60 e-Letters

published between 2020 and 2023

  • Answer to response of professor Kawada

    Our findings demonstrate that serum C-reactive protein (CRP) does not predict survival in amyotrophic lateral sclerosis (ALS), neither in a univariate model nor in a multivariate model including other established prognostic factors for survival in ALS. In contrast, in a similar multivariate model, serum neurofilament light chain (NfL) is an independent predictor of survival in ALS. Further, we investigated the combination of serum CRP and NfL within the same multivariate survival model. The results indicated that elevated levels of serum NfL (Hazard ratio: 1.83 [95% CI: 1.23-2.74] p = 0.003), but not of serum CRP (Hazard ratio: 0.93 [95% CI = 0.63-1.37], p = 0.7), are associated with a shorter survival in ALS. From these data, we can conclude that there is no evidence that combining both markers would improve the prediction of survival in ALS.

    Moreover, we determined the disease progression rate (DPR) at time of sampling for 368 patients with ALS. The DPR was calculated as (48 – ALS-FRS-R)/(disease duration). We found a significant correlation between the DPR and serum NfL levels (rs = 0.519 [95% CI = 0.437-0.592], p < 0.0001) as well as serum CRP levels (rs = 0.294 [95% CI = 0.194-0.387], p < 0.0001). Accordingly, patients with a DPR in the upper quartile had significantly elevated levels of serum NfL (median [range]: 183 [11.1-738] pg/mL vs. 67.9 [0.300-262] pg/mL, p < 0.0001) and serum CRP (median [range]: 0.336 [0.0150-30.0] mg/dL vs. 0.0775 [0.0150-2.7...

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  • Brain Atrophy is Inevitable Following Deep Brain Stimulation and Not Likely Caused by the Lead

    Brain Atrophy is Inevitable Following Deep Brain Stimulation and Not Likely Caused by the Lead

    To the Editor,

    We read the observational DBS cohort study by Kern DS et al with great interest. We agree that deep brain stimulation (DBS) implantation has been associated with brain atrophy. We previously published an experience that not cited in the present study and we wonder whether the authors accidentally cited one of our review articles rather than the primary source (2014). It is critical for the DBS field to be aware of the clinical implications of atrophy.

    Kern DS et al analyzed 32 Parkinson’s disease (PD) patients who completed bilateral staged DBS implant surgeries targeting the subthalamic nucleus (STN)(1). The patients had an average duration between the two DBS surgeries of 141 days and this duration offered an opportunity to compare pre-post atrophy measures. The authors observed a significant reduction in whole brain volumes of the ipsilateral or first implanted side. Also, the authors noted that all basal ganglia-thalamocortical brain regions (BGTC) ipsilateral to the DBS implantation had significantly reduced volumes, whereas non-BGTC structures seemed to be unaffected. The authors suggested the possibility that intracranial volumetric changes may occur following STN DBS electrode implantation as a direct result of the implantation itself.

    We believe it unlikely that DBS electrode implantation is a primary reason for volume loss. We...

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  • Hemiplegic migraine, genetic mutations, and cortical spreading depression: a presumed pathophysiologic nexus that defies scientific logic

    I read the article by Stefano et al with interest.1 Genetic predisposition per se cannot explain discrete self-limited recurrent attacks of headache and aura manifestations of hemiplegic migraine, with the state/clinical predisposition appearing and disappearing seemingly inexplicably over several decades or the life-time of a sufferer.2

    More than two decades ago, I elucidated a fundamental clinico-theoretical principle for the understanding of migraine-linked physiologic mechanisms that has well-stood the test of time, technology and biologic commonsense: “No systemic influence can explain the characteristic lateralizing headache of migraine, unilateral, bilateral, side-shifting or side-locked”.3 Over the last fifty years, some of the "systemic" influences believed to play key pathogenetic roles in migraine include serotonin, platelets, catecholamines, calcitonin-gene related peptide, magnesium depletion, stress, post-stress state, and recurrent micro thrombo-embolisms across the patent foramen ovale at the level of the cardiac inter-atrial septum. 4,5,6 Little vertical and biologically-plausible robust generalizable progress, however, has been made in gestalt understanding of the disorder well into the 21st century.7 Trait-linked genetic association is also a “systemic” influence. Ion transporters – as well as the three main causative genes—CACNA1A, ATP1A2 and SCN1A—which encode for ion transporters1 do not offer clues to the mechanistic physiological b...

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  • Mechanisms of ischaemic stroke in COVID-19: more data are needed

    Dear Editor,

    We thank Dr Venketasubramanian for their interest in our paper and for their considered response. We agree that some of our patients had alternative causes for stroke in addition to the marked prothrombotic and inflammatory state related to COVID-19, and that this point is relevant to interpreting our findings.

    We also agree that it can be difficult to define one specific “cause” for an ischaemic stroke despite detailed investigation, since many patients have a complex combination of risk factors (e.g. diabetes, hypertension, dyslipidaemia), disease processes (e.g. atherosclerosis, cerebral small vessel disease, atrial fibrillation), and potential mechanisms (e.g. large artery thrombo-embolism, cardiac embolism, small vessel occlusion). Nevertheless, our key observation was that a 16-day period we saw 6 strikingly similar patients, all with large vessel occlusions, elevated D-dimer, ferritin and CRP, 8-24 days following proven COVID-19 illness (and in one patient during the asymptomatic phase (1), suggesting the emergence of a distinct pattern of cerebral ischaemia associated with a prothrombotic inflammatory state.

    As correctly identified, Patient 2 had atrial fibrillation and previous mitral valve repair (not a metallic valve), but stroke occurred despite above-therapeutic anticoagulation with INR 3.6; this is unusual, so we concluded that the clear thrombotic state may therefore have been contributory (D-dimer 7,750). Similarly, al...

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  • Neurological manifestations of COVID-19: Sleep-wake disorders are probable after SARS-CoV-2 infection

    Alain Buguet1, Manny W. Radomski2, Jacques Reis3, Raymond Cespuglio4, Peter S. Spencer5, Gustavo C. Román6
    Authors’s affiliations
    • UMR 5246 CNRS, Claude-Bernard Lyon-1 University, Villeurbanne, France
    • Physiology, Faculty of Medicine, University of Toronto, Canada
    • Faculté de Médecine, Université de Strasbourg, Strasbourg, France
    • Neurocampus Michel Jouvet, Claude-Bernard Lyon-1 University, Lyon, France
    • Department of Neurology, School of Medicine, Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, Oregon, USA
    • Department of Neurology, Neurological Institute, Houston Methodist Hospital, USA, and Weill Cornell Medical College, Cornell University, New York, NY, USA
    • Correspondence to Prof. Alain Buguet, Malaria Research Unit, UMR 5246 CNRS, Claude-Bernard Lyon-1 University, 69622 Villeurbanne, France; a.buguet@free.fr

    We read with interest the Post-Script comment by Liu et al. highlighting the neurological manifestations of SARS-CoV-2 infection. We would like to contribute additional information on the neurology of COVID-19, as recently published by our group at the World Federation of Neurology.1 In addition to the reported disorders affecting central and peripheral nervous system as well as muscle, we add sleep-wake disorders to the list of conditions that may be associated with COVID-19 both during and fol...

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  • Mechanism for ischaemic stroke in COVID-19 - full evaluation needed

    Dear Editor

    It is with great interest that I read the excellent paper by Beyrouti R, et al, on the characteristics of ischaemic stroke among patients with COVID-19(1). There is great interest in the prothromotic state seen in this illness – in this series, high D-dimer and fibrinogen levels in 6/6, positive lupus anticoagulant in 4/5, moderate anti-cardiolipin titres in 1/6.

    But I note that there are still some traditional mechanisms in these patients that may have been the cause of the stroke that may not have been fully elucidated, or if they were, were not reported in the paper. I see that patients 2 and 3 had atrial fibrillation, on warfarin, with supra-therapeutic (3.6, artificial heart valve) and sub-therapeutic (1.03) INRs respectively. The results of echocardiography and cardiac rhythm monitoring were not reported for any patient. Thus cardioembolism is still possible as a cause of stroke. Patients 2 to 5 had hypertension and at least one other atherosclerotic vascular risk factor (eg diabetes mellitus, hypercholesterolaemia, smoking, stroke). All patients save 1 was above 60 years of age. Vascular imaging was only reported for 2 cases (5 - CTA and 6 - MRA). Atherothromboelbolism may have caused stroke in some of the patients.

    I refer to case series of stroke seen during the 2002-2204 SARS epidemic, also due to a corona virus (2); all had large artery ischaemic strokes, at least 2 of 4 assessed patients had a cardioembolic source, with anot...

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  • Corona viruses and Stroke

    Dear Editor,

    The editorial by Manji et al.1 on the neurology of the COVID-19 pandemic cites Mao et al2.’s report describing 5 ischemic strokes in 214 COVID-19 patients. Helms et al3,. and Zhang et al4. have also since reported ischemic stroke in patients with severe SARS-CoV-2 infection, with the latter linking stroke to antiphospholipid antibodies4. In addition, Oxley et al. describe large-vessel stroke in 5 young patients5. In this context, I would like to highlight our 2003 study of ischemic stroke in severe SARS-CoV-1 infection, the corona virus responsible for Severe Acute Respiratory Syndrome (SARS)6. Five out of a total of 206 SARS patients in the country developed large artery ischemic stroke7, four of whom were critically ill. They were not significantly older (56±13 years) than other critically-ill SARS patients (50±16 years, Anova p=0.45). Besides episodes of hypotension, we suspected thromboembolism as a possible mechanism of stroke. Four of the eight SARS patients, who had autopsy examination, revealed evidence of pulmonary thromboemboli8. One was a 39-year-old man, with no stroke risk factors, who died two weeks after contracting SARS; his autopsy revealed unilateral occipital lobe infarction, sterile vegetations on multiple valves, deep venous thrombosis and pulmonary embolism. This prompted the subsequent use of low molecular weight heparin (LMWH) in critically-ill patients, at doses to achieve anti-Xa levels of 0.5-1.0IU/ml. Nevertheless, one-thir...

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  • Study rigor may not impact finding of neuroablation superiority over deep brain stimulation for obsessive-compulsive disorder


    Obsessive-compulsive disorder (OCD) is a neuropsychiatric disease characterized by distressing thoughts or urges that often require repetitive behaviors to suppress. OCD affects 2-3% of the general population and can have debilitating effects on normal functioning.[1] While most cases of OCD can be addressed through psychotherapy and/or medication, about 10% remain refractory, requiring neurosurgical intervention, such as neuroablation (ABL) or deep brain stimulation (DBS). These options possess their own respective advantages and disadvantages. ABL lacks the hardware concerns of DBS (e.g. device failure, battery replacement, etc.) and may be incisionless (e.g. stereotactic radiosurgery). Alternatively, DBS is non-lesional, and stimulation parameters can be titrated. While both ABL and DBS appear to be effective for refractory OCD, there is no clear consensus on their relative superiority/non-inferiority.

    Our group previously sought to address this question by comparing the two treatments’ relative utility. [1] Using a random-effects, inverse-variance weighted meta-analysis of 56 studies, utility was calculated from Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores and adverse event (AE) incidence. In our analysis, no significant differences were found between stereotactic radiosurgery and radiofrequency ablation, so their studies were combined and all considered under ABL. Ultimately, ABL yielded a significantly greater utility compared to...

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  • RE: Neurofilament light chain and C reactive protein explored as predictors of survival in amyotrophic lateral sclerosis

    De Schaepdryver et al. assessed the prognostic ability of serum neurofilament light chain (NfL) and C-reactive protein (CRP) in patients with amyotrophic lateral sclerosis (ALS) (1). Although two indicators can significantly predict the prognosis, the superiority by the combination of NfL and CRP should be checked for the analysis. I want to discuss NfL and ALS prognosis from recent publications.

    Verde et al. conducted a prospective study to determine the diagnostic and prognostic performance of serum NfL in patients with ALS (2). Serum NfL positively correlated with disease progression rate in patients with ALS, and higher levels were significantly associated with shorter survival. In addition, serum NfL did not differ among patients in different ALS pathological stages, and NfL levels were stable over time within each patient.

    Regarding the first query, Thouvenot et al. reported that serum NfL could be used as a prognostic marker for ALS at the time of diagnosis (3). Gille et al. recognized the relationship of serum NfL with motor neuron degeneration in patients with ALS (4). They described that serum NfL was significantly associated with disease progression rate and survival, and it could be recommended as a surrogate biomarker of ALS. These two papers presented no information whether NfL can be used for monitoring of ALS progression in each patient.

    De Schaepdryver et al. used two indicators, and I suspect that the authors can present information r...

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  • RE: Neurofilament light chain in serum for the diagnosis of amyotrophic lateral sclerosis

    Verde et al. conducted a prospective study to determine the diagnostic and prognostic performance of serum neurofilament light chain (NFL) in patients with amyotrophic lateral sclerosis (ALS) (1). Serum NFL positively correlated with disease progression rate in patients with ALS, and higher levels were significantly associated with shorter survival. In addition, serum NFL did not differ among patients in different ALS pathological stages, and NFL levels were stable over time within each patient. I have a concern about their study.

    Gille et al. also recognized the relationship of serum NFL with motor neuron degeneration in patients with ALS (2). They also recognized that serum NFL was significantly associated with disease progression rate and survival. Serum NFL can be recommended as a surrogate biomarker of ALS.

    Regarding the first concern, Thouvenot et al. also checked if serum NFL can be used as a prognostic marker for ALS at the time of diagnosis (3). By Cox regression analysis, NFL, weight loss and site at onset were independent predictive factors of mortality, and higher NFL concentration at the time of diagnosis is the strongest prognostic fact

    I recently discussed on serum neurofilament light chain in patients with amyotrophic lateral sclerosis (4), and these consistent results should also be verified by a meta-analysis of prospective studies.


    1. Verde F, Steinacker P, Weishaupt JH, et al. Neurofilament light chain in se...

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