Ten-year follow-up after mitoxantrone induction for early highly active relapsing-remitting multiple sclerosis: An observational study of 100 consecutive patients.

BACKGROUND: Six monthly courses of mitoxantrone were approved in France in 2003 for patients with highly active multiple sclerosis (MS). OBJECTIVE: To report the 10-year clinical follow-up and safety of mitoxantrone as an induction drug followed by maintenance therapy in patients with early highly active relapsing-remitting MS (RRMS) and an Expanded Disability Status Scale (EDSS) score<4, 12months prior to mitoxantrone initiation. METHODS: In total, 100 consecutive patients with highly active RRMS from the Rennes EDMUS database received monthly mitoxantrone 20mg combined with methylprednisolone 1g for 3 (n=75) or 6months (n=25) followed by first-line disease-modifying drug (DMD). The 10-year clinical impact was studied through clinical activity, DMD exposure, and adverse events. RESULTS: Twenty-four percent were relapse-free over 10years and the mean annual number of relapses was 0.2 at 10years. The mean EDSS score remained significantly improved for up to 10years, changing from 3.5 at mitoxantrone initiation to 2.7 at 10years. The probability of disability worsening and improvement from mitoxantrone initiation to 10years were respectively 27% and 58%, and 13% converted to secondary progressive MS. Patients only remained untreated or treated with a first-line maintenance DMD for 6.5years in average. In our cohort, mitoxantrone was generally safe. No leukemia was observed and six patients developed neoplasms, including 4 solid cancers. CONCLUSION: Monthly mitoxantrone for 3 or 6months, followed by maintenance first-line treatment, may be an attractive therapeutic option for patients with early highly active RRMS, particularly in low-income countries.

Prognostic value of spinal cord MRI in multiple sclerosis patients.

Multiple sclerosis [MS] is a common inflammatory, demyelinating and neurodegenerative disease of the central nervous system that affects both the brain and the spinal cord. In clinical practice, spinal cord MRI is performed far less frequently than brain MRI, mainly owing to technical limitations and time constraints. However, improvements of acquisition techniques, combined with a strong diagnosis and prognostic value, suggest an increasing use of spinal cord MRI in the near future. This review summarizes the current data from the literature on the prognostic value of spinal cord MRI in MS patients in the early and later stages of their disease. Both conventional and quantitative MRI techniques are discussed. The prognostic value of spinal cord lesions is clearly established at the onset of disease, underlining the interest of spinal cord conventional MRI at this stage. However, studies are currently lacking to affirm the prognostic role of spinal cord lesions later in the disease, and therefore the added value of regular follow-up with spinal cord MRI in addition to brain MRI. Besides, spinal cord atrophy, as measured by the loss of cervical spinal cord area, is also associated with disability progression, independently of other clinical and MRI factors including spinal cord lesions. Although potentially interesting, this measurement is not currently performed as a routine clinical procedure. Finally, other measures extracted from quantitative MRI have been established as valuable for a better understanding of the physiopathology of MS, but still remain a field of research.

Can we stop immunomodulatory treatments in secondary progressive multiple sclerosis?

BACKGROUND AND PURPOSE: The benefits of immunomodulatory treatments in secondary progressive multiple sclerosis (SPMS) are unclear, calling into question their continuation. In the present observational study, we investigated the effect of treatment withdrawal on the clinical course of SPMS. METHODS: We included 100 consecutive patients with SPMS who regularly attended our multiple sclerosis clinic. Inclusion criteria were (i) secondary progressive phenotype for at least 2 years, (ii) immunomodulatory treatment for at least 6 months and (iii) treatment stopped with no plans to switch to another. Clinical and magnetic resonance imaging (MRI) data before and after treatment discontinuation were assessed. Factors associated with relapses and/or MRI activity were identified. RESULTS: Mean treatment duration was 60.4 ± 39.3 months, and mean follow-up duration after treatment withdrawal was 62.4 ± 38.4 months. The annualized relapse rate remained stable at 1 and 3 years after treatment withdrawal [0.09, 95% confidence interval (CI), 0.05-0.17 and 0.07, 95% CI, 0.05-0.11, respectively], relative to the 3 years prior to treatment withdrawal (0.12, 95% CI, 0.09-0.16). Sixteen patients experienced a relapse and 19 had a gadolinium-positive MRI scan without relapse during follow-up. A gadolinium-positive MRI scan within the previous 3 years before treatment withdrawal and Expanded Disability Status Scale score of <6 were positively associated with relapse and/or MRI activity after discontinuation (P = 0.0004 and P = 0.03, respectively). CONCLUSION: In this retrospective study, including a limited number of patients with SPMS, the annualized relapse rate remained stable after treatment withdrawal, relative to before treatment withdrawal. Further prospective studies are needed to confirm this result and provide evidence-based guidelines for daily practice.

Ten-year prognosis in multiple sclerosis: a better outcome in relapsing-remitting patients but not in primary progressive patients.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) prognosis remains a challenge for both patients and physicians. Complementary to natural history studies, updated population-based data from the first event suggestive of MS, at the time of the first approved disease modifying drug (DMD), are needed. Our objective was to provide a 10-year history of MS from clinical onset at time of first approved DMDs in a population-based cohort. METHODS: A population-based cohort of patients whose first clinical event suggestive of MS had occurred in Brittany between 2000 and 2001 was prospectively selected. History of relapses, treatments and disability up to 10 years after onset were collected. RESULTS: In all, 278 patients with either attack-onset (n = 244) or progressive-onset (n = 34) were recruited. Amongst attack-onset patients, 30% remained as clinically isolated syndrome and 70% had a second relapse after a median time of 1.7 years (95% confidence interval 1.2-2.4). 80% of relapsing-remitting MS patients received DMDs for at least 6 months. 29% reached disability status scale (DSS) 3 and 8% DSS 6. Amongst progressive-onset patients, 100% reached DSS 3 and 59% DSS 6. CONCLUSION(S): Our population-based study reports a lower risk of disability progression at 10-year follow-up in the relapsing-remitting MS group than previously reported. This better prognosis was not observed in the progressive-onset MS group. This finding impacts the prognosis given to patients in clinical practice.

Register-based incidence of multiple sclerosis in Brittany (north-western France), 2000-2001.

OBJECTIVES: To report on multiple sclerosis (MS) incidence in Brittany, north-western France. MATERIALS & METHODS: From 2000, we set up a population-based register for patients presenting a putative incident MS (PIMS), that is first symptoms compatible with MS onset. We used 3 medical sources of case ascertainment (neurologists, CSF, regional MS-Clinic). Eligibility criteria required both clinical onset and being permanent resident of Brittany in 2000 or 2001. From 2010, all medical records were tracked, the 10-year follow-up allowing previously reported data to be updated. RESULTS: Of 313 eligible PIMS, there were 208 definite MS (both McDonald and Poser criteria), 41 CIS-probable MS (Poser criteria), 32 CIS-possible MS and 32 non-MS. Our incident cohort of 249 MS cases with definite/probable MS (sex ratio 2.95) gave a crude annual incidence of 4.28 per 100,000 inhabitants (6.22 for women, 2.23 for men), and age-standardized rates (adjustment to the European population) of 4.41 [3.32-5.51], 6.68 [4.75-8.60], and 2.21 [1.12-3.31], respectively. Age-specific rates by gender and initial course showed that attack onset MS peaked at 25-29 years and progressive onset MS at 40-44 years in women (20-24 years and 45-49 years in men, respectively). CONCLUSIONS: Brittany is confirmed a high-risk region for MS. Our data show marked differences in sex-specific pattern of MS incidence by clinical course and point out 25- to 29-year-old women as having the highest MS risk. While temporal variations cannot be excluded, comparison with overall French data suggests that other factors rather than latitude may influence the MS risk in France.

Osteogenic distraction to treat solitary median maxillary central incisor (SMMCI) syndrome: a case report.

Solitary median maxillary central incisor (SMMCI) syndrome is a rare developmental disorder characterized by a single symmetrical maxillary central incisor. Only a small number of cases with comprehensive dental treatment have been reported in the literature. No surgical treatment has been proposed before. We report the case of an 8-year-old girl who presented SMMCI syndrome associated with an Angle class II occlusion and a maxillary transverse deficiency. After the failure of two rapid maxillary expansions, a surgical option was proposed: osteogenic maxillary distraction. The distraction, associated with multi-bracketed fixed orthodontic treatment, created enough space to place a prosthetic central incisor without dental extractions. Osteogenic distraction is an interesting option to treat patients with SMMCI.

Interaction between posture and maxillomandibular deformity: a systematic review.

Maxillomandibular deformity (MMD) and body posture appear to be correlated. However, no systematic literature review of the available evidence to support this correlation has been performed to date. The aim of this study was to conduct a systematic literature review on posture and MMD. This systematic literature review was registered in the PROSPERO database. Systematic searches of the MEDLINE, Scopus, Cochrane Library, and Web of Science databases were performed. In total, 13 clinical studies were included. Nine found a significant association between MMD and body posture or body balance: two studies showed a correlation between increased cervical lordosis and skeletal class III MMD, two studies showed an interaction between mandibular deviation and scoliosis, four studies demonstrated a significant association between lumbar column and pelvis anatomy and MMD, and one study found a correlation between displacement of the centre of mass and MMD. However, the level of evidence is low; the methods used to evaluate body posture and MMD were inconsistent. Orthognathic surgery could modify body posture. Although there seems to be an interaction between body posture and facial deformity, the number of studies is too small and the level of evidence too low to strongly support this association.

Automatic 3-Dimensional Cephalometric Landmarking via Deep Learning.

The increasing use of 3-dimensional (3D) imaging by orthodontists and maxillofacial surgeons to assess complex dentofacial deformities and plan orthognathic surgeries implies a critical need for 3D cephalometric analysis. Although promising methods were suggested to localize 3D landmarks automatically, concerns about robustness and generalizability restrain their clinical use. Consequently, highly trained operators remain needed to perform manual landmarking. In this retrospective diagnostic study, we aimed to train and evaluate a deep learning (DL) pipeline based on SpatialConfiguration-Net for automatic localization of 3D cephalometric landmarks on computed tomography (CT) scans. A retrospective sample of consecutive presurgical CT scans was randomly distributed between a training/validation set (n = 160) and a test set (n = 38). The reference data consisted of 33 landmarks, manually localized once by 1 operator(n = 178) or twice by 3 operators (n = 20, test set only). After inference on the test set, 1 CT scan showed "very low" confidence level predictions; we excluded it from the overall analysis but still assessed and discussed the corresponding results. The model performance was evaluated by comparing the predictions with the reference data; the outcome set included localization accuracy, cephalometric measurements, and comparison to manual landmarking reproducibility. On the hold-out test set, the mean localization error was 1.0 ± 1.3 mm, while success detection rates for 2.0, 2.5, and 3.0 mm were 90.4%, 93.6%, and 95.4%, respectively. Mean errors were -0.3 ± 1.3° and -0.1 ± 0.7 mm for angular and linear measurements, respectively. When compared to manual reproducibility, the measurements were within the Bland-Altman 95% limits of agreement for 91.9% and 71.8% of skeletal and dentoalveolar variables, respectively. To conclude, while our DL method still requires improvement, it provided highly accurate 3D landmark localization on a challenging test set, with a reliability for skeletal evaluation on par with what clinicians obtain.

Clinical impact of two types of mandibular retention devices - A CAD/CAM design and a traditional design - On upper airway volume in obstructive sleep apnea patients.

OBJECTIVE: This pilot randomized crossover study evaluated the outcomes of two custom-made mandibular retention devices (MRDs), a computer-aided design (CAD)/computer-aided manufacturing (CAM) device (Narval CC™) and a non-CAD/CAM device (Narval™), on oropharyngeal airway volume in patients with obstructive sleep apnoea (OSA). METHODS: 12 OSA patients were recruited from an University Hospital for MRD therapy with either CAD/CAM or non-CAD/CAM first. A cone-beam computed tomography evaluation (CBCT) and polysomnography assessment was performed during baseline assessment and at the end of each study period. RESULTS: Upper airway volume increased significantly with the CAD/CAM device (7725 +/- 6540 mm3, p = 0.008) but not with the non-CAD/CAM device (3805 +/- 7806 mm3, p = 0.13). The CAD/CAM device was also associated with a significant decrease in AHI (mean AHI after treatment 9.4±6.7 events/h, p = 0.003) and oxygen desaturation index (mean ODI of ≥ 3%/h 11.9 ± 6.8, p = 0.011). Changes in AHI (14.7 +/- 11.7 events/h, p = 0.083) and ODI (15.5 +/- 19.2, p = 0.074) were not statistically significant with the non-CAD/CAM device. The vertical dimension of occlusion increased significantly following treatment with both MRD devices (both p = 0.003), but was significantly less pronounced with the CAD/CAM device (mean difference: -2.7 +/- 1.7 mm, p = 0.003). Final mandibular protrusion after titration was the same with both devices (85%, p = 0.317). CONCLUSION: The CAD/CAM (Narval CCTM) device was associated with a significant increase in upper airway volume that may be caused by a lower degree of vertical separation between the jaws when compared to the non-CAD/CAM design.

SMILE: a predictive model for Scoring the severity of relapses in MultIple scLErosis.

BACKGROUND: In relapsing-remitting multiple sclerosis (RRMS), relapse severity and residual disability are difficult to predict. Nevertheless, this information is crucial both for guiding relapse treatment strategies and for informing patients. OBJECTIVE: We, therefore, developed and validated a clinical-based model for predicting the risk of residual disability at 6 months post-relapse in MS. METHODS: We used the data of 186 patients with RRMS collected during the COPOUSEP multicentre trial. The outcome was an increase of ≥ 1 EDSS point 6 months post-relapse treatment. We used logistic regression with LASSO penalization to construct the model, and bootstrap cross-validation to internally validate it. The model was externally validated with an independent retrospective French single-centre cohort of 175 patients. RESULTS: The predictive factors contained in the model were age > 40 years, shorter disease duration, EDSS increase ≥ 1.5 points at time of relapse, EDSS = 0 before relapse, proprioceptive ataxia, and absence of subjective sensory disorders. Discriminative accuracy was acceptable in both the internal (AUC 0.82, 95% CI [0.73, 0.91]) and external (AUC 0.71, 95% CI [0.62, 0.80]) validations. CONCLUSION: The predictive model we developed should prove useful for adapting therapeutic strategy of relapse and follow-up to individual patients.

Reduced head and brain size for age and disproportionately smaller thalami in child-onset MS.

OBJECTIVE: Whole brain and regional volume measurement methods were used to quantify white matter, gray matter, and deep gray matter structure volumes in a population of patients with pediatric-onset multiple sclerosis (MS). METHODS: Subjects included 38 patients (mean age 15.2 ± 2.4 years) and 33 age- and sex-matched healthy control (HC) participants. MRI measures included intracranial volume, normalized brain volume, normalized white and gray matter volume, and volumes of the thalamus, globus pallidus, putamen, and caudate. Because these volumes vary across age and sex in children, we normalized the volume measurements for MS and control groups by computing z scores using normative values obtained from healthy children enrolled in the MRI Study of Normal Brain Development. RESULTS: The intracranial volume z score was significantly lower in the patients with MS (-0.45 ± 1.16; mean ± SD) compared with the HC participants (+0.25 ± 0.98; p = 0.01). Patients with MS also demonstrated significant decreases in normalized brain volume z scores (-1.09 ± 1.49 vs -0.05 ± 1.22; p = 0.002). After correction for global brain volume, thalamic volumes in the MS population remained lower than those of HCs (-0.68 ± 1.72 vs 0.15 ± 1.35; p = 0.02), indicating an even greater loss of thalamic tissue relative to more global brain measures. Moderate correlations were found between T2-weighted lesion load and normalized thalamic volumes (r = -0.44, p < 0.01) and normalized brain volume (r = -0.47, p < 0.01) and between disease duration and normalized thalamic volume (r = -0.58, p < 0.001) and normalized brain volume (r = -0.46, p < 0.01). CONCLUSIONS: When compared with age- and sex-matched control subjects, the onset of MS during childhood is associated with a smaller overall head size, brain volume, and an even smaller thalamic volume.

MRI correlates of cognitive impairment in childhood-onset multiple sclerosis.

OBJECTIVE: Brain MRI measures were correlated with neuropsychological function in 35 pediatric-onset multiple sclerosis (MS) patients and 33 age- and sex-matched healthy controls. METHOD: Mean age of MS patients was 16.3 ± 2.3 years with average disease duration of 4.3 ± 3.1 years. Cortical gray matter, thalamic, and global brain volumes were calculated for all participants using a scaling factor computed using normalization of atrophy method to normalize total and regional brain volumes for head size. T1- and T2-weighted lesion volumes were calculated for MS patients. RESULTS: Cognitive impairment (CI) was identified in 29% of the MS cohort. Cognitive deficits predominantly involved attention and processing speed, expressive language, and visuomotor integration. Relative to controls, the MS group showed significantly lower thalamic volume (p < .001), total brain volume (p < .008), and gray matter volume (p < .015). Corpus callosum area and thalamic volume differentiated patients identified as having CI from those without CI (p < .05). Regression models controlling for disease duration and age indicated that thalamic volume accounted for significant incremental variance in predicting global IQ, processing speed, and expressive vocabulary (ΔR2 ranging from .43 to .60) and was the most robust MRI predictor of cognition relative to other MRI metrics. CONCLUSIONS: The robust association between cognitive function and reduced size of thalamus and global brain volume in pediatric-onset MS patients implicate neurodegenerative processes early in the disease course, and suggest that plasticity of an immature central nervous system is not sufficient to protect patients from the deleterious consequences of MS on cognitive neural networks. (PsycINFO Database Record (c) 2011 APA, all rights reserved).

Natalizumab and drug holiday in clinical practice: an observational study in very active relapsing remitting multiple sclerosis patients.

BACKGROUND: In order to reduce the risk of progressive multifocal leucoencephalopathy when using natalizumab for more than 12 months, a 6-month drug holiday has been discussed. However, the consequences on short term disease activity have been poorly assessed. OBJECTIVE: The aim of this study was to assess clinical and radiological disease activity within 6 months after stopping natalizumab in very active relapsing remitting Multiple Sclerosis (RRMS) patients. METHODS: In 8 hospitals from Western France, we retrospectively collected clinical and MRI data from consecutive RRMS patients treated with natalizumab for at least 6 months, and who stopped the drug for various reasons except therapeutic failure. Patients didn't receive any other disease modifying treatment after discontinuing natalizumab. RESULTS: A total of 27 patients with very active RRMS before natalizumab start (mean annualized relapse rate of 2.3, MRI activity in 21 of 27 patients) were studied. Within 6 months after discontinuing natalizumab, 18 patients (67%) experienced clinical relapse and 3 additional patients had radiological activity, without clinical relapse. Four patients (15%) experienced a rebound activity, with severe relapse and 20 or more gadolinium enhancing lesions on MRI. CONCLUSION: Such observational data didn't support the concept of drug holiday when using natalizumab in very active RRMS.