621 e-Letters

  • Migraine and risk of stroke: complexities of population-based studies that do allow emergence of migraine science from the shadows of the past 100 years.

    I read the review by Øie et al. on the possible link between migraine and stroke (1). The authors believe that migraineurs are more likely to have unfavourable vascular risk factors. The increased risk of stroke seems to be more apparent among migraineurs without traditional risk factors (1). The mechanism behind the migraine- stroke association is unknown and clinical implications are uncertain (1).

    While migraine and stroke are independently common disorders, the occurrence of migraine-related stroke, in particular ischemic stroke in migraine with aura (MA), is uncommon to rare. Risk of ischaemic stroke associated with migraine without aura (MO) is uncertain (1). MO is by far the larger cohort (~80%), and, the striking absence of link of MO with ischemic stroke (1) merits greater attention. Additionally, as underscored by the authors, longer cumulative exposure to MA, as would be expected with early onset of migraine, is not associated with increased stroke risk in late life (1), an unexplained clinical paradox. The link between migraine and stroke is extremely tenuous and needs a careful re-examination. The authors (1) make no attempt to clarify that, fundamentally, no pathophysiologic difference between MA and MO has been established, and, both cohorts believed to be nosologically distinct respond equally well to abortive and preventive management strategies. What is truly challenging is the scientific basis and logic of the entirely arbitrary creation of noso...

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  • Response to Commentary by Prof. Gupta: Hemiplegic migraine, genetic mutations, and cortical spreading depression: a presumed pathophysiologic nexus that defies scientific logic

    We read with interest the commentary from Prof Gupta (1). Migraine is a complex and heterogeneous disorder with multifactorial pathogenesis (2). In fact, it is a well-known fact that both genetic and environmental factors are involved in the etiopathogenesis of migraine (2). Conversely, hemiplegic migraine (HM) is a complex monogenic disorder related to a mutation in genes encoding for ion transporters (3). Even if many consider HM as a subtype of migraine, this condition offers insight in migraine pathophysiology, especially in the case of migraine with aura, as well as in other conditions overlapping between headache and epilepsy, such as the so called “Ictal Epileptic Headache”, a new concept defined in the last decade (4–6).
    Our knowledge on the pathophysiology of both migraine and HM is evolving with new insights coming from the last years (3). However, we partially agree that ….“No systemic influence can explain the characteristic lateralizing headache of migraine, unilateral, bilateral, side-shifting or side-locked” (7,8). Interestingly, new data have come from neurophysiology: hyperexcitability/dysexcitability (5) in migraine has been clearly demonstrated in migraine sufferers with more prominent results especially in migraine with aura (5,9,10). These data could make a reasonable link between the genesis of hyperexcitability/dysexcitability of multisensory cortices, cortical spreading depression (CSD) and the “headache” phase of migraine, mediated by the tri...

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  • Letter: Response to McWhirter et al (2020)

    McWhirter et al. (2020) reviewed the published literature on Performance Validity Tests (PVTs), concluding that high false positive (Fp) rates were common in clinical (non-forensic) samples, exceeding 25%. In their discussion, they stated: “The poor quality of the PVT evidence base examined here, with a lack of blinding to diagnosis and potential for selection bias, is in itself a key finding of the review.” They also conclude that the use of a forced choice format with cut scores that are significantly above chance on two alternative forced choice tests (e.g., TOMM), raises questions about the utility of the forced choice paradigm, essentially characterizing these PVTs as “floor effect” procedures. As such, McWhirter et al. then argued that failure at above chance cutoffs represents “functional attentional deficit in people with symptoms of any sort,” rather than invalid test performance due to intent to fail.

    Throughout the paper, the authors refer to PVTs as “effort tests”, a characterization that is no longer in use in the United States, in part because PVTs require little effort to perform for persons experiencing significant cognitive impairment (1). Rather, PVTs have been defined as representing invalid performance that is not an accurate representation of actual ability. Continuing to refer to PVTs as “effort tests” allows McWhirter et al. to more easily mischaracterize the tests as sensitive attentional tasks affected by variable “effort” rather than measur...

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  • Response to McWhirter et al

    Dear Editor

    Response to McWhirter et al (2020):

    In their article, Performance validity test failure in clinical populations - a systematic review, McWhirter and colleagues (2020) present the ‘base rates’ of performance validity test (PVT) failure (or what are commonly referred to as effort tests) and offer an analysis of PVT performance from their perspective as neurologists and neuropsychiatrists.

    As a group of senior practicing clinical neuropsychologists, we are pleased that they have drawn attention to an important issue, but we have significant concerns about the methodology used and with several of the conclusions drawn within the review. We present this response from the perspective of U.K. neuropsychology practice, and as practitioners involved in research and formulating clinical guidance on the use of PVTs. In preparing this response, we were aware of parallel concerns of our U.S. counterparts (Larrabee et al) but we have submitted separate responses due to the word limit.

    The systematic review methodology used by McWhirter et al. has resulted in a limited number of papers being included, and there is no indication of the quality of the studies included. All of the literature search and analytic procedures appear to have been undertaken by one person alone, hence there was no apparent control for human error, bias, omission or inaccurate data extraction. Also, it is unclear to us to what extent McWhirter and colleagues had the knowle...

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  • 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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