eLetters

42 e-Letters

published between 2017 and 2020

  • Autonomic symptoms as a predictor of disease progression and survival in patients with progressive supranuclear palsy

    Oliveira et al. evaluated the association between autonomic symptoms and progressive supranuclear palsy (PSP) with special reference to disease progression and survival (1). Adjusted hazard ratios (HRs) (95% confidence interval [CIs]) of early constipation and early urinary symptoms for the risk of first disease milestone of PSP were 0.88 (0.83 to 0.92) and 0.80 (0.75 to 0.86), respectively. In addition, adjusted HRs (95% CIs) of early constipation and early urinary symptoms for survival were 0.73 (0.64 to 0.84) and 0.88 (0.80 to 0.96), respectively. Furthermore, Richardson syndrome phenotype was significantly associated with shorter survival. The authors concluded that earlier urinary symptoms and constipation are closely associated with rapid disease progression and shorter survival in patients with PSP. I have two comments about their study.

    First, Glasmacher et al. conducted a meta-analysis to explore prognostic factors and survival in patients with PSP and multiple system atrophy (MSA) (2). In patients with PSP, adjusted HR (95% CI) of Richardson's phenotype against Parkinson's phenotype for shorter survival was 2.37 (1.21 to 4.64). In addition, adjusted HR (95% CI) of early fall for shorter survival in patients with PSP and MSA was 2.32 (1.94 to 2.77). Although some clinical symptoms are overlapping by common neurological damages, risk assessment for PSP and for MSA should be separately conducted. Stable estimates with enough number of samples and ev...

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  • Ultra-high-dose methylcobalamin in amyotrophic lateral sclerosis

    Kaji et al. evaluated the efficacy and safety of intramuscular ultra-high-dose methylcobalamin in 373 patients with amyotrophic lateral sclerosis (ALS) (1). The primary endpoints were death or full ventilation support. Although there was no significant difference between treated and control group, 50 mg methylcobalamin-treated patients with early start within 12 months' duration of diagnosis showed longer time intervals to the primary event and keep the Revised ALS Functional Rating Scale (ALSFRS-R) score than the placebo group. The adverse effects by this treatment were similar and low prevalence among placebo, 25 mg or 50 mg groups. The authors recommend to verify the prognosis by this medication, and I have some concerns about their study.

    First, the authors did not allow the change of riluzole administration and did not handle patients with edaravone treatment. I think that the vitamin B12 analog treatment in combination with recent neuro-protective drugs might be acceptable for future trials (2). In addition, the efficacy for ALS by methylcobalamin should be specified by adjusting several confounders for the analysis.

    Relating to vitamin therapy for ALS, Rosenbohm et al. investigated the association of serum retinol-binding protein 4 (RBP4) with the onset and prognosis of ALS (3). Adjusted ORs (95% C) of the highest quartile of RBP4 against lowest quartile for incident ALS was 0.36 (0.22-0.59). In addition, serum RBP4 was inversely associated with m...

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  • Reducing Uncertainty and Expanding Patient Engagement in Deep Brain Stimulation Trials for Tourette Syndrome

    We appreciate the editorial by Dr. Muller-Vahl [1] about our recent article [2]. The large, international study group who co-authored our paper collectively felt that it would be useful to provide clarification of a few important points regarding the International Tourette Syndrome (TS) Deep Brain Stimulation (DBS) Database and Registry, the International Neuromodulation Registry, and our published analysis.

    There is widespread agreement on the need for more randomized controlled trials (RCTs) to evaluate the efficacy of DBS for many indications, including TS, and there has been substantial discussion in the medical community about how these trials should be organized and carried out [3]. Our approach to overcome the challenges with the modest amount of data available for surgical therapies for TS has been to use symbiotic data sharing [4]. This approach encourages the broadening of investigative teams after publication of clinical studies to perform additional analyses and to develop new hypotheses. The key concept behind this approach is that new investigators work in a close, collaborative relationship with the teams that conducted the initial data collection. In addition, a recent viewpoint from the Food & Drug Administration in the United States reported that “For some devices, opportunities exist for leveraging alternative data sources, such as existing registries or modeling techniques, to allow regulators to have a good idea of the risks and benefits of...

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  • The utility of CSF biomarkers in idiopathic normal pressure hydrocephalus?

    Dear Editor,
    The original article by Jeppsson et al. provides substantial perspectives regarding the diagnostic
    significance of cerebrospinal fluid (CSF) biomarkers in discriminating patients with idiopathic normal pressure hydrocephalus (iNPH) from patients with other neurodegenerative disorders. 1 They have found that patients with iNPH had, compared with healthy individuals, lower concentrations of P-tau and APP-derived proteins in combination with elevated MCP-1 1. Moreover, compared with the non-iNPH disorders group, iNPH was characterized by the same significant change; low concentration of tau proteins and APP-derived proteins, and elevated MCP-1. I sincerely appreciate the authors for conducting such a large-scale study of a strictly interesting topic. However, I would like to make some comments hoping to provide a better understanding of some points and some perspectives to be kept in mind while planning future related studies
    In my opinion, the investigation of CSF biomarkers in patients with iNPH may provide several insights in addition to discriminating the iNPH patients from other neurodegenerative diseases. Certainly, these study results may give the opportunity to understand the unknown pathophysiological aspects of iNPH, thereby, even leading to new classifications of the disease. Actually, there may be many questions to be clarified regarding diagnostic approach, evaluation of the iNPH patients and even identification of the disease. 2,3...

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  • Split weakness signs in ALS
     I note the clinical analysis of differential weakness in ALS in elbow flexion (biceps brachii) compared to elbow extension (triceps) reported by Khalaf et al.1 This is described as analogous to similar 'split' muscle weakness around the ankle joint and, particularly, as that found in flexor digitorum indicis (FDI) compared to abductor digit minim (ADM) in the hand in the disease. It should be remembered that, although characteristic of ALS, this differential pattern of weakness has repeatedly been found not to be unique to ALS, even from the first descriptions.2,3 As the authors, and Vucic in his editorial remark,1,4 the cause of this interesting pattern of weakness in ALS remains uncertain. The finding of an association between the pattern of weakness and increased excitability in the upper motor neuron system in ALS does not necessarily provide primary support for an upper motor neuron (UMN) causation.  Nonetheless this pattern of weakness must be important in the disease. It is worth remembering that differential susceptibility to neurogenic lower motor neuron weakness is also a characteristic feature of some peripheral neuropathies, e.g., the Charcot-Marie-Tooth syndromes. Furthermore, differential muscle weakness and atrophy is a characteristic finding that is important in clinical diagnosis in the myriad different genetically determined muscular dystrophies.5 Although the causation of this differential susceptibility of certain muscles in this la...
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  • Authors' response to 'An overestimation?'

    We, the authors, thank Berthier for his comments on our study of 49 individuals with self-reported Foreign Accent Syndrome.

    In response, we would first like to clarify that we do not use Berthier’s term ‘psychogenic’, but ‘functional’ in our paper, referring to foreign accent symptoms due to changes in neural function rather than (or in addition to) the direct effects of a structural lesion. The body-mind dualism implied by the terms ‘psychological/psychogenic’ vs ‘neurogenic’ no longer holds water. Berthier himself notes that the differentiation between “functional” and “structural” may be artificial and that there has been great progress in “unveiling of the neural basis” of functional disorders. As we frequently emphasise in explaining the diagnosis to individuals with functional neurological disorders, their symptoms are definitely ‘real’; not ‘imagined’; and have a basis in changes in neural function which we are beginning to understand more clearly [1,2].

    We accept the limitations provided by our method of data collection, including limited data about investigations and a likelihood of selection bias where those with predominantly functional FAS may be somewhat over-represented in our sample. We wish to clarify, however, that cases were classified as ‘probably functional’ on the basis of reported positive clinical features of a functional disorder (e.g. periods of return to normal accent, adoption of stereotypical behaviours) and not by the presence...

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  • An overestimation of diagnosing functional foreign accent syndrome?

    Elucidating the nature of the foreign accent syndrome (FAS) can contribute to improve its diagnosis and treatment approaches. To understand this apparently rare syndrome, McWhirter et al. 1 studied a large case series of 49 subjects self-reporting having FAS. The participants were recruited via unmoderated online FAS support groups and surveys shared with neurologists and speech-language therapists from several countries. Participants completed an online protocol including validated scales tapping somatic symptoms, anxiety and depression, social-occupational function, and illness perception. They were also requested to provide speech samples recorded via computers or smartphones during oral reading and picture description. The overall clinical presentation of FAS in each participant was classified by consensus reached by three authors (2 neuropsychiatrists and 1 neurologist) in (1) “probably functional”, (2) “possibly structural” or (3) “probably structural”, wherein (1) meant no evidence of a neurological event or injury suggestive of a functional disorder but with no spontaneous remission; (2) alluded to the presence of some features suggestive of a functional disorder but with some uncertainty about a possible structural basis; and (3) denoted the evidence of a neurological event or injury coincident with the onset of FAS. The recorded speech samples were examined by experts to diagnose FAS and their frequent associated speech-language deficits (apraxia of speech, dysar...

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  • 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...

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  • 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...

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  • 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...

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