Spanish consensus on the use of natalizumab (Tysabri(®))--2011

Introduction

Natalizumab is very effective at reducing relapses and delaying disease progression in patients with relapsing-remitting multiple sclerosis (RRMS). However, treatment has also been associated with a risk of progressive multifocal leukoencephalopathy (PML). The aim of this article is to provide a consensus view on the assessment and stratification of these risks, and to improve the management of natalizumab-treated patients.

Development

At an initial meeting of experts on multiple sclerosis (the authors of this consensus), the relevant topics of the consensus were determined and assigned for further elaboration. Topics included how to establish benefit and risk in general, stratification for risk of PML, informing patients of benefits/risks, and how to monitor patients during treatment and after discontinuing treatment. During the drafting phase, all available information published or presented at international meetings was reviewed. After a series of review sessions and meetings, the final draft was produced.

Conclusions

Although natalizumab is a very effective drug, its use needs to be considered carefully in view of possible adverse effects and the risk of PML in particular. The neurologist should carefully explain the risks and benefits of treatment in terms the patient can best understand. Before starting treatment, baseline laboratory tests and magnetic resonance imaging (MRI) should be available for future comparisons in the event of suspected PML. The risk of PML should be stratified into high, medium and low risk groups according to presence or absence of anti-JC virus antibodies, prior immunosuppressive therapy, and treatment duration. The follow-up, and frequency of MRI scans in particular, should depend on the risk group to which patient belongs. As our understanding of the risk factors for PML develops, it should be possible to offer patients increasingly individualised therapy. This is a consensus that establishes general recommendations, but neurologists must use their clinical expertise to monitor patients individually.     

Measuring evoked responses in multiple sclerosis.

Evoked potentials (EPs) have been widely utilised in Multiple Sclerosis (MS) patients to demonstrate the involvement of sensory and motor pathways. Their diagnostic value is based on the ability to reveal clinically silent lesions and to objectivate the central nervous system damage in patients who complain frequently of vague and indefinite disturbances which frequently occurs in the early phases of the disease. The advent of magnetic resonance imaging (MRI) techniques has greatly reduced the clinical utilisation of EPs, which is not fully justifiable, as the information provided by EPs are quite different from those provided by MRI. The abnormalities of evoked responses reflect the global damage of the evoked nervous pathway and are significantly correlated with the clinical findings, while the vast majority of MRI lesions are not associated to symptoms and signs. Transversal and longitudinal studies have demonstrated that EP changes in MS are more strictly related to disability than MRI lesion burden. On the contrary, MRI is more sensitive than EPs in revealing the disease activity. Evoked responses modifications observed in MS are not disease-specific; moreover longitudinal studies showed latency and morphology changes of evoked responses not always related to clinical changes. Such a dissociation can be explained both by technical factors and by subclinical disease activity. To reduce the negative impact of technical aspects, only reproducible parameters of the evoked responses should be used to monitor disease evolution and therapeutic interventions.     

Clinical and Magnetic Resonance Imaging Changes Correlate in a Clinical Trial Monitoring Cyclosporine Therapy for Multiple Sclerosis

Magnetic resonance imaging (MRI) was used to monitor cyclosporine therapy for chronic progressive multiple sclerosis in a multicenter clinical trial and an analysis was performed to determine whether there was a correlation between clinical changes and MRI changes. MRI was performed on 163 patients at the onset and completion of the 2–year study. Burden of disease (BOD, lesion load) was quantitated by a single observer using a computer program. Active lesions were also identified. The Expanded Disability Status Scale (EDSS) score was determined every 3 months. MRI data did not show any effect of cyclosporine treatment on BOD progression (mean 24.5% increase/yr) or lesion activity. However, there was a statistically significant positive correlation between the baseline total BOD value and the baseline EDSS score (r = 0.221, p = 0.005) and a positive correlation between the percent changes in BOD from baseline to exit and EDSS score (r = 0.186, p = 0.018). The study supports the concepts that MRI is a useful technique in monitoring therapeutic trials and that MRI is a direct measure of pathology.     

Hypointense and hyperintense lesions on magnetic resonance imaging in secondary-progressive MS patients.

Cranial magnetic resonance imaging (MRI) is widely used to monitor disease activity in clinical trials in multiple sclerosis (MS). The purpose of this study is to examine lesion burden as determined from hypointense regions on postcontrast T1-weighted scans (or black holes), and lesion burden on conventional T2-weighted scans, from a cohort of secondary progressive MS patients who participated in a placebo-controlled, randomized, double-blind cross-over trial assessing the therapeutic efficacy of cladribine. T2 lesion volumes and black hole volumes are approximately normal distributed when log-transformed, and are highly correlated (adjusted R2 = 0.63). Changes in clinical scores could be predicted with a reasonable degree of precision from baseline scores and changes in T2 lesion volumes (adjusted R2 values 0.52-0.7). Stratification schemes for clinical trials should include the acute proportion of the disease (enhancing T1 lesions), degree of permanent damage (black holes), and T2 lesion volume.     

Pharmacogenomics and Multiple Sclerosis: Moving Toward Individualized Medicine

Notwithstanding the availability of disease-modifying treatments including interferon-β, glatiramer acetate, and natalizumab, a considerable proportion of multiple sclerosis (MS) patients experience continued progression of disease, clinical relapses, disease activity on MRI, and adverse effects. Application of gene expression, proteomic or genomic approaches is universally accepted as a suitable strategy toward the identification of biomarkers with predictive value for beneficial/poor clinical response to therapy and treatment risks. This review focuses on recent progress in research on the pharmacogenomics of disease-modifying therapies for MS. Although MS drug response biomarkers are not yet routinely implemented in the clinic, the diversity of reported, promising molecular markers is rapidly increasing. Even though most of these markers await further validation, given time, this research is likely to empower neurologists with an enhanced armamentarium to facilitate rational decisions on therapy and patient management.     

L’IRM est-elle utile dans le suivi des patients atteints de sclérose en plaques ? Non

Is regular MRI monitoring useful in clinical practice in multiple sclerosis patients treated with disease modifying therapy (DMT) drugs? My answer is no. Tacking a DMT drug is not by itself a pertinent criterion for requiring a systematic MRI monitoring in MS patients. Five clinical criteria should be taken into consideration before prescribing regular MRI examinations. The clinical form of the disease: MRI monitoring in DMT treated patients, has been demonstrated as useful only in pure relapsing-remitting MS patients. Up to now, there is no convincing demonstration of therapeutic efficacy with any DMT drug, neither first-line nor second-line drugs in patients with primary or secondary progressive MS disease. The duration of the disease, epidemiological data leading to the concept of a two-stage disability progression in MS, emphasizes the importance of treating as early as possible RRMS patients in order to stop accumulation of new focal MRI CNS lesions. In this regard, an annual monitoring for the 5 first years of the disease looks reasonable in order to better personalize the treatment choice among the few approved DMT drugs. The duration of the treatment: a first MRI assessment at month 6 after initiating a new DMT drug is adequate in order to better distinguish responder versus no responder. The persistence of Gado + lesions at 6 months is a strong indication for considering alternative treatment. The disease activity: both criteria, clinical and MRI, are needed to recognized very active or aggressive relapsing MS patients, leading to decide a rapid use of second-line treatment therapy. The treatment choice: in JC positive MS patients treated with natalizumab, the risk of PML is as high as more than 1 % in those JC + MS patients that are treated continuously more than 24 months. A regular MRI monitoring (3 or 6 months) is recommended in order to detect as early as possible MRI abnormalities suggesting PML.     

Management of isolated optic neuritis in France: survey of neurologists and ophthalmologists

BACKGROUND: Acute isolated optic neuritis is often the first manifestation of multiple sclerosis (MS). Despite the results of several clinical trials its management remains controversial. With the advent of new disease-modifying agents for the treatment of MS, management of isolated optic neuritis has become more complicated. The goal of this study was to evaluate the current clinical practice of French ophthalmologists and neurologists in the management of acute isolated optic neuritis, and to evaluate the impact of recently published randomized clinical trials on their practice. METHODS: A survey, including 24 questions on the diagnosis and treatment of acute isolated optic neuritis was sent to all neurologists and to a sample of ophthalmologists in France. RESULTS: The responses of 655 neurologists and 141 ophthalmologists were analyzed. This study shows mostly that patients initially present more frequently to ophthalmologists, and are subsequently referred to neurologists. Most optic neuritis patients undergo a brain MRI and a lumbar puncture. Although most patients receive high dose intravenous steroids, up to 15% of neurologists and 21% of ophthalmologists still recommend oral prednisone (1 mg/kg per day). Steroids are often prescribed for the wrong reason, including to improve final visual acuity or decrease the risk of MS. Disease modifying agents are sometimes prescribed outside of the official French recommendations. CONCLUSION: The evidence-based guidelines are only partially followed by practitioners managing patients with acute optic neuritis.     

Drug safety in multiple sclerosis: From reporting to signal detection and benefit-risk management

BackgroundPharmacovigilance (PV) rules emerged in the late 60s-early 70s. Since that time, the World Health Organization Center for International Drug Monitoring carries out the corresponding tasks. Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system that generally starts in young adults between 20 and 40 years of age. Over the last 25 years, MS patients have benefited from the development of a plethora of disease modifying drugs (DMD). These changes in the therapeutic armamentarium have been associated with some serious adverse reactions challenging health authorities and neurologists involved in treatment and care for MS patients.MethodsThe present review aims to describe, for MS DMDs, how adverse drug reactions are reported during clinical trials and the post-marketing period and how important signal detection and benefit-risk management have been in this disease until now. Several examples are reported to illustrate the different steps of PV processes.ConclusionImprovement of the PV system procedures has led to significant progress in the detection of signals, allowing better assessment of the benefit-risk balance and the implementation of risk management plans for MS treatments. The involvement of neurologists is essential to improve knowledge on the benefit-risk balance of these drugs. In addition, adverse drug reactions reporting by persons with MS should be encouraged.     

Prognosis-modifying therapy in multiple sclerosis

The neurologist's views on disease therapy have changed over recent years from nihilism to reasonable optimism, thanks to the development of MS-specific therapies (interferon beta and COP-1) and to the remarkable advances in the understanding of the pathogenesis of the disease. Available immunological, clinical and pathological data suggest that the early treatment of RRMS patients with immunomodulatory drugs could be more advantageous compared to treatment started later in the disease course.The early reduction of relapse rate as well as of the extent of pathological lesions, should be the strategy for patients particularly in the first phases of the disease. Early treatment has a robust rationale both in prevention of irreversible pathological changes and in reducing clinical and MRI activity with favorable prognostic implications. For the near future, interferon beta and COP-1 seem to be the pharmacological agents best qualified to be utilized for this purpose.     

Conventional magnetic resonance sequences in multiple sclerosis

The role of magnetic resonance imaging (MRI) in multiple sclerosis (MS) has received considerable attention in recent years. MRI has the potential to provide indices of disease activity and progression in clinical trials. Moreover, there is now widespread agreement that conventional MRI sequences are useful not only in diagnosing the disease but also in evaluating the natural course of the disease and the response to therapy. Conventional spin echo (CSE) sequences are widely accepted as sensitive techniques for the evaluation and quantification of brain MS lesions. Fast spin echo (FSE) sequences are now used as an alternative to CSE. They have the advantage of a considerable reduction in imaging time. Fast-fluid attenuation inversion recovery (fast-FLAIR) sequences, in which the signal from cerebrospinal fluid is suppressed, also provide a reliable means to evaluate the total lesion burden in patients with MS. Despite some limitations in the detection of infratentorial lesions, Fast-FLAIR sequences are useful in clinical studies. Compared with lesions load on conventional T2-weighted sequences, an increase in hypointense lesion load on CSE T1-weighted sequences correlates more strongly with increased disability in MS patients. This might be an additional useful MRI parameter to monitor disease progression in long-term studies. Gadolinium-enhanced T1-weighted images provide highly sensitive markers for detecting MRI activity, which represent the primary MRI endpoint for screening promising disease-modifying therapies, especially in phase II trials.     

The evolving face of human immunodeficiency virus-related progressive multifocal leukoencephalopathy: Defining a consensus terminology

There is a need for consistent definition of human immunodeficiency virus (HIV)-associated cases of progressive multifocal leukoencephalopathy (PML), especially following the profound disease changes that have resulted from the use of highly active antiretroviral therapy (HAART). According to the criteria used for diagnosis, PML cases should be either referred to as “histology-confirmed,” with evidence of JC virus (JCV) infection in brain, “laboratory-confirmed,” with detection of JCV DNA in cerebrospinal fluid (CSF), or “possible,” in the presence of typical clinical and radiological picture, but no demonstration of JCV infection. Disease outcome should be defined by the evidence or lack of evidence of disease activity, rather than using survival or other variables. Disease activity should be based on clinical (scored neurological examination), radiological (magnetic resonance imaging), and virological (JCV DNA levels in CSF) indicators, to be assessed regularly, e.g., every 3 months until evidence of disease arrest or death. Furthermore, parallel assessments of other HIV-associated manifestations, including CD4+ cell counts and viral load, are required. A standard patient classification would be helpful for clinical management of PML patients, for their inclusion in clinical studies, and also will increase our current knowledge of PML and its evolution in relation with HAART.     

The evolving face of human immunodeficiency virus-related progressive multifocal leukoencephalopathy: defining a consensus terminology

There is a need for consistent definition of human immunodeficiency virus (HIV)-associated cases of progressive multifocal leukoencephalopathy (PML), especially following the profound disease changes that have resulted from the use of highly active antiretroviral therapy (HAART). According to the criteria used for diagnosis, PML cases should be either referred to as "histology-confirmed," with evidence of JC virus (JCV) infection in brain, "laboratory-confirmed," with detection of JCV DNA in cerebrospinal fluid (CSF), or "possible," in the presence of typical clinical and radiological picture, but no demonstration of JCV infection. Disease outcome should be defined by the evidence or lack of evidence of disease activity, rather than using survival or other variables. Disease activity should be based on clinical (scored neurological examination), radiological (magnetic resonance imaging), and virological (JCV DNA levels in CSF) indicators, to be assessed regularly, e.g., every 3 months until evidence of disease arrest or death. Furthermore, parallel assessments of other HIV-associated manifestations, including CD4+ cell counts and viral load, are required. A standard patient classification would be helpful for clinical management of PML patients, for their inclusion in clinical studies, and also will increase our current knowledge of PML and its evolution in relation with HAART.     

Long term follow-up of multiple sclerosis by standardized, non-contrast-enhanced magnetic resonance imaging.

The usefulness of non-contrast-enhanced, standardized magnetic resonance imaging for the longterm follow-up of MS patients was evaluated in a retrospective study in 36 patients with clinically definite MS. All had remitting-relapsing diseases courses. Sixteen patients remained clinically stable during follow-up. Mean duration of follow-up was 22 months (SD: 11). A mean number of 3 MRI examinations was performed in each of the patients (SD: 1). Subclinical evolution was detected in 56% of the stable patients, indicating that clinical data alone are insufficient to assess disease activity. The relapsing patients showed significantly more and larger changes on MRI than stable patients (P less than 0.001), indicating that MRI is well suited as a follow-up parameter in conjunction with clinical data. The time courses of these quantitative changes and of the qualitative changes of putative MS lesions on MRI are discussed. It is concluded that MRI is a good indicator of global disease activity in multiple sclerosis patients, which makes MRI very useful for the evaluation of therapeutic trials.     

The contribution of enhancing lesions in monitoring multiple sclerosis treatment: is gadolinium always necessary?

Journal of Neurology - MRI is highly sensitive for monitoring of disease activity and treatment efficacy in MS. Patients treated with disease modifying therapy (DMT), who experience MRI activity,...     

Awareness of potential valvulopathy risk with pergolide and changes in clinical practice after label change: a survey among European neurologists

In response to concern about the reported frequency of ergot-associated valvulopathy in patients with Parkinson's disease (PD), Eli Lilly and Company updated the Risk Minimization Program for pergolide, changing the Summary of Product Characteristics (SmPC) and distributing a Dear Doctor Letter (DDL) highlighting the new label changes. A survey was conducted subsequently to assess neurologists' awareness of the revised SmPC and their resulting changes in practice. A random sample of 20.3% of neurologists ( n  = 4056) from 12 eligible EU countries were invited to participate. Of the target population of 247 neurologists who treated patients with PD, used pergolide in 2005, and were willing to participate, 244 (99%) responded. Overall awareness of the DDL and the SmPC changes was 94.2%. Over half (58.3%) of neurologists indicated that they prescribe pergolide exclusively as second-line treatment, although some (21.9%) used pergolide exclusively as first-line treatment. In response to the DDL, most neurologists perform echocardiograms before treatment (67.5%) and during treatment (76.7%), and over half (55%) avoid prescribing doses >5 mg/day. Overall, use of a DDL to communicate an SmPC change was effective in increasing the awareness of pergolide-associated valvulopathy and in modifying neurologists' clinical practice to minimize this risk.     

Neurophysiologic follow-up of long-term dietary treatment in adult-onset adrenoleukodystrophy

OBJECTIVE: To monitor the effects of dietary treatment in adult-onset adrenoleukodystrophy (ALD) by means of somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs). BACKGROUND: SEPs and MEPs have proved useful in revealing signs of progressively severe, central dying-back axonopathy in early stages of adult-onset ALD. METHODS: Eight patients with adult-onset ALD underwent clinical examination, brain and spine MRI, and SEP and MEP studies before and after 3 years of Lorenzo's oil dietary therapy. RESULTS: Before treatment, brain MRI was normal in five patients. Three of these patients had pure spinal SEP abnormalities and in the remaining two patients SEPs showed signs of involvement of both the spinal and cerebral somatosensory tracts. After treatment, the three patients with pure spinal abnormalities showed clinical and neurophysiologic worsening, whereas the two patients with a more advanced stage of disease (exhibited by SEPs) showed substantially unchanged clinical and neurophysiologic features. The patients with abnormal brain MRI at the onset of treatment showed clinical and neurophysiologic worsening. CONCLUSIONS: Lorenzo's oil therapy had no effect on patients with evidence of inflammatory brain lesions. Moreover, in patients without clear signs of inflammatory damage, this treatment does not modify significantly the natural course of the disease. However, because effective treatments should begin before the onset of severe neurologic symptoms, SEPs and MEPs should be considered to evaluate the effectiveness of other experimental treatments in the patient with a negative brain MRI.     

Clinical Uses of the Quality-of-Life in Epilepsy Inventory

Summary: The quality-of-life in epilepsy (QOLIE) inventory was designed to assess adult epilepsy patients. Responses to a draft 99-question inventory administered to patients with low to moderate seizure frequency will be used to generate two or three separate instruments. The largest and most comprehensive of these will serve as a research tool for investigators and may be helpful in designing studies that compare the effects of approved or investigational antiepileptic drugs. This instrument may also be useful in documenting patient outcomes following expensive diagnostic studies, such as video-electroencephalogram monitoring, or other therapeutic interventions, such as epilepsy surgery. An intermediate-sized instrument may serve as a clinical tool for neurologists and epileptologists. A brief instrument may serve as a quick clinical survey for primary care physicians, neurologists, and specialists in epileptology. The abbreviated clinical inventories are intended to provide rapid assessment of quality-of-life issues in the office setting. Such assessments can help physicians and patients identify previously unrecognized problems and may lead to changes in care.     

The role of MRI as a surrogate outcome measure in multiple sclerosis

The need for more specific and more sensitive outcome measures for use in testing new therapies in multiple sderosis (MS) is generally accepted. This need has been accentuated by the realization that the ability to conduct large placebo-controlled trials will be limited in the future. From the first use of magnetic resonance imaging (MRI) to study MS, the ability of this imaging technique to identify areas of the central nervous system damage by the disease process in MS has been impressive. Thus, the possibility that MRI could serve as a surrogate outcome measure in clinical trials in MS has been attractive. The use of MRI as a surrogate outcome measure has been examined by an international group of investigators with expertise in clinical aspects of MS, the use of MRI in MS, and in experimental therapeutics. The group agreed that MRI does not represent a validated surrogate in any clinical form of MS. It was also agreed, however, that MRI does provide a reflection of the underlying pathology in the disease, but no single MRI measurement in isolation was seen as sufficient to monitor disease. The use for multiple imaging techniques, especially new, emerging techniques that may better reflect the underlying pathology, was seen as particularly important in monitoring studies of patients with either secondary or primary progressive MS. The choice of MRI techniques used to monitor new therapies needs to be consistent with the proposed mechanisms of the new therapy and phase of the disease. It was also noted, however, that additional validation is required for nonconventional imaging techniques. Finally, the participants noted that clinical trials using MRI as a primary outcome measure may fail to fully identify the effects of the therapy on dinical measures and that the risk and cost-benefit ratio of the treatment might be unresolved. Thus, before MRI is used as a primary outcome measure, new approaches to trial design must be given careful consideration.     

Krankheitsbewältigungstraining bei Multipler Sklerose

BACKGROUND: Multiple sclerosis (MS) is a challenging disease for patients, the social environment, and therapists. We analysed how coping training and compliance of MS patients are assessed by neurologists in private practice.METHOD: One thousand five hundred and seventy-five neurologists in private practice were asked to fill in short, standardised, anonymous questionnaires concerning number of MS patients treated per year, experience with coping training methods, assessments of requirements, aims, location, and suitable trainer, financial aspects of coping training, assessment of patient compliance concerning immunomodulating therapies, and possibilities of increasing compliance.RESULTS: The response rate was 25.7% (404 questionnaires). Of these, 344 (21.8%) could be included in the analysis. Many neurologists had no experience with coping training methods but saw a reasonable demand, especially for newly diagnosed MS patients, those with psychological problems, and for their relatives. Most of them would like to provide such training themselves in their own locations. Useful aims of coping training included reduction of anxiety, uncertainty, and depression and increased patient compliance and well-being. They proposed that coping training should mainly be financed by health care insurers and patients. Neurologists assessed the compliance of MS patients concerning immunomodulating therapies as being moderate to high. Increased compliance was understood as better doctor-patient conversations, involvement of MS nurses, and support from self-help groups.CONCLUSION: There is a reasonable need of coping training for MS patients that is also seen by privately practicing neurologists, the main therapists for MS patients. The selection of adequate and scientifically reliable training should be improved. Thus coping with the disease, compliance, and well-being can all be improved.     

De-escalation from natalizumab in multiple sclerosis: recurrence of disease activity despite switching to glatiramer acetate

Natalizumab (NAT) is an effective therapy for relapsing–remitting multiple sclerosis (MS), but is associated with an increased risk of progressive multifocal leucoencephalopathy after 2 years therapy. Thus, NAT treated patients often decide to stop NAT therapy after 2 years. Reports on recurrence of disease activity after NAT discontinuation are controversial. We studied disease activity in 13 MS patients who stopped NAT therapy and either remained without disease modifying therapy (no DMT, n = 6), or switched to glatiramer acetate (GLAT, n = 7). Annual relapse rate (ARR), expanded disability status scale (EDSS), and number of patients with contrast-enhancing-lesions (Gd+) on MRI before, during and within 1 year after NAT were determined. We observed recurrence of disease activity in both groups (5/7 GLAT treated patients and 6/6 patients without DMT) within 12 months after cessation of NAT (mean time to first relapse was 5.5 months for all patients). One of the GLAT treated patients and three patients without DMT had severe relapses with sustained EDSS worsening. No differences in ARR, EDSS and MRI parameters were seen between both groups. Patients with relapses after NAT therapy, however, tended to show higher disease activity (EDSS, ARR) before initiation of NAT therapy compared to patients without relapses. Duration of NAT treatment was not associated with higher disease activity after NAT discontinuation. In this observation the majority of patients showed reappearance of disease activity after discontinuation of NAT regardless of whether they switched to GLAT or remained without DMT. Further treatment strategies are warranted for patients who discontinue NAT therapy.