607 e-Letters

  • Pain Responsiveness: A Useful Clinical Tool?

    The recently published paper ‘Abnormal pain perception is associated with thalamo-cortico-striatal atrophy in C9orf72 expansion carriers in the GENFI cohort’ by Convery et al.[1] draws attention to a topic of great importance in the field of frontotemporal dementia (FTD) research. In this study, Convery and colleagues investigated differences in pain responsiveness within a group of patients with genetic FTD. Changes in pain responsiveness compared to baseline were captured using a scale designed by the group, and patients were scored from 0-3 (0 = no change, 0.5 = questionable or very mild change, 1 = mild change, 2 = moderate change, 3 = severe change). Within the sample, symptomatic C9orf72 mutation carriers (9/31) experienced greater changes in pain responsiveness than symptomatic MAPT (1/10) and GRN (1/24) mutation-carriers or normal controls (1/181). Within the C9orf72 mutation carriers, these changes were associated with thalamo-cortico-striatal atrophy.
    This research brings attention to an important but little-investigated clinical feature of FTD. Changes in pain responsiveness, including both increases and decreases, have now been reported in both sporadic and genetic FTD, along with other somatic complaints.[1–4] However, the changes are not widely captured in either clinical or research settings, and the field lacks standardized and objective measurements to do so. The ability to measure changes in pain responsiveness may be a useful clinical marker to di...

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  • Reply to: Mental health and suicide in former professional soccer players

    We thank White and colleagues for their correspondence on our article(1) and note many of the observations raised are already addressed by our robust study design and discussed in the original manuscript text. Importantly, we are quite clear throughout that this is a study designed to investigate whether there is higher risk of common mental health disorder in former professional soccer players than anticipated from general population controls.

    Undoubtedly, there will be physically active individuals in our general population control group, including a number who might have participated in some form of contact sport. However, we would suggest this does not define our over 23,000 matched general population controls as a cohort of ‘non-elite’ athletes, as proposed by White et al. Instead, we would assert this merely underlines their legitimacy as a general population control cohort for comparison with our cohort of almost 8000 former professional soccer players.

    Potential study limitations regarding healthy worker effect, illness behavior in former professional soccer players and use of hospitalization datasets are addressed in detail in our manuscript text. Regarding data on duration of hospital stay and therapy, while these might indeed be of interest in follow-on studies regarding illness severity, we would suggest that they are not immediately relevant to a study designed to address risk of common mental health disorder.

    As White et al observe, wh...

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  • Response to: Mental health and suicide in former professional soccer players

    Russell et al. (1) published a retrospective cohort study with a population of former professional soccer players with known high neurodegenerative mortality. Findings showed that they are at lower risk of common mental health disorders and have lower rates of suicide than a matched general population. These findings are surprising and different from previous studies, which have used first-hand clinical accounts of ex-athletes who have lived with neurodegeneration (1). We suggest there may be reasons for this disparity and welcome critical dialogue with the authors of this research.

    Cohort Comparison
    Russell et al. has compared their soccer cohort with a matched population cohort. However, the matched cohort may also include those who have experienced repetitive head impacts, such as amateur soccer players, rugby players or boxers. Therefore, the study represents differences of elite versus non-elite rather than sport versus non-sport. While Russell recognises the healthy worker effect (2), it may have a greater influence in this study than presented.

    Soccer Stoicism
    Men’s engagement in health-seeking behaviours has been a long-standing concern in health care and is often attributed to factors such as stigma, hypermasculinity and stoicism (3). Furthermore, working-class sports such as soccer, require the acceptance of pain, suffering, and physical risk, so these players are more likely to ‘suffer in silence’ than the general population (4). Give...

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  • Guillain-Barre syndrome and other neurological complication in SARS-CoV-2: Role of antiganglioside antibodies and treatment option

    I read an interesting case report of GBS with antiganglioside antibodies in SARS-CoV-2 by Civardi et al1. We are also seeing various complications like GBS, pseudotumorcerebri, precipitation of stroke, seizures etc2 but do not have the access to antiganglioside antibodies but, all those who can afford and get it done we should try for that and get it documented for academic and research purpose in this pandemic of modern time of advanced technology. We may screen for ganglioside antibodies to assess autoimmunity in Covid-19 patients3. The gangliosides are particularly abundant in the brain and in the nervous system; they participate in maintenance and repair of neuronal cells, memory formation and synaptic transmission4. So we have to be watchful in this regard towards impairment of these neurological functions i.e. new autoimmune disorder like GBS, multiple sclerosis(MS), neuromyelitis optica spectrum disorders(NMO-SD), chronic inflammatory demyelinating neuropathy(CIDP) etc. and precipitation of neurodegenerative and cognitive disorders in acute, convalescent ant post recovery follow up. Of course the paediatric population is less affected but as the gangliodides also take part in the development and regeneration of neurons the SARS-CoV-2 may affect the growth and development of paediatric population.
    As the intravenous immunoglobulins(IVIg) and plasmapharesis are useful in the treatment of GBS with antiganglioside antibodies the trial of IVIg, and monoclonal a...

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  • Response to Larrabee et al

    We read Larrabee and colleagues’ e-letter response to our systematic review on Performance Validity Testing (PVT). Whilst we welcome debate, and we recognize that some clinicians will disagree with our conclusions, we were disappointed that they misrepresented our paper in formulating their response:

    1. The authors state “Throughout the paper, the authors refer to PVTs as “effort tests”, a characterization that is no longer in use in the United States..”. In reality we used the term “effort test” only twice in our paper; in the introduction: “(PVTs), also historically called effort tests” and once in the methods in describing our search terms. By contrast we use the term PVT on 45 occasions.

    2. We are concerned that they then go on to misrepresent the results of our review. We found a wide variation in results in different clinical groups and in different tests. We noted that failure rates for some groups and some tests exceeds 25%. We did not conclude that all failure rates were as high as this, but rather that failing a PVT was not a rare phenomenon but was reasonably common in a range of clinical groups.

    We presented results to support our conclusion that the PVT literature is problematic with regards to blinding to diagnosis and potential for selection bias.

    We also uphold our speculation that an alternate explanation for failure on forced choice tests at above chance cutoffs may result from attentional deficit related to other symptoms. W...

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  • Guillain-Barré syndrome in developing countries in the COVID-19 era

    Dear sir,

    Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become one of the most severe pandemic the world has ever seen. Based on data from Johns Hopkins University, around 26.3 million cases have been detected and around 0.9 million patients have died of COVID-19 globally as of September 04, 2020. The neurological sequelae of COVID-19 include a para/post-infectious, immune or antibody-mediated phenomenon, which classically manifests as Guillain-Barré syndrome (GBS).[1, 2]

    We read the systematic review by Uncini et al with great interest. In an instant systematic review, the authors reported 42 patients of GBS associated with COVID-19 from 33 retrieved articles. All of these articles had been reported from 13 developed countries.[3] The authors mentioned regarding the chronology of publication of case reports/series starting from China followed by Iran, France, Italy, Spain and USA which seemed to be related to the track of SARS-CoV-2 infection spread. However, the authors did not discuss why such cases/series had remained under-reported from developing countries. A comprehensive, advanced search of PubMed using the terms ‘SARS-CoV-2’ OR ‘COVID-19’ AND ‘Guillain-Barré syndrome’ on September 04, 2020, led to retrieval of two additional articles from developing countries, one each from Brazil and Morocco.[4 ,5] As of September 04, 2020, Brazil and India had the 2nd and 3rd highest number of COVI...

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  • Response to Kemp et al.

    We read with interest Kemp and colleagues response to our recent systematic review on Performance Validity Testing (PVT). In response to specific criticisms raised:

    1- The searches and data extraction were conducted by one investigator. We agree this is a potential limitation although only if papers were missed, or data was erroneously transcribed, and it can be demonstrated this would have changed the conclusions. Although Kemp and colleagues place great weight on this, the evidence they put forward to support their contention was limited. Of the four citations in their letter, reference 2 and reference 4 were in fact included (see our supplementary tables and our reference 57)(1,2). Reference 3 was, by coincidence, published simultaneously with our manuscript submission and was not available to us(3).

    Reference 1 did not fit the terms of our search strategy and was not included although it would have been eligible(4). It was an unblinded study of the ‘coin in hand test’, a brief forced choice screening test for symptom exaggeration, administered to 45 patients with mixed dementias. It found 11% scored at or above a 2 error cut off and the authors proposed a new set of cut offs for interpretation; it was in keeping with our conclusions. We’d be happy to consider any other specific omissions or quality assessment issues not discussed which the authors consider would have altered the conclusions of the review.

    2- The authors criticise our understanding...

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  • 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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