We would like to thank the author for pointing out the fact that a proper disease control in myasthenia gravis (MG) probably predicts a favourable outcome during SARS-CoV-2 infection.
MG exacerbation was only observed in one patient (case 1) treated successfully with immunoglobulins (IVIG) as described. No MG crisis was reported during this period in non-infected patients.
None of the four patients described in our case report received COVID-19 related treatment, namely antiviral and/or hydroxychloroquine. Case 4 received antibiotherapy for 5 days (azythromicine and tazobactam).
Regarding case 2, this patient presents with recurring symptoms of fever and shortness of breath since March 2020. In this regard a chest CT and repeated D-dimers were performed in October, showing negative results.
In clinical practice, neuropathies are groups of disorders with curable, treatable, and non-treatable aetiologies, the later accounting for most of the cases.[1] Every newly identified disorder either on the basis of etiology or syndromic group responding to particular treatment brings hope for few more patients.
This study by Shin J Oh et al [2] brings hope for some patients who were previously either classified as axonal neuropathy of undetermined cause orin the evolutionary phase of a neurodegenerative diseases (such as anterior horn cell diseases). Thus, in the absence of any evidence, such patients usually remained deprived of any immunotherapies and succumbed to the progressive disease. Now with this piece of information, it can be inferred that all those patients presenting with chronic (more than 2 months), symmetrical or asymmetrical, proximal and distal weakness without any evidence of demyelination (i.e. axonal) on nerve conduction studies and without any known secondary causes of axonal polyneuropathy could qualify for immunotherapy when nerve biopsy or CSF protein > 55 mg/dl shows evidence of inflammation. Thus, chronic inflammatory polyneuropathy syndrome would be a more apt diagnosis with two variants: demyelinating (usual Chronic inflammatory demyelinating polyneuropathy, CIDP) and axonal, much like Guillain-Barre syndrome.
However, it can be noted that all the patients included in the study did not qualify for CIAP. There were six patients w...
In clinical practice, neuropathies are groups of disorders with curable, treatable, and non-treatable aetiologies, the later accounting for most of the cases.[1] Every newly identified disorder either on the basis of etiology or syndromic group responding to particular treatment brings hope for few more patients.
This study by Shin J Oh et al [2] brings hope for some patients who were previously either classified as axonal neuropathy of undetermined cause orin the evolutionary phase of a neurodegenerative diseases (such as anterior horn cell diseases). Thus, in the absence of any evidence, such patients usually remained deprived of any immunotherapies and succumbed to the progressive disease. Now with this piece of information, it can be inferred that all those patients presenting with chronic (more than 2 months), symmetrical or asymmetrical, proximal and distal weakness without any evidence of demyelination (i.e. axonal) on nerve conduction studies and without any known secondary causes of axonal polyneuropathy could qualify for immunotherapy when nerve biopsy or CSF protein > 55 mg/dl shows evidence of inflammation. Thus, chronic inflammatory polyneuropathy syndrome would be a more apt diagnosis with two variants: demyelinating (usual Chronic inflammatory demyelinating polyneuropathy, CIDP) and axonal, much like Guillain-Barre syndrome.
However, it can be noted that all the patients included in the study did not qualify for CIAP. There were six patients with secondary causes (mostly M-band associated) for whom, treatment of the primary cause is indicated just like the demyelinating counterpart (CIDP secondary to gammopathies). However, this study paves the way for use of immunotherapy in a selected group of patients and defines the inclusion criteria for further research and drug trials. Future prospective multicentre studies with the above inclusion criteria are warranted.
Reference:
1. Samuelsson K, Press R. Chronic axonal idiopathic polyneuropathy: is it really benign. Current Opinion in Neurology. 2020 Oct;33(5):562–567.
2. Oh SJ, Lu L, Alsharabati M, Morgan MB, King P. Chronic inflammatory axonal polyneuropathy. J Neurol Neurosurg Psychiatry. 2020 Nov 1;91(11):1175–80.
We read with interest the comments of Keddie and Colleagues who suggested caution in accepting a causation link between SARS-CoV-2 infection and Guillain-Barré syndrome (GBS) and in interpreting results from our study “Guillain-Barrè syndrome and COVID-19: an observational multicentre study from two Italian hotspot regions" (1).
We believe they have misinterpreted the message of our paper and have drawn conclusions that was not our intention to draw.
Their first consideration is that our paper cannot demonstrate a causation link between COVID-19 and GBS. Of course, we agree. In fact, we did not talk about any causal nexus. It is well known that, in statistics, “causation” indicates a relationship between two events where one event is affected by the other. In order to demonstrate “causation”, prospective studies are needed. Our study is based on retrospective findings and identified an increased rate of GBS cases concomitantly with the COVID-19 spread in our regions. On this basis, we could not (and indeed we did not) conclude for a definite causative relationship but we suggested a pathogenic link for which COVID-19 could represent a trigger for GBS, as already suggested by other authors (2).
Keddie et al. claimed some possible methodological biases. Part of them is obviously related to the retrospective nature of the study and have been listed as limitations of the study at the end of our paper. They calculated the 95% confidence intervals of the...
We read with interest the comments of Keddie and Colleagues who suggested caution in accepting a causation link between SARS-CoV-2 infection and Guillain-Barré syndrome (GBS) and in interpreting results from our study “Guillain-Barrè syndrome and COVID-19: an observational multicentre study from two Italian hotspot regions" (1).
We believe they have misinterpreted the message of our paper and have drawn conclusions that was not our intention to draw.
Their first consideration is that our paper cannot demonstrate a causation link between COVID-19 and GBS. Of course, we agree. In fact, we did not talk about any causal nexus. It is well known that, in statistics, “causation” indicates a relationship between two events where one event is affected by the other. In order to demonstrate “causation”, prospective studies are needed. Our study is based on retrospective findings and identified an increased rate of GBS cases concomitantly with the COVID-19 spread in our regions. On this basis, we could not (and indeed we did not) conclude for a definite causative relationship but we suggested a pathogenic link for which COVID-19 could represent a trigger for GBS, as already suggested by other authors (2).
Keddie et al. claimed some possible methodological biases. Part of them is obviously related to the retrospective nature of the study and have been listed as limitations of the study at the end of our paper. They calculated the 95% confidence intervals of the incidence rates as 0.08 per 100,000 per month in 2019 (95% C.I.: 0.04-0.15) and 0.2 per 100,000 per month in 2020 (C.I.: 0.14-0.28) and concluded for an overlap between confidence intervals. Actually the 95% confidence intervals based on the numbers of cases and population we reported in our study were 0.077 per 100,000 per month in 2019 (C.I.: 0.041-0.132) and 0.202 per 100,000 per month in 2020 (C.I. 0.140-0.282) (MedCalc, MedCalc Software Ltd, Belgium). Thus, there is no overlap of confidence intervals. Moreover, judging the significance of differences by examining the overlap between two confidence intervals has been debated and discouraged by the statistical community (3).
As a second point, Keddie et al. suggested that the denominator (COVID-19 positive cases) could be underestimated because testing was limited to symptomatic subjects. We clearly acknowledged in the paper that the real number of COVID-19-positive patients was likely higher than that in the official data and this could cause an overestimation of the GBS incidence in the COVID-19-positive population. On the other hand, it should be stressed that also the numerator can be biased. During the Italian outbreak, many Neurological Units were closed in order to provide medical staff for COVID-19 Units and many neurological patients (COVID-19 positive and negative) could not be admitted. Thus, it is likely that GBS cases (either COVID-19 positive or negative) were not recognized. This might also justify the lower number of COVID-19 negative GBS observed in 2020.
Similar problems arose in evaluating the incidence of GBS in Latin America and Caribbean countries during the 2015-20216 Zika virus epidemic because only about 25% of subjects infected by Zika virus showed clinical manifestations and difficulties were encountered in certainty of laboratory diagnosis in regions where other flavivirus are endemic. Nonetheless, a recent meta-analysis of observational studies concluded that GBS increased 2.6 times over background rates during Zika outbreak (4).
Keddie et al. claimed that the denominator for rate calculation of GBS in COVID-19 patients should be substituted with the seroprevalence in the same population (630,000, based on a 7.5% prevalence in Lombardy reported by ISTAT) (5). Again, we agree that the real denominator is difficult to obtain, as we reported in the limitations of the study. However, it should be noted that the reported SARS-CoV-2 seroprevalence tests were performed from May 25, 2020 to July 15, 2020, i.e., in a period subsequent to the months considered in our study and disclosed in August 2020 (6). We do not know and cannot enucleate the seroprevalence in the months of March and April and, for this reason, we preferred to work on the real data of nasopharyngeal swabs rather than on estimated data referring to a period subsequent to that considered in our study.
Findings about duration of seropositivity are discordant (7,8) and whether levels of IgG specific for SARS-CoV-2 antigen persist or decay remains a debated issue (7). We also want to point out that many asymptomatic subjects are seropositive and this raises further questions: 1) Is it correct to investigate a COVID-19/GBS relationship in seropositive patients without active or recent infectious signs? 2) Do we know if asymptomatic patients with positive nasopharyngeal swab are prone to develop para- or post-infectious complications? To date, our answers are no.
Obviously, we cannot exclude that some COVID-19 positive GBS patients represented a casual association and we never excluded this possibility. However, the fact remains that GBS was 2.6 time increased in the same hospitals between 2019 and 2020 and that the incidence of GBS in March and April 2019 (0.077/100 000/month; estimated rate 0.93/100 000/year) was consistent with a previous epidemiological study showing a GBS incidence of 0.75–1.09/100 000/year in Lombardy (9), therefore suggesting a true increased incidence of GBS during the pandemic peak in Northern Italy.
We acknowledge as a limitation of the study the fact that, in many cases, was not possible to exclude other infective antecedents and this is true also for most of reported cases of GBS associated with SARS-CoV2 infection from all over the world (10). Again, this was due to the severe and exceptional health emergency we suffered in Northern Italy during the first epidemic wave.
About the pathogenesis of COVID-19 related GBS, it is untrue that we used data from modelling studies suggesting interaction of the SARS-CoV-2 spike protein with ganglioside GM1 to support a causative link (11). Actually, in our discussion we just mentioned this hypothesis as a “possibility” (“an immune cross-reaction between epitopes within the spike-bearing gangliosides and sugar residues of surface peripheral nerve glycolipids is also possible”) without claiming any causative link.
We also were far from wanting to prove that GBS associated with SARS-CoV-2 infection fulfilled the Witebsky’s criteria for autoimmune disease, that as far as we know in the field of GBS, have been fulfilled only for the acute motor axonal neuropathy variant with anti-GM1 antibodies (12).
In conclusion, isolated or small series of GBS cases associated with SARS-CoV 2 infection were described from all over the world in the first pandemic months (10) and have reached to November 19th 2020 a total of 139 cases especially reported from Italy (38.1%). Our study showed an increased incidence of GBS during COVID-19 outbreak in Northern Italy. Despite the limitations mentioned in the paper and inherent to a retrospective study we deem that these results suggest a relationship.
Keddie et al. reported in their disclosures that they have a similar paper due to be published in a larger cohort and reaching different conclusion. We do not have any detail about their study but different reasons can be hypothesized to explain the differences in results including that the circulating SARS-CoV-2 in Northern Italy and England during the first pandemic wave might have been genetically different with eventually a different capability to trigger GBS (13).
Anyway, currently we are conducting a follow-up analysis on GBS incidence for the months following April 2020 and ISTAT data will be certainly taken into account and evaluated in order to obtain further findings on this debated area.
References
1. Filosto M, Cotti Piccinelli S, Gazzina S, et al. Guillain-Barré syndrome and COVID-19: an observational multicentre study from two Italian hotspot regions. J Neurol Neurosurg Psychiatry 2020; jnnp-2020-324837
2. Rahimi K. Guillain-Barre syndrome during COVID-19 pandemic: an overview of the reports. Neurol Sci 2020; 41: 3149-3156
3. Schenker N, Gentleman JF. On judging the significance of differences by examining the overlap between confidence intervals. The American Statistician 2001; 55:3, 182-186
4. Capasso A, Ompad DC, Vieira DL, Wilder-Smith A, Tozan Y. Incidence of Guillain-Barre´ Syndrome (GBS) in Latin America and the Caribbean before and during the 2015–2016 Zika virus epidemic: A systematic review and meta-analysis. PLoS Negl Trop Dis 2019; 13: e0007622
5. ISTAT, Ministero della Salute. Primi risultati dell’indagine di sieroprevalenza sul SARS-CoV-2. 2020; https://www.istat.it/it/files/2020/08/ReportPrimiRisultatiIndagineSiero.pdf
6.Ministero della Salute, http://www.salute.gov.it/portale/news/p3_2_1_1_1.jsp?lingua=italiano&men...
7.Isho B, Abe KT, Zuo M et al. Persistence of serum and saliva antibody responses to SARS-CoV-2 spike antigens in COVID-19 patients. Science Immunology 2020; 52: eabe5511
8. Escribano P, Álvarez-Uría A, Alonso R, Catalán P, Alcalá L, Muñoz P, Guinea J. Detection of SARS-CoV-2 antibodies is insufficient for the diagnosis of active or cured COVID-19. Sci Rep 2020; 10: 19893
9. Beghi E, Bogliun G. The Guillain-Barrè syndrome (GBS). implementation of a register of the disease on a nationwide basis. Italian GBS Study Group. Ital J Neurol Sci 1996; 17 :355–6
10. 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. J Neurol Neurosurg Psychiatry 2020; 91:1105–10
11. Fantini J, Di Scala C, Chahinian H, et al. Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection. Int J Antimicrob Agents 2020; 55: 105960
12. Yuki N. Ganglioside mimicry and peripheral nerve disease Muscle Nerve 2007; 35: 691-711
13. Pachetti M., Marini B., Benedetti F., Giudici F., Mauro E., Storici P. et al. Emerging SARS-CoV-2 mutation hot spots include a novel RNA-dependent-RNA polymerase variant. J Transl Med 2020; 18: 17
We appreciate the authors for describing their patients’ data in myasthenia with COVID-19 which would help clinicians caring for such patients.1 We have the following comments and queries. We would like to point out that, three out of the four patients who had SARS-CoV-2 infection were not having any infiltrates on chest x-ray, suggesting that these patients had mild COVID-19 infection.2 It is also noteworthy that all these patients who had a normal chest radiograph were either on very low dose azathioprine or no immunosuppressant apart from low dose steroids. As the authors rightly point out, the myasthenia disease activity prior to infection with SARS-CoV-2 is an important predictor of the severity of the myasthenic crisis. It is possible that patients with better control of symptoms or those on appropriate immunosuppression don’t develop a crisis with mild COVID-19. Secondly, it would be interesting to know what specific therapy for COVID-19 was offered to these patients. It is possible that steroids given as a part of therapy for COVID-19 could also act to stabilize disease activity in myasthenia. Similarly, IVIg given to manage Myasthenic crisis could have prevented progression in the severity of COVID-19. Likewise, myasthenic patients who receive drugs such as hydroxychloroquine and macrolides can have precipitation of myasthenic crisis.3,4 In case 2, we would also be interested to know if other causes of chest pain and breathlessness like pulmonary thromboembolism w...
We appreciate the authors for describing their patients’ data in myasthenia with COVID-19 which would help clinicians caring for such patients.1 We have the following comments and queries. We would like to point out that, three out of the four patients who had SARS-CoV-2 infection were not having any infiltrates on chest x-ray, suggesting that these patients had mild COVID-19 infection.2 It is also noteworthy that all these patients who had a normal chest radiograph were either on very low dose azathioprine or no immunosuppressant apart from low dose steroids. As the authors rightly point out, the myasthenia disease activity prior to infection with SARS-CoV-2 is an important predictor of the severity of the myasthenic crisis. It is possible that patients with better control of symptoms or those on appropriate immunosuppression don’t develop a crisis with mild COVID-19. Secondly, it would be interesting to know what specific therapy for COVID-19 was offered to these patients. It is possible that steroids given as a part of therapy for COVID-19 could also act to stabilize disease activity in myasthenia. Similarly, IVIg given to manage Myasthenic crisis could have prevented progression in the severity of COVID-19. Likewise, myasthenic patients who receive drugs such as hydroxychloroquine and macrolides can have precipitation of myasthenic crisis.3,4 In case 2, we would also be interested to know if other causes of chest pain and breathlessness like pulmonary thromboembolism were considered and ruled out as COVID-19 is known to be associated with a hypercoagulable state. In this series, none of the patients died, however, other series have reported a mortality of more than 30% in myasthenic crisis associated with COVID-19.5 It would also be interesting if the authors could present a comparative analysis of their patients who presented with myasthenic crisis with and without COVID-19 during this pandemic period to study the severity of crisis and response to therapy.
1. Hübers A, Lascano AM, Lalive PH. Management of patients with generalised myasthenia gravis and COVID-19: four case reports. J Neurol Neurosurg Psychiatry. 2020;91(10):1124-1125. doi:10.1136/jnnp-2020-323565
2. (Released by National Health Commission & National Administration of Traditional Chinese Medicine on March 3 2020). Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7). Chinese Medical Journal. 2020;133(9):1087–1095. doi:10.1097/CM9.0000000000000819
3. Elavarasi A, Goyal V. Hydroxychloroquine and myasthenia gravis-can one take this risk? Annals of Indian Academy of Neurology. 2020;23(3):360. doi:10.4103/aian.AIAN_363_20
4. Argov Z, Mastaglia FL. Disorders of Neuromuscular Transmission Caused by Drugs. N Engl J Med. 1979;301:409-413. doi:DOI: 10.1056/NEJM197908233010805
5. Camelo-Filho AE, Silva AMS, Estephan EP, et al. Myasthenia Gravis and COVID-19: Clinical Characteristics and Outcomes. Front Neurol. 2020;11. doi:10.3389/fneur.2020.01053
We were interested to read the study of Filosto et al [1] concluding a significant link between Guillain-Barre Syndrome (GBS) and COVID-19 infection in Northern Italy at the peak of the 1st wave SARS-CoV2 pandemic. We urge caution in accepting such a causative conclusion using a retrospective observational study; causation is not conclusively proven and is drawn from potentially biased data and small case numbers of a rare condition, and a rate calculation without confidence intervals to infer uncertainty.
Only 34 cases of GBS, of whom 30 were COVID-19 positive, are reported over a 2-month period, with a denominator population of 8,400,107. We calculated the 95% confidence intervals of the incidence rates as 0.08 per 100,000 per month (95% C.I.: 0.04-0.15) in 2019 and 0.2 per 100,000 per month (95% C.I.: 0.14-0.28) in 2020. The overlapping confidence intervals do not support a statistically significant increase in GBS rates from 2019 to 2020. Furthermore, the simple multiplication of the monthly rate by 12 to create an approximate annualised incidence potentially amplifies the inaccuracy. We suggest that the 2.6-fold difference in GBS incidence from 2019 to 2019 is prone to meaningful statistical error.
During the initial stages of the pandemic the denominator of COVID-19 positive cases will have been under-reported because testing was limited to the symptomatic and presenting populations. We are told that 62,679 inhabitants of the regi...
We were interested to read the study of Filosto et al [1] concluding a significant link between Guillain-Barre Syndrome (GBS) and COVID-19 infection in Northern Italy at the peak of the 1st wave SARS-CoV2 pandemic. We urge caution in accepting such a causative conclusion using a retrospective observational study; causation is not conclusively proven and is drawn from potentially biased data and small case numbers of a rare condition, and a rate calculation without confidence intervals to infer uncertainty.
Only 34 cases of GBS, of whom 30 were COVID-19 positive, are reported over a 2-month period, with a denominator population of 8,400,107. We calculated the 95% confidence intervals of the incidence rates as 0.08 per 100,000 per month (95% C.I.: 0.04-0.15) in 2019 and 0.2 per 100,000 per month (95% C.I.: 0.14-0.28) in 2020. The overlapping confidence intervals do not support a statistically significant increase in GBS rates from 2019 to 2020. Furthermore, the simple multiplication of the monthly rate by 12 to create an approximate annualised incidence potentially amplifies the inaccuracy. We suggest that the 2.6-fold difference in GBS incidence from 2019 to 2019 is prone to meaningful statistical error.
During the initial stages of the pandemic the denominator of COVID-19 positive cases will have been under-reported because testing was limited to the symptomatic and presenting populations. We are told that 62,679 inhabitants of the region had positive COVID-19 swabs during the study, but this is unlikely to provide an accurate population-based rate of COVID-19 infection. More specifically, given that hospital admissions were the only ascertainment source for GBS cases in this study, we are not given comparative information on the rate of COVID-19 positivity in the hospital population, which was likely to have been very high as the Northern Italy healthcare system was reportedly overwhelmed. It is possible, or probable, that a large proportion of the hospitalised population were COVID-19 positive independent of other factors. It is thus likely that these data report a coincidental association between COVID-19 and GBS rather than a causative one.
The COVID-19 seroprevalence rate in the Italian Instituto Nazionale di Statistica (ISTAT) study for Lombardy was the highest in Italy at 7.5%. [2] From this rate, the estimated number of COVID-19 cases would be approximately 630,000 across the seven cities, compared to the 62 679 reported from swabs in the Filosto study. Using seroprevalence as the denominator, we believe the reported calculated incidence reduces from 47.9 to approximately 4.76 per 100,000 COVID-19 infections. The 7.5% seroprevalence may also be an underestimate because of selection bias (under half the planned sample size were tested) or imperfect sensitivity of the assay. It is striking that the seroprevalence reported in London from the NHS Blood Transfusion Service at a similar time was 17.5%;[3] Northern Italy, recognised as one of the hardest hit populations worldwide, seemingly had a seroprevalence of less than half that. Without major differences in health care structure and economic status of these two European countries it is difficult to explain the discrepancy other than the recorded seroprevalence figures were lower than actual infection rates.
Importantly, no account is given for the dramatic 3.3-fold decline in non-COVID GBS to 0.29/100000 per year either. One potential reason for the apparent decline is the mis-attribution of GBS causation, where COVID-19 causation is applied to every COVID-19 positive GBS case. The authors do not explore the possibility of alternative causes of GBS and incidental COVID-19 infection. For example, four of the COVID-19 cases had gastrointestinal symptoms but causation was still attributed to COVID-19 despite a gastroenteritis being the commonest precursor of GBS and occurring less frequently as a COVID-19 specific feature. The authors have presented no data on the exclusion of other causes of GBS such as Campylobacter serology etc. and this is of relevance, as without excluding other causes as far as possible the possibility of misattribution again exists.
Part of the justification Filosto et al make for the causative link is published data to support an interaction of the SarCoV2 spike protein with ganglioside GM1, referencing in silico modelling studies. [4] These studies model shape and energy efficient interactions of the Receptor Binding Domain (RBD) of the spike (S-)protein of SARS-CoV2 with the ACE2 Receptor. Convincing in silico predictive data of the subsequent available N-Terminal Domain of the S-Protein also indicate energy efficient potential binding sites for two GM1 molecules. However, these are models and interactions have not been shown to occur in or ex-vivo. Furthermore, there are no data to suggest that ACE2 receptors are present in peripheral nerve axons or myelin to provide the basis of binding to a colocalised ganglioside.
GBS is a para- or more likely post-infectious autoimmune neuropathy, although acute polyradiculoneuropathies indistinguishable from classical Campylobacter jejuni enteritis associated GBS may occur by direct infection in Zika- and West Nile viruses and others. These cases of GBS occur with short latency whereas classical GBS occurs one to three (and possibly up to six) weeks after infection after an immune response induction. In the series of Filosto et al their median time from infection to GBS was 23 days (IQR 16-34), almost all within the COVID-19 symptom period (5 cases started after COVID symptoms resolved and thus are most consistent with a post-infectious timing). Thus, if it proposed that covalent binding to gangliosides is a mechanism for direct infection of peripheral nerves this would be considered too long a latency, and if an immune response is the key, then COVID-19 spike protein binding to a ganglioside is possibly irrelevant to the pathogenesis. Clearly more work is required to establish whether a definitive temporal relationship exists between COVID-19 and GBS, and more so the pathogenic mechanism which links infection to neuropathy.
The Witebsky Postulates, with some minor modifications, have stood the test of time to provide support for autoimmune linkage of a pathogen to a disease.[5] None are really fulfilled here and we should be very cautious about drawing causative conclusions from observational studies of small numbers of patients where the prevalence of COVID-19 in the population is so high as to have affected very many people who may have been presenting to hospital anyway.
Lastly, it is reassuring that the treatment and outcomes of patients are no different between COVID-19 positive and negative GBS patients and that given the lack of any spike in GBS presentations in Northern Italy (with the total incidence rate being 2.43/100000) we do not expect an additional pandemic of acute neuromuscular paralysis.
Stephen Keddie, Julia Pakpoor, Aisling Carr, Michael P Lunn
References
1. Filosto M, Cotti Piccinelli S, Gazzina S, et al. Guillain-Barré syndrome and COVID-19: an observational multicentre study from two Italian hotspot regions. J Neurol Neurosurg Psychiatry 2020;0:jnnp-2020-324837. doi:10.1136/jnnp-2020-324837
2. ISTAT, Ministero della Salute. Primi risultati dell’indagine di sieroprevalenza sul SARS-CoV-2. 2020;:10.
3. Public Health England. Sero-surveillance of COVID-19. 2020.https://www.gov.uk/government/publications/national-covid-19-surveillanc... (accessed 13 Jul 2020).
4. Fantini J, Di Scala C, Chahinian H, et al. Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection. Int J Antimicrob Agents 2020;55. doi:10.1016/j.ijantimicag.2020.105960
5. Witebsky E, Rose NR, Terplan K, et al. Chronic thyroiditis and autoimmunization. J Am Med Assoc 1957;164:1439–47. doi:10.1001/jama.1957.02980130015004
We read with great interest the article by Macerollo et al. entitled “Non-invasive intervention for motor signs of Parkinson’s Disease: the effect of vibratory stimuli.”[1] The authors evaluated the use of a wearable device called the "Emma Watch" that produces a constant vibratory stimulus (200 Hz) to the wrist with frequencies of 20 bpm or 60 bpm in terms of motor function of the arms of 16 patients with Parkinson’s disease (PD).[1] Motor performance was assessed through three different tasks: a nine-peg hole test, a STYAR tracing task, and a SPIRAL tracking test.[1] The authors found that patients with PD who used the device with 200 Hz peripheral vibration modulated by 60 bpm as they carried out these tasks performed better in terms of speed and precision.[1] The final conclusion was that vibrotactile stimulation can improve motor function in patients with PD.[1] It is important to comment that the authors did not discuss their results in terms of other studies in the literature, including one systematic review published in 2014 [2] and another with a meta-analysis published in 2020. [3] In these studies, vibratory stimulation in patients with PD was generally seen to yield positive results with regard to balance and gait. [2,3] From a historical point of view, the pioneering and seminal work of Jean-Martin Charcot, who used a vibrating chair to treat patients with PD, should also be noted.[4,5]
1. Macerollo A, Holz C, Cletheror D, et al. Non-invasiv...
We read with great interest the article by Macerollo et al. entitled “Non-invasive intervention for motor signs of Parkinson’s Disease: the effect of vibratory stimuli.”[1] The authors evaluated the use of a wearable device called the "Emma Watch" that produces a constant vibratory stimulus (200 Hz) to the wrist with frequencies of 20 bpm or 60 bpm in terms of motor function of the arms of 16 patients with Parkinson’s disease (PD).[1] Motor performance was assessed through three different tasks: a nine-peg hole test, a STYAR tracing task, and a SPIRAL tracking test.[1] The authors found that patients with PD who used the device with 200 Hz peripheral vibration modulated by 60 bpm as they carried out these tasks performed better in terms of speed and precision.[1] The final conclusion was that vibrotactile stimulation can improve motor function in patients with PD.[1] It is important to comment that the authors did not discuss their results in terms of other studies in the literature, including one systematic review published in 2014 [2] and another with a meta-analysis published in 2020. [3] In these studies, vibratory stimulation in patients with PD was generally seen to yield positive results with regard to balance and gait. [2,3] From a historical point of view, the pioneering and seminal work of Jean-Martin Charcot, who used a vibrating chair to treat patients with PD, should also be noted.[4,5]
1. Macerollo A, Holz C, Cletheror D, et al. Non-invasive intervention for motor signs of Parkinson’s Disease: the effect of vibratory stimuli. J Neurol Neurosurg Psychiatry 2020; September. Online ahead of print.
2. Sharififara S, Coronado RA, Romero S, Azari H, Thigpen M. The effects of whole body vibration on mobility and balance in Parkinson’s Disease: a systematic review. IJMS 2014; 39 (4): 318-326.
3. Marazzi S, Kiper P, Palmer K, Agostini M, Turolla A. Effects of vibratory stimulation on balance and gait in Parkinson’s Disease: a systematic review and meta-analysis. Eur J Phys Rehabil Med 2020; Jan 14. Doi: 10.23736/S1973-9087.20.06099. Online ahead of print.
4. Goetz CG. Jean-Martin Charcot and his vibratory chair for Parkinson Disease. Neurology 2009; 73 (6): 475-478.
5. Kapur SS, Stebbins G, Goetz CG. Vibration therapy for Parkinson’s Disease: Charcot´s studies revisited. J Parkinsons Dis 2012; 2 (1): 23-27.
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
We would like to thank the author for pointing out the fact that a proper disease control in myasthenia gravis (MG) probably predicts a favourable outcome during SARS-CoV-2 infection.
MG exacerbation was only observed in one patient (case 1) treated successfully with immunoglobulins (IVIG) as described. No MG crisis was reported during this period in non-infected patients.
None of the four patients described in our case report received COVID-19 related treatment, namely antiviral and/or hydroxychloroquine. Case 4 received antibiotherapy for 5 days (azythromicine and tazobactam).
Regarding case 2, this patient presents with recurring symptoms of fever and shortness of breath since March 2020. In this regard a chest CT and repeated D-dimers were performed in October, showing negative results.
In clinical practice, neuropathies are groups of disorders with curable, treatable, and non-treatable aetiologies, the later accounting for most of the cases.[1] Every newly identified disorder either on the basis of etiology or syndromic group responding to particular treatment brings hope for few more patients.
Show MoreThis study by Shin J Oh et al [2] brings hope for some patients who were previously either classified as axonal neuropathy of undetermined cause orin the evolutionary phase of a neurodegenerative diseases (such as anterior horn cell diseases). Thus, in the absence of any evidence, such patients usually remained deprived of any immunotherapies and succumbed to the progressive disease. Now with this piece of information, it can be inferred that all those patients presenting with chronic (more than 2 months), symmetrical or asymmetrical, proximal and distal weakness without any evidence of demyelination (i.e. axonal) on nerve conduction studies and without any known secondary causes of axonal polyneuropathy could qualify for immunotherapy when nerve biopsy or CSF protein > 55 mg/dl shows evidence of inflammation. Thus, chronic inflammatory polyneuropathy syndrome would be a more apt diagnosis with two variants: demyelinating (usual Chronic inflammatory demyelinating polyneuropathy, CIDP) and axonal, much like Guillain-Barre syndrome.
However, it can be noted that all the patients included in the study did not qualify for CIAP. There were six patients w...
We read with interest the comments of Keddie and Colleagues who suggested caution in accepting a causation link between SARS-CoV-2 infection and Guillain-Barré syndrome (GBS) and in interpreting results from our study “Guillain-Barrè syndrome and COVID-19: an observational multicentre study from two Italian hotspot regions" (1).
Show MoreWe believe they have misinterpreted the message of our paper and have drawn conclusions that was not our intention to draw.
Their first consideration is that our paper cannot demonstrate a causation link between COVID-19 and GBS. Of course, we agree. In fact, we did not talk about any causal nexus. It is well known that, in statistics, “causation” indicates a relationship between two events where one event is affected by the other. In order to demonstrate “causation”, prospective studies are needed. Our study is based on retrospective findings and identified an increased rate of GBS cases concomitantly with the COVID-19 spread in our regions. On this basis, we could not (and indeed we did not) conclude for a definite causative relationship but we suggested a pathogenic link for which COVID-19 could represent a trigger for GBS, as already suggested by other authors (2).
Keddie et al. claimed some possible methodological biases. Part of them is obviously related to the retrospective nature of the study and have been listed as limitations of the study at the end of our paper. They calculated the 95% confidence intervals of the...
We appreciate the authors for describing their patients’ data in myasthenia with COVID-19 which would help clinicians caring for such patients.1 We have the following comments and queries. We would like to point out that, three out of the four patients who had SARS-CoV-2 infection were not having any infiltrates on chest x-ray, suggesting that these patients had mild COVID-19 infection.2 It is also noteworthy that all these patients who had a normal chest radiograph were either on very low dose azathioprine or no immunosuppressant apart from low dose steroids. As the authors rightly point out, the myasthenia disease activity prior to infection with SARS-CoV-2 is an important predictor of the severity of the myasthenic crisis. It is possible that patients with better control of symptoms or those on appropriate immunosuppression don’t develop a crisis with mild COVID-19. Secondly, it would be interesting to know what specific therapy for COVID-19 was offered to these patients. It is possible that steroids given as a part of therapy for COVID-19 could also act to stabilize disease activity in myasthenia. Similarly, IVIg given to manage Myasthenic crisis could have prevented progression in the severity of COVID-19. Likewise, myasthenic patients who receive drugs such as hydroxychloroquine and macrolides can have precipitation of myasthenic crisis.3,4 In case 2, we would also be interested to know if other causes of chest pain and breathlessness like pulmonary thromboembolism w...
Show MoreTo the Editor
We were interested to read the study of Filosto et al [1] concluding a significant link between Guillain-Barre Syndrome (GBS) and COVID-19 infection in Northern Italy at the peak of the 1st wave SARS-CoV2 pandemic. We urge caution in accepting such a causative conclusion using a retrospective observational study; causation is not conclusively proven and is drawn from potentially biased data and small case numbers of a rare condition, and a rate calculation without confidence intervals to infer uncertainty.
Only 34 cases of GBS, of whom 30 were COVID-19 positive, are reported over a 2-month period, with a denominator population of 8,400,107. We calculated the 95% confidence intervals of the incidence rates as 0.08 per 100,000 per month (95% C.I.: 0.04-0.15) in 2019 and 0.2 per 100,000 per month (95% C.I.: 0.14-0.28) in 2020. The overlapping confidence intervals do not support a statistically significant increase in GBS rates from 2019 to 2020. Furthermore, the simple multiplication of the monthly rate by 12 to create an approximate annualised incidence potentially amplifies the inaccuracy. We suggest that the 2.6-fold difference in GBS incidence from 2019 to 2019 is prone to meaningful statistical error.
During the initial stages of the pandemic the denominator of COVID-19 positive cases will have been under-reported because testing was limited to the symptomatic and presenting populations. We are told that 62,679 inhabitants of the regi...
Show MoreWe read with great interest the article by Macerollo et al. entitled “Non-invasive intervention for motor signs of Parkinson’s Disease: the effect of vibratory stimuli.”[1] The authors evaluated the use of a wearable device called the "Emma Watch" that produces a constant vibratory stimulus (200 Hz) to the wrist with frequencies of 20 bpm or 60 bpm in terms of motor function of the arms of 16 patients with Parkinson’s disease (PD).[1] Motor performance was assessed through three different tasks: a nine-peg hole test, a STYAR tracing task, and a SPIRAL tracking test.[1] The authors found that patients with PD who used the device with 200 Hz peripheral vibration modulated by 60 bpm as they carried out these tasks performed better in terms of speed and precision.[1] The final conclusion was that vibrotactile stimulation can improve motor function in patients with PD.[1] It is important to comment that the authors did not discuss their results in terms of other studies in the literature, including one systematic review published in 2014 [2] and another with a meta-analysis published in 2020. [3] In these studies, vibratory stimulation in patients with PD was generally seen to yield positive results with regard to balance and gait. [2,3] From a historical point of view, the pioneering and seminal work of Jean-Martin Charcot, who used a vibrating chair to treat patients with PD, should also be noted.[4,5]
1. Macerollo A, Holz C, Cletheror D, et al. Non-invasiv...
Show MoreDear 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...
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