Magdolna Simó

Switch to Natalizumab versus Fingolimod in Active Relapsing-Remitting Multiple Sclerosis

In patients suffering multiple sclerosis activity despite treatment with interferon β or glatiramer acetate, clinicians often switch therapy to either natalizumab or fingolimod. However, no studies have directly compared the outcomes of switching to either of these agents.

Ultrasonography of MADSAM neuropathy: Focal nerve enlargements at sites of existing and resolved conduction blocks

Using the emerging technique of peripheral nerve ultrasonography, multiple focal nerve swellings corresponding to sites of existing conduction blocks have been described in demyelinating polyneuropathies. We report two cases of multifocal acquired demyelinating sensory and motor neuropathy (MADSAM). In the first, multiple focal nerve enlargements were detected by ultrasound at sites of previous conduction blocks, well after complete clinical and electrophysiological resolution. In the second case, existing proximal conduction blocks could be localized by ultrasound. Our cases highlight the importance of nerve ultrasound in identifying conduction blocks and demonstrate that ultrasonographic morphological changes may outlast functional recovery in demyelinating neuropathies.

Vestibular click-evoked myogenic potentials: sensitivity and factors determining abnormality in patients with multiple sclerosis

Vestibular evoked myogenic potential (VEMP) assesses the sacculo-spinal pathway. The aim of our study was to examine sensitivity and factors determining abnormality of VEMP, indicative of brainstem dysfunction, in patients with multiple sclerosis (MS). Thirty healthy subjects and 30 MS patients were examined. All healthy subjects showed a normal biphasic response. Twelve of the 30 MS patients (40%) had abnormal recordings. There was a significant difference between MS patients and control subjects with respect to P13 latency (longer in the MS group) and P13-N23 amplitude (lower in the MS group). VEMP abnormalities were statistically significantly related to the presence of brainstem demyelinative lesions and a weaker correlation was found with disease duration. Clinical signs of vestibular dysfunction at any point during the course of the disease did not seem to affect the chances of obtaining abnormal VEMPs. Although the sensitivity of VEMP in detecting abnormality in MS patients is relatively low, its significance is evident in that it is the only electrophysiological method that is able to detect dysfunction in central vestibular pathways. Multiple Sclerosis 2007; 13: 193–198. http://msj.sagepub.com

Treatment effectiveness of alemtuzumab compared with natalizumab, fingolimod, and interferon beta in relapsing-remitting multiple sclerosis: a cohort study

BACKGROUND Alemtuzumab, an anti-CD52 antibody, is proven to be more efficacious than interferon beta-1a in the treatment of relapsing-remitting multiple sclerosis, but its efficacy relative to more potent immunotherapies is unknown. We compared the effectiveness of alemtuzumab with natalizumab, fingolimod, and interferon beta in patients with relapsing-remitting multiple sclerosis treated for up to 5 years. METHODS In this international cohort study, we used data from propensity-matched patients with relapsing-remitting multiple sclerosis from the MSBase and six other cohorts. Longitudinal clinical data were obtained from 71 MSBase centres in 21 countries and from six non-MSBase centres in the UK and Germany between Nov 1, 2015, and June 30, 2016. Key inclusion criteria were a diagnosis of definite relapsing-remitting multiple sclerosis, exposure to one of the study therapies (alemtuzumab, interferon beta, fingolimod, or natalizumab), age 65 years or younger, Expanded Disability Status Scale (EDSS) score 6·5 or lower, and no more than 10 years since the first multiple sclerosis symptom. The primary endpoint was annualised relapse rate. The secondary endpoints were cumulative hazards of relapses, disability accumulation, and disability improvement events. We compared relapse rates with negative binomial models, and estimated cumulative hazards with conditional proportional hazards models. FINDINGS Patients were treated between Aug 1, 1994, and June 30, 2016. The cohorts consisted of 189 patients given alemtuzumab, 2155 patients given interferon beta, 828 patients given fingolimod, and 1160 patients given natalizumab. Alemtuzumab was associated with a lower annualised relapse rate than interferon beta (0·19 [95% CI 0·14-0·23] vs 0·53 [0·46-0·61], p<0·0001) and fingolimod (0·15 [0·10-0·20] vs 0·34 [0·26-0·41], p<0·0001), and was associated with a similar annualised relapse rate as natalizumab (0·20 [0·14-0·26] vs 0·19 [0·15-0·23], p=0·78). For the disability outcomes, alemtuzumab was associated with similar probabilities of disability accumulation as interferon beta (hazard ratio [HR] 0·66 [95% CI 0·36-1·22], p=0·37), fingolimod (1·27 [0·60-2·70], p=0·67), and natalizumab (0·81 [0·47-1·39], p=0·60). Alemtuzumab was associated with similar probabilities of disability improvement as interferon beta (0·98 [0·65-1·49], p=0·93) and fingolimod (0·50 [0·25-1·01], p=0·18), and a lower probability of disability improvement than natalizumab (0·35 [0·20-0·59], p=0·0006). INTERPRETATION Alemtuzumab and natalizumab seem to have similar effects on annualised relapse rates in relapsing-remitting multiple sclerosis. Alemtuzumab seems superior to fingolimod and interferon beta in mitigating relapse activity. Natalizumab seems superior to alemtuzumab in enabling recovery from disability. Both natalizumab and alemtuzumab seem highly effective and viable immunotherapies for multiple sclerosis. Treatment decisions between alemtuzumab and natalizumab should be primarily governed by their safety profiles. FUNDING National Health and Medical Research Council, and the University of Melbourne.

In vivo evaluation of retinal neurodegeneration in patients with multiple sclerosis.

Objective To evaluate macular morphology in the eyes of patients with multiple sclerosis (MS) with or without optic neuritis (ON) in previous history. Methods Optical coherence tomography (OCT) examination was performed in thirty-nine patients with MS and in thirty-three healthy subjects. The raw macular OCT data were processed using OCTRIMA software. The circumpapillary retinal nerve fiber layer (RNFL) thickness and the weighted mean thickness of the total retina and 6 intraretinal layers were obtained for each eye. The eyes of MS patients were divided into a group of 39 ON-affected eyes, and into a group of 34 eyes with no history of ON for the statistical analyses. Receiver operating characteristic (ROC) curves were constructed to determine which parameter can discriminate best between the non-affected group and controls. Results The circumpapillary RNFL thickness was significantly decreased in the non-affected eyes compared to controls group only in the temporal quadrant (p = 0.001) while it was decreased in the affected eyes of the MS patients in all quadrants compared to the non-affected eyes (p<0.05 in each comparison). The thickness of the total retina, RNFL, ganglion cell layer and inner plexiform layer complex (GCL+IPL) and ganglion cell complex (GCC, comprising the RNFL and GCL+IPL) in the macula was significantly decreased in the non-affected eyes compared to controls (p<0.05 for each comparison) and in the ON-affected eyes compared to the non-affected eyes (p<0.001 for each comparison). The largest area under the ROC curve (0.892) was obtained for the weighted mean thickness of the GCC. The EDSS score showed the strongest correlation with the GCL+IPL and GCC thickness (p = 0.007, r = 0.43 for both variables). Conclusions Thinning of the inner retinal layers is present in eyes of MS patients regardless of previous ON. Macular OCT image segmentation might provide a better insight into the pathology of neuronal loss and could therefore play an important role in the diagnosis and follow-up of patients with MS.

Different Patterns of Nerve Enlargement in Polyneuropathy Subtypes as Detected by Ultrasonography

The purpose of our study was to examine how the pathologic type of polyneuropathy affects nerve size as assessed by high-resolution ultrasonography with a 15 MHz transducer. Cross-sectional area (CSA) of the C5-C7 nerve roots and several upper and lower limb nerves at multiple sites was measured in 38 patients with acquired diffuse sensorimotor demyelinating or axonal polyneuropathy and in 34 healthy control subjects. Significant differences were found among the groups for all nerve and root segments: Both types of polyneuropathy are characterized by nerve enlargement in comparison to controls, but in different patterns. In demyelinating polyneuropathies, an additional degree of nerve thickening appears in proximal upper limb nerves and cervical nerve roots compared with axonal polyneuropathies. With respect to the other nerves, a similar degree of nerve enlargement was observed in both patient groups. These results highlight that ultrasonography may be a complementary tool in differentiating polyneuropathies.

Ultrasonography of ulnar neuropathy at the elbow: Axonal involvement leads to greater nerve swelling than demyelinating nerve lesion

OBJECTIVE To evaluate nerve size parameters measured by ultrasound in patients with ulnar neuropathy at the elbow (UNE) and to correlate them with the type of nerve lesion. METHODS The largest cross sectional area (CSA(max)) of the ulnar nerve around the elbow and the cubital-to-humeral nerve area ratio (CHR) were measured in 50 elbows with UNE and in 87 elbows of 50 healthy subjects. CSA(max) and CHR were compared between controls and patients with predominantly demyelinative and axonal nerve involvement. Subgroups of patients with pure sensory and mixed sensorimotor axonal lesion were also compared. RESULTS In patients with axonal nerve involvement, a significantly larger CSA(max) and CHR were found when compared to those with predominantly demyelinating nerve lesion; both groups differed significantly from healthy controls. CSA(max) values in patients with sensorimotor axonal lesion were significantly higher than in those with pure sensory axonal involvement. CONCLUSION CSA(max) and CHR highly correlate with the type of nerve pathology in UNE, with a significantly larger nerve swelling seen in axonal lesions, as compared to demyelinating lesions. SIGNIFICANCE In addition to helping in the localization of nerve lesion, ultrasonography may also reflect the type and degree of nerve lesion as assessed by electrophysiological means.

Utility of oligoclonal IgG band detection for MS diagnosis in daily clinical practice

An early and accurate diagnosis of multiple sclerosis (MS) is very important, since it allows early treatment initiation, which reduces the activity of the disease. Oligoclonal IgG band (OCGB) detection is a good ancillary tool for MS diagnosis. However, it was argued that its usefulness was limited by the high interlaboratory variability. In the last years, different techniques for OCGB detection have appeared. We performed a blinded aleatorized multicenter study in 19 Spanish hospitals to assess the accuracy and reproducibility of OCGB detection in this new scenario. We studied cerebrospinal fluid (CSF) and serum samples from 114 neurological patients. Every hospital contributed to the study with triplicated pairs of CSF and serum samples of six patients and analyzed 18 different samples. Global analysis rendered a sensitivity of 92.1%, a specificity of 95.1% and a Kappa value of 0.81. This shows that current techniques for OCGB detection have good accuracy and a high interlaboratory reproducibility and thus, represent a good tool for MS diagnosis. When we analyzed separately the different techniques used for OCGB detection, the highest concordance was observed in western blot with alkaline phosphatase detection (kappa=0.91). This indicates that high sensitivity techniques improve the reproducibility of this assay.

Predictive role of evoked potential examinations in patients with clinically isolated optic neuritis in light of the revised McDonald criteria

To analyse the sensitivity and role of somatosensory and motor evoked potentials (EP) in patients with a first episode of clinically isolated optic neuritis (ON) in predicting the development and course of multiple sclerosis (MS), 27 patients with ON underwent EP and magnetic resonance imaging (MRI) examinations at presentation. Follow-up MRI scans were also performed (mean: 20, range: 4—48 months). It was found that 2/27 patients did not fulfill the MRI (McDonald) and clinical criteria of MS upon follow-up and also had normal EP results. Abnormal EP results were found in 6/27 patients and all of them had follow-up MRI results fulfilling the revised McDonald criteria of MS; 4/6 patients in this group were also diagnosed as clinically definitive MS. The majority, 19/27 patients had normal EP results, but went on to develop MS based on follow-up MRI results and McDonald criteria. Of these patients, however, only 3/19 converted to clinically definitive MS as well. The baseline MRI was abnormal in similar proportions (4/6 and 12/19) in these last two groups of patients. Thus, abnormal EP examinations at the first episode of ON can be considered as a predictive factor only for the earlier clinical conversion to MS — in this respect, however, being more sensitive than the initial MRI — and as such they may contribute to the delineation of the patient group who may benefit from early immunomodulatory treatment. They do not however have a predictive value for the development of MS itself as diagnosed by the McDonald criteria. Multiple Sclerosis 2008; 14: 472—478. http://msj.sagepub.com

Nerve fiber layer and macular thinning measured with different imaging methods during the course of acute optic neuritis.

Purpose TO compare retinal nerve fiber layer thickness (RNFLT) and inner macula thickness changes measured with Fourier-domain optical coherence tomography (FD-OCT) and scanning laser polarimetry during the course of acute optic neuritis (ON). Methods Nine eyes of 7 consecutive patients with multiple sclerosis (MS) were prospectively imaged from the onset of ON for 6 to 12 months. Nine healthy eyes were imaged for 12 to 19 months. Results Retinal nerve fiber layer thickness measured with FD-OCT initially increased in all eyes with diffuse optic disc edema. Inner macula thickness and Polarimetric RNFLT decreased already in the acute phase, in all eyes. All parameters stabilized at 2 to 5 months. The relative structural loss was different with the different Methods. Poor image quality with polarimetry occurred in 2 eyes in the acute phase of ON. In the control eyes all parameters were stable. Conclusions Change of RNFLT and macular thickness during the course of acute ON in MS strongly depends on the method used for the measurement. Inner macula thickness, measured with FD-OCT, was especially useful for the follow-up, since it was not influenced by initial disc edema and had consistently high image quality.