Our study shows that a substantial and significant reduction in contrast sensitivity is detected with the SVEP in children with NF-1 who have OPGs with normal visual acuity, compared with NF-1 children without OPGs and normal control subjects.
The ability of our contrast sensitivity measure to identify patients with NF-1 with OPG was moderate, with sensitivity at 0.67. Conversely, a specificity of 0.87 suggests that the measure was quite good at identifying patients who did not have OPG, because, as can be seen in
Figure 4 , there was an overlap between the contrast sensitivity distributions of patients with NF-1 with no OPG and those patients with OPG and higher contrast sensitivity. However, there was a clear subgroup of patients with OPG who had markedly reduced sensitivity.
Although the moderate sensitivity in identifying patients with OPG may appear troubling, it is important to remember that this group of patients is almost completely clinically silent
(Table 2) , meaning that the sensitivity of the eye examination is effectively 0. Conversely, the SVEP was able to identify OPG in approximately two thirds of this sample in the absence of other visual symptoms. Further, SVEP contrast sensitivity appears to be particularly effective for screening out the presence of OPG in our sample, since the contrast sensitivity in patients with NF-1 with no OPG is altogether normal. Taken together, these results suggest that SVEP contrast sensitivity may be an effective functional measure for detecting the presence of optic pathway gliomas in patients with NF-1. Thus, an electrophysiological measure appears to detect functional consequences of OPGs in these patients most readily.
Optic pathway gliomas account for 0.6% to 5.1% of all brain tumors in childhood. Furthermore, up to 70% of OPGs are associated with NF-1.
29 Although they generally behave in a benign manner, OPGs can lead to vision loss or less commonly, extend to nearby brain regions and cause other signs and symptoms. The period of greatest risk for development of symptomatic OPGs is during the first 6 years of life.
5 Currently, the NF-1 Optic Pathway Glioma Task Force recommends once-yearly complete ophthalmic examinations for screening NF-1 children younger than 7 years of age who are asymptomatic,
30 although it is known that a significant number of OPGs remain clinically silent or undetectable.
5 Longer intervals between examinations are suggested for older children. Neuroimaging as screening examinations in patients with NF-1 without clinical signs or symptoms has not been recommended, apparently because of the risks to young patients associated with anesthesia and CT radiation and the high costs of the neuroimaging examinations. The guidelines do recommend MRI neuroimaging when there are abnormal ophthalmic findings. For children with an established OPG diagnosis, regular ophthalmic examinations with neuroimaging are also suggested.
The ophthalmic examination in uncooperative children can be difficult, and pediatric vision tests (e.g., single-letter matching tests) have been known to overestimate visual acuity. Cognitive impairment can be associated with NF-1
31 and this adds another potential factor that can limit clinical examination techniques that require a subjective response, even in older children. Clinically normal examination findings (e.g., a normal optic nerve head appearance) do not definitively rule out the existence of OPG. A normal pupillary examination result is also not definitive. None of the patients in our OPG group had a relative afferent pupillary defect (RAPD). Symmetrical involvement of the optic nerves or chiasmal gliomas would eliminate the presence of an RAPD. However, 5 of the 16 patients in the OPG group had a unilateral glioma. In these patients, one explanation of an absent RAPD may be that the relative difference in the afferent defect in these patients was so small that a clinical examination of the pupils did not detect it. Another possibility is that a pupillary examination in certain children may be difficult because of variable fixation activity and an active near response to the examiner.
Conventional pattern VEPs have been proposed as a screening test for children with asymptomatic NF-1, but there are inherent limitations in this method. Although one study demonstrated 100% sensitivity and 60% specificity for the pattern VEP in detecting optic pathway gliomas in children,
6 the authors acknowledged that the test is limited by the age at which the child will cooperate with the long procedure and that reliable results may not be obtained in subjects younger than 5 years. Other studies have not found VEPs to be sensitive tests in detecting OPGs.
32 Another limitation is the question of specificity. Some degree of abnormality can be found in as many as 62.5% of VEPs of children with NF-1 without MRI evidence of OPGs.
33
It is unknown why there is such a high incidence of conventional VEP abnormalities occurring in patients with NF-1 with no OPG. One speculation is that formation of unidentified bright objects (UBOs) on brain MRI may be linked with VEP abnormalities.
33 UBOs are hyperintense, T
2-weighted foci that are commonly found in the MRI scans of patients with NF-1. Their nature is unclear, but they occur in up to 60% of patients.
34 Nine (64.3%) of 14 patients in the nOPG group in our study had UBOs. It may be that the slight reduction in contrast sensitivity in the patients with NF-1 without OPGs in the present study is the result of UBOs. This reduction was not statistically significant, however, compared with normal controls. The effect of NF-1 cerebral abnormalities appears to produce only minimal, if any, disruption in visual functioning, as measured with the SVEP, whereas our results suggest that the presence of OPGs produces a far greater disruption.
There are many advantages to the use of the SVEP in this age group. SVEPs have been used reliably to obtain acuity and contrast estimates in children and infants and so may serve as an ideal measure for assessment of patients with NF-1. Each sweep trial is short, taking only approximately 10 seconds, and places fewer demands on the young patient’s attention span compared with the conventional VEP. As with other VEP tests, it does not require a subjective response, and so it can overcome the lack of verbalization and the often limited cooperation in the younger or cognitively impaired patient. The SVEP is also a noninvasive test, as it does not necessitate the use of anesthesia or sedation and avoids any exposure to ionizing irradiation, as occurs in CT neuroimaging.
Finally, why might contrast sensitivity be selectively affected? There is evidence that contrast sensitivity is reduced in other patients who have compressive lesions in the anterior visual pathways.
9 Similar to patients with OPG in the present study, these deficits are even apparent in patients with normal acuity, color vision, visual fields, and pupillary reactions. Because the magnocellular ganglion cells mediate contrast sensitivity at low spatial frequencies and because these cells have large receptive fields and ganglion-cell sizes,
35 it has been proposed that compression of the optic nerve has its earliest effects on these large-caliber axons.
9 With a large-caliber axon, there is less longitudinal resistance to compression, and so they are more susceptible to disruptions from compressive lesions. Another possible explanation is that compressive lesions produce more extensive ischemic pruning of retinal ganglion cells in larger dendritic trees.
9 This pruning may also account for the presence of SVEP abnormalities without an RAPD in our patients with OPG with unilateral glioma. Magnocellular cell involvement may have a greater effect on contrast sensitivity measurements at low spatial frequencies, than on the clinical observation of an RAPD. There is also evidence that compressive lesions may impair fovea-specific pathways earlier.
36 Because the sweep VEP measures central retinal fields more specifically, it is possible that early OPG lesions would become manifest in sweep VEP abnormalities before an abnormal pupillary reaction. Thus, testing of contrast sensitivity at low spatial frequencies may be a particularly sensitive method for detection of compressive lesions of the anterior visual pathway.
One limitation of our study in the nOPG group is the time gap between neuroimaging and SVEP testing, which may have been as long as 18 months. Although it is still possible that an optic glioma might have arisen during that time frame, since most of our patients were older than the high-risk age of less than 6 years,
5 it is highly unlikely. Another drawback is that, despite the lesser demand on patient attention with the SVEP method compared with conventional VEP, there were still a proportion of recordings that did not fulfill the strict criteria for scoring, possibly because of the patients’ inattention and fatigue. For the purposes of this study, most of our subjects came in for one recording session only. If poor recordings were obtained the first time, a repeat visit might have produced better data.
There have been criticisms against the usage of VEPs for routine evaluation of children with NF-1, in part due to the controversy surrounding the management of optic gliomas. The natural history can be quite variable, with most tumors behaving in a benign fashion and a few with rapid progression with vision loss. Rare instances of spontaneous improvement of vision have been reported.
37 Because most decisions to treat are based on clinical or radiologic progression,
29 one could contend that presymptomatic detection with VEPs has no benefit. In contrast, the use of SVEP would be useful as a baseline and in tracking the course of known OPGs in infants who might be receiving chemotherapy but in whom examination of the fundi and optic nerves alone would give an inadequate assessment of clinical response to treatment.
Radiotherapy and chemotherapy has been shown to slow progression of optic gliomas in symptomatic patients and can result in stabilization, although not always improvement in vision. Chemotherapy has, in recent studies, been particularly promising. One- or two-drug chemotherapy regimens have been used, with good progression-free survival rates.
38 39 In younger children with OPGs, radiotherapy is preferably avoided due to its potential neuropsychological and cognitive adverse effects on the developing brain.
40
Although it has not been established whether very early treatment can prevent the development of symptoms altogether, there has been a suggestion that presymptomatic treatment may be beneficial.
41 Of importance, earlier diagnosis of OPGs would also allow closer monitoring of the patient, and earlier detection of visual loss. Early detection can be especially important in the young patient with rapidly progressive OPG, some of whom may have confusing ocular examination findings with failing visual function, but as yet undetectable optic atrophy. The SVEP contrast sensitivity could also be used as a sensitive outcome measure, to measure improvement, or stability of vision, in future treatment trials.