Background There is a paucity of literature describing risk factors for vision loss in paediatric idiopathic intracranial hypertension (IIH). We investigate the final visual function, spectral domain optical coherence tomography (SD-OCT) and enhanced depth imaging (EDI)-OCT findings in children with papilledema caused by IIH.
Methods Medical records of 31 patients with paediatric IIH (age ≤17 years) were retrospectively reviewed. Optic disc photographs on presentation and automated perimetry, SD-OCT and EDI-OCT imaging on final follow-up visit were statistically analysed to identify patient characteristics and anatomic findings associated with irreversible vision loss.
Results Permanent visual acuity or visual field loss developed in 19% of study eyes. Papilledema of modified Frisén grade ≥3 on presentation was highly predictive of permanent vision loss (p<0.001), while associations between pubertal status and visual function outcome failed to reach statistical significance. SD-OCT revealed optic atrophy in 13% and photoreceptor loss in 19% of eyes, with both findings highly associated with vision loss (p<0.0001). Optic disc drusen was noted in 48% of study eyes by EDI-OCT but was not found to be predictive of visual outcome.
Conclusions Clinical observation of high papilledema grade on presentation is predictive of poor visual outcomes. Vision loss is associated not only with optic atrophy but also with photoreceptor damage. Interestingly, a high proportion of study eyes had optic disc drusen, which was not associated with vision loss, but can be a diagnostic challenge in distinguishing true papilledema from pseudopapilledema.
- Optic Nerve
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.
Patients with idiopathic intracranial hypertension (IIH) often present with headache and visual symptoms due to elevated intracranial pressure (ICP) not caused by an intracranial mass, venous sinus thrombosis or central nervous system inflammation.1 A hallmark finding of IIH is papilledema. When profound or chronic, papilledema may lead to irreversible visual field defects, decreased visual acuity and the development of optic atrophy from death of retinal ganglion cells (RGCs) and their axons that comprise the retinal nerve fibre layer (RNFL).2 To alleviate symptoms and prevent permanent visual disability, IIH is typically treated with dietary interventions combined with pharmacotherapy to reduce cerebrospinal fluid (CSF) production3 or surgical intervention via optic nerve sheath fenestration (ONSF) or CSF diversion procedures.4
Monitoring of papilledema severity and early detection of optic atrophy in patients with IIH have been greatly aided by advances in spectral domain optical coherence tomography (SD-OCT). This non-invasive imaging modality is now commonly used to measure the thickness of the peripapillary RNFL in IIH, glaucoma and other optic neuropathies.5–7 Moreover, the high resolution of SD-OCT has allowed pathology of specific layers of the retina to be analysed qualitatively and quantitatively, and we have recently described examples of focal atrophy of retinal layers in the macula in adult patients with IIH that is distinct from the already-well-described RGC and RNFL changes.8
Though less common than in adults, IIH may affect the paediatric population.9 The longstanding belief that paediatric patients are less prone to poor visual outcomes has been challenged in recent years.10–12 The demographics of paediatric IIH are dictated by patients’ pubertal status: pubertal patients tend to be obese females (similar to the adult population), while pre-pubertal children show no tendency towards a particular sex or body habitus.13 ,14
In this retrospective longitudinal study, we aimed to address the relative paucity of information regarding visual outcomes in paediatric IIH and to examine potential predictors of visual morbidity. We applied SD-OCT and enhanced depth imaging (EDI)-OCT to assess anatomic abnormalities of the retina and optic nerve that may correlate with visual disability following treatment of IIH.
All patients with IIH age 17 and under, presenting to the paediatric neuro-ophthalmology clinic between 1 January 2010 and 31 August 2013, were included. Patients were required to meet the revised diagnostic criteria for IIH proposed by Friedman, Liu and Digre: (1) observation of papilledema or sixth nerve palsy, (2) otherwise normal neurological examination, (3) contrast-enhanced neuroimaging excluding secondary aetiologies of elevated ICP, (4) normal CSF composition and (5) lumbar puncture opening pressure exceeding 28 cm H2O (or 25 cm H2O if not sedated).1 Inclusion additionally required optic disc photography performed on presentation and Spectralis (Heidelberg, Carlsbad, California, USA) SD-OCT imaging of the macula obtained following treatment.
Data collected from the initial patient visit included age, gender, pubertal status (as determined by menarche in females and growth of facial hair in boys), serum haemoglobin (if available), visual acuity and optic disc photos. Type of therapy administered (eg, diuretics, ONSF, CSF diversion procedures) and assessments of visual acuity and visual field (using the automated Humphrey Field Analyzer/HFA II-i; Carl Zeiss Meditec, Dublin, California, USA) were documented. Using optic disc photographs, the severity of papilledema on presentation for both eyes of each patient was graded by the modified Frisén scale15 by a masked reader (MAE-D), and the eye with more severe disc swelling (or the right eye if the papilledema was symmetric) was selected for further analysis. Humphrey visual fields were categorised as normal or demonstrating an enlarged blindspot, single or double arcuate scotoma, central scotoma or paracentral scotoma; the latter two classifications required depressions within 10° of fixation, with a foveal threshold <30 dB being denoted a central scotoma and a foveal threshold of ≥30 dB denoted a paracentral scotoma. Finally, raw Spectralis SD-OCT and (when available) EDI-OCT data were inspected in a masked fashion for each patient, and the presence of retinal or optic nerve pathology was documented.
Data analysis was performed through the construction of contingency tables and χ2 testing in order to test the predictive value for adverse visual outcomes of various patient characteristics on presentation. Poor visual outcomes were classified as permanent central vision loss (visual acuity of 20/40 or worse or a central/paracentral scotoma on visual field testing) or permanent peripheral vision loss (single or double arcuate scotoma on visual field testing). Correlation between anatomic abnormalities on final SD-OCT imaging and adverse visual outcomes were similarly tested.
Thirty-one patients met criteria for inclusion in the study (table 1), with an average follow-up time of 30.7±16.2 months (mean±SD). There were 12 pubertal (all female) and 19 pre-pubertal (12 male, 7 female) children. The mean age on presentation was 15.4±1.4 years for pubertal children and 7.8±3.4 years for pre-pubertal children. The mean grade of papilledema on presentation was 2.6±1.4 in the study eyes overall, with no significant difference between pubertal and pre-pubertal group (p=0.26). On presentation, 23 patients had normal visual acuity (20/20–20/30), 5 had moderately diminished visual acuity (20/40–20/80) and 3 had profound visual acuity loss (20/100—light perception) in the study eyes.
Twenty-four patients were successfully managed with acetazolamide alone, while seven required surgical intervention: three underwent unilateral ONSF (all in the study eyes) and four underwent CSF diversion procedures. All study eyes presenting with normal visual acuity maintained normal acuity, while all eight presenting with abnormal visual acuity demonstrated some degree of improvement over the course of treatment (figure 1). Ultimately, 28 study eyes had normal visual acuity, 2 had moderately diminished visual acuity (one pubertal, one pre-pubertal) and 1 had profound loss of visual acuity (pubertal). Automated perimetry data were available for 23 patients (11 of 12 pubertal and 12 of 19 pre-pubertal). Five patients (four pubertal, one pre-pubertal) demonstrated permanent peripheral visual field loss in the study eye, and four patients (three pubertal, one pre-pubertal) demonstrated permanent central or paracentral scotomas. A total of seven patients had at least one form of permanent visual field loss in the study eye.
Final SD-OCT images of the optic nerve head and macula were reviewed for the study eye of each patient. RNFL OCT demonstrated a final average RNFL thickness of 106.9±29.1 µm. Four eyes (all pubertal) demonstrated optic atrophy, defined as average RNFL thickness <80 µm. Only two of these patients underwent RNFL OCT during the early phase of their disease and were observed to develop optic atrophy at 2 and 4 months, respectively, after initial presentation. Buried optic disc drusen were noted on EDI-OCT of the optic nerve head in 13 of the 27 eyes in which this was performed (figure 2A). B-scan ultrasonography had been performed on five of these eyes and confirmed the presence of drusen (figure 2B). Review of optic disc photos from presentation and after treatment revealed that cases of optic disc drusen did not represent misdiagnosis of IIH due to pseudopapilledema as the disc swelling improved following treatment of elevated ICP (figure 2C,D). Photoreceptor ellipsoid zone abnormalities were seen on macular SD-OCT in six eyes (19%), including frank focal loss of the ellipsoid zone in five eyes and ellipsoid zone irregularity in one eye (figure 2E,F). SD-OCT on initial presentation was available for four of these eyes, and all four demonstrated evidence of photoreceptor damage during the acute phase of papilledema.
Patient characteristics on presentation were analysed to determine which factors may be predictive of poor visual outcomes (table 2). Grade of papilledema was classified as mild (grade 0–2) or moderate-to-severe (grade 3–5). Eyes that ultimately developed permanent peripheral scotomas, central/paracentral scotomas or any visual loss were invariably those with moderate-to-severe papilledema (all p≤0.008). Moderate-to-severe papilledema was also highly predictive of optic atrophy (p=0.008) and photoreceptor damage (ellipsoid zone irregularity/loss; p=0.0008) on final SD-OCT. The study eyes of pubertal patients were significantly more likely to demonstrate optic atrophy (p=0.003) or photoreceptor damage (p=0.012); however, differences in peripheral field loss, paracentral/central scotomas and any vision loss by pubertal status did not reach statistical significance. Severe anaemia (serum haemoglobin <10 g/100 mL) on presentation was only present in 1 of 25 patients for which this value was available; this patient developed photoreceptor loss and a paracentral scotoma in the study eye. The presence of optic disc drusen was found to have no correlation with final visual outcomes, optic atrophy or photoreceptor loss.
The clinical significance of anatomic abnormalities on final OCT imaging was assessed through correlation to final visual function (table 3). Both photoreceptor damage and optic atrophy were significantly associated with peripheral vision loss, central/paracentral scotoma and any vision loss (all p<0.04). It should be noted, however, that there is a very high correlation between photoreceptor damage and optic atrophy. Four of six eyes with photoreceptor damage also demonstrated evidence of coexisting optic atrophy. Conversely, each of the four eyes with optic atrophy had evidence of photoreceptor damage.
To our knowledge, this is the first study to correlate anatomic OCT findings to final visual function outcomes in a cohort of patients with paediatric IIH. Supporting the prevailing view in the field, our pubertal patients were overwhelmingly female (100%); in contrast, a majority of our pre-pubertal patients (63%) were male. While medical or surgical treatment of elevated ICP was effective in stabilising or improving visual acuity, a sizeable portion of study eyes (23%) were left with permanent visual dysfunction. Pubertal children were significantly more likely to develop optic atrophy or photoreceptor damage by OCT, but any increased propensity to develop adverse visual outcomes did not meet statistical significance. Clinical grading of papilledema by the modified Frisén scale on presentation was the strongest predictor of visual morbidity as none of the eyes with a papilledema grade of 2 or less developed permanent vision loss, whereas 50% of eyes with grade 3 or worse papilledema suffered permanent vision loss. While patients with paediatric IIH are known to be at risk for permanent visual disability,9 ours is the first study to demonstrate moderate-to-severe papilledema on presentation as a risk factor for this feared outcome in the paediatric population.
One unexpected finding was the high rate of buried optic disc drusen identified by EDI-OCT. While the prevalence of optic disc drusen in the general population has been estimated at 2.0% in autopsy studies,16 we uncovered evidence of buried drusen in 48% of study eyes. Optic disc drusen and papilledema have been reported to coexist in patients with paediatric IIH,17 and it is interesting to speculate that optic disc drusen may play a role in the development of papilledema in IIH. Drusen may form as a result of axoplasmic stasis due to small foraminal openings as the optic nerve pierces the sclera’s lamina cribrosa, causing calcifications to accumulate in axonal mitochondria, which are subsequently extruded extracellularly.18 It could be that eyes with small foraminal openings for optic nerve axons are particularly prone to the compressive effects of elevated ICP and would therefore be more likely to manifest with papilledema. Of note, the presence of optic disc drusen did not correlate with vision loss in our patients, including, surprisingly, visual field defects.
Of particular interest, nearly one-fifth of our patients demonstrated evidence of permanent photoreceptor damage by OCT. While thinning of the RNFL and RGC layer on OCT is a hallmark of optic atrophy and not unexpected in severe IIH, it is not obvious how retinal photoreceptors would suffer damage in this disease. Notably, all four eyes that developed optic atrophy also demonstrated photoreceptor damage on OCT.
There have been prior reports of photoreceptor damage (particularly to cones) in patients with optic neuropathies, including glaucoma, optic neuritis, ischaemic and compressive optic neuropathies, and IIH.19 ,20 One proposed explanation is that retrograde trans-synaptic degeneration may occur from the inner to the outer retina. For this to occur, retrograde degeneration would have to proceed across two series of synapses: the RGC/bipolar cell synapse in the inner plexiform layer and the bipolar cell/photoreceptor synapse in the outer plexiform layer. One recent primate study in which half of the retina’s RGCs were experimentally ablated without any subsequent photoreceptor loss casts significant doubt on retrograde trans-synaptic degeneration as a mechanism for photoreceptor damage in optic neuropathies.21
Another potential cause of photoreceptor pathology in IIH is a mechanical insult due to choroidal folds in the macula that commonly develop in papilledema. This may be analogous to ellipsoid zone disruption observed following resolution of hypotony maculopathy with choroidal folds.22 Adequate imaging of the macula during acute papilledema was available in four of our patients with photoreceptor loss, but none demonstrated choroidal folds at that time.
Alternatively, it may be instructive to compare IIH to central retinal vein occlusion (CRVO), which typically produces severe inner retinal oedema and in some cases widespread ischaemia. In IIH cases with severe papilledema, the retinal veins dilate due to slowed venous outflow through the central retinal vein as it exits through the swollen optic disc. Though CRVO results in ischaemia to the inner retina (while the photoreceptors of the outer retina remain perfused by the choroidal circulation), ellipsoid zone loss can be observed on OCT following resolution of the acute phase of CRVO. This ellipsoid zone loss seems unrelated to whether subretinal fluid was present following the venous occlusion.23 Likewise, in our study, when OCT imaging during the acute phase of papilledema was reviewed for the six eyes that developed photoreceptor damage, only two eyes were found to have had subretinal fluid in this area of the retina. Thus it seems unlikely that focal serous retinal detachment is the mechanism of photoreceptor damage in IIH. One alternative mechanism for photoreceptor damage is pathology of Müller glia, the only cell type to span all three cellular layers of the retina. These glia not only perform a scaffolding role in the retina but also are thought to support photoreceptors by providing lactate as an energy substrate24 and recycling the potentially excitotoxic neurotransmitter glutamate.25 It would be interesting to investigate whether injury to Müller glia in IIH and potentially other optic neuropathies explains the photoreceptor damage observed by us and others.8 ,19 ,20
Our study is limited by its retrospective nature. There was also significant variability in length of follow-up between patients. Furthermore, the key finding of photoreceptor ellipsoid zone loss or irregularity is of undetermined clinical significance. Some children were too young for reliable visual field testing to correlate the location of scotomas with that of the ellipsoid zone pathology. In the future, it would be interesting to perform multifocal electroretinography in these patients to demonstrate that zones of ellipsoid zone loss indeed represent dead or dysfunctional photoreceptors rather than merely changes in the photoreceptors’ reflective properties on OCT.
To conclude, this longitudinal study of paediatric IIH revealed that higher grade (≥3) papilledema on initial presentation is associated with a high risk of permanent vision loss. Optic disc drusen was noted by EDI-OCT in nearly half of study eyes, but did not correlate with visual outcomes. Finally, photoreceptor damage was identified in a significant number of patients with moderate-to-severe papilledema and was strongly associated with vision loss and coexisting optic atrophy.
Contributors SMG and MAE-D: design of the study, conduct of the study and manuscript preparation. SMG, MTB, and MAE-D: data analysis and interpretation, manuscript review and final approval of the manuscript.
Competing interests None declared.
Ethics approval Duke University Medical Center Institutional Review Board.
Provenance and peer review Not commissioned; externally peer reviewed.