620 e-Letters

  • Response to: Comparison of fingolimod, dimethyl fumarate and teriflunomide for multiple sclerosis: when methodology does not hold the promise

    We thank Dr Platt and colleagues for their critical review of our work, especially of the methodology that we have used in this study. It is understandable that comparative studies of treatment effectiveness trigger constructive discussions among industry and academics. We also vehemently agree that rigorous methodology and cautious interpretation of results is mandatory, especially for analyses of observational data.1 2 Therefore, in this letter, we will provide additional clarifications in response to the concerns raised.

    We appreciate that the categories that are underrepresented in multivariable logistic regression models may lead to inflation of estimates of the corresponding coefficients and their variance. Such inflation would, however, result in an overly conservative matching rather than the opposite. Due to the use of a caliper, patients with an extreme propensity score can not be matched to patients within the bulk of the distribution of the propensity scores. Such patients were excluded from the matched cohorts.

    The issue of residual imbalance is important in any non-randomised comparative study. We acknowledge that the standardised mean difference in annualised relapse rates (ARR) between teriflunomide and fingolimod exceeded the nominal threshold of 20%. It is therefore reassuring that the sensitivity analyses, in which the residual imbalance fell below the accepted threshold of 20% (patients with prior on-treatment relapses, Cohen’s d 14%, and...

    Show More
  • Comparison of fingolimod, dimethyl fumarate and teriflunomide for multiple sclerosis: when methodology does not hold the promise

    Dear Editor,

    We read with interest the article by Kalincik et al. [1] comparing fingolimod, dimethyl fumarate and teriflunomide in a cohort of relapsing-remitting multiple sclerosis (MS) patients. The authors investigated several endpoints and performed various sensitivity analyses, and we commend them for reporting technical details in the online supplementary material. We, however, have some concerns about the design, analysis and reporting of the study.

    1. In the primary analyses, three separate propensity score models were developed to construct a matched cohort for each of the three pairwise comparisons. Supplementary Table 6 clearly indicates the existence of zero or low frequencies in some variables (e.g., most active previous therapy and magnetic resonance imaging [MRI] T2 lesions). Yet, those variables were used as covariates in the propensity score models, unsurprisingly resulting in extremely high point estimates and standard errors (SE; as reported in Supplementary Table 7). For example, teriflunomide was not the most active therapy for any patient in the dimethyl fumarate cohort (n=0 from Supplementary Table 6), but that category was nevertheless included in the propensity score model, leading to an unrealistic point estimate of 18.65 with SE of 434.5 (Supplementary Table 7). Even higher SEs (greater than 1000) are observed in the other propensity score models. Propensity scores estimated from these poorly constructed models were then used to cr...

    Show More
  • Seizures and movement disorders : cortico-subcortical networks

    Seizures and movement disorders : cortico-subcortical networks

    Dr Aileen McGonigal

    Aix Marseille Univ, Inserm, INS, Institut de Neurosciences des Systèmes, Marseille, France
    APHM, Timone Hospital, Clinical Neurophysiology, Marseille, France

    Corresponding author: Dr Aileen McGonigal, Service de Neurophysiologie Clinique, CHU Timone, AP-HM, Marseille, France
    Email : aileen.mcgonigal@univ-amu.fr
    Tel: 00 33 491384995
    Fax:00 33 491385826

    To the Editors

    I was interested to read the recent review by Dr Freitas and colleagues1. This interesting article highlights diagnostic challenges, clinical overlap and possible shared pathophysiological processes in epileptic seizures and movement disorders. I would like to add a couple of points that seem important to acknowledge.
    Firstly, in terms of clinical expression, the authors rightly mention that automatic movements occurring during focal epileptic seizures can sometimes resemble those seen in certain movement disorders, and they give the examples of orofacial automatisms (most often seen in temporal lobe seizures), as well as hyperkinetic behaviors. While the authors highlight sleep-related epilepsy as the main cause of hyperkinetic behavior, in fact hyperkinetic behavior may be seen in seizures from various cortical origins both in wakefulness and in sleep. It should be recognized that especially (though not exclusivel...

    Show More
  • Refining diagnosis of early POEMS syndrome

    We applaud Suichi et al.[1] for proposing new diagnostic criteria for POEMS syndrome. There is clearly a need for simplified validated criteria that permit early diagnosis of this rare, elusive and devastating paraneoplastic disorder, especially because early local or systemic treatment of the underlying plasma cell malignancy can dramatically improve prognosis.[2] Our recent clinical experience[3] is in full agreement with the three proposed cardinal features of POEMS syndrome, namely polyneuropathy, vascular endothelial growth factor (VEGF) level elevation, and the presence of monoclonal protein. The authors argue that the triad alone may be insufficiently specific; therefore they propose the additional requirement of two of four secondary features, namely extravascular fluid accumulation, skin changes, organomegaly, and sclerotic bone lesion.

    We would like to draw attention to clinical and methodological aspects that could further enhance or refine the diagnosis of POEMS syndrome. First, the process of diagnosis starts with clinical suspicion. Polyneuropathy is usually the earliest symptom of POEMS syndrome. POEMS syndrome should be considered in any patient with a severely progressive polyneuropathy of acute to subacute onset that is not otherwise explained, and VEGF level measurement should be offered. Routine screening for monoclonal protein (with immunofixation) and skeletal survey may be negative initially, and could remain negative for a long duration into...

    Show More
  • Brain perivascular enhancement: MOG or GFAP- antibody related?

    Komatsu et al. presented an interesting clinicopathological case of anti-myelin oligodendrocyte glycoprotein (MOG) demyelinating disease of the CNS. (1) Their patient had a rather unusual subacute encephalopathic presentation with extensive supratentorial fluid-attenuation inversion recovery white matter hyperintensities. The authors focused mainly on the conspicuous MRI punctuate and curvilinear enhancement pattern within the hemispheric lesions.
    It is well established that intraparenchymal punctuate and curvilinear gadolinium enhancement may arise in the context of Moyamoya syndrome, various endotheliopathies and most commonly, in disorders causing small vessels blood-brain barrier disruption. (2)These entities are associated histologically with perivascular cellular infiltrates and include inflammatory autoimmune diseases (i.e. primary or secondary angiitis of the CNS, neurosarcoidosis, histiocytosis and demyelinating diseases of the CNS), pre-lymphoma states (i.e. sentinel lesions of primary CNS lymphoma), non-Hodgkin lymphoma (i.e. intravascular lymphoma) and CLIPPERS syndrome. (2) Notably, among demyelinating disorders, multiple sclerosis and aquaporin-4 antibody (AQP4-Ab) neuromyelitis optica spectrum disorders (NMOSD) manifest this specific neuroimaging pattern in rare cases. (2,3)
    We agree with Komatsu et al. that their case is the first report of the perivascular enhancement in anti-MOG antibody disease. Indeed, gadolinium enhancement was observed in...

    Show More
  • Re: A unifying theory for cognitive abnormalities in functional neurological disorders, fibromyalgia and chronic fatigue syndrome

    Re: A unifying theory for cognitive abnormalities in functional neurological disorders, fibromyalgia and chronic fatigue syndrome

    Viraj Bharambe Specialist registrar in neurology
    John C Williamson Specialist registrar in neurology
    Andrew J Larner Consultant Neurologist

    Cognitive Function Clinic
    Walton Centre for Neurology and Neurosurgery
    Lower Lane
    L9 7LJ
    e-mail: a.larner@thewaltoncentre.nhs.uk

    Teodoro et al. present evidence for shared cognitive symptoms in fibromyalgia, chronic fatigue syndrome, and functional neurological disorders, and hypothesize that functional cognitive disorders (FCD) may share similar symptoms.1 We present data which speak to this issue.

    We have previously reported preliminary data examining performance on the mini-Addenbrooke’s Cognitive Examination (MACE) by patients diagnosed with fibromyalgia2 as part of a larger study of MACE.3 Here, we update these data for fibromyalgia patients (n = 17; F:M = 17:0; age range 33-56 years, median 49) and compare them to MACE performance by patients diagnosed with FCD (n = 43; F:M = 18:25; age range 28-82 years, median 58).4

    There was no statistical difference (p > 0.1) in the proportions of patients scoring below the two cut-off scores (≤21/30, ≤25/30) defined in the index MACE report.5 Looking at MACE subscores (Attention, Registration,...

    Show More

    Dear Editor,
    We have read with great interest the work by Scarpazza et al that provided a longitudinal MRI evaluation of natalizumab-related Progressive Multifocal Leukoencephalopathy (NTZ-PML) lesions in Multiple Sclerosis (MS) patients (1).
    Their central finding was the high percentage (78.1%) of patients, who eventually developed NTZ-PML, in whom highly suggestive lesions were already retrospectively detectable on pre-diagnostic MRI exams. Furthermore, the pre-diagnostic phase proved to be relatively long (150.8±74.9 days), with an estimated percentage increase of the lesions’ volume of 62.8% per month (1).
    Given the widely recognized crucial role of a timely NTZ-PML identification in reducing mortality and residual disability (1), these results present the neurological and neuroradiological communities with an important clinical challenge, prompting a major effort to ensure an early diagnosis of this condition.
    Although redefining the timing of MRI surveillance, with up to one brain MRI exam every 3-4 months for high-risk patients, appears as a justified strategy, we think that improving the accuracy of early identification of NTZ-PML is also mandatory.
    In our opinion, such achievement should be pursued using two complementary approaches: (i) a specific training addressed to neuroradiologists working in the field of MS, who should be aware of the relevance of even very small asymptomatic PML lesions and how to differentiate them from new M...

    Show More
  • Author reply: Higher burden of common neurological diseases in women than in men

    Dear Editor,

    We thank Abat et al. for re-emphasizing an important interpretation of our work, namely that sex-differences in life-expectancy likely influenced the presented lifetime risks [1]. Indeed, in our paper we repeatedly discussed in several sections (for instance in the methods) that differences in life-expectancy between men and women could differentially affect their lifetime risk. It was for this reason that we consequently decided to analyze the data in a sex-specific manner while taking the competing risk of death into account in order to prevent potential overestimation.

    Abat et al. unfortunately also allege that we attributed the observed sex-differences in disease risk to sex-specific effects on a biological level. The authors have seemingly missed our discussion at length arguing that observed differences in lifetime risk may be primarily attributed to the effects of differences in life-expectancy between men and women: “Apart from a longer life-expectancy in general, these findings may be explained by smaller differences in life-expectancy between men and women in the Netherlands (1.8 years), compared with the USA (4.8 years). With longer life-expectancy, individuals in this study simply had more time to develop these diseases in a timeframe with high age-specific incidence rates.”

    It seems thus that ours and Abat and co-authors’ interpretation of our findings is pretty much congruent, i.e. age, irrespective of sex, should be consid...

    Show More
  • Higher burden of common neurological diseases in women than in men: it is because women live longer!

    To the Editor,
    We read with interest the work from Licher et al. [1] in which the authors tried to quantify the burden of common neurological diseases (i.e. dementia, stroke and parkinsonism) in 12 102 individuals (6 982 women and 5 120 men) aged ≥ 45 years and free from these diseases at baseline. All these individuals were recruited between 1990 and 2016 into the prospective population-based Rotterdam Study. At the end of their analyzes, the authors concluded that one in two women and one in three men will develop dementia, stroke or parkinsonism during their lifetime, and that the risk for women to develop both stroke and dementia during their life is almost twice that of men [1].
    By reading the article from Licher et al. [1], we were extremely surprised by the fact that the authors did not consider the impact of the difference in life expectancies between men and women on their results and conclusions. This is particularly well underlined by the fact that the authors did not clearly precise the age structures of the two populations they studied [1]. In our view, this information is critical as, although the reasons for this difference are still debated and may probably be multi-factorial [2], it is well known that women live longer than men. This trend is confirmed by the 2018 World Health Statistics report [3] that estimates that in 2016, the life expectancies of men and women at birth were respectively 69.8 and 74.2 years at the international level. The...

    Show More
  • The complex NMDAR-antibody associated movement disorder is highly-distinctive

    We thoroughly enjoyed reading the comment on our paper which analysed expert ratings of the movement disorder associated with NMDAR antibody-encephalitis.1 Thompson et al’s elegant pathophysiological explanation provides an excellent framework of the most plausible neural structures involved in NMDAR-antibody encephalitis. Further, they note these movements can occur in semi-conscious patients, and this concurs well with the previous description of anti-gravity movements in the context of ‘status dissociatus’.2 A review of our 76 videos, revealed Thompson et al’s account of “variable, complex jerky semi-rhythmic movements….in the obtunded state” in 45 (59%) of cases. Therefore, this complex description was not present in almost half of patients. Furthermore, our recent clinical experiences note some NMDAR-antibody patients with abnormal movements but without obtundation: perhaps, given the known stepwise progression of many cases, this is a function of increasingly early disease recognition.3

    By contrast to Thompson et al, our published study design intentionally used conventional phenomenological terms to define the movement disorder associated with NMDAR antibody-encephalitis.1 This approach aimed to define a pragmatic method, available to all clinicians, which could identify and faithfully communicate this complex movement disorder, with the important aim of earlier disease recognition. The results identified a dominant set of recognised classifications – dyston...

    Show More