Stephen J. Jones

Retinal nerve fiber layer axonal loss and visual dysfunction in optic neuritis.

Axonal loss is thought to be a likely cause of persistent disability after a multiple sclerosis relapse; therefore, noninvasive in vivo markers specific for axonal loss are needed. We used optic neuritis as a model of multiple sclerosis relapse to quantify axonal loss of the retinal nerve fiber layer (RNFL) and secondary retinal ganglion cell loss in the macula with optical coherence tomography. We studied 25 patients who had a previous single episode of optic neuritis with a recruitment bias to those with incomplete recovery and 15 control subjects. Optical coherence tomography measurement of RNFL thickness and macular volume, quantitative visual testing, and electrophysiological examination were performed. There were highly significant reductions (p < 0.001) of RNFL thickness and macular volume in affected patient eyes compared with control eyes and clinically unaffected fellow eyes. There were significant relationships among RNFL thickness and visual acuity, visual field, color vision, and visual‐evoked potential amplitude. This study has demonstrated functionally relevant changes indicative of axonal loss and retinal ganglion cell loss in the RNFL and macula, respectively, after optic neuritis. This noninvasive RNFL imaging technique could be used in trials of experimental treatments that aim to protect optic nerves from axonal loss. Ann Neurol 2005

Optic nerve diffusion tensor imaging in optic neuritis.

Diffusion tensor magnetic resonance imaging (DT-MRI) provides in vivo information about the pathology of multiple sclerosis lesions. Increases in mean diffusivity (MD) and reductions in fractional anisotropy (FA) have been found and may represent axonal disruption. The optic nerve is an ideal structure for study by DT-MRI but previous clinical studies did not obtain the full diffusion tensor necessary to calculate MD and FA. In this study, a technique that was specifically developed to achieve full diffusion tensor measurements from the optic nerve (zonal oblique multislice (ZOOM) echoplanar imaging) was applied to 25 patients with a single unilateral episode of optic neuritis at least one year previously, and 15 controls. The intraorbital nerves were segmented on non-diffusion-weighted images and the regions of interest transferred to MD, FA, and eigenvalue maps to obtain quantitative data. Quantitative visual testing and electrophysiology were also performed. In affected nerves, mean MD and mean orthogonal eigenvalue lambda( perpendicular) were elevated, and mean FA reduced compared with clinically unaffected contralateral nerves (P < 0.001) and control nerves (P < 0.001). The mean principal eigenvalue lambda\\ was significantly increased in affected nerves compared to contralateral unaffected nerves (P = 0.04) but not compared to control nerves (P = 0.13). There was no association of clinical measures of visual function in affected eyes with the DT-MRI parameters but there was a significant correlation of the whole field visual evoked potential (VEP) amplitude with MD (r = -0.57, P = 0.006) and lambda( perpendicular) (r = -0.56, P = 0.007). These findings suggest that optic nerve DT-MRI measures provide an indication of the structural integrity of axons.

Effects of intravenous methylprednisolone on outcome in MRI-based prognostic subgroups in acute optic neuritis

Treatment of acute optic neuritis with steroids has been shown to hasten visual recovery without affecting the final degree of recovery. However, MRI-clinical studies indicate that patients with long optic nerve lesions, particularly those that involve the nerve within the optic canal, may have a worse prognosis for recovery of vision. Partly because such lesions could lead to swelling and subsequent ischemic optic nerve damage, steroids could have a selective beneficial effect on this subgroup of patients. The present randomized trial was designed to test this possibility. Sixty-six patients with acute optic neuritis received IV saline or IV methylprednisolone. The clinical, psychophysical, electrophysiologic, and MRI outcomes were assessed after 6 months. Patients with short lesions presented earlier than those with long lesions (involving three or more 5-mm-thick slices of any part of the optic nerve, as well as its intracanalicular portion), and lesion length was significantly less in patients presenting within a week of onset of symptoms. Lesions also tended to lengthen during follow-up in individual patients. Treatment did not limit lesion length in either the long or short lesion subgroup and had no significant effect on final visual outcome. We conclude that steroids do not improve visual outcome or lesion length in patients with acute optic neuritis.

Adaptive cortical plasticity in higher visual areas after acute optic neuritis

The ability to distinguish adaptive cortical reorganization may help to target future therapeutic strategies after neurological insult. We investigated cortical plasticity by prospectively applying visual functional magnetic resonance imaging (fMRI) and optic nerve MRI to 20 patients with acute optic neuritis at baseline, 1, 3, 6, and 12 months. We performed three types of correlation analyses to investigate the relationships between fMRI activity, clinical function, and optic nerve structure. The first analysis directly correlated the fMRI response to clinical function or optic nerve structure and found dynamic relations especially within the first 3 months. The second analysis used a novel technique that modeled the fMRI response and optic nerve structure together with clinical function, to determine the contribution fMRI made to clinical function after accounting for structural factors. Significant effects were found at baseline only, within the right peristriate cortex, and bilaterally in the lateral occipital complexes, which are normally involved in higher order visual processing. The third analysis investigated the relation between the modeled visual recovery rate and fMRI response but found no significant effects. The key findings of this study are from the second analysis and suggest a genuine adaptive role for cortical reorganization within extrastriate visual areas early after optic neuritis. Ann Neurol 2005;57:622–633

Visual recovery following acute optic neuritis--a clinical, electrophysiological and magnetic resonance imaging study.

Abstract.This study reports the prospective follow–up of a cohort of patients with acute optic neuritis examined with serial visual tests, visual evoked potentials (VEPs), conventional and triple–dose gadolinium (Gd)–enhanced magnetic resonance imaging (MRI) to examine which factors are important in visual recovery. Thirty–three patients were recruited with acute unilateral optic neuritis. A clinical and VEP assessment was performed on each. Optic nerve MRI was performed using fast spin echo (FSE) (on all) and triple-dose Gdenhanced T1–weighted sequences (n = 28). Optic nerve lesion lengths were measured. Serial assessments were performed on 22 of the patients up to one–year. Serial Gd–enhanced optic nerve imaging was performed on 15 of the patients until enhancement ceased. The final 30–2 Humphrey visual field mean deviation (MD) was 2.55 dB higher in patients in the lowest quartile of initial Gd–enhanced lesion length compared with the other quartiles (p < 0.01) but recovery was not related to the duration of enhancement. The initial recovery of Humphrey MD was 4.60 dB units per day in patients with good eventual recoveries (MD > –6.0 dB) and 0.99 dB per day in poor-recovery patients (p = 0.02).Good–recovery patients had mean central field VEP amplitudes 2.29 µV higher during recovery than poor-recovery patients (p = 0.047). The results suggest that factors which are associated with a better prognosis are: having a short acute lesion on triple–dose gadolinium enhanced imaging, higher VEP amplitudes during recovery and a steep gradient of the initial improvement in vision.

Corticosteroids do not prevent optic nerve atrophy following optic neuritis

Corticosteroids shorten the period of functional impairment following relapses in optic neuritis and multiple sclerosis (MS); however they have not, thus far, been shown to affect the final level of function compared with placebo.1 There has been recent interest in the use of corticosteroids as neuroprotective agents by their effect of decreasing nitric oxide (NO) production by mononuclear cells.2 NO is toxic to axons in vitro.3 Pulsed corticosteroid treatment has been reported to reduce the development of cerebral atrophy, a putative marker of neuronal loss,4 over a five year period in relapsing remitting MS.5 Optic nerve atrophy has been shown to develop following optic neuritis.6 This study assesses whether a single course of intravenous methylprednisolone (IVMP) during an attack of acute optic neuritis prevents the development of optic nerve atrophy following optic neuritis. Magnetic resonance imaging (MRI) data from a recent randomised placebo controlled trial of IVMP in acute optic neuritis were retrospectively evaluated.7 The design, conduct and clinical results of the trial have been reported previously.7 Briefly, 66 patients with a first episode of acute unilateral optic neuritis within 30 days of onset were enrolled into the study. The median duration of symptoms before randomisation was eight days (range 1–30). Six of the patients had clinically definite MS, another 14 had clinically probable MS, and the rest had clinically isolated optic neuritis. Their optic nerves were imaged with a short tau inversion recovery (STIR) sequence (TR 2500 ms, TE 40 ms, TI 175 ms, matrix 256×128, field of view 16 cm × 16 cm, 2 excitations, 5 mm contiguous slices) and were then randomised to receive either 1 g/day IVMP for three days or intravenous saline. Reimaging was performed six months later. In addition, at six months, a detailed clinical assessment …

Long-term recovery and fellow eye deterioration after optic neuritis, determined by serial visual evoked potentials

Abstract Twelve optic neuritis patients (part of a larger group in whom the effects of intravenous methylprednisolone treatment were previously reported), were followed-up 3 years from the onset of symptoms with visual evoked potentials (VEPs), contrast sensitivity and visual field examination. Findings from the previously “unaffected” eyes, none of which had had symptomatic optic neuritis, were also assessed. Between 6 months and 3 years after the onset of symptoms the VEPs of the affected eyes showed a significant shortening of mean latency (whole field, 131–123 ms; central field, 136–125 ms). Conversely, the responses of the previously unaffected eyes showed a contemporaneous latency prolongation (significant for the whole field, 110–113 ms) which exceeded the expected effect of aging. Contrast sensitivity tests showed no significant change in the affected eyes but a mild deterioration in the unaffected eyes, while the visual fields showed no overall pattern of improvement or deterioration. If the strong tendency for VEP latencies to shorten is due to ongoing remyelination, the lack of significant improvement in visual function may be because the visual deficit at 6 months is due to irreversible axonal loss rather than demyelination. The absence of functional deterioration in the affected eye, while VEPs and contrast sensitivity deteriorated in the unaffected eye, suggests that long-term remyelination may for a while counteract the effects of insidious demyelination and axonal degeneration which affect the visual pathway during clinical remission.

Quantification of optic nerve head topography in optic neuritis: a pilot study

Aims: To investigate optic nerve head topography in patients with optic neuritis compared to controls using the Heidelberg retina tomograph-II (HRT-II) and to determine if detected changes are related to visual function and electrophysiology. Methods: 25 patients with a previous single episode of unilateral optic neuritis and 15 controls were studied with HRT-II, visual evoked potentials, and pattern electroretinogram. Patients also had testing of visual acuity, visual field, and colour vision. Results: In affected eyes compared to fellow eyes, there was reduction of both the mean retinal nerve fibre layer (RNFL) thickness at the disc edge (p = 0.009) and the neuroretinal rim volume (p = 0.04). In affected eyes compared to control eyes, the three dimensional optic cup shape measure was increased (p = 0.01), indicative of an abnormal cup shape. There were no other significant differences in HRT-II measures. Within patient interocular difference correlation was used to investigate the functional relevance of these changes and demonstrated associations between RNFL thickness change and changes in visual acuity, visual field, and colour vision. Colour vision change was also associated with change in neuroretinal rim volume. Conclusions: HRT detects functionally relevant changes in RNFL thickness and neuroretinal rim volume between eyes affected by optic neuritis and unaffected fellow eyes.

Scanning Laser Polarimetry Quantification of Retinal Nerve Fiber Layer Thinning Following Optic Neuritis

Abstract: Background: Several studies with optical coherence tomography (OCT) have demonstrated thinning of the retinal nerve fiber layer (RNFL) in patients with optic neuritis and multiple sclerosis. Similar studies have not been performed with scanning laser polarimetry (SLP), which relies on different physical phenomena. This study was designed to use SLP to measure axonal loss following a single episode of optic neuritis and to determine if there is a relationship between the degree of axonal loss and the degree of residual visual dysfunction. Methods: Twenty-five patients with a single episode of optic neuritis and 15 control subjects were studied with SLP using the GDxVCC device to determine RNFL thickness in relation to visual acuity, visual fields, color vision, visual evoked potentials (VEPs), and previously published OCT data. Results: SLP detected significant RNFL thinning in affected eyes compared to clinically unaffected fellow eyes in patients and in control eyes (P < 0.001). Reduced RNFL thickness was associated with significantly worse logMAR visual acuity, visual field mean deviation, and color vision. RNFL thinning correlated with reduced whole visual field and central visual field measures and VEP amplitudes. Superior and inferior quadrant RNFL thinning was related to corresponding regional visual field loss. There was a scaling factor between SLP and OCT RNFL measurements but only modest agreement. Conclusions: SLP detected functionally relevant axonal loss in eyes affected by optic neuritis. There was a scaling factor between RNFL measurements obtained with SLP and OCT but only modest agreement. Care should therefore be taken when comparing RNFL data from studies using these different devices.

The “enhanced N35” somatosensory evoked potential: its associations and potential utility in the clinical evaluation of dystonia and myoclonus

In median nerve somatosensory evoked potentials, the cortical N35 amplitude sometimes exceeds the P25 amplitude (C3’/C4’ referred to Fz; “enhanced N35” feature). Six hundred consecutive patient median nerve SEPs were retrospectively analysed and compared with 27 controls. The feature was more often present in patients with dystonia (62%) than in patients with other disorders (22%; relative risk for the condition 2.8; Fisher’s exact p = 0.003) or control subjects (7.4%; odds ratio 20; p = 0.0006). Similarly, the feature was more often present in patients with myoclonus (38%) than in patients with other disorders (22%; relative risk 1.7; p = 0.02) or control subjects (odds ratio 7.5; p = 0.006).There was no clear relationship of the feature to short latency SEP abnormalities except in cases of myoclonus. Further comparison was made of the characteristics of 72 patients each, with and without the feature, whose short latency SEP components were normal. The relationship of the feature to dystonia or myoclonus held true in this case-controlled arm of the study. The sensitivity and specificity were 65% and 78% respectively for any form of dystonia; 43% and 79% respectively for any form of myoclonus. The feature was even more specific in both conditions when compared with controls (93%). Most cases of dystonia with an identifiable cause in this study were of secondary forms. It is known that this feature often occurs in association with “giant” SEPs in some myoclonic conditions. However, its occurrence in dystonia may be a useful new finding in an established test, helping to identify a condition where there is increasing evidence for disordered sensorimotor integration.