Optic Neuritis In Multiple Sclerosis

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) Echo Planar 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.

Magnetic Resonance Imaging (MRI) measures of Brain Atrophy are often considered to be a marker of Axonal Loss in Multiple Sclerosis (MS) but evidence is limited. Optic Neuritis is a common manifestation of MS and results in Optic Nerve Atrophy.

Retinal Nerve Fiber Layer (RNFL) imaging is a non-invasive way of detecting axonal loss following Optic Neuritis.

We hypothesise that if the Optic Nerve Atrophy that develops following Optic Neuritis is contributed to by Axonal Loss, it will correlate with thinning of the RNFL.

Twenty-five patients were studied at least 1 year after a single unilateral attack of Optic Neuritis without recurrence, with a selection bias towards incomplete recovery.

They had MR quantification of Optic Nerve cross-sectional area and optic nerve lesion length, as well as Optical Coherence Tomography (OCT) measurement of mean RNFL thickness and Macular volume, quantitative visual testing, and Visual Evoked Potentials (VEPs). Fifteen controls were also studied.

Significant Optic Nerve Atrophy (mean decrease 30% versus controls), RNFL thinning (mean decrease 33% versus controls), and Macular volume loss occurred in patients' affected eyes when compared with patients' unaffected eyes and healthy controls.

The Optic Nerve Atrophy was correlated with the RNFL thinning, Macular volume loss, Visual Acuity, Visual Field mean deviation, and whole field VEP amplitude but not latency.

These findings suggest that Axonal loss contributes to Optic Nerve Atrophy following a single attack of Optic Neuritis.

By inference, Axonal Loss due to other post-inflammatory Brain lesions is likely to contribute to the global MRI measure of Brain Atrophy in Multiple Sclerosis.

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.

Objective
To investigate if IV ImmunoGlobulin (IVIG) treatment in the acute phase of Optic Neuritis (ON) could improve visual outcome and reduce MRI disease activity 6 months after onset of ON.

Methods
Sixty-eight patients with ON were randomized within 4 weeks from onset of symptoms. Thirty-four patients were randomized to IVIG 0.4 g/kg body wt, and 34 patients were randomized to placebo.

Infusions were given at days 0, 1, 2, 30, and 60. Contrast sensitivity, visual acuity, and color vision were measured at baseline and after 1 week, 1 month, and 6 months.

Pattern reversal Visual Evoked Potential studies and Gadolinium-enhanced MRI were performed at baseline and after 1 and 6 months. Clinical relapses during follow-up were recorded.

Results
There was no difference in the primary outcome, contrast sensitivity after 6 months, between patients randomized to treatment with IVIG or placebo.

In addition, there was no significant difference in the secondary outcome measures, improvement in the visual function measures and MRI, at any time during follow-up.

At baseline, a significantly higher number of patients in the IVIG group had one or more enhancing lesions on MRI and IVIG-treated patients had a significantly higher number of enhancing lesions on MRI than patients treated with placebo.

No difference was found in number of patients with one or more enhancing lesions or number of enhancing lesions in subsequent scans between treatment groups. Number of relapses was equal in the two treatment groups during follow-up.

Conclusions
There was no effect of IV ImmunoGlobulin (IVIG) on long-term visual function following acute Optic Neuritis, nor was there an effect of IVIG treatment in reducing latency on Visual Evoked Potentials and thus preserving function of Axons of the Optic Nerve.

This study assessed Optic Nerve mean area on serial MRI in a cohort of patients with a first episode of acute unilateral Optic Neuritis to assess the effects of a single acute inflammatory DeMyelinating lesion.

Twenty-nine patients with a median delay from onset of visual symptoms of 13 days (range 7-24 days) were recruited.

After a clinical examination and Visual Evoked Potential (VEP) measurement, each patient had their Optic Nerves imaged with a coronal fat-saturated short echo fast Fluid-Attenuated Inversion Recovery sequence.

Twenty-one patients had serial examinations after 2, 4, 8, 12, 26 and 52 weeks.

In addition, 32 control subjects had their Optic Nerves imaged up to three times. The mean cross-sectional area of the Intra-Orbital portion of each Optic Nerve was calculated by a blinded observer using a computer-assisted contouring technique.

At baseline, the mean area of diseased Optic Nerves was 16.1 mm2 compared with 13.4 mm2 for healthy contralateral Optic Nerves (20.1% higher, P < 0.0001) and 13.6 mm2 for controls (18.4% higher, P = 0.0003).

The diseased Optic Nerve mean area declined over time, from initial swelling to later atrophy. The mean decline at 52 weeks was -0.0018 mm2/day (95% confidence interval -0.0038 to -0.00051).

At 52 weeks, the mean area of diseased Optic Nerves was 11.3 mm2 compared with 12.8 mm2 for healthy contralateral Optic Nerves (11.7% lower, P = 0.032) and 13.1 mm2 for controls (13.7% lower, P = 0.008).

The 52 week diseased Optic Nerve mean area was not significantly affected by the baseline mean area.

There was an association between baseline Optic Nerve mean area and logMAR Visual Acuity (rS = 0.46, P = 0.012) and visual field mean deviation (rS = -0.55, P = 0.002), but there was no evidence of an association between 1 year mean area and visual outcome.

There was no evidence of association between baseline, rates of decline or 1 year diseased Optic Nerve mean areas and any of the baseline, 1 year or time-averaged VEP variables.

The present study shows a consistent pattern of changes associated with individual inflammatory DeMyelinating lesions in the Optic Nerve.

Acutely, there was swelling, consistent with the presence of acute inflammation, which was related to visual impairment.

Over the longer term, there was loss of tissue. The lack of association between 1 year Optic Nerve mean area and visual outcome may reflect a mild loss of tissue, redundancy or remodelling of function.

Multiple Sclerosis (MS) is a chronic inflammatory disease of the CNS which leads to DeMyelination, Axonal destruction and Neuronal loss in the early stages.

Available therapies mainly target the inflammatory component of the disease but fail to prevent NeuroDegeneration.

To investigate the effect of Ciliary NeuroTrophic Factor (CNTF) on the survival of Retinal Ganglion Cells (RGCs), the Neurons that form the Axons of the Optic Nerve, we used a rat model of Myelin Oligodendrocyte Glycoprotein-induced Experimental Autoimmune Encephalomyelitis.

Optic Neuritis in this model was diagnosed by recording Visual Evoked Potentials, and RGC function was monitored by measuring ElectroRetinograms.

This study demonstrates that CNTF has a NeuroProtective effect on affected RGCs during acute Optic Neuritis.

Furthermore, we demonstrate that CNTF exerts its NeuroProtective effect through activation of the Janus kinase/signal transducer and activator of transcription pathway, mitogen activated protein kinases and a shift in the Bcl-2 family of proteins towards the anti-Apoptotic side.

In summary, our results demonstrate that CNTF can serve as an effective NeuroProtective treatment in a rat model of MS that especially reflects the NeuroDegenerative aspects of this disease.

In serial studies of Multiple Sclerosis lesions, reductions in Magnetization Transfer Ratio (MTR) are thought to be due to DeMyelination and Axonal Loss, with later rises due to ReMyelination.

This study followed serial changes in MTR in acute Optic Neuritis in combination with clinical and ElectroPhysiological measurements to determine if the MTR changes over time mirror the picture in Multiple Sclerosis lesions, further validating MTR as a marker of tissue integrity.

Twenty-nine patients were recruited who had acute Optic Neuritis for a median of 13 days (range 7-24 days) since the onset of visual symptoms.

A clinical examination and measurement of Visual Evoked Potentials (VEP) was performed on each patient.

Their Optic Nerves were imaged with a fat-saturated Fast Spin Echo (FSE) sequence and a Magnetization Transfer sequence. Twenty-one had multiple subsequent examinations over the course of 1 year.

In addition, 27 control subjects had their Optic Nerves imaged up to three times over 1 year. A blinded observer segmented the Optic Nerves from the MTR maps.

Lesions were defined on the acute FSE images and, from the coordinates, the ratio of mean lesion MTR : healthy nerve MTR (lesion ratio) was calculated for each dataset.

The time-averaged mean MTR in control Optic Nerves was 47.7 per cent units (pu).

In diseased Optic Nerves, baseline mean MTR was 47.3 pu, with a mean lesion ratio of 0.98.

The diseased Optic Nerve MTR and lesion ratio declined over time with a nadir at about 240 days at a mean MTR value of 44.2 pu and mean lesion ratio of 0.91.

Subsequently, diseased Optic Nerve MTR appeared to rise; after 1 year the diseased Optic Nerve mean MTR was 45.1 pu (mean lesion ratio 0.93), although the difference was not significant compared with the nadir value.

For each 0.01 increase in time-averaged lesion ratio logMAR Visual Acuity recovery improved by 0.03 (95% CI, 0.002, 0.08, P = 0.02).

Time-averaged VEP central field latency was shorter by 6.1 ms (95% CI 1.5, 10.7, P = 0.012) per 1 pu rise in time-averaged diseased Optic Nerve MTR.

The early fall in diseased Optic Nerve MTR is consistent with DeMyelination and Wallerian Degeneration of transected Axons.

The late nadir compared with studies of Multiple Sclerosis lesions may have been due to slow clearance of myelin debris. ReMyelination may have influenced subsequent MTR changes.

The observations support using MTR to monitor symptomatic DeMyelinating lesions.

Optic Neuritis (ON) is the first clinical manifestation in approximately 20% of patients with Multiple Sclerosis (MS).

The inflammation and DeMyelination of the Optic Nerve are characterized by symptomatic Visual impairment and RetroBulbar Pain, and associated with decreased Visual Acuity, Decreased Color and Contrast Sensitivity, delayed Visual Evoked Potentials and Visual Field Defects.

Spontaneous recovery of Vision typically occurs within weeks or months after onset, depending on the resolution of inflammation, ReMyelination, restoration of Conduction in Axons which persist DeMyelinated and Neuronal plasticity in the Cortical and SubCortical Visual Pathways.

To assess where recovery takes place along the Visual Pathway, Visual activation was studied in the Lateral Geniculate Nucleus (LGN), the main Thalamic Relay Nucleus in the Visual Pathway and in three areas of the Visual Cortex: the Lateral Occipital Complexes (LOC), V1 and V2.

We conducted a longitudinal functional Magnetic Resonance Imaging (fMRI) study of Regions Of Interest (ROI) of activation in LGN and Visual Cortex in 19 patients with acute ON at onset, 3 and 6 months from presentation.

With fMRI we measured the activation in the ROIs and compared activation during monocular stimulation of the affected and unaffected eye.

In the acute phase the activation of LGN during visual stimulation of the affected eye was significantly reduced (P < 0.01) compared to the unaffected eye.

This difference in LGN activation between the affected and unaffected eye diminished during recovery, and after 180 days the difference was no longer significant (P = 0.59).

The decreased difference during recovery was mainly due to an increase in the fMRI signal when stimulating the affected eye, but included a component of a decreasing fMRI signal from LGN when stimulating the unaffected eye.

In LOC, V1 and V2 activation during Visual stimulation of the affected eye in the acute phase was significantly reduced (P < 0.01) compared to the unaffected eye, and during recovery the difference diminished with no significant differences left after 180 days.

As the pattern of activation in LOC, V1 and V2 resembled the development in LGN we found no evidence of additional Cortical adaptive changes.

The reduced activation of the LGN to stimulation of the unaffected eye is interpreted as a shift away from early compensatory changes established in the acute phase in LGN and may indicate very early plasticity of the Visual Pathways.

Objective
To examine the relation between low-contrast letter Acuity, an emerging Visual outcome for Multiple Sclerosis (MS) clinical trials, and Brain MRI abnormalities in an MS cohort.

Methods
T₂ lesion volume and Brain Parenchymal Fraction were determined for whole Brain and within Visual pathway regions of interest. Magnetization Transfer Ratio Histograms were examined.

Vision testing was performed binocularly using low-contrast letter Acuity (2.5%, 1.25% contrast) and high-contrast Visual Acuity (VA).

Linear regression, accounting for age and disease duration, was used to assess the relation between Vision and MRI measures.

Results
Patients (n = 45) were aged 44 +/- 11 years, with disease duration of 5 years (range < 1 to 21), Expanded Disability Status Scale score of 2.0 (0 to 6.0), and binocular Snellen Acuity of 20/16 (20/12.5 to 20/25).

The average T₂ lesion volume was 18.5 mm(3). Patients with lower (worse) low-contrast letter Acuity and high-contrast VA scores had:

Greater T₂ lesion volumes in Whole Brain (2.5% contrast: p = 0.004; 1.25%: p = 0.002; VA: p = 0.04)

Area 17 White Matter (2.5%: p < 0.001; 1.25%: p = 0.02; VA: p = 0.01)

Optic Radiations (2.5%: p = 0.001; 1.25%: p = 0.02; VA: p = 0.007).

Within Whole Brain, a 3-mm(3) increase in lesion volume corresponded, on average, to a 1-line worsening of low-contrast acuity, whereas 1-line worsening of high-contrast Acuity corresponded to a 5.5-mm(3) increase.

Conclusions
Low-contrast letter Acuity scores correlate well with Brain MRI lesion burden in Multiple Sclerosis (MS), supporting validity for this vision test as a candidate for clinical trials.

Disease in the PostGeniculate White Matter is a likely contributor to Visual Dysfunction in MS that may be independent of acute Optic Neuritis history.

Magnetization Transfer Imaging is an MRI technique that provides quantitative information about in vivo tissue integrity, including Myelin and Axonal content, and is expressed as the Magnetization Transfer Ratio (MTR).

The Optic Neuritis lesion can model the MS lesion in vivo and permits use of non-invasive markers of Optic Nerve Myelination (Visual Evoked Potential [VEP] latency) and Retinal NeuroAxonal Loss (Optical Coherence Tomography [OCT]) to provide further information about the in vivo substrates of Optic Nerve MTR.

Twenty-five patients with Optic Neuritis were studied using an Optic Nerve MTR sequence, quantitative Visual function testing, VEPs and OCT, along with 15 controls.

MTR was reduced in affected Nerves compared to both clinically unaffected Nerves from patients and control Nerves (P < 0.001).

Whole-Nerve MTR correlated modestly with central-field VEP latency but more strongly when lesion-only MTR was measured, when a modest correlation with whole-field VEP latency emerged.

OCT-quantified Retinal NeuroAxonal Loss also correlated with MTR.

In conclusion, markers of Optic Nerve Myelination and Axonal Loss both correlate with Optic Nerve MTR.

Because Axonal Loss following Optic Neuritis also results in Myelin Loss, the relative contributions of the two pathological conditions to the MTR measures cannot be estimated from this study.

Aims
To investigate the role of the Major Histocompatibility Complex in Irish patients with Optic Neuritis (ON) and determine whether HLA-DRB1 genotypes are a risk factor for the development of Multiple Sclerosis (MS) in such patients.

Method
All patients were Caucasian, had Irish ancestry and had MRI of Brain and Optic Nerves within 2-3 weeks of presentation.

Patients were referred to a Neurologist if MRI findings were consistent with a diagnosis of MS.

HLA-DRB1 allele and phenotype frequencies for 78 patients with a clinical diagnosis of acute ON were compared with those for 250 healthy bone marrow donors.

Results
An ON/MS positive patient was 3.4 times more likely than an ON/MS negative patient to be DRB1*15 positive.

No difference in age profile was detected between ON/MS positive and ON/MS negative patients or between the ON male and female subgroups.

No gender or HLA-DRB1 association was identified for ON/MS negative patients. Female gender was significantly increased among ON/MS positive patients with a p value of 0.0053.

Conclusions
DRB1*15 is a significant predisposing factor for ON. This ON patient cohort has also provided an opportunity to evaluate the relationship of HLA genotype with the risk of MS development.

The findings of this study indicate that Irish individuals presenting with ON and who are HLA DRB1*15 positive have a higher risk than HLA DRB1*15 negative patients of presenting with MRI findings indicative of MS.

This study has also demonstrated that female gender is a risk factor for developing MS in the Irish population.