Sativex(®) and clinical-neurophysiological measures of spasticity in progressive multiple sclerosis.

Despite the proven efficacy of Sativex(®) (9-delta-tetrahydrocannabinol plus cannabidiol) oromucosal spray in reducing spasticity symptoms in multiple sclerosis (MS), little is known about the neurophysiological correlates of such effects. The aim of the study was to investigate the effects of Sativex on neurophysiological measures of spasticity (H/M ratio) and corticospinal excitability in patients with progressive MS. This was a randomized, double-blind, placebo-controlled, crossover study. Consecutive subjects with progressive MS and lower limb spasticity referred to our center were randomized to 4 weeks' treatment (including 2 weeks' titration) with Sativex or placebo, with crossover after a 2-week washout. Clinical and neurophysiological measures (H/M ratio and cortical excitability) of spasticity were assessed. The H/M ratio was the primary outcome, with sample size calculation of 40 patients. Of 44 recruited patients, 34 were analyzed due to 6 drop-outs and 4 exclusions, which lowered the power of the study to show differences between treatments. Neurophysiological measures did not differ significantly according to treatment and did not correlate significantly with clinical response. Response on the modified Ashworth scale (at least 20 % improvement) was significantly more frequent after Sativex than placebo (50 vs 23.5 %; p = 0.041; McNemar). Side effects did not differ significantly according to treatment. Our findings confirm the clinical benefit of Sativex on MS spasticity. The lack of corresponding changes in corticospinal excitability and on the monosynaptic component, of the stretch reflex, although in a limited sample size, points to the involvement of other spinal and supraspinal mechanisms in the physiopathology of spasticity in progressive MS.

Practice of yoga may cause damage of both sciatic nerves: a case report.

Sciatic nerve traumatic damage very rarely occurs bilaterally. We describe the case of a 67-year-old woman who reported a bilateral traumatic lesion of the sciatic nerve during practice of yoga. Nerve conduction studies showed a bilateral sciatic nerve neuropathy, mostly affecting the peroneal component. Lumbar plexus MRI documented regular anatomical features of the main principal nerve roots with bilateral T2 signal alteration of roots L4, L5 and S1 that extended into the sciatic nerves showing both increase in size, probably related to chronic injury of nerves, and an alteration in diffusion signal that suggested a recent acute overlapped process.

Deep gray matter T2 hypointensity is present in patients with clinically isolated syndromes suggestive of multiple sclerosis.

Gray matter (GM) magnetic resonance imaging (MRI) T2 hypointensity, a putative marker of iron deposition, is a frequent finding in patients with clinically definite (CD) multiple sclerosis (MS). The objective of this study was to assess: (a) how early deep GM T2 hypointensity occurs in MS, by studying patients with clinically isolated syndromes (CIS) suggestive of MS, and (b) whether they contribute to predict subsequent evolution to CDMS. Dual-echo scans using two different acquisition protocols were acquired from 47 CIS patients and 13 healthy controls (HC). Normalized T2-intensity of the basal ganglia and thalamus was quantified. Patients were assessed clinically at the time of MRI acquisition and after three years. During the observation period, 18 patients (38%) evolved to CDMS. At the baseline, only the GM T2-intensity of the left caudate nucleus was significantly reduced in CIS patients in comparison with the HC (p = 0.04). At the baseline, the T2 intensity of the left caudate nucleus was significantly lower (p = 0.01) in CIS patients with disease dissemination in space (DIS), but not in those without DIS, compared to the HC. The baseline T2 lesion volume, but not GM T2 hypointensity, was associated with evolution to CDMS (hazard ratio = 1.60, 95% confidence interval (CI) = 1.05-2.42; p = 0.02). In CIS patients, deep GM is not spared, suggesting that iron-related changes and neurodegeneration occurs early. The magnitude of such damage is only minor and not associated with an increased risk of evolution to CDMS.

Determinants of disability in multiple sclerosis at various disease stages: a multiparametric magnetic resonance study.

OBJECTIVE: To investigate whether diffusion-tensor magnetic resonance imaging and whole brain N-acetylaspartate (WBNAA) proton magnetic resonance spectroscopy can provide complementary pieces of information to achieve a better understanding of the factors associated with disability in multiple sclerosis (MS). DESIGN: Cross-sectional survey. SETTING: Referral hospital-based MS center. PATIENTS: Ten healthy control subjects, 27 patients with a clinically isolated neurological syndrome, 21 patients with relapsing-remitting MS, and 29 patients with secondary progressive MS. MAIN OUTCOME MEASURES: Conventional and diffusion-tensor magnetic resonance imaging, as well as WBNAA proton magnetic resonance spectroscopy, of the brain was performed. T2-hyperintense lesion volumes were measured. The mean values of mean diffusivity (MD) and fractional anisotropy of T2-visible lesions were computed. Histograms of MD and fractional anisotropy values were produced for normal-appearing white matter and gray matter (GM). RESULTS: Patients with a clinically isolated neurological syndrome had a significantly (P=.002) lower WBNAA concentration than control subjects. Patients with relapsing-remitting MS had significantly higher T2 lesion volume (P=.007), mean lesion MD (P=.003), normal-appearing white matter fractional anisotropy peak height (P=.03), and a lower WBNAA concentration (P<.001) than patients with a clinically isolated neurological syndrome. Patients with secondary progressive MS had significantly higher T2 lesion volume (P=.01), lower mean normal-appearing white matter fractional anisotropy (P=.003), higher mean GM MD (P=.004), and lower GM MD peak height (P=.01) than patients with relapsing-remitting MS. Disease duration, GM MD peak height, and WBNAA concentration entered a multivariate model, explaining nearly 70% of the disability variance. CONCLUSIONS: The accumulation of macroscopic lesions and normal-appearing white matter damage seems to occur mainly during the earliest clinical phases of MS, whereas pathological features of GM may be a hallmark of the late progressive stage of the disease. This supports the notion of MS as a "2-stage" disease.

Evidence for axonal pathology and adaptive cortical reorganization in patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis.

Previous work has suggested that functional reorganization of cortical areas might have a role in limiting the clinical impact of axonal pathology in patients with established multiple sclerosis (MS). Since there is evidence for irreversible tissue damage even in patients with early MS, we assessed, using functional MRI (fMRI) and a general search method, the brain pattern of movement-associated cortical activations in patients at presentation with clinically isolated syndromes (CIS) suggestive of MS. To elucidate the role of cortical reorganization in these patients, we also investigated the extent to which the fMRI changes correlated with the extent of overall axonal injury of the brain. From 16 right-handed patients at presentation with CIS and 15 right-handed, age- and sex-matched healthy volunteers, we obtained: (1). fMRI (repetitive flexion-extension of the last four fingers of the right hand), (2). conventional MRI scans, and (3). a new, unlocalized proton MR spectroscopy ((1)HMRS) sequence to measure the concentration of N-acetylaspartate of the whole brain (WBNAA). Compared to controls, patients with CIS had more significant activations of the contralateral primary somatomotor cortex (SMC), secondary somatosensory cortex, and inferior frontal gyrus. They also had significant decreased WBNAA concentration. Relative activation of the contralateral primary SMC was strongly correlated with WBNAA levels (r = -0.78, P < 0.001). This study shows that axonal pathology and functional cortical changes over a rather distributed sensorimotor network occur in patients at presentation with CIS suggestive of MS and that these two aspects of the disease are strictly correlated. This suggests that the increased functional recruitment of the cortex in these patients might have an adaptive role in limiting the clinical impact of irreversible tissue damage.