Malpetti et al. examined neuroinflammation in subcortical regions for predicting clinical progression in patients with progressive supranuclear palsy (PSP) (1). Principal component analysis (PCA) was applied for the analysis, and neuroinflammation and tau burden in the brainstem and cerebellum significantly correlated with the subsequent annual rate of change in the score of Progressive Supranuclear Palsy Rating Scale. Namely, PCA-derived [11C]PK11195 positron emission tomography (PET) markers of neuroinflammation and tau pathology significantly correlated with regional brain volume, but MRI volumes alone did not predict the clinical progression. I present some information with special reference to treatment strategies.
As there are no modifiable lifestyle factors to suppress progression of PSP (2), keeping quality of life by symptom-controlling medications has been recommended. Morgan et al. reported that symptomatic medications, most often for parkinsonism and depression, were prescribed for 87% of patients with PSP, whose satisfaction was poor in most cases (3). Although there have been no effective neuroprotective therapies and/or disease-modifying agents for patients with tauopathies and synucleinopathies, Jabbari et al. recently identified that genetic variation at the leucine-rich repeat kinase 2 (LRRK2) locus was significantly associated with survival in PSP, which might be based on the effect of long noncoding RNA on LRRK2 expression (4). As LRRK2 is associ...
Malpetti et al. examined neuroinflammation in subcortical regions for predicting clinical progression in patients with progressive supranuclear palsy (PSP) (1). Principal component analysis (PCA) was applied for the analysis, and neuroinflammation and tau burden in the brainstem and cerebellum significantly correlated with the subsequent annual rate of change in the score of Progressive Supranuclear Palsy Rating Scale. Namely, PCA-derived [11C]PK11195 positron emission tomography (PET) markers of neuroinflammation and tau pathology significantly correlated with regional brain volume, but MRI volumes alone did not predict the clinical progression. I present some information with special reference to treatment strategies.
As there are no modifiable lifestyle factors to suppress progression of PSP (2), keeping quality of life by symptom-controlling medications has been recommended. Morgan et al. reported that symptomatic medications, most often for parkinsonism and depression, were prescribed for 87% of patients with PSP, whose satisfaction was poor in most cases (3). Although there have been no effective neuroprotective therapies and/or disease-modifying agents for patients with tauopathies and synucleinopathies, Jabbari et al. recently identified that genetic variation at the leucine-rich repeat kinase 2 (LRRK2) locus was significantly associated with survival in PSP, which might be based on the effect of long noncoding RNA on LRRK2 expression (4). As LRRK2 is associated with some forms of Parkinson's disease (PD), the potential effect of LRRK2 modulation should be examined as a disease-modifying therapy for PSP and other related tauopathies, including PD.
VandeVrede et al. reviewed tau-targeted therapies in clinical trials (5), and also presented the history and future directions of disease-modifying therapy (6). Although an effective disease-modifying therapy has not been developed yet, information on some genetic variations might lead to the development of new medications in the future (4).
References
1. Malpetti M, Passamonti L, Jones PS, et al. Neuroinflammation predicts disease progression in progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 2021 Mar 17. doi: 10.1136/jnnp-2020-325549. [Epub ahead of print]
2. Glasmacher SA, Leigh PN, Saha RA. Predictors of survival in progressive supranuclear palsy and multiple system atrophy: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2017;88:402-411.
3. Morgan JC, Ye X, Mellor JA, et al. Disease course and treatment patterns in progressive supranuclear palsy: A real-world study. J Neurol Sci 2021;421:117293.
4. Jabbari E, Koga S, Valentino RR, et al. Genetic determinants of survival in progressive supranuclear palsy: a genome-wide association study. Lancet Neurol 2021;20:107-116.
5. VandeVrede L, Boxer AL, Polydoro M. Targeting tau: Clinical trials and novel therapeutic approaches. Neurosci Lett 2020;731:134919.
6. VandeVrede L, Ljubenkov PA, Rojas JC, et al. Four-Repeat Tauopathies: Current Management and Future Treatments. Neurotherapeutics 2020;17:1563-1581.
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 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 read with great interest the recent article by Mac Grory et al.1 The authors conducted a comprehensive review on the carotid network as a possible chain factor of cryptogenic embolic stroke, particularly in young patients without risk factors. This condition accounts for approximately 25% of ischemic strokes and has less severe sequelae than other forms of strokes, making the topic of the association of stroke and other diseases interesting to open discussion, in order to intervene and prevent serious recurrent strokes that will lead to irreversible sequelae.1
The carotid network is defined as a fibromuscular dysplasia of the intima in the carotid arteries, which causes a deficiency in intraluminal filling along the posterior wall of the carotid bulb, this can be observed through imaging such as ultrasound or CT angiography.2 This pathological entity has been reported as a sub diagnostic,2 because it is little known and does not have the epidemiological impact it should have, even more so because most sufferers are asymptomatic.3 Although there are studies that state that this condition occurs more frequently in a population < 55 years (average 45 - 50 years)4, there are cohorts that report cases near 30 years. In addition, another aspect to highlight is that these studies are carried out mainly in developed countries, so the epidemiological distribution of this condition in low- and middle-income countries is not clearly known, who possess genetic characteris...
We read with great interest the recent article by Mac Grory et al.1 The authors conducted a comprehensive review on the carotid network as a possible chain factor of cryptogenic embolic stroke, particularly in young patients without risk factors. This condition accounts for approximately 25% of ischemic strokes and has less severe sequelae than other forms of strokes, making the topic of the association of stroke and other diseases interesting to open discussion, in order to intervene and prevent serious recurrent strokes that will lead to irreversible sequelae.1
The carotid network is defined as a fibromuscular dysplasia of the intima in the carotid arteries, which causes a deficiency in intraluminal filling along the posterior wall of the carotid bulb, this can be observed through imaging such as ultrasound or CT angiography.2 This pathological entity has been reported as a sub diagnostic,2 because it is little known and does not have the epidemiological impact it should have, even more so because most sufferers are asymptomatic.3 Although there are studies that state that this condition occurs more frequently in a population < 55 years (average 45 - 50 years)4, there are cohorts that report cases near 30 years. In addition, another aspect to highlight is that these studies are carried out mainly in developed countries, so the epidemiological distribution of this condition in low- and middle-income countries is not clearly known, who possess genetic characteristics other than those of the first world.1,2,5
Currently, under the ravages of the pandemic by COVID-19, cases of cryptogenic stroke have been reported in young patients positive for COVID-19 without risk factors, representing the stroke as the debut of this disease, a true mystery when compared to other similar groups.6 Although it is known that the state of hypercoagulability precipitates the presentation of thromboembolic events, the question of why in certain groups of young people with no cardiovascular risk factors this neurological complication develops, compared to other groups quickly arises. 6
We consider that the carotid network may be the risk factor that triggers the presentation of stroke in young patients without cardiovascular factors with COVID-19, which along with the state of hypercoagulability, facilitates the presentation of transient ischemic events, the main form of manifestation of these particular cases.6 Based on the above and what is proposed by Mac Grory et al.1, it is necessary to take into account this association when establishing the therapeutic plan of stroke in young people who develop this complication. Likewise, multicenter studies of the best quality should be carried out to accurately determine the prevalence of carotid fibromuscular dysplasia in young patients, especially in low- and middle-income countries, where there is the greatest number of under-registrations.
REFERENCES
1. Mac Grory B, Emmer BJ, Roosendaal SD, Zagzag D, Yaghi S, Nossek E. Carotid web: an occult mechanism of embolic stroke. Journal of Neurology, Neurosurgery & Psychiatry. 2020; 91(12):1283-9.
2. Ren T, Sun S, Qu X, Gao Y. Carotid Web Misdiagnosis. World Neurosurg. 2020; 140:128-130.
3. Hu H, Zhang X, Zhao J, Li Y, Zhao Y. Transient Ischemic Attack and Carotid Web. AJNR Am J Neuroradiol. 2019; 40(2):313-318.
4. Joux J, Boulanger M, Jeannin S, et al. Association Between Carotid Bulb Diaphragm and Ischemic Stroke in Young Afro-Caribbean Patients. Stroke. 2016; 47(10):2641-4.
5. Yu Y, Wang B, Zheng S, Kou J, Gu X, Liu T. Carotid web and ischemic stroke: a CT angiography study. Clin Imaging. 2020; 67:86-90.
6. Fifi JT, Mocco J. COVID-19 related stroke in young individuals. Lancet Neurol. 2020; 19(9):713-715.
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]
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.
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 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.
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
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
Malpetti et al. examined neuroinflammation in subcortical regions for predicting clinical progression in patients with progressive supranuclear palsy (PSP) (1). Principal component analysis (PCA) was applied for the analysis, and neuroinflammation and tau burden in the brainstem and cerebellum significantly correlated with the subsequent annual rate of change in the score of Progressive Supranuclear Palsy Rating Scale. Namely, PCA-derived [11C]PK11195 positron emission tomography (PET) markers of neuroinflammation and tau pathology significantly correlated with regional brain volume, but MRI volumes alone did not predict the clinical progression. I present some information with special reference to treatment strategies.
As there are no modifiable lifestyle factors to suppress progression of PSP (2), keeping quality of life by symptom-controlling medications has been recommended. Morgan et al. reported that symptomatic medications, most often for parkinsonism and depression, were prescribed for 87% of patients with PSP, whose satisfaction was poor in most cases (3). Although there have been no effective neuroprotective therapies and/or disease-modifying agents for patients with tauopathies and synucleinopathies, Jabbari et al. recently identified that genetic variation at the leucine-rich repeat kinase 2 (LRRK2) locus was significantly associated with survival in PSP, which might be based on the effect of long noncoding RNA on LRRK2 expression (4). As LRRK2 is associ...
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 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 read with great interest the recent article by Mac Grory et al.1 The authors conducted a comprehensive review on the carotid network as a possible chain factor of cryptogenic embolic stroke, particularly in young patients without risk factors. This condition accounts for approximately 25% of ischemic strokes and has less severe sequelae than other forms of strokes, making the topic of the association of stroke and other diseases interesting to open discussion, in order to intervene and prevent serious recurrent strokes that will lead to irreversible sequelae.1
The carotid network is defined as a fibromuscular dysplasia of the intima in the carotid arteries, which causes a deficiency in intraluminal filling along the posterior wall of the carotid bulb, this can be observed through imaging such as ultrasound or CT angiography.2 This pathological entity has been reported as a sub diagnostic,2 because it is little known and does not have the epidemiological impact it should have, even more so because most sufferers are asymptomatic.3 Although there are studies that state that this condition occurs more frequently in a population < 55 years (average 45 - 50 years)4, there are cohorts that report cases near 30 years. In addition, another aspect to highlight is that these studies are carried out mainly in developed countries, so the epidemiological distribution of this condition in low- and middle-income countries is not clearly known, who possess genetic characteris...
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...
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...
Show MoreIn 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 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.
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 MoreI 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...
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