Thomas M. Jenkins

Assessing structure and function of the afferent visual pathway in multiple sclerosis and associated optic neuritis

The afferent visual pathway is commonly affected in MS. Assessment of the afferent visual pathway using clinical, imaging and electrophysiological methods not only provides insights into the pathophysiology of MS, but also provides a method of investigating potential therapeutic measures in MS. This review summarises the various assessment methods, in particular imaging techniques of the visual pathway. Retinal nerve fibre layer (RNFL) thickness is usually reduced following an episode of optic neuritis. Techniques such as optical coherence tomography, scanning laser polarimetry, and confocal scanning laser ophthalmoscopy are used to quantify RNFL thickness. MRI of the optic nerve is not routinely used in the diagnosis of MS or optic neuritis, but is valuable in atypical cases and in research. T2- weighted images of the optic nerve usually show the hyperintense lesion in optic neuritis and gadolinium enhancement is seen in the acute attack. Quantifying atrophy of the optic nerve using MRI gives an indication of the degree of axonal loss. Magnetization transfer ratio (MTR) of the optic nerve provides an indication of myelination. Diffusion tensor imaging (DTI) of the optic nerve and optic radiation provide information about the integrity of the visual white matter tracts. Functional MRI following visual stimulation is used to assess the contribution of cortical reorganisation to functional recovery following optic neuritis. Investigations including logMAR visual acuity, Sloan contrast acuity, Farnsworth- Munsell 100-hue colour vision tests and Humphrey perimetry provide detailed quantitative information on different aspects of visual function. Visual evoked potentials identify conduction block or delay reflecting demyelination. These collective investigative methods have advanced knowledge of pathophysiological mechanisms in MS and optic neuritis. Relevant ongoing studies and future directions are discussed.

Neuroplasticity predicts outcome of optic neuritis independent of tissue damage

To determine whether lateral occipital complex (LOC) activation with functional magnetic resonance imaging (fMRI) predicts visual outcome after clinically isolated optic neuritis (ON). To investigate the reasons behind good recovery following ON, despite residual optic nerve demyelination and neuroaxonal damage.

Contiguous-slice zonally oblique multislice (CO-ZOOM) diffusion tensor imaging: examples of in vivo spinal cord and optic nerve applications

To describe and demonstrate a new technique that allows diffusion tensor imaging of small structures such as the spinal cord (SC) and optic nerve (ON) with contiguous slices and reduced image distortions using a narrow field of view (FOV).

Combining tractography and cortical measures to test system-specific hypotheses in multiple sclerosis

The objective was to test three motor system-specific hypotheses in multiple sclerosis patients: (i) corticospinal tract and primary motor cortex imaging measures differ between multiple sclerosis patients and controls; (ii) in patients, these measures correlate with disability; (iii) in patients, corticospinal tract measures correlate with measures of the ipsilateral primary motor cortex. Eleven multiple sclerosis patients with a history of hemiparesis attributable to a lesion within the contralateral corticospinal tract, and 12 controls were studied. We used two advanced imaging techniques: (i) diffusion-based probabilistic tractography, to obtain connectivity and fractional anisotropy of the corticospinal tract; and (ii) FreeSurfer, to measure volume, thickness, surface area, and curvature of precentral and paracentral cortices. Differences in these measures between patients and controls, and relationships between each other and to clinical scores, were investigated. Patients showed lower corticospinal tract fractional anisotropy and smaller volume and surface area of the precentral gyrus than controls. In patients, corticospinal tract connectivity and paracentral cortical volume, surface area, and curvature were lower with increasing disability; lower connectivity of the affected corticospinal tract was associated with greater surface area of the ipsilateral paracentral cortex. Corticospinal tract connectivity and new measures of the primary motor cortex, such as surface area and curvature, reflect the underlying white and grey matter damage that contributes to disability. The correlation between lower connectivity of the affected corticospinal tract and greater surface area of the ipsilateral paracentral cortex suggests the possibility of cortical adaptation. Combining tractography and cortical measures is a useful approach in testing hypotheses which are specific to clinically relevant functional systems in multiple sclerosis, and can be applied to other neurological diseases.

Dissecting structure–function interactions in acute optic neuritis to investigate neuroplasticity

Structural MRI, electrophysiology, and functional MRI (fMRI) elucidate different aspects of damage and repair in demyelinating diseases. We combined them to investigate why patients with optic neuritis (ON) exhibit a wide variation in severity of acute visual loss, with the following objectives: (1) To determine how structural and electrophysiological changes in the anterior and posterior visual pathways contribute to acute visual loss. (2) To combine these data with fMRI, to investigate whether cortical activity modulates visual acuity. The visual system of 28 patients with acute unilateral ON was assessed. Linear regression modeling was used to identify parameters associated with acute visual loss, and to determine whether fMRI activity was associated with vision, after accounting for structural and electrophysiological predictors, age, and gender. Optic nerve lesion length and visual evoked potential (VEP) amplitude were associated with visual loss. Bilateral activation in the extra‐striate occipital cortex correlated directly with vision, after adjusting for optic nerve lesion length, VEP amplitude, and demographic characteristics. These data suggest that acute visual loss is associated with the extent of inflammation and conduction block in the optic nerve, but not with pathology in the optic radiations or occipital cortex. The association of better vision with greater fMRI responses, after accounting for factors which reduce afferent input, suggests a role for adaptive neuroplasticity within the association cortex of the dorsal stream of higher visual processing. Longitudinal studies will clarify whether different extra‐striate cortical regions play a role in adaptive plasticity in the acute and chronic stages of injury. Hum Brain Mapp, 2010.

Early pericalcarine atrophy in acute optic neuritis is associated with conversion to multiple sclerosis

Background Previous work showed that pericalcarine cortical volume loss is evident early after presentation with acute clinically isolated optic neuritis (ON). The aims of this study were: (1) to determine whether pericalcarine atrophy in patients with ON is associated with conversion to multiple sclerosis (MS); (2) to investigate whether regional atrophy preferentially affects pericalcarine cortex; and (3) to investigate potential causes of early pericalcarine atrophy using MRI. Methods 28 patients with acute ON and 10 controls underwent structural MRI (brain and optic nerves) and were followed-up over 12 months. Associations between the development of MS, optic nerve, optic radiation and pericalcarine cortical damage measures were investigated using multiple linear regression models. Regional cortical volumetric differences between patients and controls were calculated using t tests. Results The development of MS at 12 months was associated with greater whole brain and optic radiation lesion loads, shorter acute optic nerve lesions and smaller pericalcarine cortical volume at baseline. Regional atrophy was not evident in other sampled cortical regions. Pericalcarine atrophy was not directly associated with whole brain lesion load, optic radiation measures or optic nerve lesion length. However, the association between pericalcarine atrophy and MS was not independent of these parameters. Conclusions Reduced pericalcarine cortical volumes in patients with early clinically isolated ON were associated with the development of MS but volumes of other cortical regions were not. Hence pericalcarine cortical regions appear particularly susceptible to early damage. These findings could be explained by a combination of pathological effects to visual grey and white matter in patients with ON.

Optical coherence tomography should be part of the routine monitoring of patients with multiple sclerosis: No

http://msj.sagepub.com 1299 Optical coherence tomography (OCT) is an exciting technique that has been applied to multiple sclerosis (MS) research for around the last 10 years. OCT enables rapid, non-invasive in vivo measurement of retinal nerve fibre layer (RNFL) thickness, reflecting neuroaxonal density within the optic nerve. Early studies applied to post-acute optic neuritis1 demonstrate neuroaxonal loss. Further research extended the scope of OCT, finding that its measures appeared to be a useful surrogate of generalised brain axonal loss in MS patients; progressive RNFL thinning was evident even in the absence of a history of optic neuritis,2 and RNFL thickness was associated with cerebral volume measurements.3 RNFL thinning is evident in patients with secondary progressive MS,4 but also earlier in the disease course in clinically isolated syndrome5 and in forms of MS with minimal disability.6 RNFL thickness shows clinical correlations with disability measures such as visual acuity1 and Expanded Disability Status Scale (EDSS) scores.3

Optic neuritis: the eye as a window to the brain.

Purpose of review Acute optic neuritis is a common clinical problem, requiring a structured assessment to guide management and prevent visual loss. The optic nerve is the most accessible part of the central nervous system, so optic neuritis also represents an important paradigm to help decipher mechanisms of damage and recovery in the central nervous system. Important developments include the advent of optical coherence tomography as a biomarker of central nervous system axonal loss, the discovery of new pathological antibodies, notably against aquaporin-4 and, more recently, myelin oligodendrocyte protein, and emerging evidence for sodium channel blockade as a novel therapeutic approach to address energy failure in neuroinflammatory disease. Recent findings We will present a practical approach to assessment of optic neuritis, highlighting the role of optical coherence tomography, when to test for new antibodies and the results of recent trials of sodium channel blockers. Summary Optic neuritis remains a clinical diagnosis; increasingly optical coherence tomography is a key ancillary investigation. Patients with ‘typical’ optic neuritis, commonly a first presentation of multiple sclerosis, must be distinguished from ‘atypical’ optic neuritis, who require testing for new pathological antibodies and require more aggressive-targeted treatment. Sodium channel blockade is an emerging and novel potential therapeutic pathway in neuroinflammatory disease.

A longitudinal functional MRI study of non-arteritic anterior ischaemic optic neuropathy patients

Background Non-arteritic anterior ischaemic optic neuropathy (NA-AION) can cause disabling visual loss and traditionally, visual prognosis has been considered poor, although recent studies have demonstrated improvements in visual acuity in about 30% of patients over time. The aim of the study was to determine whether there was significant cortical reorganisation with functional MRI (fMRI) after acute NA-AION by comparing affected individuals with healthy controls. Methods 9 patients with NA-AION were studied acutely and then after 1, 2, 3 and 6 months. 23 healthy volunteers underwent scanning at least twice. At each time point, patients were assessed clinically and with fMRI. For the fMRI experiments, subjects underwent monocular visual stimulation (wearing goggles with flashing LED displays). Results When stimulating the affected eye, occipital activation was reduced in patients compared with controls. Also, within the NA-AION group, activation in the right Brodmann areas (BA) 44 and 45 was seen during the early phase of the condition. The same areas were activated within the NA-AION group several months later for fellow eye stimulation. When the NA-AION and healthy control groups were formally compared however, these areas (BA 44/45) were not significantly different. NA-AION subjects did show greater activation in visual related areas compared with controls when stimulating the fellow eye. Visual acuity was correlated with more occipital cortex activation when stimulating the affected eye. Conclusions There is cortical re-organisation of the fMRI response in extra-visual areas, seen when both affected and fellow eyes are stimulated after NA-AION.

Oculopharyngeal myopathy with inflammation and calcinosis: an unusual phenotype

The case is reported of a patient with progressive proximal and distal weakness, dysphagia, respiratory weakness, calcifications, ptosis and ophthalmoparesis with inflammation, rimmed vacuoles and positive amyloid and ubiquitin on muscle biopsy. The histopathological features fit best with inclusion body myositis, but ophthalmoparesis and ptosis have not previously been described. The clinical phenotype fits best with hereditary inclusion body myopathy or distal-oculopharyngeal muscular dystrophy, but the degree of inflammation seen is unusual. None of these are associated with calcinosis.