Dear editor,
We read with great interest the article by Rousseau et al. “Location of intracranial aneurysms is the main factor associated with rupture in the ICAN population.”1
They compared ruptured intracranial aneurysms (RIAs) with unruptured cerebral aneurysms (UCAs) in the ICAN registry, and analyzed factors that were considered associated with subarachnoid hemorrhage in previous literature. As a result, they found the location of the aneurysm showed the largest hazard ratio as much as 6.05 and showed their result with beautiful info-graphic.
We should be careful that their result is derived from comparisons between the aneurysms, which caused subarachnoid hemorrhage and UCAs that was found without bleeding. Hence, the meaning is different from that of ISUIA2, UCAS Japan3, and other studies, which investigated the risk of bleeding from the known UCAs. As noted in the discussion of the headache, which prefers UCAs to RIAs, the factors examined may be seeing factors, which lead to brain examination without causing subarachnoid hemorrhage in France.
As in the title, they focused on the location of the aneurysm, and found ACA and posterior circulation aneurysms have high odds ratio of 4.99 and 6.05 respectively comparing with ICA aneurysms. As in ISUIA study, they included internal carotid- posterior communicating artery (IC-Pcom) aneurysms in the posterior circulation aneurysms, and “ICA” includes other aneurysms occurring on the ICA. However...
Dear editor,
We read with great interest the article by Rousseau et al. “Location of intracranial aneurysms is the main factor associated with rupture in the ICAN population.”1
They compared ruptured intracranial aneurysms (RIAs) with unruptured cerebral aneurysms (UCAs) in the ICAN registry, and analyzed factors that were considered associated with subarachnoid hemorrhage in previous literature. As a result, they found the location of the aneurysm showed the largest hazard ratio as much as 6.05 and showed their result with beautiful info-graphic.
We should be careful that their result is derived from comparisons between the aneurysms, which caused subarachnoid hemorrhage and UCAs that was found without bleeding. Hence, the meaning is different from that of ISUIA2, UCAS Japan3, and other studies, which investigated the risk of bleeding from the known UCAs. As noted in the discussion of the headache, which prefers UCAs to RIAs, the factors examined may be seeing factors, which lead to brain examination without causing subarachnoid hemorrhage in France.
As in the title, they focused on the location of the aneurysm, and found ACA and posterior circulation aneurysms have high odds ratio of 4.99 and 6.05 respectively comparing with ICA aneurysms. As in ISUIA study, they included internal carotid- posterior communicating artery (IC-Pcom) aneurysms in the posterior circulation aneurysms, and “ICA” includes other aneurysms occurring on the ICA. However, in the real world, we experience subarachnoid hemorrhage due to bleeding from internal carotid- anterior choroidal artery aneurysms and less often (superiorly projecting large) paraclinoid aneurysm, which accounts less than 5%. According to the baseline characteristics of this study (Table 1), the ICA aneurysms occupy 33.4% in the RIA group, while it is only 11.8% in the UCA group. It should be misleading to use such small risk aneurysms as a reference for comparison and to say that the hazard ratio is high. The ISUIA study4 was first criticized for its inclusion of aneurysms within the cavernous sinus that did not cause subarachnoid hemorrhage, and they were no longer included in subsequent analyses. Similarly, given the proportion of aneurysms that cause subarachnoid hemorrhage, it is time to stop discussing anterior choroidal artery aneurysms and paraclinoid aneurysms collectively.
References
1. Rousseau O, Karakachoff M, Gaignard A, et al. Location of intracranial aneurysms is the main factor associated with rupture in the ICAN population. J Neurol Neurosurg Psychiatry 2020;23(324371):2020-324371.
2. Wiebers DO, Whisnant JP, Huston J, 3rd, et al. Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet 2003;362(9378):103-10. [published Online First: 2003/07/18]
3. Morita A, Kirino T, Hashi K, et al. The natural course of unruptured cerebral aneurysms in a Japanese cohort. N Engl J Med 2012;366(26):2474-82. doi: 10.1056/NEJMoa1113260 [published Online First: 2012/06/29]
4. International Study of Unruptured Intracranial Aneurysms Investigators. Unruptured intracranial aneurysms--risk of rupture and risks of surgical intervention. N Engl J Med 1998;339(24):1725-33. doi: 10.1056/nejm199812103392401 [published Online First: 1998/12/29]
Jacobs et al. investigated the association of environmental factors and prodromal features with incident Parkinson's disease (PD) with special reference to the interaction of genetic factors [1]. The authors constructed polygenic risk scores (PRSs) for the risk assessment. Family history of PD, family history of dementia, non-smoking, low alcohol consumption, depression, daytime somnolence, epilepsy and earlier menarche were selected as PD risk factors. The adjusted odds ratio (OR) (95% confidence interval [CI]) of the highest 10% of PRSs for the risk of PD was 3.37 (2.41 to 4.70). I have some concerns about their study.
Regarding risk/protective factors of PD, Daniele et al. conducted a case-control study to performed a simultaneous evaluation of potential factors of PD [2]. Among 31 environmental and lifestyle factors, 9 factors were extracted by multivariate analysis. The adjusted OR (95% CI) of coffee consumption, smoking, physical activity, family history of PD, dyspepsia, exposure to pesticides, metals, and general anesthesia were 0.6 (0.4-0.9), 0.7 (0.6-0.9), 0.8 (0.7-0.9), 3.2 (2.2- 4.8), 1.8 (1.3-2.4), 2.3 (1.3- 4.2), 5.6 (2.3-13.7), 2.8 (1.5-5.4), and 6.1 (2.9-12.7), respectively. Family history of PD and non-smoking were common risk factors, which had also been reported by several prospective studies.
Regarding smoking, Angelopoulou et al. investigated the association between environmental factors and PD subtypes (early-onset, mid-and-late on...
Jacobs et al. investigated the association of environmental factors and prodromal features with incident Parkinson's disease (PD) with special reference to the interaction of genetic factors [1]. The authors constructed polygenic risk scores (PRSs) for the risk assessment. Family history of PD, family history of dementia, non-smoking, low alcohol consumption, depression, daytime somnolence, epilepsy and earlier menarche were selected as PD risk factors. The adjusted odds ratio (OR) (95% confidence interval [CI]) of the highest 10% of PRSs for the risk of PD was 3.37 (2.41 to 4.70). I have some concerns about their study.
Regarding risk/protective factors of PD, Daniele et al. conducted a case-control study to performed a simultaneous evaluation of potential factors of PD [2]. Among 31 environmental and lifestyle factors, 9 factors were extracted by multivariate analysis. The adjusted OR (95% CI) of coffee consumption, smoking, physical activity, family history of PD, dyspepsia, exposure to pesticides, metals, and general anesthesia were 0.6 (0.4-0.9), 0.7 (0.6-0.9), 0.8 (0.7-0.9), 3.2 (2.2- 4.8), 1.8 (1.3-2.4), 2.3 (1.3- 4.2), 5.6 (2.3-13.7), 2.8 (1.5-5.4), and 6.1 (2.9-12.7), respectively. Family history of PD and non-smoking were common risk factors, which had also been reported by several prospective studies.
Regarding smoking, Angelopoulou et al. investigated the association between environmental factors and PD subtypes (early-onset, mid-and-late onset, familial and sporadic) [3]. The adjusted OR (95% CI) of smoking for PD overall, mid-and-late onset PD, familial PD, and sporadic PD were 0.48 (0.35-0.67), 0.46 (0.32-0.66), 0.53 (0.34-0.83) and 0.46 (0.32-0.65), respectively. In addition, there was an inverse linear association of PD with pack-years of smoking, except for early-onset PD. Additionally, the adjusted OR (95% CI) of coffee consumption for PD overall, early-onset PD, and familial PD were 0.52 (0.29-0.91), 0.16 (0.05-0.53) and 0.36 (0.17-0.75), respectively. Although the mechanism of the association might be difficult to be confirmed, smokers have a trend of high prevalence of coffee consumption.
Finally, Li et al. evaluated whether the genetic profile might modify PD development and cerebrospinal fluid (CSF) pathological biomarkers by using single nucleotide polymorphisms (SNPs) and PRSs [4]. Some SNPs had significant correlations with PD, and PRSs could predict PD risk and the age at onset. In contrast, the CSF α-synuclein level had no significant correlation with the PRSs in normal subjects. Anyway, further studies are needed to verify PD determinants and gene-environment interactions.
References
1. Jacobs BM, Belete D, Bestwick J, et al. Parkinson's disease determinants, prediction and gene-environment interactions in the UK Biobank. J Neurol Neurosurg Psychiatry. 2020 Oct;91(10):1046-1054.
2. Daniele B, Roberta P, Andrea F, et al. Risk factors of Parkinson's disease: Simultaneous assessment, interactions and etiological subtypes. Neurology. 2020 Sep 17 doi: 10.1212/WNL.0000000000010813
3. Angelopoulou E, Bozi M, Simitsi AM, et al. The relationship between environmental factors and different Parkinson's disease subtypes in Greece: Data analysis of the Hellenic Biobank of Parkinson's disease. Parkinsonism Relat Disord. 2019 Oct;67:105-112.
4. Li WW, Fan DY, Shen YY, et al. Association of the polygenic risk score with the incidence risk of Parkinson's disease and cerebrospinal fluid α-Synuclein in a Chinese cohort. Neurotox Res. 2019 Oct;36(3):515-522.
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...
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 differentiate FTD from other neurodegenerative diseases,[4] and, if the C9orf72 results of Convery et al. are replicated, as an indicator of possible genetic underpinnings.
Recent findings raise the possibility that changes in pain responsiveness differ between FTD phenotypes. Increased pain responsiveness has been reported in patients with semantic-variant primary progressive aphasia (svPPA), particularly in those with right-temporal atrophy, which stands in contrast to decreased pain responsiveness observed in behavioral-variant FTD (bvFTD).[2–5] These findings, in conjunction with those of Convery et al., highlight the importance of capturing directionality of change as well as severity. Similarly, analyses of different phenotypes within the FTD spectrum will be critical to broaden the clinical relevance of this research to sporadic FTD, as some phenotypes are rarely genetic (e.g., svPPA). In the Convery et al. paper, the overwhelming majority of symptomatic participants had bvFTD, which is typical for genetic cohorts. However, the extension of this research into sporadic cases raises the exciting question of whether changes in responsiveness to pain can distinguish between FTD phenotypes, which implicate overlapping but distinct neuroanatomical circuits. This question has great theoretical, as well as clinical, importance.
The Convery et al. paper highlights that altered responsiveness to pain was present in symptomatic but not presymptomatic genetic mutation carriers. It thus remains unclear whether altered pain responsiveness is an early feature of the disease or develops later. Elucidating this timeline will clarify the clinical utility of this research: whether it is useful for early diagnosis or for distinguishing between phenotypes after the dementia syndrome has developed.
As we continue to expand this line of research, it will be essential to develop both subjective and objective measurements of pain responsiveness and other somatic changes in patients with FTD. Refining our understanding of these changes has the potential to be useful in clinical and research settings alike.
1 Convery RS, Bocchetta M, Greaves CV, et al. Abnormal pain perception is associated with thalamo-cortico-striatal atrophy in C9orf72 expansion carriers in the GENFI cohort. J Neurol Neurosurg Psychiatry Published Online First: 5 August 2020. doi:10.1136/jnnp-2020-323279
2 Barker MS, Silverman HE, Fremont R, et al. ‘Everything hurts!’ Distress in semantic variant primary progressive aphasia. Cortex J Devoted Study Nerv Syst Behav 2020;127:396–8. doi:10.1016/j.cortex.2020.03.002
3 Snowden JS, Bathgate D, Varma A, et al. Distinct behavioural profiles in frontotemporal dementia and semantic dementia. J Neurol Neurosurg Psychiatry 2001;70:323–32. doi:10.1136/jnnp.70.3.323
4 Fletcher PD, Downey LE, Golden HL, et al. Pain and temperature processing in dementia: a clinical and neuroanatomical analysis. Brain J Neurol 2015;138:3360–72. doi:10.1093/brain/awv276
5 Ulugut Erkoyun H, Groot C, Heilbron R, et al. A clinical-radiological framework of the right temporal variant of frontotemporal dementia. Brain J Neurol 2020;143:2831–43. doi:10.1093/brain/awaa225
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.
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, while our data reporting lower risk of hospitalization for common mental health disorder in former professional soccer players might appear ‘surprising’, this is perhaps a reflection of methodological limitations and biases in previous reporting in this issue, as discussed in our text. As such, as a robust study specifically designed to address many previous limitations and minimize biases, we would disagree with White et al’s suggestion that our ‘surprising’ observations are ‘not necessarily a significant contribution’ to this field.
1 Russell ER, McCabe T, Mackay DF, et al Mental health and suicide in former professional soccer players Journal of Neurology, Neurosurgery & Psychiatry Published Online First: 21 July 2020. doi: 10.1136/jnnp-2020-323315
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...
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). Given the effectiveness of masculine socialisation through sport participation, the absence of elevated medical reporting between male athletes and non-athletes does not indicate an actual absence of a larger disease profile. The lack of ex-elite athletes engaging with mental health support at a hospital may rather be indicative of health-avoidance behaviours.
Mental Health Concerns Defined by Hospital Admission
Using hospital admission records as the primary definition for mental health concerns is problematic. Hospital admission is reserved for the most severe acute psychiatric concerns. Therefore, such records miss many mental health concerns that are better managed in primary and community care settings. This may be particularly pertinent for this study, given that many of the sample have diagnosed dementia, and may be fully supported with their neuro-psychiatric needs by health care professionals outside the hospital context.
The Bigger Picture
It appears that only a selective subsection of data, or part of the picture, has been reported. No information on the length of visit to hospital, extent and nature of medical interventions, public health burden, number or frequency of visits by an individual and any further care has been provided. This information may illuminate other explanations for why there is a difference in common mental health disorders for soccer and match control samples.
Concluding thoughts
Russell et al assert research, “… has placed greater emphasis on psychiatric symptomatology in CTE. Nevertheless, data supporting this association are weak”. This study does little to support or contest this position. While the results presented are novel, they are not necessarily a significant contribution to the debate on the relationship between soccer participation, common mental health disorders and other neurological
References
(1) Russell, E. R., McCabe, T., Mackay, D. F., Stewart, K., MacLean, J. A., Pell, J. P., & Stewart, W. (2020). Mental health and suicide in former professional soccer players. Journal of Neurology, Neurosurgery and Psychiatry.
(2) Li CY, Sung FC. A review of the healthy worker effect in occupational epidemiology. Occup Med 1999;49:225–9.
(3) Wang Y, Hunt K, Nazareth I, Freemantle N, Petersen I. Do men consult less than women? An analysis of routinely collected UK general practice data. BMJ Open. 2013;3(8):e003320
(4) Anderson, E., & White, A. (2017). Sport, theory and social problems: A critical introduction. Routledge.
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...
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 antibodies in other neurological complications with SARS-CoV-2 along with monitoring of antiganglioside antibodies may prove to be a game changer, as it has been claimed to be effective in general treatment of COVID-195. Besides this there are emerging data that chloroquine which is under investigation for treating COVID-19, binds with high-affinity sialic acids and GM1 gangliosides and, in the presence of chloroquine, the SARS-CoV viral spike cannot bind gangliosides to infect the targeted cells. If it is confirmed to be beneficial and safety is established, chloroquine may have an additional therapeutic value in future patients with COVID-19–triggered GBS in conjunction with IVIg3.
References-
1. Civardi C, Collini A, Geda D J, Geda C. Antiganglioside antibodies in Guillain-Barré syndrome associated with SARS-CoV-2 infection. http://dx.doi.org/10.1136/jnnp-2020-324279
2. Shubhakaran K, Bhargava A, Sutaria N et al. Unpublished data.
3. Marinos C. Dalakas. Guillain-Barré syndrome: The first ocumented COVID-19–triggered autoimmune neurologic disease More to come with myositis in the offing. DOI:https://doi.org/10.1212/NXI.0000000000000781
4. Cutillo G, Saariaho A-H, Meri S. Physiology of gangliosides and the role of antiganglioside antibodies in human diseases. Cell Mol Immunol 2020;17:313–22.doi:10.1038/s41423-020-0388-9
5. Alan A. Nguyen, Saddiq B. Habiballah, Craig D. Platt, Raif S. Geha, Janet S. Chou, and Douglas R. McDonald. Immunoglobulins in the treatment of COVID-19 infection: Proceed with caution! Clin Immunol. 2020 Jul; 216: 108459. doi: 10.1016/j.clim.2020.108459
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...
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. We were explicit that there are likely to be many reasons that a person might fail a PVT, and invite further research and discussion of the various causes of PVT failure that might help to explain the observed variation in failure rates across a range of diverse clinical conditions.
3. We did not ignore the importance of using multiple PVTs. On the contrary we explicitly stated “the manner in which we have described PVT failure rates does not necessarily reflect how they are used in practice by skilled neuropsychologists” and that “Guidance documents recommend that multiple performance validity measures should be used, including both free-standing and embedded indicators ...” But that was not the subject of the study which was the performance of individual tests.
4. They allege that we did not mention any of the previous published meta-analyses summarizing data from multiple investigations. However, the Sollman and Berry review they suggest has a quite different focus from our study, and the majority of studies included were of mixed clinical populations (e.g. ‘psychiatric’, or ‘neurological’ or ‘head injury’ without severity specified)(1). It was not relevant to our question.
Larrabee et al. raise three valid points of criticism:
1. That we were inaccurate in our portrayal of the Novitski paper. We have reviewed the Novitski et al. paper and although % fail rate was accurately transcribed we agree the study was erroneously included, as the included mTBI patients had already failed the WMT(2). Although interestingly, 36% of the amnestic MCI sample in this paper (who were not administered the WMT) also failed RBANS digit span <9. Of note, the mTBI group in the Novitski paper was not included in our Figure 2, due to the rather higher-than-usual cutoff score of 9. This isolated error does not alter our overall conclusions.
2. They challenge our statement that there is little consensus amongst experts on the use of PVTs. However Kemp et al, in further correspondence with us, stated explicitly that the view of these tests as ones of malingering was old fashioned and largely no longer accepted, whereas Larrabee and colleagues refer to them as just that. The British Psychological Society refer to them as ‘effort’ tests throughout their guidance whereas Larrabee and colleagues criticize such nomenclature. It seems to us even from the responses to our paper that there is a lack of consensus.
3. Finally, while Larrabee et al. report that our results are “not representative of the research database” we counter with an assurance that this data was just that: a systematic extraction of all available date from the research base on PVTs.
2. Novitski J, Steele S, Karantzoulis S, Randolph C. The Repeatable Battery for the Assessment of Neuropsychological Status Effort scale. Arch Clin Neuropsychol [Internet]. 2012;27(2 PG-190–195):190–5.
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...
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 COVID-19 cases (Johns Hopkins data), yet only one case of COVID-19-associated GBS had been reported from Brazil and no case had been reported from India. An Italian study reported a 5.4-fold increase in the incidence of GBS during this pandemic.[2] In contrast, the number of GBS cases in Bangladesh, a developing country, had decreased during the pandemic (personal communication with country coordinator (Bangladesh) of International GBS Outcome Study (IGOS), August 2020), even though Bangladesh reported the highest number of GBS cases worldwide in the IGOS.
The lack of or inadequate testing facilities and structural barriers to getting tested for COVID-19, i.e., excessive waiting time or lack of one-stop services may contribute to under-reporting of COVID-19-associated GBS in developing countries. We assume that some patients with GBS in developing countries did not seek hospital care due to the lock-down, lack of public transport services, social stigma and fear of nosocomial infection. However, it requires further exploration if truly there were no COVID-19-associated GBS cases in developing countries or these cases had remained under-reported.
Patients of GBS associated with COVID-19 may not present with typical symptoms. For instance, the first reported case of GBS associated with SARS-CoV-2 infection was para-infectious, rather than the classical post-infectious presentation.[1] Some cases of GBS may also be negative for SARS-CoV-2 in reverse transcriptase polymerase chain reaction (RT-PCR) tests, as reported by an Italian study.[2] Moreover, if a patient develops GBS long after the acute infection subsides, RT-PCR testing for SARS-CoV-2 may also be negative. Analysis of serum IgG and IgM for SARS-CoV-2 may help to confirm or exclude antecedent SARS-CoV-2 infection, though such tests may not be available in developing countries—which may also result in underreporting of COVID-19-associated GBS.
The high number of reported cases of COVID-19-associated GBS worldwide provides evidence of a possible association between GBS and COVID-19. Therefore, during this pandemic, clinicians and neurologists should be aware that patients presenting with GBS, even in the absence of cough, fever, respiratory distress or any systemic symptoms, may represent the first manifestation of COVID-19. During this global pandemic, the differential diagnosis of COVID-19-associated GBS should be considered for all cases of GBS, until and unless confirmed otherwise. We call for attention of the clinicians, especially neurologists in developing countries to strengthen surveillance system for identification, reporting and better management of COVID-19-associated GBS.
References
1. Zhao H, Shen D, Zhou H, et al. Guillain-Barré syndrome associated with SARS-CoV-2 infection: causality or coincidence? Lancet Neurol 2020;19(5):383-84. doi: 10.1016/s1474-4422(20)30109-5
2. Gigli GL, Bax F, Marini A, et al. Guillain-Barré syndrome in the COVID-19 era: just an occasional cluster? J Neurol 2020:1-3. doi: 10.1007/s00415-020-09911-3
3. Uncini A, Vallat J-M, Jacobs BC. Guillain-Barré syndrome in SARS-CoV-2 infection: an instant systematic review of the first six months of pandemic. Journal of Neurology, Neurosurgery &amp; Psychiatry 2020:jnnp-2020-324491. doi: 10.1136/jnnp-2020-324491
4. El Otmani H, El Moutawakil B, Rafai MA, et al. Covid-19 and Guillain-Barré syndrome: More than a coincidence! Revue neurologique 2020;176(6):518-19. doi: 10.1016/j.neurol.2020.04.007
5. Frank CHM, Almeida TVR, Marques EA, et al. Guillain-Barré Syndrome Associated with SARS-CoV-2 Infection in a Pediatric Patient. J Trop Pediatr 2020 doi: 10.1093/tropej/fmaa044
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.
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 of how PVTs are used in clinical practice, stating that PVTs should not interpreted on a stand-alone basis but in combination as part of a wider assessment. We agree and made that point explicitly in the paper. Nonetheless an understanding of the accuracy of individual tests remains of key importance in the weight accorded to individual tests in that wider assessment. They state that the way we presented single test failure rates is not the way the tests should be used. Again, we agree and pointed this out in the paper. However, they also misrepresent us, as we did not score or interpret the tests ourselves, nor did we conflate different forms of testing - we reported all the available data as the authors presented it.
3- The third point they make is that we are not saying anything new. We agree in as much as we have methodically documented and grouped in one paper data that was in the public domain. In particular, the authors suggest that ‘base rate failure is well understood’ but in our experience that is not the case; indeed the British Psychological Society’s own guidelines state “Further evidence on UK base rates of cognitive impairment and failure on effort tests in a range of clinical presentations and service settings is needed”(2). There are no other papers that synthesise this data in clinical populations to give readers an overview of these base rates. More importantly, the evidence we found, showed a wide variety of use and interpretation of PVTs. Kemp and colleagues go on to describe how studies should ideally be done to compare clinical populations. We agree and discuss this in our closing remarks. The problem is that evidence to date falls far short of this ideal.
As we made clear in the paper, we agree that PVTs may be useful in the correct context and with an understanding of their limitations. We were not “dismissive” of the developing PVT literature and we believe this should be a literature open to scrutiny by all.
1. Sieck BC, Smith MM, Duff K, Paulsen JS, Beglinger LJ. Symptom validity test performance in the Huntington Disease Clinic. Arch Clin Neuropsychol. 2013;28(2 PG-135–43):135–43.
2. British Psychological Society. Assessment of Effort in Clinical Testing of Cognitive Functioning for Adults. 2009.
3. Sherman EMS, Slick DJ, Iverson GL. Multidimensional Malingering Criteria for Neuropsychological Assessment: A 20-Year Update of the Malingered Neuropsychological Dysfunction Criteria. Arch Clin Neuropsychol. 2020;00:1–30.
4. Schroeder RW, Peck CP, Buddin WH, Heinrichs RJ, Baade LE. The Coin-in-the-Hand Test and Dementia. Cogn Behav Neurol. 2012 Sep;25(3):139–43.
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...
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 nosology-based clinical “entities” such as MA and MO, a purely phenomenologic biologically-implausible clinical cul-de-sac that was underscored almost 2 decades previously, and that creates exponentially increasing but confusing data, and, does not allow a unifying overarching hypothesis for migraine to emerge (2). This distancing of science from reason and logic is one of the major factors in the continued limited pathophysiologic understanding of migraine (3,4).
The authors underscore the risk between migraine-related stroke and systemic blood pressure (1). A strong inverse relationship
between BP (systolic, diastolic, and pulse-pressure) and different headache types in an 11-year prospective perspective has been observed, consistent with previous studies (5). Migraine patients tend to maintain a low blood pressure, an adaptive homeostatic measure probably linked to aberrations in the ANS-ocular choroidal blood flow-intraocular pressure (6,7). A low blood pressure retards systemic cerebrovascular atherosclerosis and can be expected to promote longevity. An adaptive physiologic mechanism protects most patients of hypertension from headache; sudden changes in blood pressure with rapid alterations in the ANS-ocular choroid-IOP nexus rather than sustained elevations of blood pressure cause headache in hypertensive patients (7). No systemic influence, including blood pressure, can rationalize the typical lateralizing headache (unilateral, bilateral, side-shifting, or side-locked) of migraine (8,9). Cross-sectional observations do not elucidate the cause-effect paradigm between migraine and blood pressure, but, like-meta-analyses, can present evidences that cannot be reconciled with a larger picture, can be misleading, and cannot correct entrenched pathophysiologic beliefs. The authors clarify that the coronary and carotid arteries of individuals with active migraine are found to be less severely affected by atherosclerosis than in individuals without migraine (1), an insight lost in the huge mass of cross-sectional often conflicting data. Migraine is believed to underlie an evolutionary advantage for longevity (10).
The authors raise the issue of cigarette tobacco smoking as a prominent link to ischemic stroke (1) without in-depth comprehension of the effects of cigarette smoking chemicals, alteration of hematologic, or the cardinal effects of nicotine in the context of migraine, as placed in the migraine scientific domain over a decade ago. The analgesic, vasomotor, and behavior control actions of nicotine are well-defined, and, likely relate to release of arginine vasopressin, serotonin, and norepinephrine by nicotine, among other neuropeptides, at the level of the brain (11). The tripartite nexus of vasopressin-serotonin-norepinephrine is a well-defined variably-exhaustive adaptive/protective mechanism that delays onset of migraine headache in a variety of clinical conditions and circumstances, as well as prevents development of migraine in ~80% of the general population despite almost global exposure in humans to psycho-social non-oxidative stress (6,12,13). Post-stress headache is a typical feature of migraine (10), a characteristic that mandates the operation of a protective mechanism (6). Stress, a euphemism for our ignorance about cellular-level physiological mechanisms that play a key role in migraine, is again a complex issue. Depression is the commonest comorbidity of migraine, and nicotine withdrawal may produce depressive symptoms or precipitate a major depressive episode, while antidepressants may relieve these features (14). Secondly, nicotine may have antidepressant effects that maintain smoking (14). In effect, nicotine, like tricyclic antidepressants, has a migraine-remitting combined central serotonergic and noradrenergic agonistic action at the level of the brain/CNS synapse (11). Cigarette smoking cannot be linked uncritically to migraine-related stroke without such considerations.
In a similar vein, the authors infer an ischemic stroke-inducing effect of estrogen/oral contraceptives (1). In migraine research, it has become amply clear that estrogen withdrawal, rather than its intake as a combination oral contraceptive, is associated with occurrence of migraine attacks (15,16). Any link between estrogen use in female migraine patients and possible development of ischemic stroke (1) cannot be allowed to blunt the clear perspective of migraine protective role of estrogen.
Worsening of migraine during the first trimester of pregnancy (1) indicates loss of a protective/adaptive mechanism. Bioavailablity of placental vasopressinase, a cysteine aminopeptidase that degrades AVP but not desmopressin, progressively increases during pregnancy, as reviewed (12). Thus, forty percent of female migraine patients do not improve with pregnancy (12). Also, hypernatremia associated with hyperemesis gravidrarum decreases the biological vasomotor and analgesic activity of basal and stimulated secretion of AVP (12).
The authors do not consider the role of alcohol, a most commonly consumed recreational drug worldwide. Binge alcohol consumption, the major form of excess alcohol intake in the United States, is linked to vasoconstriction in the cerebral circulation and increased risk of stroke (17,18). Unaware of this important difference between daily alcohol and binge alcohol drinking, I, a migraineur since over 4 decades, developed a TIA for 20-30 minutes with collapse and complete loss of consciousness, and with ensuing confusion and agitation during recovery in 2017 at an airport lounge within approximately 20 minutes of consumption of >150 ml of 40% alcohol (unpublished observation).
Cortical spreading depression, genetic factors, patent foramen ovale, and atrial fibrillation (1) are too poorly understood to make any meaningful contribution to a discussion of migraine-linked stroke (4,13, 19,20). Silent structural infarct-like brain lesions (21) and white matter hyperintensities (22) are perfect examples of the stunting of critical thinking by technology, statistics, and meta-analyses in the absence of a robust core understanding of migraine mechanisms (13).
Future advances (1) can make little headway unless the massive synoptic task of removal of conceptual deadwood of the past is undertaken, including serendipity-based non-working hypotheses such as cortical spreading depression and patent foramen ovale-linked genesis of migraine as well as surmises and speculations linked to a body of fictional myths and assumptions (13). Absence of a biologically-plausible overview/scaffolding for migraine pathophysiologic mechanisms is the crippling missing link for in-depth scientific comprehension of the disorder (6).
Science is a process of systematic demystification. Migraine research is a classic example wherein increasing mystification through untrammeled application of technology at the bench, the accountant mentality of holding numbers/statistics including the p-value as sacred and inviolable, personal philosophic and scientific bias most clearly obvious in the critical omissions of major syntheses already available, and convoluted thinking are expected to yield significant biological dividend. Laboratory medicine is intrinsically reductionist (10), the exclusive focus on 1-2 factors obscuring the whole – seeing the trees for the wood (6). Migraine research stands the cusp of a major course correction.
REFERENCES
1. Øie LR, Kurth T, Gulati S, et al. Migraine and risk of stroke. J Neurol Neurosurg Psychiatry 2020;91:593–604. doi:10.1136/jnnp-2018-318254
2. Gupta VK. Rapid Response: Classification of primary headaches: pathophysiology versus nosology? BMJ. Published online 22 January 2004. Available at: https://www.bmj.com/rapid-response/2011/10/30/classification-primary-hea...
3. Gupta VK. Migraine: “how” versus what of a disease process. BMJ Rapid response published online 08 February 2006. Available at: https://www.bmj.com/rapid-response/2011/10/31/migraine-“how”-versus-“what”-disease-process
4. Gupta VK. Pathophysiology of migraine: an increasingly complex narrative to 2020. Future Neurol 2019;14, No. 2 Commentary. Published Online: 24 May 2019. https://doi.org/10.2217/fnl-2019-0003 (OPEN ACCESS)
5. Fagernӕs CF, Heuch I, Zwart J-A, Winsvold BS, Linde M, Hagen K. Blood pressure as a risk factor for headache and migraine: a prospective population-based study. Eur J Neurol 2015;22:155-162.
6. Gupta VK. (Editor) Adaptive Mechanisms in Migraine. A Comprehensive Synthesis in Evolution. Breaking the Migraine Code. New York: Nova Science Publications, 2009.
7. Gupta VK. Systemic hypertension, headache, and ocular hemodynamics: a new hypothesis. MedGenMed 2006;8:63.
8. Gupta VK. Nitric oxide and migraine: another systemic influence postulated to explain a lateralizing disorder. Eur J Neurol 1996;3:172--173.
9. Gupta VK. Migrainous scintillating scotoma and headache is ocular in origin: A new hypothesis. Med Hypotheses. 2006;66:454--460. doi: 10.1016/j.mehy.2005.11.010.
10. Blau JN. Migraine: theories of pathogenesis. Lancet 1992;339:1202--1207.
11. Gupta VK. Antimigraine action of nicotine: theoretical basis and potential clinical application. Eur J Emerg Med 2007;14:243--244.
12. Gupta VK. A clinical review of the adaptive role of vasopressin in migraine. Cephalalgia 1997;17:561--567.
13. Gupta VK. CSD, BBB and MMP-9 elevations: animal experiments versus clinical phenomena in migraine. Expert Rev Neurother 2009;9:1595–1614.
14. Hughes JR, Stead LF, Hartmann-Boyce J, Cahill K, Lancaster T. Antidepressants for smoking cessation. Cochrane Database Syst Rev 2014;CD000031. doi: 10.1002/14651858.CD000031.pub4.
15. Gupta VK. Migraine and sex hormones: epidemiological data stimulate rethinking of etiologic role of estrogen. Headache 2004;44:933--934.
16. MacGregor EA. Migraine, menopause and hormone replacement therapy. Post Reprod Health 2018;24:11-18. doi: 10.1177/2053369117731172.
17. Bukiya A, Dopico AM, Leffler CW, Fedinec A. Dietary cholesterol protects against alcohol-induced cerebral artery constriction.
Alcohol Clin Exp Res. 2014;38:1216-26. doi: 10.1111/acer.12373. 18. Liu P, Xi Q, Ahmed A, Jaggar JH, Dopico AM. Essential role for smooth muscle BK channels in alcohol-induced cerebrovascular constriction. Proc Natl Acad Sci U S A. 2004;28;101:18217-18222.
19. Gupta VK. Patent foramen ovale closure and migraine: science and sensibility, Expert Rev Neurother 2010;10: 1409-1422. (OPEN ACCESS)
20. Gupta VK. Reader response: Migraine with visual aura is a risk factor for incident atrial fibrillation: A cohort study. Neurology. Published online: December 07, 2018. Available at: https://n.neurology.org/content/reader-response-migraine-visual-aura-ris...
21. Gupta V. Silent or non-clinical infarct-like lesions in the posterior circulation territory in migraine: brain hypoperfusion or hyperperfusion? Brain 129, 2006, Page E39, https://doi.org/10.1093/brain/awh697 (Free Access by Editor)
22. Gupta VK. White matter hyperintensities: pearls and pitfalls in interpretation of MRI abnormalities. Stroke 2004; 35:2756-2757.
Dear editor,
Show MoreWe read with great interest the article by Rousseau et al. “Location of intracranial aneurysms is the main factor associated with rupture in the ICAN population.”1
They compared ruptured intracranial aneurysms (RIAs) with unruptured cerebral aneurysms (UCAs) in the ICAN registry, and analyzed factors that were considered associated with subarachnoid hemorrhage in previous literature. As a result, they found the location of the aneurysm showed the largest hazard ratio as much as 6.05 and showed their result with beautiful info-graphic.
We should be careful that their result is derived from comparisons between the aneurysms, which caused subarachnoid hemorrhage and UCAs that was found without bleeding. Hence, the meaning is different from that of ISUIA2, UCAS Japan3, and other studies, which investigated the risk of bleeding from the known UCAs. As noted in the discussion of the headache, which prefers UCAs to RIAs, the factors examined may be seeing factors, which lead to brain examination without causing subarachnoid hemorrhage in France.
As in the title, they focused on the location of the aneurysm, and found ACA and posterior circulation aneurysms have high odds ratio of 4.99 and 6.05 respectively comparing with ICA aneurysms. As in ISUIA study, they included internal carotid- posterior communicating artery (IC-Pcom) aneurysms in the posterior circulation aneurysms, and “ICA” includes other aneurysms occurring on the ICA. However...
Jacobs et al. investigated the association of environmental factors and prodromal features with incident Parkinson's disease (PD) with special reference to the interaction of genetic factors [1]. The authors constructed polygenic risk scores (PRSs) for the risk assessment. Family history of PD, family history of dementia, non-smoking, low alcohol consumption, depression, daytime somnolence, epilepsy and earlier menarche were selected as PD risk factors. The adjusted odds ratio (OR) (95% confidence interval [CI]) of the highest 10% of PRSs for the risk of PD was 3.37 (2.41 to 4.70). I have some concerns about their study.
Regarding risk/protective factors of PD, Daniele et al. conducted a case-control study to performed a simultaneous evaluation of potential factors of PD [2]. Among 31 environmental and lifestyle factors, 9 factors were extracted by multivariate analysis. The adjusted OR (95% CI) of coffee consumption, smoking, physical activity, family history of PD, dyspepsia, exposure to pesticides, metals, and general anesthesia were 0.6 (0.4-0.9), 0.7 (0.6-0.9), 0.8 (0.7-0.9), 3.2 (2.2- 4.8), 1.8 (1.3-2.4), 2.3 (1.3- 4.2), 5.6 (2.3-13.7), 2.8 (1.5-5.4), and 6.1 (2.9-12.7), respectively. Family history of PD and non-smoking were common risk factors, which had also been reported by several prospective studies.
Regarding smoking, Angelopoulou et al. investigated the association between environmental factors and PD subtypes (early-onset, mid-and-late on...
Show MoreThe 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.
Show MoreThis 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...
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...
Show MoreRussell 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
Show MoreMen’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...
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.
Show MoreAs the intravenous immunoglobulins(IVIg) and plasmapharesis are useful in the treatment of GBS with antiganglioside antibodies the trial of IVIg, and monoclonal a...
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...
Show MoreDear 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...
Show MoreWe 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...
Show MoreI 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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