Emmanuelle Leray

Evidence for a two-stage disability progression in multiple sclerosis

It is well documented that disability accumulation in multiple sclerosis is correlated with axonal injury and that the extent of axonal injury is correlated with the degree of inflammation. However, the interdependence between focal inflammation, diffuse inflammation and neurodegeneration, and their relative contribution to clinical deficits, remains ambiguous. A hypothesis might be that early focal inflammation could be the pivotal event from which all else follows, suggesting the consideration of multiple sclerosis as a two-stage disease. This prompted us to define two phases in the disease course of multiple sclerosis by using two scores on the Kurtzke Disability Status Scale as benchmarks of disability accumulation: an early phase, ‘Phase 1’, from multiple sclerosis clinical onset to irreversible Disability Status Scale 3 and a late phase, ‘Phase 2’, from irreversible Disability Status Scale 3 to irreversible Disability Status Scale 6. Outcome was assessed through five parameters: Phase 1 duration, age at Disability Status Scale 3, time to Disability Status Scale 6 from multiple sclerosis onset, Phase 2 duration and age at Disability Status Scale 6. The first three were calculated among all patients, while the last two were computed only among patients who had reached Disability Status Scale 3. The possible influence of early clinical markers on these outcomes was studied using Kaplan–Meier estimates and Cox models. The analysis was performed in the Rennes multiple sclerosis database (2054 patients, accounting for 26 273 patient-years) as a whole, and according to phenotype at onset (1609 relapsing/445 progressive onset). Our results indicated that the disability progression during Phase 2 was independent of that during Phase 1. Indeed, the median Phase 2 duration was nearly identical (from 6 to 9 years) irrespective of Phase 1 duration (<3, 3 to <6, 6 to <10, 10 to <15, ≥15 years) in the whole population, and in both phenotypes. In relapsing onset multiple sclerosis, gender, age at onset, residual deficit after the first relapse and relapses during the first 2 years of multiple sclerosis were found to be independent predictive factors of disability progression, but only during Phase 1. Our findings demonstrate that multiple sclerosis disability progression follows a two-stage process, with a first stage probably dependant on focal inflammation and a second stage probably independent of current focal inflammation. This concept has obvious implications for the future therapeutic strategy in multiple sclerosis.

Mitoxantrone as induction treatment in aggressive relapsing remitting Multiple Sclerosis: treatment response factors in a 5-year follow-up observational study of 100 consecutive patients

Background: Mitoxantrone was approved by the French health authority (AFSAPPS) in October 2003 to treat patients with aggressive multiple sclerosis (MS). Objective: To report the long term effectiveness and safety of mitoxantrone as induction therapy in patients with aggressive relapsing–remitting MS, and to assess treatment response factors. Material and methods: 100 consecutive patients with aggressive relapsing–remitting MS received mitoxantrone 20 mg monthly combined with methylprednisolone 1 g for 6 months. Relapses, Expanded Disability Status Scale (EDSS) and drug safety were assessed every 6 months for up to at least 5 years. Within 6 months after induction, 73 patients received maintenance therapy (mitoxantrone every 3 months (nu200a=u200a21); interferon beta (nu200a=u200a25); azathioprine (nu200a=u200a15); methotrexate (nu200a=u200a7); glatiramer acetate (nu200a=u200a5)). Results: During the 12 months following initiation of mitoxantrone, the annual relapse rate (ARR) was reduced by 91%, 78% of patients remained relapse free, MRI activity was reduced by 89%, the mean EDSS decreased by 1.2 points (p<10−6) and 64% of patients improved by 1 point or more on the EDSS. In the longer term, the ARR reduction was sustained (0.29–0.42 for up to 5 years), the median time to the first relapse was 2.8 years and disability remained improved after 5 years. Younger age and lower EDSS score at the start of mitoxantrone treatment were predictive of better treatment response. Three patients presented with an asymptomatic decrease in left ventricular ejection fraction to less than 50% (one reversible). One patient was diagnosed with acute myeloid leukaemia (remission 5 years after diagnosis). Conclusion: Mitoxantrone monthly for 6 months as induction therapy followed by maintenance treatment showed sustained clinical benefit for up to 5 years with an acceptable adverse events profile in patients with aggressive relapsing–remitting MS.

Only physical aspects of quality of life are significantly improved by bilateral subthalamic stimulation in Parkinson's disease.

AbstractBackgroundThe wellnknown global improvement ofnquality of life (QoL) after bilateralnhigh frequency chronic deep brainnstimulation of the subthalamic nucleusn(STN DBS) in Parkinson’s diseasen(PD) is in contrast to behavioralndisturbances as observed afternsurgery. Indeed the impact of DBSnon physical versus mental aspectsnof QoL in PD remains unknown.ObjectiveTo assess the influence ofnbilateral STN DBS on physical versusnmental aspects of QoL innParkinson’s disease.MethodsThenresults of 27 patients for the UnifiednParkinson’s disease RatingnScale (UPDRS), Parkinson’s DiseasenQuestionnaire 39 (PDQ39) andnShort Form 36 health survey questionnairen(SF36) were comparednbefore surgery and after 12 monthsnof bilateral STN DBS.ResultsComparingnoff–dopa conditions beforenversus 12 months after surgery,nboth UPDRS part II and part IIInsignificantly improved: 32.6% andn52%, respectively. UPDRS part Inscores did not change significantlynat 12 months. As for PDQ39, thenglobal score significantly improvednafter surgery (21.1 %) as did fournsubscores: mobility (25.6 %), activitynof daily living (34.5 %), stigman(40.1 %) and bodily discomfortn(30 %). Three PDQ39 subscores,nhowever, showed no significantnchanges: emotional well–beingn(10.7 %), social support (3.2%) andncognition (8.5 %) and one itemneven worsened: communicationn(–7.7 %). In SF36, only physicalnitems significantly improved.ConclusionUsing clinician’s based ratingnscale, bilateral STN DBSnshowed significant improvement innPD patients at 12 month follow up.nHowever, using patient’s self–assessmentnscales, the clinical benefitnof STN DBS was more subtle: physicalnitems of QoL significantly improved,nwhereas mental items suchnas emotional well–being, socialnsupport, cognition and communicationnshowed no improvement.nOur results are suggestive of a dissociationnof motor and non–motornsymptoms control after bilateralnSTN DBS in PD patients.

Decrease of prefrontal metabolism after subthalamic stimulation in obsessive-compulsive disorder: a positron emission tomography study

BACKGROUNDnHigh-frequency bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) is a promising treatment in refractory obsessive-compulsive disorder (OCD).nnnMETHODnUsing the crossover, randomized, and double-blind procedure adopted by the STOC study, 10 patients treated with high-frequency bilateral STN DBS underwent am 18-fluorodeoxyglucose positron emission tomography (PET) investigation to highlight the neural substratum of this therapeutic approach.nnnRESULTSnThe median Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores for all 10 patients were 31 (minimum = 18, maximum = 36) with Off-Stimulation status and 19 (minimum = 0, maximum = 30) with On-Stimulation status (p = .05). The OCD patients in Off-Stimulation status showed a hypermetabolism in the right frontal middle and superior gyri, right parietal lobe, postcentral gyrus, and bilateral putamen compared with healthy control subjects. A significant decrease in cerebral metabolism was observed in the left cingulate gyrus and the left frontal medial gyrus in On-Stimulation conditions compared with Off-Stimulation conditions. In addition, the improvement assessed by Y-BOCS scores during the On-Stimulation conditions was positively correlated with PET signal changes at the boundary of the orbitofrontal cortex and the medial prefrontal cortex, between PET signal changes and the Y-BOCS scores modifications in On-Stimulation status.nnnCONCLUSIONnThis study suggests that the therapeutic effect of STN DBS is related to a decrease in prefrontal cortex metabolism.

Natalizumab and drug holiday in clinical practice: An observational study in very active relapsing remitting Multiple Sclerosis patients

BACKGROUNDnIn 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.nnnOBJECTIVEnThe 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.nnnMETHODSnIn 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 didnt receive any other disease modifying treatment after discontinuing natalizumab.nnnRESULTSnA 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.nnnCONCLUSIONnSuch observational data didnt support the concept of drug holiday when using natalizumab in very active RRMS.

3,4-Diaminopyridine safety in clinical practice: an observational, retrospective cohort study

Fatigue is one of the most common and disabling symptoms of multiple sclerosis (MS) and has a significant, often underestimated, impact on patients’ quality of life. Current management is mainly symptomatic. 3,4-diaminopyridine (3,4-DAP) is a voltage-dependent potassium channel blocker that has been used on a named patient basis in Europe for many years to improve motor function and fatigue in patients with MS and other neuromuscular disorders, and it is undergoing the European approval process for Lambert-Eaton myasthenic syndrome (LEMS). The efficacy and safety of 3,4-DAP as symptomatic therapy in MS have not been widely evaluated. This study aimed to assess the safety profile of 3,4-DAP in routine clinical practice in an observational, retrospective study. The study involved 669 patients of the Rennes Multiple Sclerosis Clinic, France, who were treated with 3,4-DAP for the relief of fatigue during the period 1998–2003. Overall, 18.2% of patients presented adverse drug reactions (ADRs) while using moderate doses of 3,4-DAP (20–30xa0mg daily or up to 80xa0mg daily for patients with LEMS) for periods of up to 51xa0months. The majority of ADRs were mild to moderate and transient or reversible at the end of treatment (mean treatment durationxa0=xa0twoxa0months) or after dose adjustment. Most did not require discontinuation. The most commonly observed ADRs were paraesthesias. There was one case of epileptic seizure, one of hepatotoxicity and one of heart palpitations thought ‘possibly’ to be linked to 3,4-DAP. These underline the need for continued monitoring during treatment with 3,4-DAP.

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

To report on multiple sclerosis (MS) incidence in Brittany, north‐western France.

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

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.

An excessive risk of suicide may no longer be a reality for multiple sclerosis patients

Background: Few recent studies have shown that there is no longer an increased risk of suicide in patients affected with multiple sclerosis (MS). Objectives: To describe suicide cases within a large French MS cohort and assess whether MS patients are at a higher risk of suicide compared with the general population. Methods: Data derives from a study on long-term mortality of 27,603 prevalent cases from 15 MS specialist centres. Of 1,569 deceased MS patients (5.7%) on 1 January 2010, 47 were suicides. Results: The mean time between MS clinical onset and death was 13.5 years (standard deviation (SD): 9.3 years; none within the first 3 years) and was significantly shorter than for MS patients who had died from other causes (mean = 21.4 (SD = 11.6), p < 0.0001). Age at death was also lower (46.3 vs 56.7). The standardized mortality rates were around 1 in several sensitivity analyses, reflecting no excess mortality in MS compared with general population. Conclusion: Our findings indicate that an excess suicide risk may no longer be true for MS patients and highlight the changing profile of cases, occurring later in the disease course. Further studies in population-based registries are needed to confirm and explain these potential changes (e.g. treatments’ impact?).

A new treatment era in multiple sclerosis: clinical applications of new concepts.

Several clinical courses have been defined in multiple sclerosis (MS), but uncertainty remains as to whether they reflect different neuropathological mechanisms. Two recent concepts have emerged which could influence the treatment strategy adopted in MS: inflammation drives axonal damage; disability progression in MS follows a two-stage process.