration that should be discussed with IIH patients is the potential risk of acetazolamide for pregnancy. While acetazolamide at high doses may produce birth defects in lab animals, there is little clinical or experimental evidence to support any adverse effect of the drug on pregnancy outcomes in humans.^17,18 Some practitioners choose to defer treatment with acetazolamide during the first trimester due to concerns for teratogenicity, but the general safety of acetazolamide in pregnancy has been endorsed by multiple authors who report large prospective and retrospective studies demonstrating no fetal loss or adverse effects in any trimester.^17,18  Of note, acetazolamide undergoes renal metabolism and as such may be contraindicated in patients with renal disease. 

Alternate IIH Treatments

For patients who cannot be treated with acetazolamide due to side effect intolerance, methazolamide and topiramate are potential alternative options. Methazolamide is a CAI with a similar side effect profile as acetazolamide. It undergoes hepatic metabolism and may be an option for patients with marked renal compromise. Both acetazolamide and methazolamide are sulfonamides; and, as such, patients should be screened for sulfa allergy prior to use. 

Topiramate has mild carbonic anhydrase activity, acts as an appetite suppressant, and additionally treats migraines, allowing for multifaceted treatment approaches in IIH. Common side effects to be discussed with patients include fatigue, cognitive difficulties, and paresthesias. It is renally-excreted, and similar to acetazolamide, it must be either used with caution or avoided altogether in patients with renal disease. Asmall open label study of 40 patients shows topiramate is c to acetazolamide, but no randomized controlled studies of topiramate have been conducted.¹⁹

Surgery Options for IIH

If a patient has fulminant disease with progressive vision loss refractory to medical therapy, or if the patient is unable to tolerate medical management, surgical treatment may be necessary. The classic surgical options include CSF diversion procedures, such as ventriculoperitoneal or lumboperitoneal shunting, and optic nerve sheath fenestration, depending on local expertise and practice patterns. As a general rule of thumb, if there is a significant headache burden, CSF diversion is preferred. If there is significant visual morbidity or risk of visual morbidity without a significant headache component, optic nerve sheath fenestration is the procedure of choice.²⁰

Venous sinus stenting is also emerging as an additional surgical option for IIH, with the goal of relieving outflow obstruction at the level of the dural venous sinuses that contributes to raised intracranial pressure. 

A Deft Diagnosis Can Reduce Risk

Careful adherence to the diagnostic criteria of IIH minimizes the risk of misdiagnosis and expedites appropriate disease management. A thorough history is essential to identify potential secondary causes of intracranial hypertension, establish the tempo of disease progression, and select the most appropriate treatment. Most patients will respond to medical therapy and weight loss alone, but select cases require surgical intervention to treat progressive visual field loss and refractory headaches. 

Drs Fong and Lao are ophthalmologists with the Hamilton Eye Institute at the University of Tennessee Health Science Center, Memphis, TN.