We appreciate the author for exploring the independent factors associated with the achievement of the treatment target (MM and MM5mg) in generalized myasthenia gravis (MG) patients, including early fast-acting treatment (EFT) [1]. This study attempted to include patients treated with EFT or non-EFT by propensity score (PS) matching to obtain a balance in baseline characters between the two groups, and to determine whether EFT was an independent factor of achieving MM5mg the treatment target by adjusting the confounding factors. The primary endpoint of this study was to reach MM5mg, and Cox regression analysis was used to explore the independent factors. Some concerns are raised here for discussion with the authors.
1. Is the starting point of the study from the beginning of immunotherapy? If so, pre-treatment factors such as gender, onset age, pre-treatment disease duration, pre-treatment worst severity, subtype, and severity at the start of treatment, need to be included. Ongoing treatment factors should include at least the dose range and duration of oral prednisone, Calcineurin inhibitors usage and intervals between their initiation time and the beginning of immunotherapy, and the number of cycles of fast-acting therapies administered 6 months after initiation of immunotherapy. All of these factors may affect the prognosis. We also wish to know whether the thymectomy was performed before or after the initiation of immunotherapy in each patient, and the interva...
We appreciate the author for exploring the independent factors associated with the achievement of the treatment target (MM and MM5mg) in generalized myasthenia gravis (MG) patients, including early fast-acting treatment (EFT) [1]. This study attempted to include patients treated with EFT or non-EFT by propensity score (PS) matching to obtain a balance in baseline characters between the two groups, and to determine whether EFT was an independent factor of achieving MM5mg the treatment target by adjusting the confounding factors. The primary endpoint of this study was to reach MM5mg, and Cox regression analysis was used to explore the independent factors. Some concerns are raised here for discussion with the authors.
1. Is the starting point of the study from the beginning of immunotherapy? If so, pre-treatment factors such as gender, onset age, pre-treatment disease duration, pre-treatment worst severity, subtype, and severity at the start of treatment, need to be included. Ongoing treatment factors should include at least the dose range and duration of oral prednisone, Calcineurin inhibitors usage and intervals between their initiation time and the beginning of immunotherapy, and the number of cycles of fast-acting therapies administered 6 months after initiation of immunotherapy. All of these factors may affect the prognosis. We also wish to know whether the thymectomy was performed before or after the initiation of immunotherapy in each patient, and the interval between the thymectomy and the first achievement of the treatment target.
2. In order to obtain a balance in clinical characters between EFT and non-EFT groups, PS matching was adopted in this study. The PS matching should be based not only on the factors that determined the choice of comparative treatments but also on the pre-treatment factors that might influence prognosis. The disease duration and severity at the start of treatment were not considered in the background factors provided in this study. More importantly, is the determination of EFT usage dependent on the factors acquired by the post hoc analysis of MM5mg achievement? Since the concept of EFT to achieve an early improvement and good prognosis gradually spread in Japan in the last decade, and EFT usage was determined individually depending on the physicians who specialized in MG among the 13 participating centers, this unmeasured confounder is advisable to be explored with a questionnaire about the factors that the physician mainly relies on to determine EFT usage. Otherwise, this unmeasured confounder can be obtained with instrumental variable analysis [2] or sensitivity analysis with an E-Value [3] to account for the unmeasured confounders.
Reference：
1.Uzawa A, Suzuki S, Kuwabara S, et al. Effectiveness of early cycles of fast-acting treatment in generalised myasthenia gravis. J Neurol Neurosurg Psychiatry. 2023 Jan 24; jnnp-2022-330519. doi: 10.1136/jnnp-2022-330519.
2.Maciejewski ML, Dowd BE, Norton EC. Instrumental Variables and Heterogeneous Treatment Effects. JAMA. 2022;327(12):1177-1178.
3.Haneuse S, VanderWeele TJ, Arterburn D. Using the E-Value to Assess the Potential Effect of Unmeasured Confounding in Observational Studies. JAMA. 2019;321(6):602-603.
Dr Smith and his colleagues have recently written an article entitled “Spasticity treatment patterns among people with multiple sclerosis: a Swedish cohort study” which was published in Journal of Neurology, Neurosurgery and Psychiatry in December 23, 2022 (1). The authors conducted a population-based cohort study containing details of 5345 patients with multiple sclerosis (MS) with a follow-up duration of about ten years to assess the prevalence and pattern of medications used by these patients for spasticity and factors associated with them. The study showed that near to 10 percents of patients with incident MS and 19 percents of those with prevalent MS received baclofen. The use of baclofen was higher among patients with higher Expanded Disability Severity Scores and younger individuals. Besides, the study showed that the rate of discontinuation of baclofen as high. The study provides strong evidence on the pattern of treatment in these patients with a proper population size and long follow-up duration; there are, however, concern that I would like to mention.
First, the authors did not consider all treatment types for spasticity. The medications included in the study were baclofen, diazepam, clonazepam, gabapentin and cannaboids. In a nationwide study of individuals who received pharmacologic treatment for spasticity in Sweden, the same country as the current study on MS patients was conducted in, the mean proportion of use of botulinum toxin was 9.2% with percen...
Dr Smith and his colleagues have recently written an article entitled “Spasticity treatment patterns among people with multiple sclerosis: a Swedish cohort study” which was published in Journal of Neurology, Neurosurgery and Psychiatry in December 23, 2022 (1). The authors conducted a population-based cohort study containing details of 5345 patients with multiple sclerosis (MS) with a follow-up duration of about ten years to assess the prevalence and pattern of medications used by these patients for spasticity and factors associated with them. The study showed that near to 10 percents of patients with incident MS and 19 percents of those with prevalent MS received baclofen. The use of baclofen was higher among patients with higher Expanded Disability Severity Scores and younger individuals. Besides, the study showed that the rate of discontinuation of baclofen as high. The study provides strong evidence on the pattern of treatment in these patients with a proper population size and long follow-up duration; there are, however, concern that I would like to mention.
First, the authors did not consider all treatment types for spasticity. The medications included in the study were baclofen, diazepam, clonazepam, gabapentin and cannaboids. In a nationwide study of individuals who received pharmacologic treatment for spasticity in Sweden, the same country as the current study on MS patients was conducted in, the mean proportion of use of botulinum toxin was 9.2% with percentage variation between 5.8% and 13.6% across healthcare regions (2) which indicates that botulinum toxin is among key treatments for spasticity in Swedish population and it would be better if the authors could add the information regarding its use to the work. Second, as the authors aimed to assess the treatment pattern and associated factors with medication use, different factors which were identified previously to be in association with medication use pattern should had been considered in this study and been taken care of in the regression modelling analysis. Besides, as treatment cessation was assessed in this study, consideration of factors that are highly associated with adherence to treatment such as socioeconomic factors would have increased the validity of the findings of the study (3, 4). Furthermore, there seems to be a mismatch between prevalent spasticity and prevalent MS diagnosis. In this study, prevalent MS diagnosis defined when a patient was diagnosed with MS before the start time of the study, 1st of July, 2005; prevalent spasticity was defined as receiving spasticity treatments within the first year of evaluation time from 1 July 2005 to 1 July 2006 and patients with prevalent spasticity were then excluded from the study. This, however, could result in bias when depicting the treatment pattern of patients with prevalent diagnosis of MS. The authors also excluded patients with possible spasticity treatments before MS diagnosis were excluded. Previous studies have shown that there might be weeks, months to years of delay from initial symptoms/signs of MS to the clinical diagnosis by a physician (5-7). The patients with MS could have clinical manifestations long before they’ve been diagnosed with MS and therefore, they probably have sought the medical treatment before the diagnosis; spasticity is among these manifestations (8). Therefore, as the authors assumed that MS is likely the cause that patients without any other registered diseases that could result in spasticity were using spasticity treatment, I believe that it would be better not to exclude “all” the patients with spasticity treatment before MS diagnosis; they could just exclude patients with baclofen use for a long time, for example one year, before the diagnosis of MS and those who were known to have other diseases as a cause for spasticity.
Acknowledgement: None.
Conflict of Interest statement: I declare no conflict of interests.
Funding: None.
References
1. Smith KA, Piehl F, Olsson T, Alfredsson L, Hillert J, Kockum I, et al. Spasticity treatment patterns among people with multiple sclerosis: a Swedish cohort study. Journal of neurology, neurosurgery, and psychiatry. 2022.
2. Forsmark A, Rosengren L, Ertzgaard P. Inequalities in pharmacologic treatment of spasticity in Sweden – health economic consequences of closing the treatment gap. Health Economics Review. 2020;10(1):4.
3. Flemmen HØ, Simonsen CS, Broch L, Brunborg C, Berg-Hansen P, Moen SM, et al. The influence of socioeconomic factors on access to disease modifying treatment in a Norwegian multiple sclerosis cohort. Multiple Sclerosis and Related Disorders. 2022;61:103759.
4. Kołtuniuk A, Chojdak-Łukasiewicz J. Adherence to Therapy in Patients with Multiple Sclerosis—Review. 2022;19(4):2203.
5. Patti F, Chisari CG, Arena S, Toscano S, Finocchiaro C, Fermo SL, et al. Factors driving delayed time to multiple sclerosis diagnosis: Results from a population-based study. Multiple Sclerosis and Related Disorders. 2022;57:103361.
6. Adamec I, Barun B, Gabelić T, Zadro I, Habek M. Delay in the diagnosis of multiple sclerosis in Croatia. Clinical Neurology and Neurosurgery. 2013;115:S70-S2.
7. Kingwell E, Leung AL, Roger E, Duquette P, Rieckmann P, Tremlett H. Factors associated with delay to medical recognition in two Canadian multiple sclerosis cohorts. Journal of the Neurological Sciences. 2010;292(1):57-62.
8. Ford H. Clinical presentation and diagnosis of multiple sclerosis. Clinical medicine (London, England). 2020;20(4):380-3.
To the Editor
I have read the work conducted by Dr. He et al. on importance of early treatment of patients with multiple sclerosis and its association with outcomes reported by the patients (1). The work entitled “Association between early treatment of multiple sclerosis and patient-reported outcomes: a nationwide observational cohort study” was first published in Journal of Neurology, Neurosurgery and Psychiatry in 7th of December, 2022. This observational study showed that earlier initiation of treatment with disease-modifying treatment in the patients with multiple sclerosis was statistically significantly associated with patient-reported physical symptoms. There are some points that I thought were uncertain and unclear in the study.
The study used a cutoff of two years to divide the participants into two groups of early treated patients who were those whose treatment was initiated within two years from the onset of the disease and late treated patients with treatment initiation between two and four years after onset. The authors justified that this classification was based on the guideline recommended by international committees advocating the initiation of disease modifying treatment in less than 12 months; however, it is not clear how this recommendation support the cutoff used in the study. In previous similar studies, a cutoff value of 6 months was mainly considered (2-4). Furthermore, it would have been better if the authors also had reported the time...
To the Editor
I have read the work conducted by Dr. He et al. on importance of early treatment of patients with multiple sclerosis and its association with outcomes reported by the patients (1). The work entitled “Association between early treatment of multiple sclerosis and patient-reported outcomes: a nationwide observational cohort study” was first published in Journal of Neurology, Neurosurgery and Psychiatry in 7th of December, 2022. This observational study showed that earlier initiation of treatment with disease-modifying treatment in the patients with multiple sclerosis was statistically significantly associated with patient-reported physical symptoms. There are some points that I thought were uncertain and unclear in the study.
The study used a cutoff of two years to divide the participants into two groups of early treated patients who were those whose treatment was initiated within two years from the onset of the disease and late treated patients with treatment initiation between two and four years after onset. The authors justified that this classification was based on the guideline recommended by international committees advocating the initiation of disease modifying treatment in less than 12 months; however, it is not clear how this recommendation support the cutoff used in the study. In previous similar studies, a cutoff value of 6 months was mainly considered (2-4). Furthermore, it would have been better if the authors also had reported the time between symptoms onset to the diagnosis and the time between the diagnosis to the treatment initiation with disease modifying agents for to have a more holistic picture.
Second, the study aimed to compare the patient-reported outcomes between two groups of the patients with multiple sclerosis, those with early treatment and those with late treatment; however, they did not consider the issue that different factors were already identified in the literature to be associated with symptoms and outcomes reported by patients and these factors should also be should be added into the statistical analyses when measuring the association of the timing of treatment and the outcomes. In a study conducted by Farran et al. on patients with multiple sclerosis in Lebanon and the Middle East and North Africa region, it was shown that age of these individuals, their gender and some sociodemographic and clinical variables could be associated with their perceived symptom and health-related quality of life (5). In this study it was mentioned in Table 1 that there were significant differences in the age and gender of the two groups of the study which could endanger the credibility of the findings in the study. Besides, the participants of these two groups had even significantly different baseline number of relapses and pretreatment Expanded Disability Status Scale; therefore, the disease status and severity might be different in these two groups, a potential source for another bias.
Authors’ contributions: Both authors contributed in all processes of the preparation of this paper.
Acknowledgement: None.
Conflict of Interest statement: I declare no conflict of interests.
Funding: None.
References
1. He A, Spelman T, Manouchehrinia A, Ciccarelli O, Hillert J, McKay K. Association between early treatment of multiple sclerosis and patient-reported outcomes: a nationwide observational cohort study. Journal of Neurology, Neurosurgery & Psychiatry. 2022:jnnp-2022-330169.
2. Karampampa K, Gyllensten H, Murley C, Alexanderson K, Kavaliunas A, Olsson T, et al. Early vs. late treatment initiation in multiple sclerosis and its impact on cost of illness: A register-based prospective cohort study in Sweden. Multiple sclerosis journal - experimental, translational and clinical. 2022;8(2):20552173221092411.
3. Kavaliunas A, Manouchehrinia A, Stawiarz L, Ramanujam R, Agholme J, Hedström AK, et al. Importance of early treatment initiation in the clinical course of multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England). 2017;23(9):1233-40.
4. Landfeldt E, Castelo-Branco A, Svedbom A, Löfroth E, Kavaliunas A, Hillert J. The long-term impact of early treatment of multiple sclerosis on the risk of disability pension. Journal of neurology. 2018;265(3):701-7.
5. Farran N, Safieddine BR, Bayram M, Abi Hanna T, Massouh J, AlKhawaja M, et al. Factors affecting MS patients’ health-related quality of life and measurement challenges in Lebanon and the MENA region. 2020;6(1):2055217319848467.
Russell et al report on the risk of neurodegenerative disease (a composite outcome including dementia, motor neuron disease (MND) and Parkinson’s disease) among former international rugby union players. Using a matched retrospective cohort design they show not only that the rugby players group had two and half times the risk of developing neurodegenerative disease, they were also more likely to die from, be hospitalised due to, or be prescribed drugs related to neurodegenerative diseases. These are important findings.
The risks for Dementia, Parkinson’s disease and MND are also estimated. It is regrettable that many media outlets (The Times, Independent, Mirror, Irish Times and the Guardian to name but a few) have focused on the secondary motor neuron disease outcome, with its odds ratio point estimate of around 15, given the considerable uncertainty attached to this figure (95% confidence interval 2.10 to 178.96). Although the other outcomes have more events, and are consequently more likely to be robust, attention has been drawn to the most eye-catching 'risk' figure, even though this is not one of the primary findings of the paper.
What seems to be missing from this report is information about how many players were diagnosed with MND, or what these findings mean in terms of the absolute risk. The authors do not report how many people had MND in the rugby group, but they do say "In the analysis of MND/ALS, zero events were recorded among the...
Russell et al report on the risk of neurodegenerative disease (a composite outcome including dementia, motor neuron disease (MND) and Parkinson’s disease) among former international rugby union players. Using a matched retrospective cohort design they show not only that the rugby players group had two and half times the risk of developing neurodegenerative disease, they were also more likely to die from, be hospitalised due to, or be prescribed drugs related to neurodegenerative diseases. These are important findings.
The risks for Dementia, Parkinson’s disease and MND are also estimated. It is regrettable that many media outlets (The Times, Independent, Mirror, Irish Times and the Guardian to name but a few) have focused on the secondary motor neuron disease outcome, with its odds ratio point estimate of around 15, given the considerable uncertainty attached to this figure (95% confidence interval 2.10 to 178.96). Although the other outcomes have more events, and are consequently more likely to be robust, attention has been drawn to the most eye-catching 'risk' figure, even though this is not one of the primary findings of the paper.
What seems to be missing from this report is information about how many players were diagnosed with MND, or what these findings mean in terms of the absolute risk. The authors do not report how many people had MND in the rugby group, but they do say "In the analysis of MND/ALS, zero events were recorded among the general population comparison group. To accommodate this, one general population observation was re-allocated from no event to event" and then say that the absolute number was "low" without explaining exactly what this means. We think it is likely that 5 events in the rugby group would be consistent with an odds ratio of 15, i.e. (5/407)/(1/1235)=15.17. Although this does appear to indicate an apparent increase in risk, we question the validity of trying to quantify the risk when this can only be achieved by modifying the data, and with such modification the conclusion has very little certainty. It is unfortunate that this may have led to misunderstanding in several media reports.
We reiterate this work is important and points towards an increase in risk for many of the outcomes reported, but the risks in public health terms for relatively rare outcomes should not be exaggerated until they can be replicated in larger samples.
The authors say their intervention did not improve independence in activities of daily living for people with dementia as measured by the BADLS. In this context they do not mention their work showing that participants improved in functional ability on their chosen personal goals.[1] Using data from 7 of 10 trial sites and devising a goal attainment scaling method to evaluate 266 goals set by 111 participating dyads, results ‘strongly suggested’ that participants improved on their individual goals.
This fits with the emerging pattern of findings from personalised rehabilitative interventions that aim to support functioning and self-management in the early stages of dementia. Positive outcomes in personal goal attainment have been demonstrated in several large trials which are not mentioned in the discussion of this paper, for example GREAT[2] and REDALI-DEM.[3] However, none of the large trials of cognitive rehabilitation or related approaches has reported improvements on general measures of functional ability or other secondary outcomes, although some significant effects have been seen in smaller trials.[4,5]
The DESCANT intervention may have had several limitations, including short duration, limited number of sessions, manualised delivery by practitioners who are not qualified health professionals, and limited scope in the choice of goals, aids, and strategies. The focus of the intervention is unlikely to have influenced many domains covered by the BADLS (e...
The authors say their intervention did not improve independence in activities of daily living for people with dementia as measured by the BADLS. In this context they do not mention their work showing that participants improved in functional ability on their chosen personal goals.[1] Using data from 7 of 10 trial sites and devising a goal attainment scaling method to evaluate 266 goals set by 111 participating dyads, results ‘strongly suggested’ that participants improved on their individual goals.
This fits with the emerging pattern of findings from personalised rehabilitative interventions that aim to support functioning and self-management in the early stages of dementia. Positive outcomes in personal goal attainment have been demonstrated in several large trials which are not mentioned in the discussion of this paper, for example GREAT[2] and REDALI-DEM.[3] However, none of the large trials of cognitive rehabilitation or related approaches has reported improvements on general measures of functional ability or other secondary outcomes, although some significant effects have been seen in smaller trials.[4,5]
The DESCANT intervention may have had several limitations, including short duration, limited number of sessions, manualised delivery by practitioners who are not qualified health professionals, and limited scope in the choice of goals, aids, and strategies. The focus of the intervention is unlikely to have influenced many domains covered by the BADLS (e.g., teeth-cleaning, toileting, drinking, mobility, transfers, etc), so the lack of effect on the primary outcome measure is not surprising and might have been anticipated. Yet despite these limitations it seems this intervention, like others, did promote personal goal attainment.
Personal goal attainment is valued by people with dementia and carers who find cognitive rehabilitation helpful and say that it enhances confidence and well-being and assists in adjusting to the diagnosis. It might also have longer-term benefits. The ETNA-3 trial[6] tested a personalised cognitive rehabilitation intervention provided by qualified health professionals comprising weekly individual sessions for 3 months followed by six-weekly maintenance sessions with telephone support for the carer over a 21-month period. This resulted in significantly lower functional disability and a six-month delay in institutionalisation at the two-year follow up relative to group cognitive training, group reminiscence therapy and usual care.
Some inaccuracies require comment. First, contrary to what is suggested in the discussion of this paper, the precursor trial to GREAT[4] adopted a rigorous design consistent with criteria for high-quality evidence.[7] Participants had eight home visits from an experienced occupational therapist, and where indicated were supported to learn to use relevant aids and adaptations. Second, it is not the case that other studies have recruited fewer participants and offered fewer sessions. ETNA-3[6] randomised 653 people with dementia in 40 trial sites and provided an extensive intervention schedule. GREAT[2] randomised 475 people with dementia in eight trial sites and offered ten sessions with up to four maintenance sessions.
In conclusion, it is time to stop setting unrealistic expectations about what outcomes interventions should achieve. Instead, we should focus on what is most meaningful for people with dementia and their families and build on what we know can be done. We know that we can enable people with dementia to improve their functioning in relation to chosen activities that are important and meaningful for them using evidence-based cognitive rehabilitation strategies, which include but are not limited to the use of aids and adaptations. A recent implementation study8 has shown that the GREAT intervention is equally effective when offered within normal services and can be provided at modest cost. Supporting functional ability in areas that are personally meaningful may have worthwhile long-term benefits for people with dementia and their families.
References
1. Chester H, Beresford R, Clarkson P, et al. The Dementia Early Stage Cognitive Aids New Trial (DESCANT) intervention: A goal attainment scaling approach to promote self-management. International Journal of Geriatric Psychiatry 2021;36(5):784-93. doi: 10.1002/gps.5479
2. Clare L, Kudlicka A, Oyebode JR, et al. Individual goal-oriented cognitive rehabilitation to improve everyday functioning for people with early-stage dementia: a multi-centre randomised controlled trial (the GREAT trial). International Journal of Geriatric Psychiatry 2019;34:709-12. doi: 10.1002/gps.5076
3. Voigt-Radloff S, de Werd MME, Leonhart R, et al. Structured relearning of activities of daily living in dementia: the randomised controlled REDALI-DEM trial on errorless learning. Alzheimer's Research and Therapy 2017;9:22. doi: 10.1186/s13195-017-0247-9
4. Clare L, Linden DE, Woods RT, et al. Goal-oriented cognitive rehabilitation for people with early-stage Alzheimer’s disease: a single-blind randomized controlled trial of clinical efficacy. American Journal of Geriatric Psychiatry 2010;18:928-39. doi: 10.1097/JGP.0b013e3181d5792a
5. Hindle JV, Watermeyer TJ, Roberts J, et al. Goal-oriented cognitive rehabilitation for dementias associated with Parkinson’s disease. International Journal of Geriatric Psychiatry 2018;33:718-28. doi: 10.1002/gps.4845
6. Amieva H, Robert PH, Grandoulier AS, et al. Group and individual cognitive therapies in Alzheimer’s disease: the ETNA3 randomized trial. International Psychogeriatrics 2016;28:707-17. doi: 10.1017/S1041610215001830
7. Bahar-Fuchs A, Clare L, Woods RT. Cognitive training and cognitive rehabilitation for mild to moderate Alzheimer's disease and vascular dementia. Cochrane Database of Systematic Reviews 2013(6) doi: 10.1002/14651858.CD003260.pub2
8. Clare L, Kudlicka A, Collins RA, et al. Implementing a home-based personalised cognitive rehabilitation intervention for people with mild-to-moderate dementia: GREAT into Practice. 2022 (preprint) doi: 10.21203/rs.3.rs-1458590/v1
Doxycycline is an important drug used in many disease conditions like Brucellosis, Lyme disease, malaria etc. One important side effect with it's use is raised intracranial pressure i.e. idiopathic intracranial pressure. So this study is a nice development as lesser duration of treatment will reduce cost of therapy, and a psychological well being because of less drug, less duration and less cost.
References-
1. J Lochhead, and J S Elston.Doxycycline induced intracranial hypertension BMJ. 2003 Mar 22; 326(7390): 641–642.
doi: 10.1136/bmj.326.7390.641.
The research study conducted by Ward et al., [1] has effectively marked an understandable association between frailty, lifestyle and genetics as factors of dementia in adults aged 60 and above. The findings of this study could potentially have major implications in the field of neuropsychiatric research in the field of geriatric studies.
One of the concerns regarding the methodology of classification of a healthy lifestyle score was that participants who were currently non-smokers were identified as a valid classification in the healthy subgroup. This is questionable due to the fact that, for this classification, no reference was cited to accept non current smokers as a valid factor in the healthy lifestyle score. According to several studies, smoking was indicated as one of the major risk factors for dementia among the elderly. [2] A 2019 Lancet commission identified that smoking was the third among nine modifiable risk factors for dementia. Furthermore a review of 37 studies in the field of association of smoking as a risk factor for dementia identified that compared to never smokers, smokers had a 30% higher chance of developing dementia in general along with a 40% higher chance of developing Alzheimers. [3] So to associate non-current smokers into a healthy lifestyle category is concerning but instead, the classification should have been rather as never-smokers and smokers (both current and non-current). An appropriate classification of smokers and non-smokers...
The research study conducted by Ward et al., [1] has effectively marked an understandable association between frailty, lifestyle and genetics as factors of dementia in adults aged 60 and above. The findings of this study could potentially have major implications in the field of neuropsychiatric research in the field of geriatric studies.
One of the concerns regarding the methodology of classification of a healthy lifestyle score was that participants who were currently non-smokers were identified as a valid classification in the healthy subgroup. This is questionable due to the fact that, for this classification, no reference was cited to accept non current smokers as a valid factor in the healthy lifestyle score. According to several studies, smoking was indicated as one of the major risk factors for dementia among the elderly. [2] A 2019 Lancet commission identified that smoking was the third among nine modifiable risk factors for dementia. Furthermore a review of 37 studies in the field of association of smoking as a risk factor for dementia identified that compared to never smokers, smokers had a 30% higher chance of developing dementia in general along with a 40% higher chance of developing Alzheimers. [3] So to associate non-current smokers into a healthy lifestyle category is concerning but instead, the classification should have been rather as never-smokers and smokers (both current and non-current). An appropriate classification of smokers and non-smokers accordingly would’ve made the findings of the study more accurate and proportionately more significantly authentic than as it currently stands.
Furthermore, an appropriate identification of non-current smokers was also absent as there was no time gap range provided as to what could be considered as current versus non-current smokers. As participants who quit smoking a month before the administering of the questionnaire versus those who quit 20 years prior to administration of the questionnaire would both be eligible to be considered as non-current smokers. In the same way, smokers who quit after 1 year of smoking and those who quit after 30 years of smoking will both be considered non current smokers but the relative effect on the lifestyle and mental health corresponding to the facet of dementia is not proportionately accountable as per the study classification. Utilising a better defined statement in the prospect of classification will give more eligibility in the view of geriatric healthy lifestyle features. It is suggested that in future studies, that the authors provide a correspondingly satisfactory classification in the terms of appropriately defined reference intervals to positively substantiate their findings.
REFERENCES
1. Ward DD, Ranson JM, Wallace LMK, et al Frailty, lifestyle, genetics and dementia risk. Journal of Neurology, Neurosurgery & Psychiatry 2022;93:343-350
2. Peters R, Poulter R, Warner J, et al. Smoking, dementia and cognitive decline in the elderly, a systematic review. BMC Geriatr 2008;8:36. doi:10.1186/1471-2318-8-36
3. All you need to know about smoking and dementia. Alzheimer’s Research UK. 2020.https://www.alzheimersresearchuk.org/blog/all-you-need-to-know-about-smo... (accessed 18 Mar 2022)
Ward et al.'s recent study on frailty, lifestyle, genetics and dementia risk (1) is a major contribution to the growing multimorbidity approach towards dementia. But it is not clear why the authors exclusively frame their discussion on practical steps to reduce dementia risk around healthy lifestyle. They paradoxically argue that "adherence to national guidelines for healthy lifestyle behaviours is central to dementia risk reduction recommendations," while also recognising that multi-domain lifestyle interventions have a weak evidence base in favour of them. An exclusive focus on lifestyle to achieve reduction of frailty and dementia overlooks social gradients of health, particularly the unequal distribution of access to the kind of safe and stimulating living and working environments in which risk reduction can take place through high-quality stimulation and the absence of stressors like noise and air pollution (2). The authors make no mention of social determinants. People with higher income are more likely to part in lifestyle interventions (3), and focusing exclusively on conscious behavioural change to achieve dementia risk reduction may therefore worsen inequalities in dementia risk (4). Therefore, to address not only dementia risk reduction but also the reduction of health inequities, as well as promoting lifestyle changes, the research community ought to stress the need for action against the social determinants of frailty and dementia (5).
Ward et al.'s recent study on frailty, lifestyle, genetics and dementia risk (1) is a major contribution to the growing multimorbidity approach towards dementia. But it is not clear why the authors exclusively frame their discussion on practical steps to reduce dementia risk around healthy lifestyle. They paradoxically argue that "adherence to national guidelines for healthy lifestyle behaviours is central to dementia risk reduction recommendations," while also recognising that multi-domain lifestyle interventions have a weak evidence base in favour of them. An exclusive focus on lifestyle to achieve reduction of frailty and dementia overlooks social gradients of health, particularly the unequal distribution of access to the kind of safe and stimulating living and working environments in which risk reduction can take place through high-quality stimulation and the absence of stressors like noise and air pollution (2). The authors make no mention of social determinants. People with higher income are more likely to part in lifestyle interventions (3), and focusing exclusively on conscious behavioural change to achieve dementia risk reduction may therefore worsen inequalities in dementia risk (4). Therefore, to address not only dementia risk reduction but also the reduction of health inequities, as well as promoting lifestyle changes, the research community ought to stress the need for action against the social determinants of frailty and dementia (5).
References
1 - Ward DD, et al. Frailty, lifestyle, genetics and dementia risk Journal of Neurology, Neurosurgery & Psychiatry Published Online First: 21 December 2021. doi: 10.1136/jnnp-2021-327396
2 - Daly T. Giving a fairer face to urban space: Progress on the long road to dementia prevention. Int J Geriatr Psychiatry. 2022 Jan;37(1). doi: 10.1002/gps.5657.
3 - Coley N, et al. Disparities in the participation and adherence of older adults in lifestyle-based multidomain dementia prevention and the motivational role of perceived disease risk and intervention benefits: an observational ancillary study to a randomised controlled trial. Alzheimers Res Ther. 2021 Sep 24;13(1):157. doi: 10.1186/s13195-021-00904-6.
4 - Walsh S, et al. A whole-population approach is required for dementia risk reduction. The Lancet Health Longevity 2022 3(1), E6-E8. doi: 10.1016/S2666-7568(21)00301-9.
5 - Daly T. The vital need for action against the social determinants of frailty. Aging Medicine. 2022 doi: 10.1002/agm2.12195
Ward et al. reported the relationships between frailty index, healthy lifestyle and polygenic risk scores, and incident all-cause dementia (1). The adjusted hazard ratio (HR) (95% CI) of participants with high frailty for incident dementia was 3.68 (3.11 to 4.35). In addition, the adjusted HR (95% CI) of participants with high genetic risk and high frailty for incident dementia was 5.81 (4.01 to 8.42).The authors emphasized of controlling frailty for dementia prevention strategies, even among subjects at high genetic risk. I have two comments about their study.
First, Lourida et al. investigated the association between healthy lifestyles and risk of dementia by considering genetic risk (2). The adjusted HR (95% CI) of participants with high genetic risk and unfavorable lifestyle for incident dementia was 2.83 (2.09 to 3.83). In addition, a favorable lifestyle was associated with a lower dementia risk among participants with high genetic risk. There was no significant interaction between genetic risk and lifestyle factors, and I suppose that unfavorable lifestyles and genetic factors independently contribute to the risk of dementia. The level of frailty may be related to lifestyles and contribute to subsequent progression of cognitive impairment.
Second, Kojima et al. conducted a meta-analysis regarding the effect of frailty on the incident dementia among community-dwelling older people (3). Th pooled HRs (95% CIs) of frailty for the incident Alzheimer disease...
Ward et al. reported the relationships between frailty index, healthy lifestyle and polygenic risk scores, and incident all-cause dementia (1). The adjusted hazard ratio (HR) (95% CI) of participants with high frailty for incident dementia was 3.68 (3.11 to 4.35). In addition, the adjusted HR (95% CI) of participants with high genetic risk and high frailty for incident dementia was 5.81 (4.01 to 8.42).The authors emphasized of controlling frailty for dementia prevention strategies, even among subjects at high genetic risk. I have two comments about their study.
First, Lourida et al. investigated the association between healthy lifestyles and risk of dementia by considering genetic risk (2). The adjusted HR (95% CI) of participants with high genetic risk and unfavorable lifestyle for incident dementia was 2.83 (2.09 to 3.83). In addition, a favorable lifestyle was associated with a lower dementia risk among participants with high genetic risk. There was no significant interaction between genetic risk and lifestyle factors, and I suppose that unfavorable lifestyles and genetic factors independently contribute to the risk of dementia. The level of frailty may be related to lifestyles and contribute to subsequent progression of cognitive impairment.
Second, Kojima et al. conducted a meta-analysis regarding the effect of frailty on the incident dementia among community-dwelling older people (3). Th pooled HRs (95% CIs) of frailty for the incident Alzheimer disease, vascular dementia, and all dementia were 1.28(1.00 to 1.63), 2.70 (1.40-5.23), and 1.33 (1.07 to 1.67), respectively. They also observed sex difference that frail women had a higher risk of incident Alzheimer disease than frail men. There is a report that the prevalence of Alzheimer disease in women is higher than that in men at the same generation (4), and frailty may also contribute to the risk of Alzheimer disease via sex-related factors.
References
1. Ward DD, Ranson JM, Wallace LMK, Llewellyn DJ, Rockwood K. Frailty, lifestyle, genetics and dementia risk. J Neurol Neurosurg Psychiatry 2021 Dec 21. doi: 10.1136/jnnp-2021-327396.
2. Lourida I, Hannon E, Littlejohns TJ, Langa KM, Hyppönen E, Kuzma E, Llewellyn DJ. Association of Lifestyle and Genetic Risk With Incidence of Dementia. JAMA 2019;322(5):430-437.
3. Kojima G, Taniguchi Y, Iliffe S, Walters K. Frailty as a Predictor of Alzheimer Disease, Vascular Dementia, and All Dementia Among Community-Dwelling Older People: A Systematic Review and Meta-Analysis. J Am Med Dir Assoc 2016;17(10):881-8.
4. Yoshida D, Ohara T, Hata J, Shibata M, Hirakawa Y, Honda T, Furuta Y, Oishi E, Sakata S, Kanba S, Kitazono T, Ninomiya T. Lifetime cumulative incidence of dementia in a community-dwelling elderly population in Japan. Neurology 2020;95(5):e508-e518.
We read with interest the letter by Bert-Marcaz et al., reporting on a 74-year-old man with vacuole, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome and chronic inflammatory demyelinating polyneuropathy [1]. We agree with the authors’ postulation that the simultaneous onset of the two diseases suggests a potentially causal link between VEXAS and the demyelinating abnormalities they observed on nerve conduction studies and nerve biopsy. We have previously reported a case of a 68-year-old man with VEXAS associated with neurological features, including ophthalmoplegia, sensorineural hearing loss and bilateral vestibulopathy [2]. Our hypothesis for the mechanism of neurological involvement was polycranial neuritis, given that there was no evidence of orbital inflammation on MRI and there was significant improvement with corticosteroids. Neurologists should consider the diagnosis of VEXAS (and other autoinflammatory syndromes of innate immunity) in patients with neurological problems who have (i) unexplained fever and elevated acute phase reactants, especially when there is a remitting and relapsing course, (ii) unexplained multisystem disease, and (iii) no evidence of infection, malignancy or autoimmune (i.e., antibody-mediated) disease.
References:
[1] Bert-Marcaz C, Briantais A, Faucher B, Corazza G, Ebbo M, Attarian S, Delmont E, Fortanier E. Expanding the spectrum of VEXAS syndrome: association with acute-onset CIDP. J Neurol Neurosurg Psychiat...
We read with interest the letter by Bert-Marcaz et al., reporting on a 74-year-old man with vacuole, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome and chronic inflammatory demyelinating polyneuropathy [1]. We agree with the authors’ postulation that the simultaneous onset of the two diseases suggests a potentially causal link between VEXAS and the demyelinating abnormalities they observed on nerve conduction studies and nerve biopsy. We have previously reported a case of a 68-year-old man with VEXAS associated with neurological features, including ophthalmoplegia, sensorineural hearing loss and bilateral vestibulopathy [2]. Our hypothesis for the mechanism of neurological involvement was polycranial neuritis, given that there was no evidence of orbital inflammation on MRI and there was significant improvement with corticosteroids. Neurologists should consider the diagnosis of VEXAS (and other autoinflammatory syndromes of innate immunity) in patients with neurological problems who have (i) unexplained fever and elevated acute phase reactants, especially when there is a remitting and relapsing course, (ii) unexplained multisystem disease, and (iii) no evidence of infection, malignancy or autoimmune (i.e., antibody-mediated) disease.
References:
[1] Bert-Marcaz C, Briantais A, Faucher B, Corazza G, Ebbo M, Attarian S, Delmont E, Fortanier E. Expanding the spectrum of VEXAS syndrome: association with acute-onset CIDP. J Neurol Neurosurg Psychiatry. 2021 Dec 6:jnnp-2021-327949. doi: 10.1136/jnnp-2021-327949
[2] Diprose WK, Jordan A, Anderson NE. Autoinflammatory syndromes in neurology: when our first line of defence misbehaves. Pract Neurol. 2021 Oct 1:practneurol-2021-003031. doi: 10.1136/practneurol-2021-003031
We appreciate the author for exploring the independent factors associated with the achievement of the treatment target (MM and MM5mg) in generalized myasthenia gravis (MG) patients, including early fast-acting treatment (EFT) [1]. This study attempted to include patients treated with EFT or non-EFT by propensity score (PS) matching to obtain a balance in baseline characters between the two groups, and to determine whether EFT was an independent factor of achieving MM5mg the treatment target by adjusting the confounding factors. The primary endpoint of this study was to reach MM5mg, and Cox regression analysis was used to explore the independent factors. Some concerns are raised here for discussion with the authors.
Show More1. Is the starting point of the study from the beginning of immunotherapy? If so, pre-treatment factors such as gender, onset age, pre-treatment disease duration, pre-treatment worst severity, subtype, and severity at the start of treatment, need to be included. Ongoing treatment factors should include at least the dose range and duration of oral prednisone, Calcineurin inhibitors usage and intervals between their initiation time and the beginning of immunotherapy, and the number of cycles of fast-acting therapies administered 6 months after initiation of immunotherapy. All of these factors may affect the prognosis. We also wish to know whether the thymectomy was performed before or after the initiation of immunotherapy in each patient, and the interva...
Dr Smith and his colleagues have recently written an article entitled “Spasticity treatment patterns among people with multiple sclerosis: a Swedish cohort study” which was published in Journal of Neurology, Neurosurgery and Psychiatry in December 23, 2022 (1). The authors conducted a population-based cohort study containing details of 5345 patients with multiple sclerosis (MS) with a follow-up duration of about ten years to assess the prevalence and pattern of medications used by these patients for spasticity and factors associated with them. The study showed that near to 10 percents of patients with incident MS and 19 percents of those with prevalent MS received baclofen. The use of baclofen was higher among patients with higher Expanded Disability Severity Scores and younger individuals. Besides, the study showed that the rate of discontinuation of baclofen as high. The study provides strong evidence on the pattern of treatment in these patients with a proper population size and long follow-up duration; there are, however, concern that I would like to mention.
Show MoreFirst, the authors did not consider all treatment types for spasticity. The medications included in the study were baclofen, diazepam, clonazepam, gabapentin and cannaboids. In a nationwide study of individuals who received pharmacologic treatment for spasticity in Sweden, the same country as the current study on MS patients was conducted in, the mean proportion of use of botulinum toxin was 9.2% with percen...
To the Editor
Show MoreI have read the work conducted by Dr. He et al. on importance of early treatment of patients with multiple sclerosis and its association with outcomes reported by the patients (1). The work entitled “Association between early treatment of multiple sclerosis and patient-reported outcomes: a nationwide observational cohort study” was first published in Journal of Neurology, Neurosurgery and Psychiatry in 7th of December, 2022. This observational study showed that earlier initiation of treatment with disease-modifying treatment in the patients with multiple sclerosis was statistically significantly associated with patient-reported physical symptoms. There are some points that I thought were uncertain and unclear in the study.
The study used a cutoff of two years to divide the participants into two groups of early treated patients who were those whose treatment was initiated within two years from the onset of the disease and late treated patients with treatment initiation between two and four years after onset. The authors justified that this classification was based on the guideline recommended by international committees advocating the initiation of disease modifying treatment in less than 12 months; however, it is not clear how this recommendation support the cutoff used in the study. In previous similar studies, a cutoff value of 6 months was mainly considered (2-4). Furthermore, it would have been better if the authors also had reported the time...
Russell et al report on the risk of neurodegenerative disease (a composite outcome including dementia, motor neuron disease (MND) and Parkinson’s disease) among former international rugby union players. Using a matched retrospective cohort design they show not only that the rugby players group had two and half times the risk of developing neurodegenerative disease, they were also more likely to die from, be hospitalised due to, or be prescribed drugs related to neurodegenerative diseases. These are important findings.
The risks for Dementia, Parkinson’s disease and MND are also estimated. It is regrettable that many media outlets (The Times, Independent, Mirror, Irish Times and the Guardian to name but a few) have focused on the secondary motor neuron disease outcome, with its odds ratio point estimate of around 15, given the considerable uncertainty attached to this figure (95% confidence interval 2.10 to 178.96). Although the other outcomes have more events, and are consequently more likely to be robust, attention has been drawn to the most eye-catching 'risk' figure, even though this is not one of the primary findings of the paper.
What seems to be missing from this report is information about how many players were diagnosed with MND, or what these findings mean in terms of the absolute risk. The authors do not report how many people had MND in the rugby group, but they do say "In the analysis of MND/ALS, zero events were recorded among the...
Show MoreThe authors say their intervention did not improve independence in activities of daily living for people with dementia as measured by the BADLS. In this context they do not mention their work showing that participants improved in functional ability on their chosen personal goals.[1] Using data from 7 of 10 trial sites and devising a goal attainment scaling method to evaluate 266 goals set by 111 participating dyads, results ‘strongly suggested’ that participants improved on their individual goals.
This fits with the emerging pattern of findings from personalised rehabilitative interventions that aim to support functioning and self-management in the early stages of dementia. Positive outcomes in personal goal attainment have been demonstrated in several large trials which are not mentioned in the discussion of this paper, for example GREAT[2] and REDALI-DEM.[3] However, none of the large trials of cognitive rehabilitation or related approaches has reported improvements on general measures of functional ability or other secondary outcomes, although some significant effects have been seen in smaller trials.[4,5]
The DESCANT intervention may have had several limitations, including short duration, limited number of sessions, manualised delivery by practitioners who are not qualified health professionals, and limited scope in the choice of goals, aids, and strategies. The focus of the intervention is unlikely to have influenced many domains covered by the BADLS (e...
Show MoreDoxycycline is an important drug used in many disease conditions like Brucellosis, Lyme disease, malaria etc. One important side effect with it's use is raised intracranial pressure i.e. idiopathic intracranial pressure. So this study is a nice development as lesser duration of treatment will reduce cost of therapy, and a psychological well being because of less drug, less duration and less cost.
References-
1. J Lochhead, and J S Elston.Doxycycline induced intracranial hypertension BMJ. 2003 Mar 22; 326(7390): 641–642.
doi: 10.1136/bmj.326.7390.641.
The research study conducted by Ward et al., [1] has effectively marked an understandable association between frailty, lifestyle and genetics as factors of dementia in adults aged 60 and above. The findings of this study could potentially have major implications in the field of neuropsychiatric research in the field of geriatric studies.
One of the concerns regarding the methodology of classification of a healthy lifestyle score was that participants who were currently non-smokers were identified as a valid classification in the healthy subgroup. This is questionable due to the fact that, for this classification, no reference was cited to accept non current smokers as a valid factor in the healthy lifestyle score. According to several studies, smoking was indicated as one of the major risk factors for dementia among the elderly. [2] A 2019 Lancet commission identified that smoking was the third among nine modifiable risk factors for dementia. Furthermore a review of 37 studies in the field of association of smoking as a risk factor for dementia identified that compared to never smokers, smokers had a 30% higher chance of developing dementia in general along with a 40% higher chance of developing Alzheimers. [3] So to associate non-current smokers into a healthy lifestyle category is concerning but instead, the classification should have been rather as never-smokers and smokers (both current and non-current). An appropriate classification of smokers and non-smokers...
Show MoreWard et al.'s recent study on frailty, lifestyle, genetics and dementia risk (1) is a major contribution to the growing multimorbidity approach towards dementia. But it is not clear why the authors exclusively frame their discussion on practical steps to reduce dementia risk around healthy lifestyle. They paradoxically argue that "adherence to national guidelines for healthy lifestyle behaviours is central to dementia risk reduction recommendations," while also recognising that multi-domain lifestyle interventions have a weak evidence base in favour of them. An exclusive focus on lifestyle to achieve reduction of frailty and dementia overlooks social gradients of health, particularly the unequal distribution of access to the kind of safe and stimulating living and working environments in which risk reduction can take place through high-quality stimulation and the absence of stressors like noise and air pollution (2). The authors make no mention of social determinants. People with higher income are more likely to part in lifestyle interventions (3), and focusing exclusively on conscious behavioural change to achieve dementia risk reduction may therefore worsen inequalities in dementia risk (4). Therefore, to address not only dementia risk reduction but also the reduction of health inequities, as well as promoting lifestyle changes, the research community ought to stress the need for action against the social determinants of frailty and dementia (5).
Re...
Show MoreWard et al. reported the relationships between frailty index, healthy lifestyle and polygenic risk scores, and incident all-cause dementia (1). The adjusted hazard ratio (HR) (95% CI) of participants with high frailty for incident dementia was 3.68 (3.11 to 4.35). In addition, the adjusted HR (95% CI) of participants with high genetic risk and high frailty for incident dementia was 5.81 (4.01 to 8.42).The authors emphasized of controlling frailty for dementia prevention strategies, even among subjects at high genetic risk. I have two comments about their study.
First, Lourida et al. investigated the association between healthy lifestyles and risk of dementia by considering genetic risk (2). The adjusted HR (95% CI) of participants with high genetic risk and unfavorable lifestyle for incident dementia was 2.83 (2.09 to 3.83). In addition, a favorable lifestyle was associated with a lower dementia risk among participants with high genetic risk. There was no significant interaction between genetic risk and lifestyle factors, and I suppose that unfavorable lifestyles and genetic factors independently contribute to the risk of dementia. The level of frailty may be related to lifestyles and contribute to subsequent progression of cognitive impairment.
Second, Kojima et al. conducted a meta-analysis regarding the effect of frailty on the incident dementia among community-dwelling older people (3). Th pooled HRs (95% CIs) of frailty for the incident Alzheimer disease...
Show MoreWe read with interest the letter by Bert-Marcaz et al., reporting on a 74-year-old man with vacuole, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome and chronic inflammatory demyelinating polyneuropathy [1]. We agree with the authors’ postulation that the simultaneous onset of the two diseases suggests a potentially causal link between VEXAS and the demyelinating abnormalities they observed on nerve conduction studies and nerve biopsy. We have previously reported a case of a 68-year-old man with VEXAS associated with neurological features, including ophthalmoplegia, sensorineural hearing loss and bilateral vestibulopathy [2]. Our hypothesis for the mechanism of neurological involvement was polycranial neuritis, given that there was no evidence of orbital inflammation on MRI and there was significant improvement with corticosteroids. Neurologists should consider the diagnosis of VEXAS (and other autoinflammatory syndromes of innate immunity) in patients with neurological problems who have (i) unexplained fever and elevated acute phase reactants, especially when there is a remitting and relapsing course, (ii) unexplained multisystem disease, and (iii) no evidence of infection, malignancy or autoimmune (i.e., antibody-mediated) disease.
References:
Show More[1] Bert-Marcaz C, Briantais A, Faucher B, Corazza G, Ebbo M, Attarian S, Delmont E, Fortanier E. Expanding the spectrum of VEXAS syndrome: association with acute-onset CIDP. J Neurol Neurosurg Psychiat...
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