Dear Editor,

I am writing to provide a more in-depth discussion on the recently published article, "Cognitive trajectory in the first year after first-ever ischaemic stroke in young adults: the ODYSSEY study." [1]. This study offers valuable insights into the intricate dynamics of cognitive recovery following ischaemic strokes in young adults, shedding light on the challenges and potential predictors of cognitive outcomes.
The central finding, highlighting the persistent prevalence of cognitive impairment in young stroke patients even one year post-event, underscores the gravity of the issue. The study's longitudinal design, incorporating cognitive assessments at distinct time points within the first year, provides a nuanced understanding of the trajectory of cognitive changes. Notably, the observation of specific improvements in processing speed, visuoconstruction, and executive functioning among initially cognitively impaired patients adds granularity to our comprehension of post-stroke recovery.
The study's discussion on the complex factors influencing cognitive recovery, such as age and lesion volume, enriches the narrative. However, the candid acknowledgment of the challenges in predicting cognitive recovery at an individual level reflects the intricate nature of post-stroke outcomes. Exploring the potential role of post-stroke fatigue and the absence of uniform predictors for recovery contribute to the depth of the article. The use of the Reliable Change Index (RCI) as a method for assessing cognitive recovery, though rigorous, prompts thoughtful consideration of its implications and potential impact on the observed outcomes.
Nevertheless, it is crucial to address the inherent limitations in the study to ensure a balanced interpretation of the results. The exclusion of cognitive data for patients with more severe strokes introduces a potential bias that warrants cautious generalization of the findings. The absence of information on interventions such as cognitive rehabilitation and the wide temporal range of baseline assessments pose challenges to the study's precision. These limitations, conscientiously noted in the article, emphasize the importance of interpreting the results within a nuanced context.
In conclusion, the "ODYSSEY study" significantly advances our understanding of cognitive recovery after ischaemic strokes in young adults. The enduring challenges faced by this population are well-captured, but a meticulous consideration of the study's limitations is paramount. Future research endeavors should strive to address these limitations, providing a more comprehensive understanding of post-stroke cognitive trajectories and guiding effective interventions for young stroke patients.
References
1. Schellekens MMI, Springer RCS, Boot EM, et alCognitive trajectory in the first year after first-ever ischaemic stroke in young adults: the ODYSSEY studyJournal of Neurology, Neurosurgery & Psychiatry Published Online First: 30 December 2023. doi: 10.1136/jnnp-2023-332104

Dear Editor,
I am writing to express my appreciation for the enlightening article titled "Childbirth Delivery Mode and the Risk of Multiple Sclerosis: A Prospective Population-Based Study" [1] recently published in your esteemed journal. The study, which examines the potential relationship between childbirth mode and the subsequent risk of multiple sclerosis (MS) development, presents a comprehensive analysis and incites intriguing discussions. The authors embarked on a commendable endeavor by conducting a meticulous prospective cohort study encompassing individuals born in Norway between 1967 and 2003. Their investigation aimed to unravel the potential influence of caesarean section (CS) births on the risk of adult-onset MS. The findings unveil an association suggesting an 18% elevated risk of MS among individuals born via CS, as compared to those born vaginally, after considering an array of confounding factors. However, the authors astutely highlight that this association does not persist when a sibling-matched analysis is undertaken. Furthermore, this intriguing connection appears to be primarily confined to individuals born preterm or via emergency CS. Such nuanced insights underline the complexities underlying the childbirth mode and MS risk paradigm, necessitating a thoughtful interpretation of the findings.
The authors acknowledge the divergent findings from previous studies, emphasizing the discrepancies between their results and those reported in an Iranian case–control study. This retrospective analysis, while reporting a substantial increase in MS risk among individuals born by CS, utilized self-reported data and was susceptible to potential biases [2]. The contrast between this study and a Danish nationwide cohort study also warrants consideration [3]. In both studies, similar estimates were observed when adjusting for pertinent factors, indicating a convergence of findings.
The study delves into intriguing potential mechanisms underlying the observed associations. The authors propose that alterations in gut microbiota, delayed immune system development, and differential cytokine responses may underpin the relationship between CS births and MS risk. The exploration of these pathways adds a layer of depth to the investigation, urging further research into the intricate interplay between childbirth experiences and immune-mediated diseases.
While the study boasts numerous strengths, such as its large population-based cohort, prospective design, and verification of MS cases by neurologists, the authors candidly delineate its limitations. The lack of generalizability to other populations due to the exclusive focus on Norwegian individuals is acknowledged, as is the absence of maternal smoking information for certain cohorts. Despite these limitations, the sibling-matched analyses and comprehensive data integration fortify the study's robustness.
In conclusion, the study "Childbirth Delivery Mode and the Risk of Multiple Sclerosis: A Prospective Population-Based Study" significantly advances our understanding of the intricate relationship between childbirth mode and MS risk. The authors' astute exploration of potential mechanisms, combined with the meticulous consideration of confounding factors, highlights the need for cautious interpretation. The association identified between CS births and MS risk, particularly in subgroups with complicated pregnancies, beckons further investigation into the underlying confounders shaping this relationship. This study underscores the importance of ongoing research into the nexus between early life experiences and long-term health outcomes, contributing valuable insights into our understanding of immune-mediated diseases.

Thank you for providing a platform for this thought-provoking study, and I look forward to witnessing future advancements in this evolving field.
References
1. Akash, K., et al., Childbirth delivery mode and the risk of multiple sclerosis: a prospective population-based study. Journal of Neurology, Neurosurgery & Psychiatry, 2023: p. jnnp-2023-331241.
2. Maghzi, A.H., et al., Cesarean delivery may increase the risk of multiple sclerosis. Mult Scler, 2012. 18(4): p. 468-71.
3. Nielsen, N.M., et al., Cesarean section and offspring's risk of multiple sclerosis: a Danish nationwide cohort study. Mult Scler, 2013. 19(11): p. 1473-7.

The authors revised this Rapid Response at BMJ's request in line with BMJ's Terms and Conditions for Rapid Responses.

Dear Editor,
In the article ‘Anomalies in the review process and interpretation of the evidence in the NICE guideline for chronic fatigue syndrome and myalgic encephalomyelitis’ published in the Journal of Neurology, Neurosurgery & Psychiatry on 10th July 2023, the authors claim NICE invented a new definition of ME. These claims are unfounded as NICE used the Institute of Medicine (IOM) criteria which is now 8 years old and was created using a more robust process than many other definitions as it drew on samples from different countries and compared the most widely used definitions of ME.
One area where NICE felt there was a gap in the IOM criteria was the lack of an empirical process alongside other methods. Leonard Jason's four-item empiric criteria were the only criteria that used adequate empiric methods, and this aligned very closely with the IOM criteria. As a result, NICE operationalised the IOM criteria for use in the NHS, with the four-item criteria helping to substantiate their approach.
NICE does not measure a trial’s success based on the researchers’ own terms but by analysing the raw data and applying the committee's agreed protocol. This allows NICE to measure whether a treatment had an effect or not. This is striking when looking at the assertion that research showed that the favoured treatments of CBT and GET were safe, when, in reality, safety data either was not collected or was incomplete or uninterpretable. These treatments have led to many complaints from people with ME that they were harmful and led to deterioration. This was illustrated in the MEAction UK 2019 report, ME services in the UK Not Fit For Purpose.
The authors of this critique also claim that NICE didn't aggregate data properly, but there are hundreds of pages of meta-analysis proving they were meticulous and gave detailed consideration to every trial they looked at. The real complaint here seems to be that NICE didn't aggregate data in the way the authors of this paper wish they had. For example, the Cochrane review of exercise in ME, which many of these authors favour, pools results from multiple different interventions with very different protocols, and this has been argued to provide an evidence base for GET by extension. But that would be like pooling the evidence for CBT, DBT, ABA, psychoanalysis and counselling, and then claiming this proves ABA alone is effective. NICE sensibly grouped "like with like", so that trials with similar protocols were grouped together, improving the accuracy and specificity of their analysis.
The criticism that NICE gave too much weight to survey evidence, and the lived experience of people with ME, was factored into the committee's decisions alongside other evidence. ‘NICE considers all types of evidence in its evaluations. This includes evidence from published and unpublished data, data from non-UK sources, databases of ongoing clinical trials, end-to-end studies, conference proceedings, and data from registries, real-world evidence and other observational sources.’
The complaint that energy management isn't evidenced is bizarre. Energy management isn't offered as a therapy and it isn't curative. It is essentially the same as the activity management of the last guideline - which many of the same authors were happy to accept when they contributed to that guideline. Energy management is essentially a continuation of those same principles of care but it is not offered or presented as a treatment. The Forward ME group of charities has also endorsed this approach.
With regard to GET and whether fixed increments in activity were required, NICE had to look at the evidence from the trials. Numerous trials refer to increments that are fixed and shouldn't be changed except with the approval of the clinician. The PACE manual for therapists explains that GET is based on the deconditioning model and discourages reductions in exercise when in a crash, ‘A central concept of GET is to MAINTAIN exercise as much as possible during a CFS/ME setback. This is to reduce the many negative consequences of rest, and to allow the body to habituate to the increase in activity. If activity and exercise is reduced at this time, the boom/bust cycle continues, and the body is not able to desensitise to the increase in activity: which is, of course, an essential component of a graded increase in exercise and activity.’ If the treatment was delivered in a different way in practice it would indicate that the GET as researched wasn’t effective in clinical settings.
Similarly, it cannot be merely assumed that because one approach is helpful elsewhere, that it is helpful here. There is no treatment that is suitable for all diseases. Chronic primary pain isn't ME and asthma isn't diabetes and it should be self-evident that different illnesses need different treatments.
We are also concerned that news coverage about this paper (and previous news coverage quoting the same authors) continues to paint people with ME as unreliable witnesses to their own illness and lives. This is a long-standing form of bias against disabled people.
In conclusion, this article reads as an attack on the 2021 NICE guideline for ME/CFS by a group of researchers who have focussed on treating ME with Graded Exercise Therapy and CBT. By contrast, the patient community welcomes the NICE guideline and the robust review of the evidence that NICE carried out. The guideline is a real improvement on the previous version and the removal of Graded Exercise Therapy as a recommended treatment was greeted with relief. It is now time for researchers and medical staff to work with people living with ME to implement the NICE guideline throughout the NHS. Further delay and obstruction will cause more harm and increase the suffering of a very vulnerable group of people.

Denise Spreag
Janet Sylvester
Malcolm Bailey

Functional neurological disorder is an important aspect with respect to burden and cost of management irrespective of gender as the authors have pointed out very rightly1.
It can be chronic but most of the times present as an emergency therby increasing panic, inpatient admissions. Smooth care, workup and appropriate guidelines for the same may help a lot in such conditions.
There is limited information, awareness, health care utilities, and economic burden of such patients which makes the situation more grim.
So there should be multidisciplinary approach i.e. physiotherapy, occupational therapy, speech and language therapy, and psychological assessment. Functional neurological disorders overlap with refractory neurological conditions i.e. headache, seizure, focal deficit etc., so better these patients be subdivided in these categories. Framing universal guidelines all across the world according to subdivisions with appropriate line of care as is being done in various other disorders may help a lot to smoothen improve management and help reduce the cost of therapy and gender bias.
References-
1. Caoimhe McLoughlin, Ingrid Hoeritzauer, Verónica Cabreira et al. http://dx.doi.org/10.1136/jnnp-2022-330192
2. Christopher D. Stephen, Vicki Fung, Codrin I. Lungu et al Alberto J. Espay Assessment of Emergency Department and Inpatient Use and Costs in Adult and Pediatric Functional Neurological Disorders. JAMA Neurol. 2021;78(1):88-101. doi:10.1001/jamaneurol.2020.3753