RR MS evolution has changed since the beginning of the availability of MS disease-modifying drugs (DMD). Before concluding a unique impact of the efficiency of DMD, careful analysis of long-term ...studies has to be conducted. Analysis of the literature points out a few bias in the long-term follow of MS patients under DMD: indication of DMD has changed since 20 years, diagnosis criteria are not the same (including the Will Rogers phenomen), and so far population are not homogeneous and comparable. Analysis criteria of the efficiency of the treatments are not the same, pending on the date of the publications. References concerning the long-term impact of DMD are in fact very limited. In addition, long-term efficiency of 2nd line treatments is not available. Another explanation of the change of MS evolution could be the lower evolutivity of MS patients since 2 decades. Analysis of placebo group in pivotal studies, argues to a decrease of the relapse annual rate and mean EDSS score in the more recent studies and recent MS diagnosed patients. To conclude, long-term evolution of MS patients is more favorable, influence of DMD is likely, but not unique.
STUDY QUESTION
Does uterine artery embolization (UAE) permit fertility in childbearing women who have extensive symptomatic fibroids and are not eligible for surgery?
SUMMARY ANSWER
Although UAE was ...effective in improving bleeding, bulking and pain symptoms, and in sparing the ovarian reserve, no woman in this study delivered successfully after UAE.
WHAT IS KNOWN ALREADY
Although pregnancies have been reported after UAE, the actual fertility rate after this treatment remains uncertain.
STUDY DESIGN, SIZE, DURATION
This prospective cohort study included 66 women who desired a future pregnancy and were treated with UAE for symptomatic fibroids.
PARTICIPANTS/MATERIALS, SETTING, METHODS
This cohort of consecutive patients had extensive symptomatic fibroids but were not eligible for abdominal myomectomy because of fibroid recurrence despite previous surgery, because of current risks of surgery, or because of patient refusal. The patients were enrolled in a tertiary referral center for fibroid treatment. All patients had a pre-operative ovarian function assessment and underwent bilateral superselective embolization of both uterine arteries using 500–1200 µm Tris acryl microspheres.
MAIN RESULTS AND THE ROLE OF CHANCE
Fibroid symptoms including menorrhagia (OR 0.08, 95% CI 0.02–0.27), metrorrhagia (OR 0.05, 95% CI 0.01–0.39), pain (OR 0.08, 95% CI 0.03–0.22) and bulk syndrome (OR 0.02, 95% CI 0.01–0.07) were significantly improved after UAE. According to magnetic resonance imaging, the dominant fibroid volume decreased by 31.8% (95% CI 12.2–51.3%). Ovarian reserve demonstrated no change after embolization. Thereafter the women were prospectively followed, and 31 of them (aged 37.3 ± 3.5 years) were actively trying to conceive. In spite of 33.4 ± 14.5 months of attempts, only 1 in 31 women became pregnant and she finally miscarried (monthly fecundability rate 0.1% 95% CI 0–0.3%).
LIMITATIONS, REASONS FOR CAUTION
The high rate of associated infertility factors in our population, and the high frequency of previous surgery, could in part explain these poor reproductive outcomes; however, they should not account for the total absence of ongoing pregnancy. Embolization might have had a negative impact on fertility in our population, which may not be related to ovarian function.
WIDER IMPLICATIONS OF THE FINDINGS
The low reproductive outcomes reported in the present study suggest that UAE should not be performed routinely in young women of childbearing age with extensive fibroids. Although this finding was established in a population for whom abdominal myomectomy was declined, a possible adverse effect of UAE on fertility potential should be considered for woman of childbearing age scheduled for embolization.
STUDY FUNDING/COMPETING INTEREST(S)
No particular funding was obtained for this study and the authors have no conflict of interest.
Background:
Despite sensitivity of MRI to diagnose multiple sclerosis (MS), prognostic biomarkers are still needed for optimized treatment.
Objective:
The objective of this paper is to identify ...cerebrospinal fluid (CSF) diagnostic biomarkers of MS using quantitative proteomics and to analyze their expression at different disease stages.
Methods:
We conducted differential analysis of the CSF proteome from control and relapsing–remitting MS (RRMS) patients followed by verification by ELISA of candidate biomarkers in CSF and serum in control, clinically isolated syndrome (CIS), RRMS and progressive MS (PMS) patients.
Results:
Twenty-two of the 527 quantified proteins exhibited different abundances in control and RRMS CSF. These include chitinase 3-like protein 1 (CHI3L1) and 2 (CHI3L2), which showed a strong expression in brain of MS patients, especially in astrocytes and microglial cells from white matter plaques. CSF and serum CHI3L1 levels increased with the disease stage and CIS patients with high CSF (>189 ng/ml) and serum (>33 ng/ml) CHI3L1 converted more rapidly to RRMS (log rank test, p < 0.05 and p < 0.001, respectively). In contrast, CSF CHI3L2 levels were lower in PMS than in RRMS patients. Accordingly, CSF CHI3L1/CHI3L2 ratio accurately discriminated PMS from RRMS.
Conclusions:
CSF CHI3L1 and CHI3L2 and serum CHI3L1 might help to define MS disease stage and have a prognostic value in CIS.
Cerebral cavernous malformations (CCMs) are hamartomatous vascular malformations characterized by abnormally enlarged capillary cavities without intervening brain parenchyma. They cause seizures and ...cerebral hemorrhages, which can result in focal neurological deficits. Three CCM loci have been mapped, and loss-of-function mutations were identified in the
KRIT1 (
CCM1) and
MGC4607 (
CCM2) genes. We report herein the identification of
PDCD10 (programmed cell death 10) as the CCM3 gene. The
CCM3 locus has been previously mapped to 3q26-27 within a 22-cM interval that is bracketed by
D3S1763 and
D3S1262. We hypothesized that genomic deletions might occur at the
CCM3 locus, as reported previously to occur at the
CCM2 locus. Through high-density microsatellite genotyping of 20 families, we identified, in one family, null alleles that resulted from a deletion within a 4-Mb interval flanked by markers
D3S3668 and
D3S1614. This de novo deletion encompassed
D3S1763, which strongly suggests that the
CCM3 gene lies within a 970-kb region bracketed by
D3S1763 and
D3S1614. Six additional distinct deleterious mutations within
PDCD10, one of the five known genes mapped within this interval, were identified in seven families. Three of these mutations were nonsense mutations, and two led to an aberrant splicing of exon 9, with a frameshift and a longer open reading frame within exon 10. The last of the six mutations led to an aberrant splicing of exon 5, without frameshift. Three of these mutations occurred de novo. All of them cosegregated with the disease in the families and were not observed in 200 control chromosomes.
PDCD10, also called “
TFAR15,” had been initially identified through a screening for genes differentially expressed during the induction of apoptosis in the TF-1 premyeloid cell line. It is highly conserved in both vertebrates and invertebrates. Its implication in cerebral cavernous malformations strongly suggests that it is a new player in vascular morphogenesis and/or remodeling.
Background and purpose
Assessing patients’ disability in multiple sclerosis (MS) requires time‐consuming batteries of hospital tests. MSCopilot is a software medical device for the self‐assessment of ...patients with MS (PwMS), combining four tests: walking, dexterity, cognition and low contrast vision. The objective was to validate MSCopilot versus the Multiple Sclerosis Functional Composite (MSFC).
Methods
This multicentre, open‐label, randomized, controlled, crossover study enrolled 141 PwMS and 76 healthy controls (HCs). All participants performed MSCopilot and MSFC tests at day 0. To assess reproducibility, 46 PwMS performed the same tests at day 30 ± 3. The primary end‐point was the validation of MSCopilot versus MSFC for the identification of PwMS against HCs, quantified using the area under the curve (AUC). The main secondary end‐point was the correlation of MSCopilot z‐scores with MSFC z‐scores.
Results
In all, 116 PwMS and 69 HCs were analysed. The primary end‐point was achieved: MSCopilot performance was non‐inferior to that of MSFC (AUC 0.92 and 0.89 respectively; P = 0.3). MSCopilot and MSFC discriminated PwMS and HCs with 81% and 76% sensitivity and 82% and 88% specificity respectively. Digital and standard test scores were highly correlated (r = 0.81; P < 0.001). The test–retest study demonstrated the good reproducibility of MSCopilot.
Conclusion
This study confirms the reliability of MSCopilot and its usability in clinical practice for the monitoring of MS‐related disability.
Atypical idiopathic inflammatory demyelinating disorders (IIDDs) of the brain have long been known to be disorders closely related to multiple sclerosis (MS), despite having distinctive clinical and ...radiological characteristics. Originally, they mostly corresponded to acute-onset variants of MS that classically had poor prognoses, such as Baló’s concentric sclerosis, Marburg variant of MS and Schilder's disease, and their relationship with MS was based on their shared pathological findings and the co-occurrence of these variants in patients with typical MS. More recently, other atypical disorders, such as solitary sclerosis, have also been described as belonging to the MS spectrum, raising the question of their links with MS. Meanwhile, multiple MS mimics have been described and need to be considered in the differential diagnosis of MS. In addition, thorough characterization of these atypical entities, including advanced MRI and biological studies, is now warranted to further improve their management.
Mutations in OPA1, a dynamin-related GTPase involved in mitochondrial fusion, cristae organization and control of apoptosis, have been linked to non-syndromic optic neuropathy transmitted as an ...autosomal-dominant trait (DOA). We here report on eight patients from six independent families showing that mutations in the OPA1 gene can also be responsible for a syndromic form of DOA associated with sensorineural deafness, ataxia, axonal sensory-motor polyneuropathy, chronic progressive external ophthalmoplegia and mitochondrial myopathy with cytochrome c oxidase negative and Ragged Red Fibres. Most remarkably, we demonstrate that these patients all harboured multiple deletions of mitochondrial DNA (mtDNA) in their skeletal muscle, thus revealing an unrecognized role of the OPA1 protein in mtDNA stability. The five OPA1 mutations associated with these DOA ‘plus’ phenotypes were all mis-sense point mutations affecting highly conserved amino acid positions and the nuclear genes previously known to induce mtDNA multiple deletions such as POLG1, PEO1 (Twinkle) and SLC25A4 (ANT1) were ruled out. Our results show that certain OPA1 mutations exert a dominant negative effect responsible for multi-systemic disease, closely related to classical mitochondrial cytopathies, by a mechanism involving mtDNA instability.
Background:
Despite a growing use of rituximab (RTX) in neuromyelitis optica (NMO), data are lacking in patients with refractory NMO (RNMO), defined as cases with at least one relapse during ...immunosuppressive therapy.
Objective:
The purpose of this study was to assess RTX as a maintenance therapy in RNMO.
Methods:
Out of a total of 305 NMO cases from a population-based cohort, 21 RNMO patients received RTX during a mean follow-up period of 31 months.
Results:
After RTX, 11 patients (52.3%) were relapse free, meaning that 47.7% were refractory to RTX. The mean annualized relapse rate decreased from 1.3 to 0.4 (p<0.001) and median EDSS from 5 to 3 (p=0.02). Body mass index (BMI) was predictive of EDSS worsening.
Conclusions:
RTX is an effective and well-tolerated treatment in RNMO. BMI could be a predictive factor for efficacy.
Objective
Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a rare manifestation related to CAA, thought to be more severe. We aimed to compare the clinical and radiological outcomes of ...CAA-ri and non-inflammatory CAA.
Materials and methods
We retrospectively included all patients with CAA-ri from 13 French centers. We constituted a sex- and age-matched control cohort with non-inflammatory CAA and similar disease duration. Survival, autonomy and cognitive evolution were compared after logistic regression. Cerebral microbleeds (CMB), intracerebral hemorrhage, cortical superficial siderosis and hippocampal atrophy were analyzed as well as CSF biomarker profile and
APOE
genotype when available. Outcomes were compared using Kaplan–Meier curves and log-rank tests.
Results
Data from 48 CAA-ri patients including 28 already reported and 20 new patients were analyzed. Over a mean of 3.1 years, 11 patients died (22.9%) and 18 (37.5%) relapsed. CAA-ri patients were more frequently institutionalized than non-inflammatory CAA patients (30% vs 8.3%,
p
< 0.001); mortality rates remained similar. MMSE and modified Rankin scale scores showed greater severity in CAA-ri at last follow-up. MRI showed a higher number of CMB at baseline and last follow-up in CAA-ri (
p
< 0.001 and
p
= 0.004, respectively). CSF showed lower baseline levels of Aß42 in CAA-ri than non-inflammatory CAA (373.3 pg/ml vs 490.8 pg/ml,
p
= 0.05). CAA-ri patients more likely carried at least one
APOE ε4
allele (76% vs 37.5%, adjusted
p
= 0.05) particularly as homozygous status (56% vs 6.2%,
p
< 0.001).
Interpretation
CAA-ri appears to be more severe than non-inflammatory CAA with a significant loss of autonomy and global higher amyloid burden, shown by more CMB and a distinct CSF profile. This burden may be partially promoted by ε4 allele.
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