Patients with idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri (PTC), often present to the ophthalmologist because of complaint of blurred vision or headache. The prompt and accurate recognition of this condition is beneficial both because it establishes the correct diagnosis with a minimum of delay and because IIH is a potentially blinding disorder. Recent advances in the study of the basic biology and the clinical pathophysiology of IIH have changed the approach to this disease condition. IIH is a clinical syndrome characterized by well-defined criteria, originally proposed by neurosurgeon Walter Dandy, MD. These criteria have undergone numerous modifications over the years as our understanding of the condition has improved. The most recent diagnostic requirements are as follows (Friedman et al. Neurology 2013; 81:1159‑65).
Diagnostic criteria for pseudotumor cerebri syndrome
- Required for diagnosis of pseudotumor cerebri syndrome
- Normal neurologic examination except for cranial nerve abnormalities
- Neuroimaging: Normal brain parenchyma without evidence of hydrocephalus, mass, or structural lesion and no abnormal meningeal enhancement on MRI, with and without gadolinium, for typical patients (female and obese), and MRI, with and without gadolinium, and magnetic resonance venography for others; if MRI is unavailable or contraindicated, contrast-enhanced CT may be used
- Normal CSF composition
- Elevated lumbar puncture opening pressure (≥ 250 mm CSF in adults and ≥ 280 mm CSF in children [250 mm CSF if the child is not sedated and not obese]) in a properly performed lumbar puncture
- Diagnosis of pseudotumor cerebri syndrome without papilledema
In the absence of papilledema, a diagnosis of pseudotumor cerebri syndrome can be made if B–E from above are satisfied, and in addition the patient has a unilateral or bilateral abducens nerve palsy
In the absence of papilledema or sixth nerve palsy, a diagnosis of pseudotumor cerebri syndrome can be suggested but not made if B–E from above are satisfied, and in addition at least 3 of the following neuroimaging criteria are satisfied:
- Empty sella
- Flattening of the posterior aspect of the globe
- Distention of the perioptic subarachnoid space with or without a tortuous optic nerve
- Transverse venous sinus stenosis
Epidemiology and etiology
The major risk factors for developing IIH remain obesity and female gender; although no new major epidemiological studies have been reported in the past decade, clinical experience supports their conclusions. The incidence of IIH has increased dramatically despite the current "epidemic of obesity," and clearly, all obese patients do not develop the condition. Overall the incidence is about 0.7/100,000; however in at‑risk populations (e.g., overweight females 15–44 years old) the incidence has been documented to be as high as 19.3/100,000. IIH is virtually nonexistent in countries where obesity is uncommon.
IIH in children (prepubertal) occurs with equal incidence in boys and girls and often follows middle ear infections/mastoiditis, or medication (antibiotic) therapy. Venous sinus thrombosis is not uncommon; most think that pediatric IIH is probably a somewhat different disease than the adult form.
Anatomic factors that increase venous pressure through resistance in the intrathoracic, intra-abdominal, or cerebral intrasinus venous compartments might play a role in causing disease. Regardless of underlying circumstances, the common element is believed be an imbalance between production (usually normal) and absorption of CSF (usually diminished), leading to an elevation of intracranial pressure. Peripheral conversion of estrogen occurs in adipose cells (hence the connection with obesity in women), leading to an increase in circulating levels of the hormone, which in turn affects the capacity of the arachnoid granulations to absorb CSF. Over-excitation of retinoic acid receptors located on the arachnoid granulations can impair CSF absorption (see risk factors below).
Studies over the past decade have provided mounting evidence implicating a role for abnormalities in cerebral venous sinus structure in patients with IIH. It has been recognized that a high proportion (>90%) of patients with IIH have uni- or bilateral transverse sinus (TS) stenosis (Farb et al. 2003, Higgins et al. 2004). However, here is significant debate about whether these sinovenous stenoses play a role in the pathophysiology of this condition or are simply a consequence of raised intracranial pressure (Rohr et al. 2007, Higgins et al. 2004, King et al. 2002, Baryshnik et al. 2004, De Simone et al. 2005, McGonigal et al. 2004). Restoring the patency of the stenotic venous sinus with stenting can normalize intracranial pressure and significantly improve or render some patients asymptomatic (Higgins et al. 2002 and 2003, Owler et al. 2003, Ogunbo et al. 2003, Rajpal et al. 2005, Metellus et al. 2005 and 2007, Rohr et al. 2007, Donnet et al. 2008, Paquet et al. 2008, Bussiere et al 2010).
Figure 1. Contrast-enhanced MRV brain in a patient with IIH. In addition to the smooth tapering stenosis noted along the right transverse sinus, the characteristic, reproducible abnormality seen a large majority of IIH patients is unilateral or bilateral focal stenosis at the junction of the distal 1/3 portion of the transverse sinus and sigmoid sinus.
In addition to demographic considerations described earlier, patients with IIH typically present with signs and/or symptoms of raised ICP. These can include headache (worse upon awakening or when supine), nausea, pulsatile tinnitus ("whooshing" sounds timed to heartbeat), transient obscurations of vision (momentary greying out of vision or positive visual phenomena (seconds)) occurring spontaneously or with change in postural/valsalva, or binocular (usually) horizontal diplopia due to abducens nerve compression the ventral pontine surface and bony clivus.
Patients with disc swelling due to raised ICP (papilledema) usually present with normal (or near normal) visual acuity, normal color vision, and equal pupillary responses. Indeed the most common clinical finding in IIH is papilledema. Swelling of the retinal nerve fiber layer (RNFL) leads to a loss of transparency of this layer, thereby obscuring visualization of underlying anatomic structures such as the disc margin, blood vessels, and eventually the optic cup.
The severity of papilledema (see Frisen grading system, Figure 2) does not necessarily correlate with the degree of visual loss at the time of presentation. Indeed some patients have advanced VF loss with fairly minimal papilledema, while others have severe disc edema and early VF changes only. This is the most widely used grading system, allowing accurate comparisons over time and across observers.
Symptoms can begin gradually over several weeks to months, or more abruptly with subacute onset of symptoms. Some patients have advanced visual field loss at the time of presentation, suggesting chronicity and ongoing damage over several months to years.
Figure 2. Frisen papilledema grading scale from grade 0 (top left) to grade 5 (bottom right). Recording the papilledema grade is a simple way to track the clinical status. Key features include C‑shaped halo of edema in grade 1 (top center), 360‑degree edema in grade 2 (top right), and progressive obscuration of vessels at the disc margin (grade 3), on the disc surface centrally (grade 4), and complete obliteration on the disc as well as extensive involvement of peripapillary retina (grade 5). Note hemorrhage and exudate are not part of the grading scheme. The presence of exudation usually indicates a more fulminant, rapid onset development of raised intracranial pressure, overwhelming the retinal vasculature's ability to compensate.
Figure 3. HVF in patients with IIH. Left eye on the left, right eye on the right. Top panel shows enlarged blind spots only, which reflects the earliest VF findings in IIH patients. The bottom panel shows a more advanced presentation with characteristic arcuate pattern of loss with eventual central involvement as seen here in the left eye. Patients progress over days to weeks in some cases, and over several months in others if undertreated. Predominant central or centrocecal VF loss without arcuate changes should raise suspicion for alternative diagnoses such as inflammatory, infectious, infiltrative, metabolic/toxic/nutritional optic neuropathies.
Patients suspected of having IIH on history require a complete ophthalmological examination including formal visual fields and dilated fundus examination. Fundus photography and OCT RNFL can also be very helpful in following these patients.
All patients in whom papilledema is suspected on clinical examination, should have a blood pressure taken in the office. Hypertensive papillopathy can present identically to IIH, without associated retinal or choroidal hypertensive findings.
All patients with suspected papilledema must have a neuroimaging study done prior to lumbar puncture. The study is done not only to ensure the absence of a space-occupying lesion that could cause brain herniation upon lumbar puncture; it also can identify hydrocephalus, hemorrhage, and other anomalies that change the diagnostic workup. Magnetic resonance imaging (MRI) with contrast enhanced MR venography (CE‑MRV) is the most complete study to obtain in patients with suspected IIH (see below). However, in the acute setting, it might be difficult to get an MRI that will be done with the specific sequences and quality desired. Thus, a computed tomography (CT) scan of the head should be performed on the day of the diagnosis of bilateral optic disc swelling if there is any delay in obtaining an MRI/MRV.
Several recent studies have looked more closely at the issue of whether certain findings on MRI can be reliably correlated with IIH; essentially, ruling in the diagnosis of IIH instead of ruling out other causes of papilledema. These findings are not suggested to be specific for IIH, but might be present in the absence of features suggestive of an alternate etiology for raised ICP, such as enlarged ventricles in hydrocephalus, pachymeningeal thickening in meningitis, or signs of dural venous thrombosis. Listed below are the various features that have been described in the literature.
MRI findings potentially suggestive of raised intracranial pressure
- Flattening of the posterior aspect of the globe(s)
- Dilated perioptic fluid cuff
- Vertical or horizontal tortuosity of the optic nerves
- Partially empty sella
- Posterior displacement of the pituitary stalk
- Flattened course of the optic chiasm
- Tight subarachnoid spaces
- Slit-like ventricles
- Inferior displacement of the cerebellar tonsils
- Optic nerve protrusion
- Significant venous stenosis
In a recent MRI/MRV study analyzing patients with known IIH, we found that flattening of the posterior aspect of the globe, partially empty sella, and significant venous stenoses to be most sensitive and specific signs, when taken within the appropriate clinical context. We have found looking for these features helpful in cases in which the typical clinical signs and symptoms of IIH are absent or ambiguous.
Lumbar puncture is mandatory for the diagnosis of PTC, not only to confirm that the opening pressure is elevated, but also to ensure that the cerebrospinal fluid formula is normal. A number of inflammatory or infectious conditions can present with disc swelling and signs and symptoms of elevated intracranial pressure, and diagnosis of these conditions when they exist is imperative. Some patients will have a normal opening pressure at the time of LP but have signs/symptoms of elevated intracranial pressure. Such patients might benefit from intracranial pressure monitoring (inpatient study, done for 24–48 hours). As with blood pressure and IOP, intracranial pressure can vary diurnally.
Figure 4. MRI findings often found in patients with raised intracranial pressure include vertical tortuosity of the optic nerve and flattening of the posterior aspect of the globe as seen in the top left image. Top right shows the appearance of a partially empty sella, while the bottom left image is an example of dilation of the perioptic fluid cuff. A typical distal transverse sinus stenosis at its junction with the sigmoid sinus is demonstrated in the bottom right frame.
Figure 5. Cerebral venous sinus thrombosis (CVST). In contrast to the venous sinus stenoses seen in IIH, thromboses typically demonstrate irregular, patchy filling and lack a specific predilection for involvement of the transverse/sigmoid sinus junction. Note the irregularities within the superior sagittal and transverse sinuses (left image) and lack of filling of the straight sinus (right image).
Testing for staging, fundamental impairment
As mentioned above, the stage of papilledema might not correlate in some cases with the degree of visual impairment. Hence, functional testing including visual acuity, color vision and most importantly, formal perimetry are essential for accurate assessment in IIH patients. Some patients might have a degree of optic atrophy and gliosis (overlying scarring) from chronic, longstanding papilledema. In the face of persistent or recurrent ICP elevation, such nerves might not demonstrate the classical features of papilledema seen in "fresh" cases. Hence, attention to retinal venous tortuosity, shunt vessels, and neuroimaging findings (discussed above) might be fruitful.
Figure 6. Chronic papilledema. Top panel shows a patient with active yet chronic elevation of ICP with optociliary shunt vessels (blue arrows) and RNFL swelling, peripapillary fluid and gliosis extending overlying the disc and retinal vessel just temporal to the disc (white arrows). The bottom panel shows fundus photos of the same patient following a ventriculoperitoneal shunt placement. Note disappearance of the shunt vessels, underlying optic atrophy and persistence of gliosis.
OCT RNFL and GCC (ganglion cell complex) can be very helpful in following IIH patients, with the exception of cases with RNFL thickening above 250–300 microns, where the utility of OCT diminishes. OCT is a helpful adjunct when correlating the degree of RNFL thickening with VF involvement. For example, if OCT demonstrates a reduction in RNFL thickness in a patient with improving visual fields, this suggests that edema is improving along with visual function as expected. However, in cases of reduction of RNFL thickness on OCT and accompanying deterioration of VF, the more likely conclusion is loss of RNFL volume due to atrophy. GCC analysis is especially good at resolving the integrity of the underlying ganglion cell layer, which is not affected by overlying edema; hence, GCC assessment provides a more accurate measure of retinal architecture and better correlation with visual function.