From 1991-2002, we treated 58 patients with multiple sclerosis (MS) using the humanised monoclonal antibody, Campath-1H, which causes prolonged T lymphocyte depletion. Clinical and surrogate markers of inflammation were suppressed. In both the relapsing-remitting (RR) and secondary progressive (SP) stages of the illness, Campath-1H reduced the annual relapse rate (from 2.2 to 0.19 and from 0.7 to 0.001 respectively; both p < 0.001). Remarkably, MRI scans of patients with SP disease, treated with Campath-1H 7 years previously, showed no new lesion formation. However, despite these effects on inflammation, disability was differently affected depending on the phase of the disease. Patients with SPMS showed sustained accumulation of disability due to uncontrolled progression marked by unrelenting cerebral atrophy, attributable to ongoing axonal loss. The rate of cerebral atrophy was greatest in patients with established cerebral atrophy and highest inflammatory lesion burden before treatment (2.3 versus 0.7 ml/year; p = 0.04). In contrast, patients with RR disease showed an impressive reduction in disability at 6 months after Campath-1H (by a mean of 1.2 EDSS points) perhaps owing to a suppression of on-going inflammation in these patients with unusually active disease. In addition, there was a further significant, albeit smaller, mean improvement in disability up to 36 months after treatment. We speculate that this represents the beneficial effects of early rescue of neurons and axons from a toxic inflammatory environment, and that prevention of demyelination will prevent long-term axonal degeneration. These concepts are currently being tested in a controlled trial comparing Campath-1H and IFN-beta in the treatment of drug-naïve patients with early, active RR MS.
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.
Axonal loss is thought to be the predominant cause of disability in progressive multiple sclerosis (MS). The retinal nerve fibre layer (RNFL) is composed largely of unmyelinated axons of retinal ganglion cells, and is accessible to study with optical coherence tomography (OCT), giving a measure of axonal loss. OCT measures of the RNFL thickness (RNFLT) and macular volume were studied in 23 patients with primary progressive multiple sclerosis (primary progressive MS) (13 male; 10 female; mean age 52 years; median EDSS 6.0; mean disease duration 11 years), and 27 patients with secondary progressive multiple sclerosis (secondary progressive MS) (8 male; 19 female; mean age 50 years; median EDSS 6; mean disease duration 22 years). Of the patients with secondary progressive MS, 14 had clinical history of optic neuritis (ON) in a single eye; the remaining patients had not had ON. Twenty healthy controls (11 male; 9 female; mean age 46 years) had RNFLT and macular volume studied. Of the patients' eyes not previously affected by ON, both the mean RNFL thickness and macular volume were reduced when compared with control values. The mean RNFL thickness and macular volume were significantly reduced in secondary progressive MS, but not in primary progressive MS when compared with control RNFL thickness and macular volume. RNFL loss was most evident in the temporal quadrant, where significant reduction was seen in primary progressive MS versus controls and in secondary versus primary progressive MS. There were significant correlations of decreased RNFLT and macular volume with measures of visual acuity, low contrast visual acuity and visual field mean deviation in the MS patients. There are significant global reductions in RNFLT and macular volume in the eyes of secondary progressive MS patients not previously affected by ON, but not in primary progressive MS patients, compared with controls. This may indicate a difference in the extent of the pathological processes that cause axonal loss in the retina, and by inference the optic nerve, in secondary progressive MS and primary progressive MS.
Diffusion tensor imaging (DTI) of the optic nerve (ON) was acquired in normal controls using zonally oblique multislice (ZOOM) DTI, which excites a small field of view (FOV) using a fast sequence with a shortened EPI echo train. This combines the benefit of low sensitivity to motion (due to the single-shot acquisition used), with the additional advantage of reduced sensitivity to magnetic field susceptibility artifacts. Reducing the bright signal from the fat and cerebrospinal fluid (CSF) surrounding the nerve are key requirements for the success of the presented method. Quantitative MRI measurements are becoming essential in clinical research because they enable one to compare quantitative results obtained at different time points in the same patients/volunteers in longitudinal studies or in different patients/volunteers in cross-sectional studies. One of the measurements that is becoming more and more popular in research projects, especially in the brain, is the diffusion tensor (DT), because from it many parameters can be derived that are rotationally-invariant (i.e., unaffected by positioning in the scanner) and have high sensitivity to the structural properties of tissues and hence to structural changes (1).Initial observations of diffusion anisotropy in the optic nerve (ON) were reported a decade ago in freshly excised ON of the garfish (2), while fairly recently the effects of pathology on the diffusion properties of the ON were shown in a study on anesthetized mice with retinal ischemia (3). Quantitative MRI of the human ON in vivo is generally very challenging because of its small size (diameter ϭ ϳ3-7 mm depending on the position along the ON), its uncontrolled motion, the presence of magnetic field susceptibility artifacts (especially near the chiasm), and high signal from the orbital fat and cerebrospinal fluid (CSF) that surrounds the ON. ON diffusion measurements are particularly difficult to obtain because of the high sensitivity of the acquisition to motion. Previous publications have measured the apparent diffusion coefficient (ADC) in the ON (as opposed to measuring the mean diffusivity (MD) from the eigenvalues of the DT) (4 -6). Preliminary applications of ON ADC measurements to disease states have also been reported. In work by Wheeler-Kingshott and Hickman, diffusion-weighted (DW) zonal oblique multislice (ZOOM) echo-planar imaging (EPI) was used to acquire coronal ADC maps of the ON in vivo (6) and to determine ADC changes in a cohort of optic neuritis patients (7). Indications of the sensitivity of the ADC for detecting pathological changes were also reported in a study of chronic optic neuritis (4). Koch et al. (8) showed the intracranial portion of the ON in a qualitative tractography study using DT maps of healthy brains, and the results of a quantitative DT study of the ON in healthy volunteers were recently reported (9).Our aim was to develop a protocol that allowed us to further assess the structural properties of the ON by measuring the full diffusion tensor (DT) (10). Ultimately, ...
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