It is with great interest that I read the excellent paper by Beyrouti R, et al, on the characteristics of ischaemic stroke among patients with COVID-19(1). There is great interest in the prothromotic state seen in this illness – in this series, high D-dimer and fibrinogen levels in 6/6, positive lupus anticoagulant in 4/5, moderate anti-cardiolipin titres in 1/6.
But I note that there are still some traditional mechanisms in these patients that may have been the cause of the stroke that may not have been fully elucidated, or if they were, were not reported in the paper. I see that patients 2 and 3 had atrial fibrillation, on warfarin, with supra-therapeutic (3.6, artificial heart valve) and sub-therapeutic (1.03) INRs respectively. The results of echocardiography and cardiac rhythm monitoring were not reported for any patient. Thus cardioembolism is still possible as a cause of stroke. Patients 2 to 5 had hypertension and at least one other atherosclerotic vascular risk factor (eg diabetes mellitus, hypercholesterolaemia, smoking, stroke). All patients save 1 was above 60 years of age. Vascular imaging was only reported for 2 cases (5 - CTA and 6 - MRA). Atherothromboelbolism may have caused stroke in some of the patients.
I refer to case series of stroke seen during the 2002-2204 SARS epidemic, also due to a corona virus (2); all had large artery ischaemic strokes, at least 2 of 4 assessed patients had a cardioembolic source, with anot...
It is with great interest that I read the excellent paper by Beyrouti R, et al, on the characteristics of ischaemic stroke among patients with COVID-19(1). There is great interest in the prothromotic state seen in this illness – in this series, high D-dimer and fibrinogen levels in 6/6, positive lupus anticoagulant in 4/5, moderate anti-cardiolipin titres in 1/6.
But I note that there are still some traditional mechanisms in these patients that may have been the cause of the stroke that may not have been fully elucidated, or if they were, were not reported in the paper. I see that patients 2 and 3 had atrial fibrillation, on warfarin, with supra-therapeutic (3.6, artificial heart valve) and sub-therapeutic (1.03) INRs respectively. The results of echocardiography and cardiac rhythm monitoring were not reported for any patient. Thus cardioembolism is still possible as a cause of stroke. Patients 2 to 5 had hypertension and at least one other atherosclerotic vascular risk factor (eg diabetes mellitus, hypercholesterolaemia, smoking, stroke). All patients save 1 was above 60 years of age. Vascular imaging was only reported for 2 cases (5 - CTA and 6 - MRA). Atherothromboelbolism may have caused stroke in some of the patients.
I refer to case series of stroke seen during the 2002-2204 SARS epidemic, also due to a corona virus (2); all had large artery ischaemic strokes, at least 2 of 4 assessed patients had a cardioembolic source, with another having a recent myocardial infarction. I feel there is value in doing as full an evaluation as is reasonably possible to determine the cause of stroke.
The TOAST criteria are widely used in clinical practice, classifying ischaemic stroke mechanisms into 1) large-artery atherosclerosis, 2) cardioembolism, 3) small-vessel occlusion, 4) stroke of other determined etiology, and 5) stroke of undetermined etiology (3). The last category includes those who had more than 1 determined cause, had no determined cause despite extensive investigation, or who had an incomplete aetiological evaluation. Thus, each case requires a full evaluation before cause is assigned; else they will be of undetermined origin.
I hope the authors could kindly provide follow-up information on the results of these investigations, when they are available, so that we may better understand the cause of the stroke in all their patients.
Thank you again for a most interesting paper.
1. Beyrouti R, Adams ME, Benjamin L, Cohen H, Farmer SF, Goh YY, Humphries F,
Jäger HR, Losseff NA, Perry RJ, Shah S, Simister RJ, Turner D, Chandratheva A,
Werring DJ. Characteristics of ischaemic stroke associated with COVID-19. J
Neurol Neurosurg Psychiatry. 2020 Apr 30. pii: jnnp-2020-323586
2. Umapathi T, Kor AC, Venketasubramanian N, Lim CC, Pang BC, Yeo TT, Lee CC, Lim
PL, Ponnudurai K, Chuah KL, Tan PH, Tai DY, Ang SP. Large artery ischaemic stroke
in severe acute respiratory syndrome (SARS). J Neurol. 2004 Oct;251(10):1227-31.
3. Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE
3rd. Classification of subtype of acute ischemic stroke. Definitions for use in a
multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment.
Stroke. 1993 Jan;24(1):35-41
The editorial by Manji et al.1 on the neurology of the COVID-19 pandemic cites Mao et al2.’s report describing 5 ischemic strokes in 214 COVID-19 patients. Helms et al3,. and Zhang et al4. have also since reported ischemic stroke in patients with severe SARS-CoV-2 infection, with the latter linking stroke to antiphospholipid antibodies4. In addition, Oxley et al. describe large-vessel stroke in 5 young patients5. In this context, I would like to highlight our 2003 study of ischemic stroke in severe SARS-CoV-1 infection, the corona virus responsible for Severe Acute Respiratory Syndrome (SARS)6. Five out of a total of 206 SARS patients in the country developed large artery ischemic stroke7, four of whom were critically ill. They were not significantly older (56±13 years) than other critically-ill SARS patients (50±16 years, Anova p=0.45). Besides episodes of hypotension, we suspected thromboembolism as a possible mechanism of stroke. Four of the eight SARS patients, who had autopsy examination, revealed evidence of pulmonary thromboemboli8. One was a 39-year-old man, with no stroke risk factors, who died two weeks after contracting SARS; his autopsy revealed unilateral occipital lobe infarction, sterile vegetations on multiple valves, deep venous thrombosis and pulmonary embolism. This prompted the subsequent use of low molecular weight heparin (LMWH) in critically-ill patients, at doses to achieve anti-Xa levels of 0.5-1.0IU/ml. Nevertheless, one-thir...
The editorial by Manji et al.1 on the neurology of the COVID-19 pandemic cites Mao et al2.’s report describing 5 ischemic strokes in 214 COVID-19 patients. Helms et al3,. and Zhang et al4. have also since reported ischemic stroke in patients with severe SARS-CoV-2 infection, with the latter linking stroke to antiphospholipid antibodies4. In addition, Oxley et al. describe large-vessel stroke in 5 young patients5. In this context, I would like to highlight our 2003 study of ischemic stroke in severe SARS-CoV-1 infection, the corona virus responsible for Severe Acute Respiratory Syndrome (SARS)6. Five out of a total of 206 SARS patients in the country developed large artery ischemic stroke7, four of whom were critically ill. They were not significantly older (56±13 years) than other critically-ill SARS patients (50±16 years, Anova p=0.45). Besides episodes of hypotension, we suspected thromboembolism as a possible mechanism of stroke. Four of the eight SARS patients, who had autopsy examination, revealed evidence of pulmonary thromboemboli8. One was a 39-year-old man, with no stroke risk factors, who died two weeks after contracting SARS; his autopsy revealed unilateral occipital lobe infarction, sterile vegetations on multiple valves, deep venous thrombosis and pulmonary embolism. This prompted the subsequent use of low molecular weight heparin (LMWH) in critically-ill patients, at doses to achieve anti-Xa levels of 0.5-1.0IU/ml. Nevertheless, one-third of severe SARS patients developed venous thromboembolism including pulmonary embolism6,7. Three of the 5 stroke patients had also received LMWH. Three patients had unremarkable procoagulant work-up. While we did not measure D-dimer systematically 2 had evidence of disseminated intravascular coagulation, both whom died. Both Mao et al. and Oxley et al. highlight the possible significance of raised D-dimer in COVID-19 patients who developed stroke2,5. Furthermore, intravenous immunoglobulin (IVIg) was given empirically to 3 of our patients, at 2, 5 and 16 days before stroke onset, that could have compounded the thromboembolic risk.
Experimental, albeit conflicting, evidence suggests that the SARS-CoV1 virus, which causes SARS, could activate transcription of a prothrombinase gene, coding Fibrinogen-like 2 (FGL2)9. FGL2 is a multi-functional protein that activates prothrombin to generate thrombin that in turn converts fibrinogen into fibrin, possibly explaining the extensive fibrin deposition in the lungs of SARS patients as well as inducing a prothrombotic state. Interestingly, the proteolytic activity of FGL2 is independent of factor X and cannot be inhibited by antithrombin III9, perhaps explaining LMWH’s apparent lack of efficacy in our patients.
Ischemic stroke appears to be an infrequent complication of corona virus infections, occurring mainly in the very ill patients with multiple contributory co-morbidities. However, in contrast to SARS, which affected fewer than 9000 people globally COVID-19 has already infected more than 2 million, a sizeable proportion of whom are critically ill. Our experience with SARS prompts us to recommend vigilance against thromboembolism in general and specifically as a mechanism for ischemic stroke, particularly if empirical treatment with IVIg or convalescent plasma is attempted.
References:
1) Manji H, Carr AS, Brownlee WJ. Neurology in the time of covid-19. J Neurol Neurosurg Psychiatry. 2020 Apr 20. pii: jnnp-2020-323414.
2) Ling Mao1; Huijuan Jin; Mengdie Wang1; et al. Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. Published online.
3) Helms J, Kremer S, Merdji H. Neurologic Features in Severe SARS-CoV-2 Infection.N Engl J Med. 2020 Apr 15. doi: 10.1056/NEJMc2008597.
4) Zhang Y, Xiao M, Zhang S. Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19.N Engl J Med. 2020 Apr 8.
5) Oxley TJ, Mocco J, Majidi S, et al. Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young. N Engl J Med. 2020 Apr 28.
6) Umapathi T, Kor AC, Venketasubramanian N,et al. Large artery ischaemic stroke in severe acute respiratory syndrome (SARS). J Neurol. 2004;251(10):1227-31.
7) Lew TW, Kwek TK, Tai D, et al. Acute respiratory distress syndrome in critically ill patients with severe acute respiratory syndrome. JAMA 2003; 290(3):374-80.
8) Chong PY, Chui P, Ling AE, Franks TJ,et al. Analysis of deaths during the severe acute respiratory syndrome (SARS) epidemic in Singapore: challenges in determining a SARS diagnosis. Arch Pathol Lab Med 128:195–204
9) Yang G, Hooper WC. Physiological functions and clinical implications of fibrinogen-like 2: A review World J Clin Infect Dis. 2013 Aug 25;3(3):37-46.
Obsessive-compulsive disorder (OCD) is a neuropsychiatric disease characterized by distressing thoughts or urges that often require repetitive behaviors to suppress. OCD affects 2-3% of the general population and can have debilitating effects on normal functioning.[1] While most cases of OCD can be addressed through psychotherapy and/or medication, about 10% remain refractory, requiring neurosurgical intervention, such as neuroablation (ABL) or deep brain stimulation (DBS). These options possess their own respective advantages and disadvantages. ABL lacks the hardware concerns of DBS (e.g. device failure, battery replacement, etc.) and may be incisionless (e.g. stereotactic radiosurgery). Alternatively, DBS is non-lesional, and stimulation parameters can be titrated. While both ABL and DBS appear to be effective for refractory OCD, there is no clear consensus on their relative superiority/non-inferiority.
Our group previously sought to address this question by comparing the two treatments’ relative utility. [1] Using a random-effects, inverse-variance weighted meta-analysis of 56 studies, utility was calculated from Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores and adverse event (AE) incidence. In our analysis, no significant differences were found between stereotactic radiosurgery and radiofrequency ablation, so their studies were combined and all considered under ABL. Ultimately, ABL yielded a significantly greater utility compared to...
Obsessive-compulsive disorder (OCD) is a neuropsychiatric disease characterized by distressing thoughts or urges that often require repetitive behaviors to suppress. OCD affects 2-3% of the general population and can have debilitating effects on normal functioning.[1] While most cases of OCD can be addressed through psychotherapy and/or medication, about 10% remain refractory, requiring neurosurgical intervention, such as neuroablation (ABL) or deep brain stimulation (DBS). These options possess their own respective advantages and disadvantages. ABL lacks the hardware concerns of DBS (e.g. device failure, battery replacement, etc.) and may be incisionless (e.g. stereotactic radiosurgery). Alternatively, DBS is non-lesional, and stimulation parameters can be titrated. While both ABL and DBS appear to be effective for refractory OCD, there is no clear consensus on their relative superiority/non-inferiority.
Our group previously sought to address this question by comparing the two treatments’ relative utility. [1] Using a random-effects, inverse-variance weighted meta-analysis of 56 studies, utility was calculated from Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores and adverse event (AE) incidence. In our analysis, no significant differences were found between stereotactic radiosurgery and radiofrequency ablation, so their studies were combined and all considered under ABL. Ultimately, ABL yielded a significantly greater utility compared to DBS (0.189±0.03 vs. 0.167±0.04, respectively; P<0.001). Due to perceived advantages of DBS over ABL, this result was surprising and inquiries were raised about the reliability of the analysis. A primary concern was whether study rigor could have impacted our finding. In this follow-up study, we performed an in-depth assessment of rigor of the ABL vs. DBS studies that previously met criteria for inclusion.
Methods:
Assessment of rigor requires the selection of a grading scale. However, as rigor scales are designed for a specific type of study, a single type of scale is incapable of properly assessing the variety of analyzed study types (e.g., RCT, cohort, and case series). To circumvent this issue, we decided to score only case series because they were the most common study type in both treatment groups. These studies were assessed with the Institute of Health Economics (IHE) quality appraisal checklist, which is a validated scale designed exclusively for case series.[2,3] These rigor scores were then used as covariates to a mixed-effects model of treatment against outcome (i.e. Y-BOCS score, adverse event (AE) incidence, and overall utility).
Results:
There were a total of 20 DBS and 17 ABL case series used in the meta-analysis; they represent 71.4% and 94.4%, respectively, of all studies in each treatment group. For overall number of patients, case series contribute 68.7% (125/182) and 97.7% (347/355) to DBS and ABL groups, respectively. In addition, they represent 40% (4/10) and 83.3% (10/12) of DBS and ABL studies that report AE incidence. DBS studies had significantly higher rigor scores than ABL studies (13.5/20 versus 11.0/20, respectively; p<0.001).
Similar to the results of Kumar et al., ABL still imparts a significantly higher utility than DBS with rigor as covariate in the mixed-effects model of treatment (p<0.0001). AE incidence was also significantly lower in ABL case studies (p=0.0024). For Y-BOCS score, ABL case series report greater percent reduction compared to DBS studies, though it was only marginally significant (p=0.0609). When rigor added to the mixed-effects model of treatment against outcome, neither the treatment group nor the rigor scores were significant predictors of % Y-BOCS score reduction (p=0.2261 and 0.4179, respectively). Similarly, neither treatment group nor rigor was a significant predictor of AE incidence (p=0.2223 and 0.4602, respectively). When considered as the sole predictor, rigor was not found to be significant predictor of % Y-BOCS score reduction (p = 0.1115). However, higher rigor scores were predictive of higher AE incidence (p = 0.0064).
Discussion:
Rigor is an important consideration as it may lend insight to a study’s validity and robustness. One hypothesis of ABL’s superiority over DBS was that ABL studies were less rigorous, producing outcomes that may be less reflective of reality. As rigor was not a significant covariate for utility, it suggests that Kumar et al.’s original conclusion of ABL superiority is accurate. However, even though rigor is not a significant covariate of % Y-BOCS score reduction, it is a significant predictor for AE incidence. Higher rigor studies generally had a higher reported AE incidence.
A notable limitation to this analysis is the exclusive use of case series. The mixed collection of study types precluded the perfect fit of a single scale to all studies. Since case series only represent a portion of all studies, our calculations slightly vary from those reported previously in Kumar et al. Nevertheless, case series represent the vast majority of studies and patients in both DBS and ABL groups. Though not a perfect facsimile, they are still highly representative. Regarding AE incidence, DBS case series constitute only 40% of overall DBS studies with AE reports. Yet, they were sufficient in establishing the significant association of high rigor and AE incidence. Given that the remaining DBS studies likely have even higher rigor (i.e. RCTs and cohort studies), an even stronger association with their inclusion is not an unreasonable inference. Furthermore, although treatment types were no longer significant predictors, this may be a consequence of working with fewer studies and overfitting data.
While study rigor was not a significant covariate for the current utility calculation, it is nevertheless an important consideration for similar meta-analyses, especially when assessing older and newer technologies. As the field of functional neurosurgery advances, there will be a greater need for similar comparisons to evaluate and guide clinical decision-making and adoption of novel techniques. Developments in DBS technologies can all plausibly improve DBS utility for OCD, necessitating further studies. Despite its limitations as an imperfect measure, study rigor may provide valuable insight into the reliability of reported data.
Bibliography:
1. Kumar KK, Appelboom G, Lamsam L, et al. Comparative effectiveness of neuroablation and deep brain stimulation for treatment-resistant obsessive-compulsive disorder: A meta-analytic study. J Neurol Neurosurg Psychiatry 2019;90:469–73. doi:10.1136/jnnp-2018-319318
2. Institute of Health Economics. Quality Appraisal Checklist for Case Series Studies. 2014;:1–2.
3. Guo B, Moga C, Harstall C, et al. A principal component analysis is conducted for a case series quality appraisal checklist. J Clin Epidemiol 2016;69:199–207.e2. doi:10.1016/j.jclinepi.2015.07.010
De Schaepdryver et al. assessed the prognostic ability of serum neurofilament light chain (NfL) and C-reactive protein (CRP) in patients with amyotrophic lateral sclerosis (ALS) (1). Although two indicators can significantly predict the prognosis, the superiority by the combination of NfL and CRP should be checked for the analysis. I want to discuss NfL and ALS prognosis from recent publications.
Verde et al. conducted a prospective study to determine the diagnostic and prognostic performance of serum NfL in patients with ALS (2). Serum NfL positively correlated with disease progression rate in patients with ALS, and higher levels were significantly associated with shorter survival. In addition, serum NfL did not differ among patients in different ALS pathological stages, and NfL levels were stable over time within each patient.
Regarding the first query, Thouvenot et al. reported that serum NfL could be used as a prognostic marker for ALS at the time of diagnosis (3). Gille et al. recognized the relationship of serum NfL with motor neuron degeneration in patients with ALS (4). They described that serum NfL was significantly associated with disease progression rate and survival, and it could be recommended as a surrogate biomarker of ALS. These two papers presented no information whether NfL can be used for monitoring of ALS progression in each patient.
De Schaepdryver et al. used two indicators, and I suspect that the authors can present information r...
De Schaepdryver et al. assessed the prognostic ability of serum neurofilament light chain (NfL) and C-reactive protein (CRP) in patients with amyotrophic lateral sclerosis (ALS) (1). Although two indicators can significantly predict the prognosis, the superiority by the combination of NfL and CRP should be checked for the analysis. I want to discuss NfL and ALS prognosis from recent publications.
Verde et al. conducted a prospective study to determine the diagnostic and prognostic performance of serum NfL in patients with ALS (2). Serum NfL positively correlated with disease progression rate in patients with ALS, and higher levels were significantly associated with shorter survival. In addition, serum NfL did not differ among patients in different ALS pathological stages, and NfL levels were stable over time within each patient.
Regarding the first query, Thouvenot et al. reported that serum NfL could be used as a prognostic marker for ALS at the time of diagnosis (3). Gille et al. recognized the relationship of serum NfL with motor neuron degeneration in patients with ALS (4). They described that serum NfL was significantly associated with disease progression rate and survival, and it could be recommended as a surrogate biomarker of ALS. These two papers presented no information whether NfL can be used for monitoring of ALS progression in each patient.
De Schaepdryver et al. used two indicators, and I suspect that the authors can present information regarding the monitoring ability for ALS progression. In combination with clinical findings, biological monitoring method might be important for medication efficacy.
References
1. De Schaepdryver M, Lunetta C, Tarlarini C, et al. Neurofilament light chain and C reactive protein explored as predictors of survival in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2020;91(4):436-437. doi: 10.1136/jnnp-2019-322309
2. Verde F, Steinacker P, Weishaupt JH, et al. Neurofilament light chain in serum for the diagnosis of amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2019 Feb;90(2):157-164. doi: 10.1136/jnnp-2018-318704
3. Gille B, De Schaepdryver M, Goossens J, et al. Serum neurofilament light chain levels as a marker of upper motor neuron degeneration in patients with amyotrophic lateral sclerosis. Neuropathol Appl Neurobiol. 2019;45(3):291-304. doi: 10.1111/nan.12511
4. Thouvenot E, Demattei C, Lehmann S, et al. Serum neurofilament light chain at time of diagnosis is an independent prognostic factor of survival in amyotrophic lateral sclerosis. Eur J Neurol. 2020;27(2):251-257. doi: 10.1111/ene.14063
Verde et al. conducted a prospective study to determine the diagnostic and prognostic performance of serum neurofilament light chain (NFL) in patients with amyotrophic lateral sclerosis (ALS) (1). Serum NFL positively correlated with disease progression rate in patients with ALS, and higher levels were significantly associated with shorter survival. In addition, serum NFL did not differ among patients in different ALS pathological stages, and NFL levels were stable over time within each patient. I have a concern about their study.
Gille et al. also recognized the relationship of serum NFL with motor neuron degeneration in patients with ALS (2). They also recognized that serum NFL was significantly associated with disease progression rate and survival. Serum NFL can be recommended as a surrogate biomarker of ALS.
Regarding the first concern, Thouvenot et al. also checked if serum NFL can be used as a prognostic marker for ALS at the time of diagnosis (3). By Cox regression analysis, NFL, weight loss and site at onset were independent predictive factors of mortality, and higher NFL concentration at the time of diagnosis is the strongest prognostic fact
I recently discussed on serum neurofilament light chain in patients with amyotrophic lateral sclerosis (4), and these consistent results should also be verified by a meta-analysis of prospective studies.
References
1. Verde F, Steinacker P, Weishaupt JH, et al. Neurofilament light chain in se...
Verde et al. conducted a prospective study to determine the diagnostic and prognostic performance of serum neurofilament light chain (NFL) in patients with amyotrophic lateral sclerosis (ALS) (1). Serum NFL positively correlated with disease progression rate in patients with ALS, and higher levels were significantly associated with shorter survival. In addition, serum NFL did not differ among patients in different ALS pathological stages, and NFL levels were stable over time within each patient. I have a concern about their study.
Gille et al. also recognized the relationship of serum NFL with motor neuron degeneration in patients with ALS (2). They also recognized that serum NFL was significantly associated with disease progression rate and survival. Serum NFL can be recommended as a surrogate biomarker of ALS.
Regarding the first concern, Thouvenot et al. also checked if serum NFL can be used as a prognostic marker for ALS at the time of diagnosis (3). By Cox regression analysis, NFL, weight loss and site at onset were independent predictive factors of mortality, and higher NFL concentration at the time of diagnosis is the strongest prognostic fact
I recently discussed on serum neurofilament light chain in patients with amyotrophic lateral sclerosis (4), and these consistent results should also be verified by a meta-analysis of prospective studies.
References
1. Verde F, Steinacker P, Weishaupt JH, et al. Neurofilament light chain in serum for the diagnosis of amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2019 Feb;90(2):157-164. doi: 10.1136/jnnp-2018-318704
2. Gille B, De Schaepdryver M, Goossens J, et al. Serum neurofilament light chain levels as a marker of upper motor neuron degeneration in patients with amyotrophic lateral sclerosis. Neuropathol Appl Neurobiol. 2019;45(3):291-304. doi: 10.1111/nan.12511
3. Thouvenot E, Demattei C, Lehmann S, et al. Serum neurofilament light chain at time of diagnosis is an independent prognostic factor of survival in amyotrophic lateral sclerosis. Eur J Neurol. 2020;27(2):251-257. doi: 10.1111/ene.14063
4. Kawada T. Serum neurofilament light chain in patients with amyotrophic lateral sclerosis. Eur J Neurol. 2020 Mar 18. doi: 10.1111/ene.14223
Oliveira et al. evaluated the association between autonomic symptoms and progressive supranuclear palsy (PSP) with special reference to disease progression and survival (1). Adjusted hazard ratios (HRs) (95% confidence interval [CIs]) of early constipation and early urinary symptoms for the risk of first disease milestone of PSP were 0.88 (0.83 to 0.92) and 0.80 (0.75 to 0.86), respectively. In addition, adjusted HRs (95% CIs) of early constipation and early urinary symptoms for survival were 0.73 (0.64 to 0.84) and 0.88 (0.80 to 0.96), respectively. Furthermore, Richardson syndrome phenotype was significantly associated with shorter survival. The authors concluded that earlier urinary symptoms and constipation are closely associated with rapid disease progression and shorter survival in patients with PSP. I have two comments about their study.
First, Glasmacher et al. conducted a meta-analysis to explore prognostic factors and survival in patients with PSP and multiple system atrophy (MSA) (2). In patients with PSP, adjusted HR (95% CI) of Richardson's phenotype against Parkinson's phenotype for shorter survival was 2.37 (1.21 to 4.64). In addition, adjusted HR (95% CI) of early fall for shorter survival in patients with PSP and MSA was 2.32 (1.94 to 2.77). Although some clinical symptoms are overlapping by common neurological damages, risk assessment for PSP and for MSA should be separately conducted. Stable estimates with enough number of samples and ev...
Oliveira et al. evaluated the association between autonomic symptoms and progressive supranuclear palsy (PSP) with special reference to disease progression and survival (1). Adjusted hazard ratios (HRs) (95% confidence interval [CIs]) of early constipation and early urinary symptoms for the risk of first disease milestone of PSP were 0.88 (0.83 to 0.92) and 0.80 (0.75 to 0.86), respectively. In addition, adjusted HRs (95% CIs) of early constipation and early urinary symptoms for survival were 0.73 (0.64 to 0.84) and 0.88 (0.80 to 0.96), respectively. Furthermore, Richardson syndrome phenotype was significantly associated with shorter survival. The authors concluded that earlier urinary symptoms and constipation are closely associated with rapid disease progression and shorter survival in patients with PSP. I have two comments about their study.
First, Glasmacher et al. conducted a meta-analysis to explore prognostic factors and survival in patients with PSP and multiple system atrophy (MSA) (2). In patients with PSP, adjusted HR (95% CI) of Richardson's phenotype against Parkinson's phenotype for shorter survival was 2.37 (1.21 to 4.64). In addition, adjusted HR (95% CI) of early fall for shorter survival in patients with PSP and MSA was 2.32 (1.94 to 2.77). Although some clinical symptoms are overlapping by common neurological damages, risk assessment for PSP and for MSA should be separately conducted. Stable estimates with enough number of samples and events cannot justify for compiling data of PSP and MSA for the analysis.
Second, dell'Aquila et al. also performed a retrospective cohort study to identify clinical predictors of survival in patients with PSP (3). Adjusted HR (95% CI) of older age at onset, early dysphagia and early cognitive deficit for mortality were 2.8 (1.3-5.7), 2.3 (1-5.3) and 3.6(1.6-8.2), respectively. As only 25 patients were used for multivariate analysis, unstable estimates with wide ranges of 95% CI were presented. But they mentioned that some clinical milestones before death should be considered as possible endpoints in further study, and Oliveira et al. presented such events for the risk assessment of PSP. Quality of life in patients with PSP might degrade according to the progression of disease, and I appreciate Oliveira et al. for selecting first disease milestone of PSP as events.
REFERENCES
1 Oliveira MCB, Ling H, Lees AJ, et al. Association of autonomic symptoms with disease progression and survival in progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 2019;90:555-61.
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;88:402-11.
3 dell'Aquila C, Zoccolella S, Cardinali V, et al. Predictors of survival in a series of clinically diagnosed progressive supranuclear palsy patients. Parkinsonism Relat Disord 2013;19:980-5.
Kaji et al. evaluated the efficacy and safety of intramuscular ultra-high-dose methylcobalamin in 373 patients with amyotrophic lateral sclerosis (ALS) (1). The primary endpoints were death or full ventilation support. Although there was no significant difference between treated and control group, 50 mg methylcobalamin-treated patients with early start within 12 months' duration of diagnosis showed longer time intervals to the primary event and keep the Revised ALS Functional Rating Scale (ALSFRS-R) score than the placebo group. The adverse effects by this treatment were similar and low prevalence among placebo, 25 mg or 50 mg groups. The authors recommend to verify the prognosis by this medication, and I have some concerns about their study.
First, the authors did not allow the change of riluzole administration and did not handle patients with edaravone treatment. I think that the vitamin B12 analog treatment in combination with recent neuro-protective drugs might be acceptable for future trials (2). In addition, the efficacy for ALS by methylcobalamin should be specified by adjusting several confounders for the analysis.
Relating to vitamin therapy for ALS, Rosenbohm et al. investigated the association of serum retinol-binding protein 4 (RBP4) with the onset and prognosis of ALS (3). Adjusted ORs (95% C) of the highest quartile of RBP4 against lowest quartile for incident ALS was 0.36 (0.22-0.59). In addition, serum RBP4 was inversely associated with m...
Kaji et al. evaluated the efficacy and safety of intramuscular ultra-high-dose methylcobalamin in 373 patients with amyotrophic lateral sclerosis (ALS) (1). The primary endpoints were death or full ventilation support. Although there was no significant difference between treated and control group, 50 mg methylcobalamin-treated patients with early start within 12 months' duration of diagnosis showed longer time intervals to the primary event and keep the Revised ALS Functional Rating Scale (ALSFRS-R) score than the placebo group. The adverse effects by this treatment were similar and low prevalence among placebo, 25 mg or 50 mg groups. The authors recommend to verify the prognosis by this medication, and I have some concerns about their study.
First, the authors did not allow the change of riluzole administration and did not handle patients with edaravone treatment. I think that the vitamin B12 analog treatment in combination with recent neuro-protective drugs might be acceptable for future trials (2). In addition, the efficacy for ALS by methylcobalamin should be specified by adjusting several confounders for the analysis.
Relating to vitamin therapy for ALS, Rosenbohm et al. investigated the association of serum retinol-binding protein 4 (RBP4) with the onset and prognosis of ALS (3). Adjusted ORs (95% C) of the highest quartile of RBP4 against lowest quartile for incident ALS was 0.36 (0.22-0.59). In addition, serum RBP4 was inversely associated with mortality by survival analysis. RBC4 can be considered as a biomarker for insulin resistance and vitamin A metabolism, and the lack of vitamin A and insulin resistance might also be related to the pathogenesis of ALS.
Finally, other medications for ALS treatment can be considered for the analysis. Freedman et al. examined the association between lipid-lowering medication and ALS risk (4). Adjusted odds ratios (ORs) (95% confidence interval [CI]) of statins and fibrates for ALS were 0.87 (0.83-0.91) and 0.88 (0.80-0.97), respectively. In contrast, other three cholesterol-lowering medications such as nitrates, bile acid sequestrants and ezetimibe did not significantly associate with ALS. Although confounders and mediators cannot be clearly identified for the prognosis of ALS, basic parameters such as smoking and body mass index might be important variables for the adjustment.
REFERENCES
1 Kaji R, Imai T, Iwasaki Y, et al. Ultra-high-dose methylcobalamin in amyotrophic lateral sclerosis: a long-term phase II/III randomised controlled study. J Neurol Neurosurg Psychiatry 2019;90:451-7.
2 Ito S, Izumi Y, Niidome T, et al. Methylcobalamin prevents mutant superoxide dismutase-1-induced motor neuron death in vitro. Neuroreport 2017;28:101-7.
3 Rosenbohm A, Nagel G, Peter RS, et al. Association of serum retinol-binding protein 4 concentration with risk for and prognosis of amyotrophic lateral sclerosis. JAMA Neurol 2018;75:600-7.
4 Freedman DM, Kuncl RW, Cahoon EK, et al. Relationship of statins and other cholesterol-lowering medications and risk of amyotrophic lateral sclerosis in the US elderly. Amyotroph Lateral Scler Frontotemporal Degener 2018;19(7-8):538-46.
We appreciate the editorial by Dr. Muller-Vahl [1] about our recent article [2]. The large, international study group who co-authored our paper collectively felt that it would be useful to provide clarification of a few important points regarding the International Tourette Syndrome (TS) Deep Brain Stimulation (DBS) Database and Registry, the International Neuromodulation Registry, and our published analysis.
There is widespread agreement on the need for more randomized controlled trials (RCTs) to evaluate the efficacy of DBS for many indications, including TS, and there has been substantial discussion in the medical community about how these trials should be organized and carried out [3]. Our approach to overcome the challenges with the modest amount of data available for surgical therapies for TS has been to use symbiotic data sharing [4]. This approach encourages the broadening of investigative teams after publication of clinical studies to perform additional analyses and to develop new hypotheses. The key concept behind this approach is that new investigators work in a close, collaborative relationship with the teams that conducted the initial data collection. In addition, a recent viewpoint from the Food & Drug Administration in the United States reported that “For some devices, opportunities exist for leveraging alternative data sources, such as existing registries or modeling techniques, to allow regulators to have a good idea of the risks and benefits of...
We appreciate the editorial by Dr. Muller-Vahl [1] about our recent article [2]. The large, international study group who co-authored our paper collectively felt that it would be useful to provide clarification of a few important points regarding the International Tourette Syndrome (TS) Deep Brain Stimulation (DBS) Database and Registry, the International Neuromodulation Registry, and our published analysis.
There is widespread agreement on the need for more randomized controlled trials (RCTs) to evaluate the efficacy of DBS for many indications, including TS, and there has been substantial discussion in the medical community about how these trials should be organized and carried out [3]. Our approach to overcome the challenges with the modest amount of data available for surgical therapies for TS has been to use symbiotic data sharing [4]. This approach encourages the broadening of investigative teams after publication of clinical studies to perform additional analyses and to develop new hypotheses. The key concept behind this approach is that new investigators work in a close, collaborative relationship with the teams that conducted the initial data collection. In addition, a recent viewpoint from the Food & Drug Administration in the United States reported that “For some devices, opportunities exist for leveraging alternative data sources, such as existing registries or modeling techniques, to allow regulators to have a good idea of the risks and benefits of the device without the need for conducting detailed trials. For the majority of devices, the benefits and risks are expected to be manifest through registries and evolve as clinical techniques are refined and the technologies themselves are rapidly modified and improved. Such a continuous improvement cycle would be impossible if every device iteration required a full trial to test its safety and efficacy” [5]. We believe that the candidate population for TS DBS therapy falls squarely within this description, particularly as new capabilities are being added to commercially available DBS systems (e.g. directional electrodes, current steering, and closed loop stimulation to name a few). Hence, the type of secondary data analysis we reported was intended to support, rather than circumvent, future RCTs.
There is not a current consensus on how future RCTs should be designed. Enrollment can be challenging given so few cases are implanted, even at centers with extensive DBS experience. We have previously published post-hoc analyses of failed RCTs using neurostimulation devices. For example, one study strongly suggested the trial would have reached its primary endpoint if it was designed to better accommodate known sources of variability such as lead location, type of stimulation, or the length of time given to assess primary outcomes [6]. Our purpose in performing these types of analyses is not to be overly critical of past RCTs, but rather to make use of lessons learned in order to design more effective future trials. While much of the TS DBS registry data in our study was open label, and therefore we cannot rule out placebo response, only a few patients chose to be explanted for lack of effectiveness. Our 12 month data on the effectiveness and safety of DBS for TS [7] revealed that one patient was explanted and one patient underwent pulse generator removal. In addition, the therapeutic effect size in most of the responders was substantial and durable. Lastly, for a few cases in which the pulse generator battery was inadvertently depleted without the patient’s knowledge, the sudden recurrence of symptoms suggests positive and reversible effects of DBS. When combined with the positive outcomes of two successful RCTs of DBS for TS [8,9], we feel that our data provide sufficient evidence to support future studies. These studies should be designed to accommodate several known sources of variability identified through the analyses of the TS DBS registry. Hence, our goal was to report how DBS for TS has been applied across multiple international sites and to generate testable hypotheses to guide future studies.
Our study revealed that the anatomical location of the applied stimulation did not fully explain the variability in clinical outcomes across patients. In an effort to further disentangle the complexities of this treatment, we are preparing a forthcoming paper that includes additional analyses on our cohort. The results suggest that there may be a common network that is correlated with clinical improvement across surgical targets, which could provide important insights on the underlying TS network and how neuromodulation can be refined. Importantly, this type of analysis would not be possible without a TS database and registry.
In closing, we agree with the value of additional RCTs as suggested by Dr. Muller-Vahl; however we must also recognize the current logistical difficulties and be creative and pluralistic in our methodologic approaches. In addition, we suggest the greater inclusion of patient voice in driving the research agenda consistent with the disability rights adage, “nothing about us without us" [10]. Instead of the prescriptive critique of Muller-Vahl, we should strive to develop more adaptive patient-centered methodologies. Through this effort we will be better positioned to meet the needs of individuals with severe TS as they consider the risks and benefits of DBS.
References
1. Muller-Vahl KR. Deep brain stimulation in Tourette syndrome: the known and the unknown. J Neurol Neurosurg Psychiatry Published Online First: 12 July 2019. doi:10.1136/jnnp-2019-321008
2. Johnson KA, Fletcher PT, Servello D, et al. Image-based analysis and long-term clinical outcomes of deep brain stimulation for Tourette syndrome: a multisite study. J Neurol Neurosurg Psychiatry Published Online First: 25 May 2019. doi:10.1136/jnnp-2019-320379
3. Fins JJ, Kubu CS, Mayberg HS, et al. Being open minded about neuromodulation trials: Finding success in our “failures”. Brain Stimul 2017;10:181–6. doi:10.1016/j.brs.2016.12.012
4. Longo DL, Drazen JM. Data Sharing. N Engl J Med 2016;374:276–7. doi:10.1056/NEJMe1516564
5. Faris O, Shuren J. An FDA Viewpoint on Unique Considerations for Medical-Device Clinical Trials. N Engl J Med 2017;376:1350–7. doi:10.1056/NEJMra1512592
6. Pathak Y, Kopell BH, Szabo A, et al. The role of electrode location and stimulation polarity in patient response to cortical stimulation for major depressive disorder. Brain Stimul 2013;6:254–60. doi:10.1016/j.brs.2012.07.001
7. Martinez-Ramirez D, Jiminez-Shahed J, Leckman JF, et al. Efficacy and Safety of Deep Brain Stimulation in Tourette Syndrome The International Tourette Syndrome Deep Brain Stimulation Public Database and Registry. JAMA Neurol 2018;32607:1–7. doi:10.1001/jamaneurol.2017.4317
8. Kefalopoulou Z, Zrinzo L, Jahanshahi M, et al. Bilateral globus pallidus stimulation for severe Tourette’s syndrome: A double-blind, randomised crossover trial. Lancet Neurol 2015;14:595–605. doi:10.1016/S1474-4422(15)00008-3
9. Ackermans L, Duits A, van der Linden C, et al. Double-blind clinical trial of thalamic stimulation in patients with Tourette syndrome. Brain 2011;134:832–44. doi:10.1093/brain/awq380
10. Charlton JI. Nothing About Us Without Us: Disability Oppression and Empowerment. Berkley: University of California Press 1998.
Dear Editor,
The original article by Jeppsson et al. provides substantial perspectives regarding the diagnostic
significance of cerebrospinal fluid (CSF) biomarkers in discriminating patients with idiopathic normal pressure hydrocephalus (iNPH) from patients with other neurodegenerative disorders. 1 They have found that patients with iNPH had, compared with healthy individuals, lower concentrations of P-tau and APP-derived proteins in combination with elevated MCP-1 1. Moreover, compared with the non-iNPH disorders group, iNPH was characterized by the same significant change; low concentration of tau proteins and APP-derived proteins, and elevated MCP-1. I sincerely appreciate the authors for conducting such a large-scale study of a strictly interesting topic. However, I would like to make some comments hoping to provide a better understanding of some points and some perspectives to be kept in mind while planning future related studies
In my opinion, the investigation of CSF biomarkers in patients with iNPH may provide several insights in addition to discriminating the iNPH patients from other neurodegenerative diseases. Certainly, these study results may give the opportunity to understand the unknown pathophysiological aspects of iNPH, thereby, even leading to new classifications of the disease. Actually, there may be many questions to be clarified regarding diagnostic approach, evaluation of the iNPH patients and even identification of the disease. 2,3...
Dear Editor,
The original article by Jeppsson et al. provides substantial perspectives regarding the diagnostic
significance of cerebrospinal fluid (CSF) biomarkers in discriminating patients with idiopathic normal pressure hydrocephalus (iNPH) from patients with other neurodegenerative disorders. 1 They have found that patients with iNPH had, compared with healthy individuals, lower concentrations of P-tau and APP-derived proteins in combination with elevated MCP-1 1. Moreover, compared with the non-iNPH disorders group, iNPH was characterized by the same significant change; low concentration of tau proteins and APP-derived proteins, and elevated MCP-1. I sincerely appreciate the authors for conducting such a large-scale study of a strictly interesting topic. However, I would like to make some comments hoping to provide a better understanding of some points and some perspectives to be kept in mind while planning future related studies
In my opinion, the investigation of CSF biomarkers in patients with iNPH may provide several insights in addition to discriminating the iNPH patients from other neurodegenerative diseases. Certainly, these study results may give the opportunity to understand the unknown pathophysiological aspects of iNPH, thereby, even leading to new classifications of the disease. Actually, there may be many questions to be clarified regarding diagnostic approach, evaluation of the iNPH patients and even identification of the disease. 2,3 For instance, the diagnosis of iNPH may be a considerably challenging issue knowing that the full triad of NPH is present in under 60% of patients and the individual components of this triad are nonspecific as they may be encountered in many other neurodegenerative disorders. 2 Nevertheless, the gold standard of the diagnosis has been indicated as the short-term response to CSF drainage. 3,4 On the other hand, although a substantial rate of patients with iNPH improve by shunt surgery (80%), a crucial topic of discussion may be that why some subgroup of patients do not benefit from shunt surgery? Some authors have suggested that the presence of a possible underdiagnosed neurodegenerative disease might the main cause of shunt unresponsiveness in this patient subgroup. Arrestingly, in patients with iNPH, the high rates of the neurodegenerative comorbidities have been reported, several times. 3,5 Besides, it is acknowledged that although the presence of comorbidities does not exclude the possibility of iNPH; comorbidities do influence the prognosis after shunt surgery. 5 More interestingly, Espay et al. preferred to identify some subgroup of patients as the hydrocephalic presentations of neurodegenerative disorders (rather than NPH). 3 However, I believe that many of these discussions may be elucidated in the era of CSF biochemical investigations. Considering the various unknown aspects about the pathophysiology and pathogenesis of iNPH, the sufficiency of the current diagnostic criteria basing on the clinical triad, neuroimaging and short-term response to CSF diversion may also be interrogated. Based on the rationale of that treatment response is a critical clue providing insights about the underlying pathophysiology, I think that the response to shunt surgery may potentially be a crucial criteria to be kept in mind while diagnosing and classifying the patients with the current diagnosis of iNPH. 6 Hence, the use of CSF biomarkers may give promising conclusions for a better understanding of the iNPH pathophysiology and provide possible new classification criteria of the disease. Besides, it is remarkable to state that iNPH has been basically explained via mechanisms of CSF dynamic disturbance, mechanical stretching of periventricular tissue by the enlarging ventricles, impairment of blood-brain barrier, impaired periventricular blood flow associated to interstitial edema, ependyma disruption, microvascular infarctions, gliosis. However, there is no notable clue to classify iNPH as a primary neurodegenerative disease. On the other hand, secondary mechanisms including disturbed elimination of neurotoxic substances such as β-amyloid, tau-protein, and pro-inflammatory cytokines (basically associated with disturbed CSF turnover) have been hypothesized to be involved in the deterioration of iNPH clinic. 7,8 Ergo, investigations of CFS biomarkers in patients with iNPH may also give substantial perspectives regarding the pathophysiological features of iNPH which might be significantly varying among iNPH patients according to the current diagnostic criteria. 6 Furthermore, although it was not investigated in this study, 1 I think that analyzing the differentiating features of CSF biomarkers in iNPH patients benefiting and non-benefiting by shunt surgery would give substantial perspectives about the discussions mentioned above. The authors refer to the previous two reports 9,10 and indicate that there have not been any promising investigations on the use of CSF biomarkers to separate responders from non-responders. Nevertheless, I would like to remind that the mentioned reports included a limited number of patients and, actually, in the report by Miyajima et al., sAPPa was found as a suitable biomarker for also the prognosis of iNPH. 9 Therefore, in my opinion, the investigation of the significance of CSF biochemical pattern in distinguishing the NPH patients of shunt responders and non-responders, certainly constitutes a crucial topic of interest. The CSF biochemical patterns may also be investigated in patients with the current diagnosis of secondary NPH which have been acknowledged to have higher treatment (shunt) response rates in comparison to patients with iNPH. 11,12 In addition, the results of these mentioned studies may provide clues about the critical question of that what extent of the reversibility of the disease is due to the mechanical factors or a possible recovery of an underlying neurodegenerative process, thereby providing crucial insights about the primary underlying pathophysiology.
Abbreviations: CSF; Cerebrospinal fluid, APP; amyloid precursor protein, MCP-1; monocyte chemoattractant protein 1
Acknowledgments: None.
Funding: None.
Conflict of interests: None.
References
1. Jeppsson A, Wikkelso C, Blennow K, et al. CSF biomarkers distinguish idiopathic normal pressure hydrocephalus from its mimics. J Neurol Neurosurg Psychiatry. Jun 5 2019.
2. Marmarou A, Young HF, Aygok GA, et al. Diagnosis and management of idiopathic normal-pressure hydrocephalus: a prospective study in 151 patients. J Neurosurg. Jun 2005;102(6):987-997.
3. Espay AJ, Da Prat GA, Dwivedi AK, et al. Deconstructing normal pressure hydrocephalus: Ventriculomegaly as early sign of neurodegeneration. Ann Neurol. Oct 2017;82(4):503-513.
4. Ishikawa M, Guideline Committe for Idiopathic Normal Pressure Hydrocephalus JSoNPH. Clinical guidelines for idiopathic normal pressure hydrocephalus. Neurol Med Chir (Tokyo). Apr 2004;44(4):222-223.
5. Williams MA, Malm J. Diagnosis and Treatment of Idiopathic Normal Pressure Hydrocephalus. Continuum (Minneap Minn). Apr 2016;22(2 Dementia):579-599.
6. Relkin N, Marmarou A, Klinge P, Bergsneider M, Black PM. Diagnosing idiopathic normal-pressure hydrocephalus. Neurosurgery. Sep 2005;57(3 Suppl):S4-16; discussion ii-v.
7. Kudo T, Mima T, Hashimoto R, et al. Tau protein is a potential biological marker for normal pressure hydrocephalus. Psychiatry Clin Neurosci. Apr 2000;54(2):199-202.
8. Kondziella D, Sonnewald U, Tullberg M, Wikkelso C. Brain metabolism in adult chronic hydrocephalus. J Neurochem. Aug 2008;106(4):1515-1524.
9. Miyajima M, Nakajima M, Ogino I, Miyata H, Motoi Y, Arai H. Soluble amyloid precursor protein alpha in the cerebrospinal fluid as a diagnostic and prognostic biomarker for idiopathic normal pressure hydrocephalus. Eur J Neurol. Feb 2013;20(2):236-242.
10. Jeppsson A, Holtta M, Zetterberg H, Blennow K, Wikkelso C, Tullberg M. Amyloid mis-metabolism in idiopathic normal pressure hydrocephalus. Fluids Barriers CNS. Jul 29 2016;13(1):13.
11. Borgesen SE. Conductance to outflow of CSF in normal pressure hydrocephalus. Acta Neurochir (Wien). 1984;71(1-2):1-45.
12. Daou B, Klinge P, Tjoumakaris S, Rosenwasser RH, Jabbour P. Revisiting secondary normal pressure hydrocephalus: does it exist? A review. Neurosurg Focus. Sep 2016;41(3):E6.
I note the clinical analysis of differential weakness in ALS in elbow flexion (biceps brachii) compared to elbow extension (triceps) reported by Khalaf et al.1 This is described as analogous to similar 'split' muscle weakness around the ankle joint and, particularly, as that found in flexor digitorum indicis (FDI) compared to abductor digit minim (ADM) in the hand in the disease. It should be remembered that, although characteristic of ALS, this differential pattern of weakness has repeatedly been found not to be unique to ALS, even from the first descriptions.2,3 As the authors, and Vucic in his editorial remark,1,4 the cause of this interesting pattern of weakness in ALS remains uncertain. The finding of an association between the pattern of weakness and increased excitability in the upper motor neuron system in ALS does not necessarily provide primary support for an upper motor neuron (UMN) causation. Nonetheless this pattern of weakness must be important in the disease. It is worth remembering that differential susceptibility to neurogenic lower motor neuron weakness is also a characteristic feature of some peripheral neuropathies, e.g., the Charcot-Marie-Tooth syndromes. Furthermore, differential muscle weakness and atrophy is a characteristic finding that is important in clinical diagnosis in the myriad different genetically determined muscular dystrophies.5 Although the causation of this differential susceptibility of certain muscles in this la...
I note the clinical analysis of differential weakness in ALS in elbow flexion (biceps brachii) compared to elbow extension (triceps) reported by Khalaf et al.1 This is described as analogous to similar 'split' muscle weakness around the ankle joint and, particularly, as that found in flexor digitorum indicis (FDI) compared to abductor digit minim (ADM) in the hand in the disease. It should be remembered that, although characteristic of ALS, this differential pattern of weakness has repeatedly been found not to be unique to ALS, even from the first descriptions.2,3 As the authors, and Vucic in his editorial remark,1,4 the cause of this interesting pattern of weakness in ALS remains uncertain. The finding of an association between the pattern of weakness and increased excitability in the upper motor neuron system in ALS does not necessarily provide primary support for an upper motor neuron (UMN) causation. Nonetheless this pattern of weakness must be important in the disease. It is worth remembering that differential susceptibility to neurogenic lower motor neuron weakness is also a characteristic feature of some peripheral neuropathies, e.g., the Charcot-Marie-Tooth syndromes. Furthermore, differential muscle weakness and atrophy is a characteristic finding that is important in clinical diagnosis in the myriad different genetically determined muscular dystrophies.5 Although the causation of this differential susceptibility of certain muscles in this latter group of disorders remains uncertain, as does the pattern of susceptibility to denervation in ALS, local factor such as structural differences or even patterns of usage in causation are implied. The causation of differential neurogenic weakness and, indeed, of UMN weakness in ALS, is likely to be complex, dependent on local factors, motor nerve dysfunction and spinal and UMN factors.
May I also point out that there is nothing new in all this? Kinnier Wilson6 gives a clear description in his textbook. He remarks that in the classic spinal type of Charcot syndrome:
“In the majority the small hand muscles are first affected, on either side indifferently. If the process begins in one arm it soon spreads to the other, either of a homologous place or another level. With loss of substance power is reduced, varying degrees of the two being found in one or other segment of the limbs. Muscles of the thenar and hypothenar groups waste as whole, that is, globally, and not in part……………..The process goes on to implicate one muscle after another proximally, wrist and finger flexors before extensors as a rule, and biceps before triceps, but a jump from the hand to the deltoid or shoulder muscle is not uncommon. When it begins in the forearm the long extensors are involved soonest, particularly those for the fingers and the ulnar side of the wrist: the supinators may hold out till the biceps weaken.”
Wilson describes various other dissociated patterns of muscle involvement in a very detailed clinical description of the spinal type of ALS, a description that attests to the precision with which he and his contemporaries examined their patients, and their subsequent careful clinical notetaking. It is always wise to remember the skill of our forebears!
1.Khalaf R, Martin S, Ellis C, et al. Relative preservation of triceps over biceps strength in upper limb-onset ALS: the ’split elbow’. J Neurol Neurosurg Psychiatry. In Press 2019. doi:10.1136/jnnp-2018-319894. [Epub ahead of print: 07 Mar 2019].
2.Wilbourn AJ, Sweeney PJ. Dissociated wasting of medial and lateral hand muscles with motor neuron disease. Can J Neurol Sci 1994;21 (suppl 2):S9
3.Schelhaas HJ, van de Warrenburg BPC, Kremer HPH, Zwarts MJ. The “split hand” phenomenon: evidence of a spinal origin. Neurology 2003;61:1619-1620
4.Vucic S. Split elbow sign: more evidence for a corticospinal origin. J Neurol Neurosurg Psychiatry. doi:10.1136/jnnp-2019-320534
5.Swash M. Six issues in muscle disease. J Neurol Neurosurg Psychiatry 2017;88:603-607 doi:10.1136/jnnp-2017-315771
6.Kinnier Wilson SA. Amyotrophic lateral sclerosis: spinal types. In Neurology. Edited by A Ninian Bruce. London. Butterworth & Co. 2nd edition. 1954 p1145
Dear Editor
It is with great interest that I read the excellent paper by Beyrouti R, et al, on the characteristics of ischaemic stroke among patients with COVID-19(1). There is great interest in the prothromotic state seen in this illness – in this series, high D-dimer and fibrinogen levels in 6/6, positive lupus anticoagulant in 4/5, moderate anti-cardiolipin titres in 1/6.
But I note that there are still some traditional mechanisms in these patients that may have been the cause of the stroke that may not have been fully elucidated, or if they were, were not reported in the paper. I see that patients 2 and 3 had atrial fibrillation, on warfarin, with supra-therapeutic (3.6, artificial heart valve) and sub-therapeutic (1.03) INRs respectively. The results of echocardiography and cardiac rhythm monitoring were not reported for any patient. Thus cardioembolism is still possible as a cause of stroke. Patients 2 to 5 had hypertension and at least one other atherosclerotic vascular risk factor (eg diabetes mellitus, hypercholesterolaemia, smoking, stroke). All patients save 1 was above 60 years of age. Vascular imaging was only reported for 2 cases (5 - CTA and 6 - MRA). Atherothromboelbolism may have caused stroke in some of the patients.
I refer to case series of stroke seen during the 2002-2204 SARS epidemic, also due to a corona virus (2); all had large artery ischaemic strokes, at least 2 of 4 assessed patients had a cardioembolic source, with anot...
Show MoreDear Editor,
The editorial by Manji et al.1 on the neurology of the COVID-19 pandemic cites Mao et al2.’s report describing 5 ischemic strokes in 214 COVID-19 patients. Helms et al3,. and Zhang et al4. have also since reported ischemic stroke in patients with severe SARS-CoV-2 infection, with the latter linking stroke to antiphospholipid antibodies4. In addition, Oxley et al. describe large-vessel stroke in 5 young patients5. In this context, I would like to highlight our 2003 study of ischemic stroke in severe SARS-CoV-1 infection, the corona virus responsible for Severe Acute Respiratory Syndrome (SARS)6. Five out of a total of 206 SARS patients in the country developed large artery ischemic stroke7, four of whom were critically ill. They were not significantly older (56±13 years) than other critically-ill SARS patients (50±16 years, Anova p=0.45). Besides episodes of hypotension, we suspected thromboembolism as a possible mechanism of stroke. Four of the eight SARS patients, who had autopsy examination, revealed evidence of pulmonary thromboemboli8. One was a 39-year-old man, with no stroke risk factors, who died two weeks after contracting SARS; his autopsy revealed unilateral occipital lobe infarction, sterile vegetations on multiple valves, deep venous thrombosis and pulmonary embolism. This prompted the subsequent use of low molecular weight heparin (LMWH) in critically-ill patients, at doses to achieve anti-Xa levels of 0.5-1.0IU/ml. Nevertheless, one-thir...
Show MoreIntroduction:
Obsessive-compulsive disorder (OCD) is a neuropsychiatric disease characterized by distressing thoughts or urges that often require repetitive behaviors to suppress. OCD affects 2-3% of the general population and can have debilitating effects on normal functioning.[1] While most cases of OCD can be addressed through psychotherapy and/or medication, about 10% remain refractory, requiring neurosurgical intervention, such as neuroablation (ABL) or deep brain stimulation (DBS). These options possess their own respective advantages and disadvantages. ABL lacks the hardware concerns of DBS (e.g. device failure, battery replacement, etc.) and may be incisionless (e.g. stereotactic radiosurgery). Alternatively, DBS is non-lesional, and stimulation parameters can be titrated. While both ABL and DBS appear to be effective for refractory OCD, there is no clear consensus on their relative superiority/non-inferiority.
Our group previously sought to address this question by comparing the two treatments’ relative utility. [1] Using a random-effects, inverse-variance weighted meta-analysis of 56 studies, utility was calculated from Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores and adverse event (AE) incidence. In our analysis, no significant differences were found between stereotactic radiosurgery and radiofrequency ablation, so their studies were combined and all considered under ABL. Ultimately, ABL yielded a significantly greater utility compared to...
Show MoreDe Schaepdryver et al. assessed the prognostic ability of serum neurofilament light chain (NfL) and C-reactive protein (CRP) in patients with amyotrophic lateral sclerosis (ALS) (1). Although two indicators can significantly predict the prognosis, the superiority by the combination of NfL and CRP should be checked for the analysis. I want to discuss NfL and ALS prognosis from recent publications.
Verde et al. conducted a prospective study to determine the diagnostic and prognostic performance of serum NfL in patients with ALS (2). Serum NfL positively correlated with disease progression rate in patients with ALS, and higher levels were significantly associated with shorter survival. In addition, serum NfL did not differ among patients in different ALS pathological stages, and NfL levels were stable over time within each patient.
Regarding the first query, Thouvenot et al. reported that serum NfL could be used as a prognostic marker for ALS at the time of diagnosis (3). Gille et al. recognized the relationship of serum NfL with motor neuron degeneration in patients with ALS (4). They described that serum NfL was significantly associated with disease progression rate and survival, and it could be recommended as a surrogate biomarker of ALS. These two papers presented no information whether NfL can be used for monitoring of ALS progression in each patient.
De Schaepdryver et al. used two indicators, and I suspect that the authors can present information r...
Show MoreVerde et al. conducted a prospective study to determine the diagnostic and prognostic performance of serum neurofilament light chain (NFL) in patients with amyotrophic lateral sclerosis (ALS) (1). Serum NFL positively correlated with disease progression rate in patients with ALS, and higher levels were significantly associated with shorter survival. In addition, serum NFL did not differ among patients in different ALS pathological stages, and NFL levels were stable over time within each patient. I have a concern about their study.
Gille et al. also recognized the relationship of serum NFL with motor neuron degeneration in patients with ALS (2). They also recognized that serum NFL was significantly associated with disease progression rate and survival. Serum NFL can be recommended as a surrogate biomarker of ALS.
Regarding the first concern, Thouvenot et al. also checked if serum NFL can be used as a prognostic marker for ALS at the time of diagnosis (3). By Cox regression analysis, NFL, weight loss and site at onset were independent predictive factors of mortality, and higher NFL concentration at the time of diagnosis is the strongest prognostic fact
I recently discussed on serum neurofilament light chain in patients with amyotrophic lateral sclerosis (4), and these consistent results should also be verified by a meta-analysis of prospective studies.
References
1. Verde F, Steinacker P, Weishaupt JH, et al. Neurofilament light chain in se...
Show MoreOliveira et al. evaluated the association between autonomic symptoms and progressive supranuclear palsy (PSP) with special reference to disease progression and survival (1). Adjusted hazard ratios (HRs) (95% confidence interval [CIs]) of early constipation and early urinary symptoms for the risk of first disease milestone of PSP were 0.88 (0.83 to 0.92) and 0.80 (0.75 to 0.86), respectively. In addition, adjusted HRs (95% CIs) of early constipation and early urinary symptoms for survival were 0.73 (0.64 to 0.84) and 0.88 (0.80 to 0.96), respectively. Furthermore, Richardson syndrome phenotype was significantly associated with shorter survival. The authors concluded that earlier urinary symptoms and constipation are closely associated with rapid disease progression and shorter survival in patients with PSP. I have two comments about their study.
First, Glasmacher et al. conducted a meta-analysis to explore prognostic factors and survival in patients with PSP and multiple system atrophy (MSA) (2). In patients with PSP, adjusted HR (95% CI) of Richardson's phenotype against Parkinson's phenotype for shorter survival was 2.37 (1.21 to 4.64). In addition, adjusted HR (95% CI) of early fall for shorter survival in patients with PSP and MSA was 2.32 (1.94 to 2.77). Although some clinical symptoms are overlapping by common neurological damages, risk assessment for PSP and for MSA should be separately conducted. Stable estimates with enough number of samples and ev...
Show MoreKaji et al. evaluated the efficacy and safety of intramuscular ultra-high-dose methylcobalamin in 373 patients with amyotrophic lateral sclerosis (ALS) (1). The primary endpoints were death or full ventilation support. Although there was no significant difference between treated and control group, 50 mg methylcobalamin-treated patients with early start within 12 months' duration of diagnosis showed longer time intervals to the primary event and keep the Revised ALS Functional Rating Scale (ALSFRS-R) score than the placebo group. The adverse effects by this treatment were similar and low prevalence among placebo, 25 mg or 50 mg groups. The authors recommend to verify the prognosis by this medication, and I have some concerns about their study.
First, the authors did not allow the change of riluzole administration and did not handle patients with edaravone treatment. I think that the vitamin B12 analog treatment in combination with recent neuro-protective drugs might be acceptable for future trials (2). In addition, the efficacy for ALS by methylcobalamin should be specified by adjusting several confounders for the analysis.
Relating to vitamin therapy for ALS, Rosenbohm et al. investigated the association of serum retinol-binding protein 4 (RBP4) with the onset and prognosis of ALS (3). Adjusted ORs (95% C) of the highest quartile of RBP4 against lowest quartile for incident ALS was 0.36 (0.22-0.59). In addition, serum RBP4 was inversely associated with m...
Show MoreWe appreciate the editorial by Dr. Muller-Vahl [1] about our recent article [2]. The large, international study group who co-authored our paper collectively felt that it would be useful to provide clarification of a few important points regarding the International Tourette Syndrome (TS) Deep Brain Stimulation (DBS) Database and Registry, the International Neuromodulation Registry, and our published analysis.
There is widespread agreement on the need for more randomized controlled trials (RCTs) to evaluate the efficacy of DBS for many indications, including TS, and there has been substantial discussion in the medical community about how these trials should be organized and carried out [3]. Our approach to overcome the challenges with the modest amount of data available for surgical therapies for TS has been to use symbiotic data sharing [4]. This approach encourages the broadening of investigative teams after publication of clinical studies to perform additional analyses and to develop new hypotheses. The key concept behind this approach is that new investigators work in a close, collaborative relationship with the teams that conducted the initial data collection. In addition, a recent viewpoint from the Food & Drug Administration in the United States reported that “For some devices, opportunities exist for leveraging alternative data sources, such as existing registries or modeling techniques, to allow regulators to have a good idea of the risks and benefits of...
Show MoreDear Editor,
Show MoreThe original article by Jeppsson et al. provides substantial perspectives regarding the diagnostic
significance of cerebrospinal fluid (CSF) biomarkers in discriminating patients with idiopathic normal pressure hydrocephalus (iNPH) from patients with other neurodegenerative disorders. 1 They have found that patients with iNPH had, compared with healthy individuals, lower concentrations of P-tau and APP-derived proteins in combination with elevated MCP-1 1. Moreover, compared with the non-iNPH disorders group, iNPH was characterized by the same significant change; low concentration of tau proteins and APP-derived proteins, and elevated MCP-1. I sincerely appreciate the authors for conducting such a large-scale study of a strictly interesting topic. However, I would like to make some comments hoping to provide a better understanding of some points and some perspectives to be kept in mind while planning future related studies
In my opinion, the investigation of CSF biomarkers in patients with iNPH may provide several insights in addition to discriminating the iNPH patients from other neurodegenerative diseases. Certainly, these study results may give the opportunity to understand the unknown pathophysiological aspects of iNPH, thereby, even leading to new classifications of the disease. Actually, there may be many questions to be clarified regarding diagnostic approach, evaluation of the iNPH patients and even identification of the disease. 2,3...
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