Anneke van der Walt

Neuroprotection in multiple sclerosis: A therapeutic challenge for the next decade

Multiple sclerosis (MS) is the commonest cause of progressive neurological disability amongst young, Caucasian adults. MS is considered to be an auto-immune disease that results from an attack against myelin, the layer which surrounds axons. The pathophysiology of MS is complex, with both demyelination and axonal degeneration contributing to what is essentially an inflammatory neurodegenerative disease. Axonal loss is increasingly being accepted as the histopathological correlate of neurological disability. Currently, the underpinnings of neurodegeneration in MS, and how to promote neuroprotection are only partly understood. No established treatments that directly reduce nervous system damage or enhance its repair are currently available. Moreover, the ability of currently available immunomodulatory therapies used to treat MS, such as interferon-beta, to prevent long-term disability is uncertain. Results from short-term randomized-controlled trials suggest a partial benefit with regards to disability outcomes, but this is yet to be established in long-term studies. Novel neuroprotective agents have been identified in preclinical studies but their development is being hampered by the absence of appropriate clinical platforms to test them. In this article, we will discuss some of the principal therapeutic candidates that could provide neuroprotection in MS and emerging methodologies by which to test them.

Axonal loss of retinal neurons in multiple sclerosis associated with optic radiation lesions

Objective: To investigate the potential links between thinning of retinal ganglion cell axons in eyes of patients with multiple sclerosis (MS) without past optic neuritis (ON) and MS-related inflammatory damage of the posterior visual pathway. Methods: Temporal retinal nerve fiber layer (tRNFL) thickness was analyzed in eyes with no history of ON (NON) from 53 patients with relapsing-remitting MS. Fifty normal age- and sex-matched controls were examined with optical coherence tomography. Low-contrast visual acuity charts were used for functional assessment of vision. The optic tract (OT) and optic radiation (OR) were identified using probabilistic tractography, and volume of T2 fluid-attenuated inversion recovery lesions and diffusion tensor imaging (DTI) indices were measured within both structures. Cross-sectional diameter of the OT was also calculated. Results: tRNFL thickness was significantly reduced in NON eyes and was associated with reduced low-contrast visual acuity. Lesions within the OR were detected in the majority of patients. There was a significant correlation between thinning of the tRNFL and OR lesion volume (adjusted for non-OR lesion volume, age, sex, and disease duration). tRNFL thickness also correlated with OR DTI indices. No OT lesions were identified in any of the patients and no relationship between retinal nerve fiber layer loss and potential markers of OT lesions was found. Conclusion: The results demonstrate a strong tract-specific association between loss of tRNFL fibers and MS-related inflammation within OR.

A double-blind, randomized, controlled study of botulinum toxin type A in MS-related tremor

Objective: To evaluate the safety and efficacy of botulinum toxin type A in disabling multiple sclerosis (MS)−related upper limb tremor. Methods: Twenty-three patients with MS contributed data from 33 upper limbs to this study. Each limb was randomized in a crossover design to receive botulinum toxin type A or placebo at baseline and the reverse treatment at 12 weeks. The 3 main outcomes were the median changes in Bain tremor rating scores for tremor severity, writing, and drawing an Archimedes spiral from baseline to 6 and 12 weeks after treatment with botulinum toxin type A compared with those after treatment with saline placebo. An independent rater scored randomized video assessments performed every 6 weeks over 6 months. Results: There was a significant improvement after botulinum toxin compared with that after placebo treatment in the Bain score for tremor severity at 6 weeks (p = 0.0005) and 12 weeks (p = 0.0001), writing at 6 weeks (p = 0.0001) and 12 weeks (p = 0.0003), and Archimedes spiral drawing at 6 weeks (p = 0.0006) and 12 weeks (p = 0.0002). More patients developed weakness after botulinum toxin treatment (42.2%) than after placebo injection (6.1%; (p = 0.0005). Weakness was mild (just detectable) to moderate (still able to use limb) and resolved within 2 weeks. Conclusions: Targeted botulinum toxin type A injections significantly improve arm tremor and tremor-related disability in patients with MS. Classification of evidence: This study provides Class III evidence that targeted injection of botulinum toxin type A is associated with significant improvement in MS-related upper limb tremor. Neurology® 2012;79:92–99

Multiple Sclerosis Susceptibility-Associated SNPs Do Not Influence Disease Severity Measures in a Cohort of Australian MS Patients

Recent association studies in multiple sclerosis (MS) have identified and replicated several single nucleotide polymorphism (SNP) susceptibility loci including CLEC16A, IL2RA, IL7R, RPL5, CD58, CD40 and chromosome 12q13–14 in addition to the well established allele HLA-DR15. There is potential that these genetic susceptibility factors could also modulate MS disease severity, as demonstrated previously for the MS risk allele HLA-DR15. We investigated this hypothesis in a cohort of 1006 well characterised MS patients from South-Eastern Australia. We tested the MS-associated SNPs for association with five measures of disease severity incorporating disability, age of onset, cognition and brain atrophy. We observed trends towards association between the RPL5 risk SNP and time between first demyelinating event and relapse, and between the CD40 risk SNP and symbol digit test score. No associations were significant after correction for multiple testing. We found no evidence for the hypothesis that these new MS disease risk-associated SNPs influence disease severity.

Optic Nerve Diffusion Tensor Imaging after Acute Optic Neuritis Predicts Axonal and Visual Outcomes

Background Early markers of axonal and clinical outcomes are required for early phase testing of putative neuroprotective therapies for multiple sclerosis (MS). Objectives To assess whether early measurement of diffusion tensor imaging (DTI) parameters (axial and radial diffusivity) within the optic nerve during and after acute demyelinating optic neuritis (ON) could predict axonal (retinal nerve fibre layer thinning and multi-focal visual evoked potential amplitude reduction) or clinical (visual acuity and visual field loss) outcomes at 6 or 12 months. Methods Thirty-seven patients presenting with acute, unilateral ON were studied at baseline, one, three, six and 12 months using optic nerve DTI, clinical and paraclinical markers of axonal injury and clinical visual dysfunction. Results Affected nerve axial diffusivity (AD) was reduced at baseline, 1 and 3 months. Reduced 1-month AD correlated with retinal nerve fibre layer (RNFL) thinning at 6 (R=0.38, p=0.04) and 12 months (R=0.437, p=0.008) and VEP amplitude loss at 6 (R=0.414, p=0.019) and 12 months (R=0.484, p=0.003). AD reduction at three months correlated with high contrast visual acuity at 6 (ρ = -0.519, p = 0.001) and 12 months (ρ = -0.414, p=0.011). The time-course for AD reduction for each patient was modelled using a quadratic regression. AD normalised after a median of 18 weeks and longer normalisation times were associated with more pronounced RNFL thinning and mfVEP amplitude loss at 12 months. Affected nerve radial diffusivity (RD) was unchanged until three months, after which time it remained elevated. Conclusions These results demonstrate that AD reduces during acute ON. One month AD reduction correlates with the extent of axonal loss and persistent AD reduction at 3 months predicts poorer visual outcomes. This suggests that acute ON therapies that normalise optic nerve AD by 3 months could also promote axon survival and improve visual outcomes.

Diffusion Tensor Imaging Correlates of Visual Impairment in Multiple Sclerosis and Chronic Optic Neuritis

PURPOSE To compare white matter (WM) injuries associated with vision loss in multiple sclerosis (MS) and optic neuritis (ON). METHODS Twenty-three patients with clinically definite relapsing-remitting MS and chronic unilateral ON and 14 neurologically healthy volunteers were monocularly tested with Sloan 100%, 2.5%, and 1.25% contrast visual acuity charts. Primary visual pathway and whole-brain WM injury were assessed with optical coherence tomography (OCT) and diffusion tensor imaging (DTI). OCT and DTI correlates of high- and low-contrast visual impairment were identified using correlation analyses. RESULTS The MS patients displayed significantly reduced retinal nerve fiber layer (RNFL) thickness and altered optic nerve and radiation DTI measures compared with the controls. In the patients, 2.5% and 1.25% contrast letter acuity in the unaffected eye correlated significantly and independently with optic nerve and optic radiation DTI measures. Visual acuity in affected eyes did not correlate with optic nerve or optic radiation DTI measures, but did correlate with DTI measures in prefrontal and temporal brain regions that were shown to connect structurally to visual cortices. CONCLUSIONS In unaffected eyes, visual impairment was associated with WM injury in the visual pathway. In contrast, irrecoverable visual impairment after ON was associated with injury to frontal WM, which potentially impairs the capacity for remapping visual processing.

Heterogeneity at the HLA-DRB1 allelic variation locus does not influence multiple sclerosis disease severity, brain atrophy or cognition

Background: HLA-DRB1*1501 (DR15) and other HLA class II alleles increase the risk of developing multiple sclerosis (MS). However, the contribution of genetic heterogeneity to the clinical course of MS remains controversial. We examined the influence of DR15 and other common DRB1 alleles (DRB1*01 (DR1), DRB1*03 (DR3) and DRB1*04 (DR4) on MS severity in a large, Australian, population-based cohort. Methods: We studied the association between common HLA-DRB1 alleles and genotypes and age of onset as well as three clinical disease severity descriptors: Multiple Sclerosis Severity Score, progression index), and the interval between the first and second attack in 978 patients with relapsing remitting MS and secondary progressive MS. We assessed cognition using the Symbol Digit Modalities Test in 811 patients and brain atrophy using the linear magnetic resonance imaging marker, the intercaudate ratio, in 745 patients. Results: Carrying DR15 significantly decreased the age of MS onset by 3.2 years in homozygotes and 1.3 years in heterozygotes. Carrying the HLA-DR15, -DR1, -DR3 or -DR4 alone or in combination did not affect clinical disease severity, cognition or cerebral atrophy. Conclusions: This study confirms that heterogeneity of HLA-DRB1 does not influence disease outcome in relapsing MS patients, with the exception of a younger age of onset in HLA-DR15 carriers.

Parallel changes in structural and functional measures of optic nerve myelination after optic neuritis

Introduction Visual evoked potential (VEP) latency prolongation and optic nerve lesion length after acute optic neuritis (ON) corresponds to the degree of demyelination, while subsequent recovery of latency may represent optic nerve remyelination. We aimed to investigate the relationship between multifocal VEP (mfVEP) latency and optic nerve lesion length after acute ON. Methods Thirty acute ON patients were studied at 1,3,6 and 12 months using mfVEP and at 1 and 12 months with optic nerve MRI. LogMAR and low contrast visual acuity were documented. By one month, the mfVEP amplitude had recovered sufficiently for latency to be measured in 23 (76.7%) patients with seven patients having no recordable mfVEP in more than 66% of segments in at least one test. Only data from these 23 patients was analysed further. Results Both latency and lesion length showed significant recovery during the follow-up period. Lesion length and mfVEP latency were highly correlated at 1 (r = 0.94, p = <0.0001) and 12 months (r = 0.75, p < 0.001). Both measures demonstrated a similar trend of recovery. Speed of latency recovery was faster in the early follow-up period while lesion length shortening remained relatively constant. At 1 month, latency delay was worse by 1.76ms for additional 1mm of lesion length while at 12 months, 1mm of lesion length accounted for 1.94ms of latency delay. Conclusion A strong association between two putative measures of demyelination in early and chronic ON was found. Parallel recovery of both measures could reflect optic nerve remyelination.

Optic Nerve Magnetisation Transfer Ratio after Acute Optic Neuritis Predicts Axonal and Visual Outcomes

Magnetisation transfer ratio (MTR) can reveal the degree of proton exchange between free water and macromolecules and was suggested to be pathological informative. We aimed to investigate changes in optic nerve MTR over 12 months following acute optic neuritis (ON) and to determine whether MTR measurements can predict clinical and paraclinical outcomes at 6 and 12 months. Thirty-seven patients with acute ON were studied within 2 weeks of presentation and at 1, 3, 6 and 12 months. Assessments included optic nerve MTR, retinal nerve fibre layer (RNFL) thickness, multifocal visual evoked potential (mfVEP) amplitude and latency and high (100%) and low (2.5%) contrast letter acuity. Eleven healthy controls were scanned twice four weeks apart for comparison with patients. Patient unaffected optic nerve MTR did not significantly differ from controls at any time-point. Compared to the unaffected nerve, affected optic nerve MTR was significantly reduced at 3 months (mean percentage interocular difference = −9.24%, p = 0.01), 6 months (mean = −12.48%, p<0.0001) and 12 months (mean = −7.61%, p = 0.003). Greater reduction in MTR at 3 months in patients was associated with subsequent loss of high contrast letter acuity at 6 (ρ = 0.60, p = 0.0003) and 12 (ρ = 0.44, p = 0.009) months, low contrast letter acuity at 6 (ρ = 0.35, p = 0.047) months, and RNFL thinning at 12 (ρ = 0.35, p = 0.044) months. Stratification of individual patient MTR time courses based on flux over 12 months (stable, putative remyelination and putative degeneration) predicted RNFL thinning at 12 months (F 2,32 = 3.59, p = 0.02). In conclusion, these findings indicate that MTR flux after acute ON is predictive of axonal degeneration and visual disability outcomes.

Multifocal VEP assessment of optic neuritis evolution

OBJECTIVE To evaluate multifocal visual evoked potentials (mfVEP) changes in optic neuritis (ON) and fellow eyes during first year after the attack. METHODS Eighty-seven patients and twenty-five controls were examined. Patients were classified as multiple sclerosis (MS) group, high risk (HR) or low risk (LR) groups for conversion to MS. mfVEP recordings and retinal nerve fiber layer (RNFL) thickness were analyzed. RESULTS Recovery of amplitude and shortening of latency was fastest within the first 3months. The largest amplitude reduction and longest latency delay of the ON eye were recorded in the MS group. This was accompanied by deterioration of both parameters in fellow eyes (p<0.03). mfVEP remained stable in fellow eyes of the LR group. Inter-eye asymmetry showed similar amount of amplitude reduction and latency delay in all three groups. RNFL thickness strongly correlated with mfVEP amplitude as early as 3 months after ON (R(2)=0.6, p=0.001). CONCLUSION mfVEP amplitude is an early predictor of post-ON axonal loss. The apparent more severe involvement of ON eyes in the MS subgroup may be due to subclinical inflammation along the visual pathway. SIGNIFICANCE Severity of amplitude reduction and latency delay after episode of ON is not MS-related. Retro-chiasmal demyelination is a possible factor contributing to amplitude and latency differences between MS and non-MS patients.