The Photopic Negative Response in Idiopathic Intracranial Hypertension

Vision loss associated with papilledema, the anterior optic nerve swelling that occurs when elevated intracranial pressure (ICP) squeezes the retro-bulbar optic nerve, is the major morbidity of idiopathic intracranial hypertension (IIH), which affects 1:100,000 individuals annually and has a 20-fold higher incidence in young, obese females.1,2 Papilledema is caused by axoplasmic stasis in the retinal ganglion cells (RGCs) that comprise the optic nerve due to mechanical compression of the RGCs by elevated ICP and/or RGC ischemia due to mechanical compression of blood vessels supplying them.3,4 Visual dysfunction in papilledema is attributed to RGC dysfunction caused by these same mechanisms and is clinically characterized using standard automated perimetry (SAP) to quantify peripheral vision, as central vision is typically not affected until late in the disease course. Standard automated perimetry is the basis for most clinical management decisions in IIH.5,6 However, abnormalities on SAP measure only some subpopulations of RGCs in the central 24 degrees of the visual field and are likely a late manifestation of ganglion cell injury.7 Furthermore, as a psychophysical test, SAP is inherently subjective and prone to patient error. This introduces uncertainty into interpreting its results with respect to RGC function.8,9 Electrophysiological measures of RGC function offer advantages over SAP because they are objective, noninvasive, quick, and have minimal patient demands. Literature regarding other optic neuropathies suggests that abnormal or absent electrophysiological responses that originate from RGCs may precede changes in SAP.7 There are multiple electrophysiological tests that are abnormal when RGC function is compromised, including the visual evoked potential (VEP), pattern electroretinogram (PERG), and photopic negative response (PhNR). The VEP, which measures the integrated function of the visual pathway from the retina to the occipital lobe, has been shown to have prolonged latency in patients who have IIH.10,11 However, its use has not been widely adopted, as a clinically relevant cutoff could not be defined. The PERG has been shown to have specificity for inner retinal dysfunction associated with RGC injury and has been demonstrated to be abnormal in patients with IIH, particularly at intermediate and high spatial frequencies.12 However, the PERG is limited to assessing function within the central visual field, which is not typically affected until late in the disease course in IIH. The PhNR is a slow negative component of the photopic full-field ERG that has promise for assessing RGC function in patients with IIH. The PhNR is generated by the spiking activity of inner retinal neurons, primarily RGCs,13,14 and is reduced in human patients with glaucoma,15 acquired optic atrophy,16,17 OPA1-associated dominant optic atrophy,18 anterior ischemic optic neuropathy, compressive optic neuropathy,19 and optic neuritis.20,21 The PhNR also has been shown to correlate well with chronic structural changes of the retinal nerve fiber layer (RNFL), a measure related to RGC structure, in chronic optic neuropathies.15,16,22 The PhNR has advantages over the PERG by being a relatively brief test and not requiring refractive correction, features that make it less prone to test-taker and examiner errors.23 Importantly, the PhNR, elicited by a full-field flash, captures RGC function throughout the entire visual field, not just the central portion stimulated in PERG. This is theoretically relevant in papilledema, in which early vision loss localizes to the peripheral visual field. The PhNR has not been recorded from patients with IIH, but it may be useful for providing important information regarding RGC function in this population. The purpose of the present study was to evaluate the PhNR in patients with IIH. The PhNR amplitude and timing, recorded in patients with IIH, were compared with measurements made in control subjects and correlated with clinical measures of visual function and optic nerve structure. The results are intended to lay the scientific and technical foundation for the use of the PhNR as a clinical tool and potential clinical trial outcome measure for IIH.