Ludo Vanopdenbosch

Vascular aspects of multiple sclerosis

Three types of vascular dysfunction have been described in multiple sclerosis (MS). First, findings from epidemiological studies suggest that patients with MS have a higher risk for ischaemic stroke than people who do not have MS. The underlying mechanism is unknown, but might involve endothelial dysfunction secondary to inflammatory disease activity and increased plasma homocysteine concentrations. Second, patients with MS have global cerebral hypoperfusion, which might predispose them to the development of ischaemic stroke. The widespread decrease in perfusion in normal-appearing white matter and grey matter in MS seems not to be secondary to axonal degeneration, but might be a result of reduced axonal activity, reduced astrocyte energy metabolism, and perhaps increased blood concentrations of endothelin-1. Data suggest that a subtype of focal MS lesions might have an ischaemic origin, and there seems to be a link between reduced white matter perfusion and cognitive dysfunction in MS. Third, the pathology of MS might be the consequence of a chronic state of impaired venous drainage from the CNS, for which the term chronic cerebrospinal venous insufficiency (CCSVI) has been coined. A number of recent vascular studies do not support the CCSVI theory, but some elements of CCSVI might be explained by slower cerebral venous blood flow secondary to the reduced cerebral perfusion in patients with MS compared with healthy individuals.

Mitochondrial mutations of Leber's hereditary optic neuropathy: a risk factor for multiple sclerosis

Abstract Multiple sclerosis (MS) and Lebers hereditary optic neuropathy (LHON) have been found to occur in combination. Based on an extensive literature search and on a clinical analysis of 55 LHON pedigrees (103 patients) and 40 patients with definite MS, this study concludes that the association of LHON and MS is more than a coincidence, and that carrying a primary LHON mutation is a risk factor for developing MS. All three primary LHON mutations occurring in the European and North American populations have been found to be associated with an MS-like syndrome. The neurological characteristics of MS associated with LHON are indistinguishable from those of MS in general, but the severe and bilateral visual symptoms and signs justify considering these patients as a clinical subgroup of MS and screening them for LHON mutations. However, screening LHON patients for MS appears to be more rewarding.

Safety and efficacy of opicinumab in acute optic neuritis (RENEW): a randomised, placebo-controlled, phase 2 trial

BACKGROUNDnThe human monoclonal antibody opicinumab (BIIB033, anti-LINGO-1) has shown remyelinating activity in preclinical studies. We therefore assessed the safety and tolerability, and efficacy of opicinumab given soon after a first acute optic neuritis episode.nnnMETHODSnThis randomised, double-blind, placebo-controlled, phase 2 study (RENEW) was done at 33 sites in Australia, Canada, and Europe in participants (aged 18-55 years) with a first unilateral acute optic neuritis episode within 28 days from study baseline. After treatment with high-dose methylprednisolone (1 g/day, intravenously, for 3-5 days), participants were assigned with a computer-generated sequence with permuted block randomisation (1:1) using a centralised interactive voice and web response system to receive 100 mg/kg opicinumab intravenously or placebo once every 4 weeks (six doses) and followed up to week 32. All study participants and all study staff, including the central readers, were masked to treatment assignment apart from the pharmacist responsible for preparing the study treatments and the pharmacy monitor at each site. The primary endpoint was remyelination at 24 weeks, measured as recovery of affected optic nerve conduction latency using full-field visual evoked potential (FF-VEP) versus the unaffected fellow eye at baseline. Analysis was by intention-to-treat (ITT); prespecified per-protocol (PP) analyses were also done. This study is registered with ClinicalTrials.gov, number NCT01721161.nnnFINDINGSnThe study was done between Dec 21, 2012, and Oct 21, 2014. 82 participants were enrolled, and 41 in each group comprised the ITT population; 33 participants received opicinumab and 36 received placebo in the PP population. Adjusted mean treatment difference of opicinumab versus placebo was -3·5 ms (17·3 vs 20·8 [95% CI -10·6 to 3·7]; 17%; p=0·33) in the ITT population, and -7·6 ms in the PP population (14·7 vs 22·2 [-15·1 to 0·0]; 34%; p=0·050) at week 24 and -6·1 ms (15·1 vs 21·2 [-12·7 to 0·5]; 29%; p=0·071) in the ITT population and -9·1 ms (13·2 vs 22·4 [-16·1 to -2·1]; 41%; p=0·011) in the PP population at week 32. The overall incidence (34 [83%] of 41 in each group) and severity of adverse events (two [5%] of 41 severe adverse events with placebo vs three [7%] of 41 with opicinumab) were similar between groups and no significant effects on brain MRI measures were noted in either group (mean T2 lesion volume change, 0·05 mL [SD 0·21] for placebo vs 0·20 mL [0·52] with opicinumab; 27 [77%] of 35 participants with no change in gadolinium-enhancing [Gd+] lesion number with opicinumab vs 27 [79%] of 34 with placebo; mean 0·4 [SD 0·79 for the placebo group and 0·85 for the opicinumab group] new Gd+ lesions per participant in both groups). Treatment-related serious adverse events were reported in three (7%) of 41 participants in the opicinumab group (hypersensitivity [n=2], asymptomatic increase in transaminase concentrations [n=1]) and none of the participants in the placebo group.nnnINTERPRETATIONnRemyelination did not differ significantly between the opicinumab and placebo groups in the ITT population at week 24. However, results from the prespecified PP population suggest that enhancing remyelination in the human CNS with opicinumab might be possible and warrant further clinical investigation.nnnFUNDINGnBiogen.

Fluoxetine in Progressive Multiple Sclerosis (FLUOX-PMS): study protocol for a randomized controlled trial

BackgroundCurrently available disease-modifying treatments acting by modifying the immune response are ineffective in progressive multiple sclerosis (MS), which is caused by a widespread axonal degeneration. Mechanisms suspected to be involved in this widespread axonal degeneration are reduced axonal energy metabolism, axonal glutamate toxicity, and reduced cerebral blood flow. Fluoxetine might theoretically reduce axonal degeneration in MS because it stimulates energy metabolism through enhancing glycogenolysis, stimulates the production of brain-derived neurotrophic factor, and dilates cerebral arterioles. The current document presents the protocol of a clinical trial to test the hypothesis that fluoxetine slows down the progressive phase of MS.Methods/DesignThe FLUOX-PMS trial is a multi-center, randomized, controlled and double-blind clinical study. A total of 120 patients with the diagnosis of either secondary or primary progressive MS will be treated either by fluoxetine (40 mg daily) or placebo for a total period of 108 weeks. The primary endpoint is the time to confirmed disease progression defined as either at least a 20% increase in the timed 25-Foot Walk or at least a 20% increase in the 9-Hole Peg Test. Secondary endpoints include the Hauser ambulation index, cognitive changes, fatigue, magnetic resonance imaging of the brain, and in a small subgroup optical coherence tomography.DiscussionThe FLUOX-PMS trial will gives us information as to whether fluoxetine has neuroprotective effects in patients with progressive MS.Trial RegistrationEudra-CT: 2011-003775-11

Safety and efficacy of natalizumab in Belgian multiple sclerosis patients: subgroup analysis of the natalizumab observational program

Natalizumab (Tysabri®) is highly efficacious in controlling disease activity in relapsing multiple sclerosis (MS) patients. As it is one of the more recent therapies for MS, there remains a need for long-term safety and efficacy data of natalizumab in a clinical practice setting. The Tysabri observational program (TOP) is an open-label, multicenter, multinational, prospective observational study, aiming to recruit up to 6,000 patients with relapsing-remitting MS from Europe, Canada and Australia. The objectives of this study are to collect long-term safety and efficacy data on disease activity and disability progression. We report here the interim results of the 563 patients included in TOP between December 2007 and 2012 from Belgium. This patient cohort was older at baseline, had longer disease duration, higher neurological impairment, and a higher baseline annualized relapse rate, when compared to patients included in the pivotal phase III AFFIRM trial. Nevertheless, the efficacy of natalizumab was comparable. The annualized relapse rate on treatment was reduced by 90.70xa0% (pxa0<xa00.0001) with a cumulative probability of relapse of 26.87xa0% at 24xa0months. The cumulative probabilities of sustained disability improvement and progression at 24xa0months were 25.68 and 9.01xa0%, respectively. There were no new safety concerns over the follow-up period. Two cases of progressive multifocal leukoencephalopathy were diagnosed. Our results are consistent with other observational studies in the post-marketing setting.

Pseudotumoral rebound of multiple sclerosis in a pregnant patient after stopping natalizumab

Natalizumab is a highly efficacious treatment for active relapsing-remitting multiple sclerosis, dramatically reducing both clinical and radiological signs of inflammation in most patients. The disease course after stopping treatment and especially the emergence of rebound activity are still a matter of debate. We present a case of dramatic reactivation of clinical disease activity with newly emerging pseudotumoral lesions in a patient who stopped treatment due to pregnancy. Both the clinical and radiological presentation suggest a rebound and necessitate close monitoring of patients stopping their treatment during pregnancy, even after a long period of stable disease.

Anti-glycine receptor antibody mediated progressive encephalomyelitis with rigidity and myoclonus associated with breast cancer.

We describe a 66-year-old woman who presented with a dramatic course of PERM. Anti-glycine receptor antibodies were found. She stabilized after plasma-exchange and partly recovered. Eighteen months later, a diagnosis of smouldering breast cancer with bone marrow metastasis was made. There are indications that this tumor was already present at first presentation. An overview of PERM and anti-glycine receptor antibodies is given.

MRI characteristics of trigeminal nerve involvement in patients with multiple sclerosis

BACKGROUNDnTrigeminal neuralgia and central sensory disturbances are common in patients with multiple sclerosis. The anatomic correlation to lesions in the trigeminal nuclei in the brainstem is not well studied.nnnOBJECTIVEnWe studied the anatomical characteristics of demyelinating lesions of the trigeminal complex in the brainstem on MRI in patients with MS and Clinically Isolated syndrome (CIS).nnnMATERIALS AND METHODSn43 Patients with MS or CIS and MRI lesions in the trigeminal complex in the brainstem were selected from a large database of patients referred for MRI because of trigeminal symptoms.nnnRESULTS AND CONCLUSIONnA linear plaque involving the intrapontine fascicular part of the trigeminal nerve and lesions of the spinal trigeminal nucleus and tract seem to be distinctive MRI findings in patients with RRMS or CIS.

Corticosteroids in the management of acute multiple sclerosis exacerbations

Multiple sclerosis (MS) is an autoimmune, inflammatory demyelinating disease of the central nervous system characterized in the majority of the patients by a relapsing-remitting disease course. For decades high-dosage corticosteroids (CS) are considered the cornerstone in the management of acute MS relapses. However, many unanswered questions remain when it comes to the exact modalities of CS administration. In this review on behalf of the Belgian Study Group for MS we define the efficacy of CS in reducing MS-related morbidity and examine whether the effect is different according to type of CS, route of administration, cumulative dosage, timing of initiation and disease course. We also review the use of CS in combination with other MS treatments and during pregnancy and lactation. Furthermore, we delineate the relevant adverse events due to a pulse CS regimen and present a decision tree that can be used when treating MS relapses in clinical practice.

NEK1 genetic variability in a Belgian cohort of ALS and ALS-FTD patients

We evaluated the genetic impact of the amyotrophic lateral sclerosis (ALS) risk gene never in mitosis gene a-related kinase 1 (NEK1) in a Belgian cohort of 278 patients with ALS (nxa0= 245) or ALS with frontotemporal dementia (ALS-FTD, nxa0= 33) and 609 control individuals. We identified 2 ALS patients carrying a loss-of-function (LOF) mutation, p.Leu854Tyrfs*2 and p.Tyr871Valfs*17, that was absent in the control group. A third LOF variant p.Ser1036* was present in 2 sibs with familial ALS but also in an unrelated control person. Missense variants were common in both patients (3.6%) and controls (3.0%). The missense variant, p.Arg261His, which was previously associated with ALS risk, was detected with a minor allele frequency of 0.90% in patients compared to 0.33% in controls. Taken together, NEK1 LOF variants accounted for 1.1% of patients, although interpretation of pathogenicity and penetrance is complicated by the observation of occasional LOF variants in unaffected individuals (0.16%). Furthermore, enrichment of additional ALS gene mutations was observed in NEK1 carriers, suggestive of a second hit model were NEK1 variants may modify disease presentation of driving mutations.