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
Imagine you are an epilepsy health professional seeing a patient with clinical symptoms of depression. What should you do? If you have read Noble et al.’s [1] recent JNNP review, entitled ‘Cognitive-behavioural therapy does not meaningfully reduce depression in most people with epilepsy…’ you may have become sceptical about the potential of CBT, or psychotherapy in general, to alleviate depression in people with epilepsy (PWE). This recent systematic review pooled data from five small randomised controlled trials (RCTs), with some elements of CBT for PWE, and performed an analysis of reliable change. ‘Pooled risk difference indicated likelihood of reliable improvement in depression symptoms was significantly higher for those randomised to CBT’, but the authors focused on the finding that ‘only’ 30% of patients receiving interventions, compared to 10% of controls, could be considered ‘reliably improved’. Emphasising the fact that over 2/3 of patients did not meet this criterion for improvement, the authors suggest CBT is ‘ineffective’, has ‘limited benefit’ and could even lead to lower ‘self–esteem’ and ‘helplessness’. Notably, the latter conclusions were based on hypothetical reactions to treatment, rather than empirically supported outcomes.
Therefore, the purpose of this letter, written by the Psychology Task Force of the International League Against...
Imagine you are an epilepsy health professional seeing a patient with clinical symptoms of depression. What should you do? If you have read Noble et al.’s [1] recent JNNP review, entitled ‘Cognitive-behavioural therapy does not meaningfully reduce depression in most people with epilepsy…’ you may have become sceptical about the potential of CBT, or psychotherapy in general, to alleviate depression in people with epilepsy (PWE). This recent systematic review pooled data from five small randomised controlled trials (RCTs), with some elements of CBT for PWE, and performed an analysis of reliable change. ‘Pooled risk difference indicated likelihood of reliable improvement in depression symptoms was significantly higher for those randomised to CBT’, but the authors focused on the finding that ‘only’ 30% of patients receiving interventions, compared to 10% of controls, could be considered ‘reliably improved’. Emphasising the fact that over 2/3 of patients did not meet this criterion for improvement, the authors suggest CBT is ‘ineffective’, has ‘limited benefit’ and could even lead to lower ‘self–esteem’ and ‘helplessness’. Notably, the latter conclusions were based on hypothetical reactions to treatment, rather than empirically supported outcomes.
Therefore, the purpose of this letter, written by the Psychology Task Force of the International League Against Epilepsy (ILAE), is to argue that caution is needed when considering the authors’ conclusions and potential implications for the psychological care of PWE. Moreover, we offer alternative interpretations of the findings and raise the pertinent issue of how psychotherapy for PWE may continue to improve. Importantly, we hope to encourage health professionals to continue to refer patients for psychotherapy, which is an effective intervention for a substantial subgroup of PWE.
Consistent with Reuber’s [2] editorial commentary, Cognitive-behavioural therapy does meaningfully reduce depression in people with epilepsy, we would like to highlight the heterogeneity of the studies pooled and how this impacts the findings. First, the interventions were very diverse, and most would not be considered standardised CBT protocols for depression. Interestingly, one trial that utilised a standardised CBT protocol, resulted in 50% reliable change reductions in depressive symptoms, equivalent to CBT in the general population [3]. Second, over 10% of patients in the analyses had depressive symptoms within the non-clinical ranges. Further, unlike previous analysis of reliable change in depression [3], this review failed to control for baseline levels of depression severity. Third, Noble et al. collapsed data from four different self-report depression measures, only one designed for PWE. Depression in PWE can have distinct symptomatology, given the presence of seizures (peri-ictal depression) and anti-seizure medication effects, both of which can limit the validity of generic depression measures [4].
Noble et al. [1] describe their conclusion that 30% reliable improvements in depressive symptoms across trials is ‘ineffective’ as a ‘value judgement’, illustrating subjectivity, which Reuber’s [2] editorial commentary argued could be interpreted completely in reverse. That is, one could conclude from the data that the treatments are ‘effective’ for PWE. There is little consensus about what we expect a ‘reliable improvement’ to be in psychological distress for PWE, or for patients with a disabling neurological disorder in general. A stated goal of epilepsy treatment is “no seizures, no side-effects.” However, many PWE continue to have seizures, and all biological treatments have potential side-effects. We argue that if just under 1 in 3 PWE reliably improve with CBT, which has no known side-effects, this is better than a possible alternative of unmanaged depression. Arguments regarding quantifying ‘reliable improvement’ aside, we do agree with Noble et al.’s [1] conclusions that there is ‘substantial room for improvement’ in the treatment of depression for PWE.
One important limitation of previous trials is the relatively short duration of psychotherapy offered to PWE, a factor that Noble et al. [1] acknowledge. Across the five RCTs, there was only an average of 7 hours (8 sessions) of psychotherapy, the adherence of which is unclear [5]. Thus, it is very likely that participants did not receive a sufficient dosage of CBT, especially given a minimum of 12 sessions is indicated for depression in the general population [3]. In addition, many PWE experience cognitive difficulties, including memory impairment, which may require more intensive and tailored CBT [5]. These limitations need to be addressed and psychotherapy should be tailored to the unique needs of PWE. One advantage of CBT is that many of the behavioural skills; such as problem solving, sleep hygiene and controlled relaxation can also be tailored to assist with the self-management of epilepsy (e.g. avoidance of seizure triggers), which Noble et al. did not consider.
Another critical area for improvement is the treatment of comorbid anxiety symptoms within psychotherapy for depression. Anxiety and depression are highly comorbid, and in clinical practice it is difficult to evaluate them separately [4]. As such, transdiagnostic treatments, which treat depression and anxiety in one protocol, are increasingly being adopted and proven to be effective in the general population. We disagree with Noble et al.’s [1] comments regarding the ‘disappointing’ evidence for the treatment of anxiety, as only one small trial is cited assessing the impact of CBT for depression (not anxiety), on a secondary anxiety measure. A conclusion of insufficient evidence would have been more accurate, given the state of the anxiety literature.
Depression in PWE remains underdiagnosed and treated, perhaps partially due to uncertainty about effective treatments [4]. At worse this results in poorer quality of life and higher suicide rates in PWE. Thus, the development of more effective psychotherapies, including alternatives to CBT, is warranted. However, the ILAE Psychology Task Force believes that it is inaccurate to label CBT as ‘ineffective’ based on the findings of Noble et al.’s [1] review. Instead, we encourage health professionals to interpret the Noble et al. [1] conclusions with caution, given the concerns raised with respect to depression outcome measures, dosage and quality of the psychotherapies, and interpretation of results. Further, even with a conservative estimate of 30% responders to the psychotherapies, we posit that CBT shows promise for treating depression in PWE and should remain a strong treatment consideration for the referring clinician.
This document was written by experts selected by the International League Against Epilepsy (ILAE) and was approved for publication by the ILAE. Opinions expressed by the authors, however, do not necessarily represent the policy or position of the ILAE.
References:
1. Noble AJ, Reilly J, Temple J, et al. Cognitive-behavioural therapy does not meaningfully reduce depression in most people with epilepsy: a systematic review of clinically reliable improvement. Journal of Neurology, Neurosurgery & Psychiatry 2018 doi: doi: 10.1136/jnnp-2018-317997
2. Reuber M. Cognitive-behavioural therapy does meaningfully reduce depression in people with epilepsy. Journal of Neurology, Neurosurgery and Psychiatry 2018 doi: 10.1136/jnnp-2018-318743
3. Ogles BM, Lambert MJ, Sawyer JD. Clinical Significance of the National Institute of Mental Health Treatment of Depression Collaborative Research Program Data. Journal of Consulting and Clinical Psychology 1995;63(2):321-26. doi: 10.1037/0022-006X.63.2.321
4. Kwon O-Y, Park S-P. Depression and Anxiety in People with Epilepsy. Journal of Clinical Neurology (Seoul, Korea) 2014;10(3):175-88. doi: 10.3988/jcn.2014.10.3.175
5. Modi AC, Wagner J, Smith AW, et al. Implementation of psychological clinical trials in epilepsy: Review and guide. Epilepsy and Behavior 2017;74:104-13. doi: 10.1016/j.yebeh.2017.06.016
Dear Editor,
I am writing to commend the authors of the article, MYH7-related myopathies: clinical, myopathological and genotypic spectrum in a multicentre French cohort [1], for their meticulous analysis of MYH7-related myopathies (MYH7-RMs). Their study significantly enhances our understanding of the diverse clinical, genetic, and myopathological manifestations associated with pathogenic variants in MYH7, which encodes the slow/beta-cardiac myosin heavy chain. By examining a multicenter cohort of 57 individuals, this study offers critical insights into phenotype variability, imaging features, and mutation-specific implications, contributing to more precise diagnostic and management strategies for this heterogeneous group of myopathies.
The study’s focus on muscle MRI findings, particularly the early and severe involvement of tibialis anterior and the concentric fibro-fatty replacement pattern, is of significant diagnostic value. The consistent and symmetrical fibro-fatty degeneration of distal muscles, coupled with the sparing of rectus femoris and adductor longus muscles in thigh regions, offers clinicians important imaging markers that can help differentiate MYH7-RMs from other myopathies, especially distal hereditary motor neuropathy (dHMN) and Pompe disease. This emphasis on early imaging features complements clinical assessments and may aid in reducing diagnostic delays, particularly in cases where high-amplitude MUPs and reduced interference patterns co...
Dear Editor,
I am writing to commend the authors of the article, MYH7-related myopathies: clinical, myopathological and genotypic spectrum in a multicentre French cohort [1], for their meticulous analysis of MYH7-related myopathies (MYH7-RMs). Their study significantly enhances our understanding of the diverse clinical, genetic, and myopathological manifestations associated with pathogenic variants in MYH7, which encodes the slow/beta-cardiac myosin heavy chain. By examining a multicenter cohort of 57 individuals, this study offers critical insights into phenotype variability, imaging features, and mutation-specific implications, contributing to more precise diagnostic and management strategies for this heterogeneous group of myopathies.
The study’s focus on muscle MRI findings, particularly the early and severe involvement of tibialis anterior and the concentric fibro-fatty replacement pattern, is of significant diagnostic value. The consistent and symmetrical fibro-fatty degeneration of distal muscles, coupled with the sparing of rectus femoris and adductor longus muscles in thigh regions, offers clinicians important imaging markers that can help differentiate MYH7-RMs from other myopathies, especially distal hereditary motor neuropathy (dHMN) and Pompe disease. This emphasis on early imaging features complements clinical assessments and may aid in reducing diagnostic delays, particularly in cases where high-amplitude MUPs and reduced interference patterns could otherwise be misinterpreted as neurogenic.
Moreover, the study’s elucidation of the genotype-phenotype relationship within MYH7-RMs reveals intriguing, though complex, patterns. While most pathogenic variants were found in the myosin tail, associated with severe distal myopathy and, in some cases, isolated cardiomyopathy, the presence of variants within the myosin head and neck domains also presented diverse manifestations. For instance, the MYH7 head domain mutation c.746G>A, p.(Arg249Gln) exhibited both scapuloperoneal (SP) myopathy and hypertrophic cardiomyopathy (HCM), consistent with findings from prior studies, suggesting a possible but not exclusive correlation between the location of variants and cardiac involvement. The authors’ insights into the structural implications of these mutations—such as alterations to the helical shape of the supercoil—add an important molecular perspective and suggest avenues for future functional studies to clarify these genotype-phenotype relationships.
The study’s characterization of the wide myopathological spectrum in MYH7-RMs—most notably the predominance of cores, type 1 fiber predominance, and fiber-type disproportion—provides an essential framework for pathologists in identifying MYH7 mutations. The authors’ observations of subsarcolemmal hyaline deposits in some patients suggest myosin storage myopathy as part of the MYH7-RM pathological spectrum, adding further depth to the study of MYH7-associated histopathological diversity. Additionally, the identification of six in-frame deletions within the myosin tail domain, all resulting in single amino acid deletions, points to a mutation type associated with specific structural disruptions, which may be of functional importance in myosin's motor activity and stability.
In conclusion, this study provides a foundational reference for clinicians, pathologists, and researchers, expanding the known clinical and genetic spectrum of MYH7-RMs and facilitating more accurate identification and management of these myopathies. The authors’ use of a multidisciplinary approach, including detailed MRI and EMG assessments, offers a holistic strategy for addressing the diagnostic complexities of MYH7-RMs, while their insights into familial patterns and genotype-phenotype correlations open promising avenues for future research in MYH7 mutation pathogenesis and individualized patient care.
Reference
1. Bahout M, Severa G, Kamoun E, et alMYH7-related myopathies: clinical, myopathological and genotypic spectrum in a multicentre French cohortJournal of Neurology, Neurosurgery & Psychiatry Published Online First: 24 October 2024. doi: 10.1136/jnnp-2024-334263
Lennon and colleagues report on the associations between sport-related concussion (SRC), non-sports-related concussion (nSRC) and long-term cognitive and behavioural outcomes in a longitudinal cohort of community-dwelling adults. Findings suggest that those with SRC showed no long-term cognitive or behavioural deficits compared with those with no concussions. Moreover, it is suggested those with SRC showed better performance in working memory and verbal reasoning at the study baseline which is hypothesized to be due to the ‘benefits of sport’ in the form of physical, social and economic benefits. The authors suggest these findings will help inform physicians and public health authorities when communicating the risks and benefits of community sports to patients and the public.
As the authors note, their findings are “at odds with much of the SRC literature”. This is likely a contributing factor to the media coverage of this research. At the time of writing, The Times, The Telegraph and the Guardian have all reported on the studies finding with variations on the benefits of ‘amateur sport’ outweighing the risk of concussion. The NIHR Applied Health Research and Care South West Peninsula, that supported the research, has also hosted a press release titled ‘Sports concussions in non-athletes not linked to long-term brain problems’. There is a common feature to all the press coverage so far: all have used images of adults or children playing what appears to be contact ru...
Lennon and colleagues report on the associations between sport-related concussion (SRC), non-sports-related concussion (nSRC) and long-term cognitive and behavioural outcomes in a longitudinal cohort of community-dwelling adults. Findings suggest that those with SRC showed no long-term cognitive or behavioural deficits compared with those with no concussions. Moreover, it is suggested those with SRC showed better performance in working memory and verbal reasoning at the study baseline which is hypothesized to be due to the ‘benefits of sport’ in the form of physical, social and economic benefits. The authors suggest these findings will help inform physicians and public health authorities when communicating the risks and benefits of community sports to patients and the public.
As the authors note, their findings are “at odds with much of the SRC literature”. This is likely a contributing factor to the media coverage of this research. At the time of writing, The Times, The Telegraph and the Guardian have all reported on the studies finding with variations on the benefits of ‘amateur sport’ outweighing the risk of concussion. The NIHR Applied Health Research and Care South West Peninsula, that supported the research, has also hosted a press release titled ‘Sports concussions in non-athletes not linked to long-term brain problems’. There is a common feature to all the press coverage so far: all have used images of adults or children playing what appears to be contact rugby.
Any reader would reasonably assume then that this research had a clear focus on ‘contact sports’. Especially so given the senior author is quoted in the NIHR press release explicitly saying, “This study suggests that there could be long-term benefits from sport which could outweigh any negative effects of concussions, which could have important implications for policy decisions around contact sport participation”. But what seems to be missing from the research article is information about exactly what ‘sport’ the participants did across the groups created for analysis.
In the supplementary material, Table S3 shows the ‘Head injury scenario questions’ used to categorise these groups. Yet little clarity is offered here. The sport-related concussion group appears to have been categorised based on responses to two questions: 1) Have you ever had a blow to the head while biking? (cycling), 2) Have you ever had a blow to the head while playing sports? (football, baseball, basketball etc). This is a very wide category to group as ‘SRC’. Without further clarification, this could plausibly include any of the following head injury events: falling off a bicycle whilst riding to work, falling over playing table tennis, being punched in the head whilst boxing or receiving a high-impact tackle playing rugby. Clearly, the context of each of these varies significantly. Interestingly, this instrument also seems to categorise head injuries sustained from rollerblading/skateboarding, horse riding and skiing as ‘Non-sport related’. Furthermore, given the focus on the benefits of ‘sport’ for long-term cognitive health, it is surprising that the sporting backgrounds of those that were in the ‘nSRC’ and ‘Mixed concussion group’ were not reported.
The definition and conceptualisation of what constitutes ‘sport’ is not clear in the article which makes interpretation of the findings difficult. ‘Community sport’ is used but what this is referring to is not explained. Given the ongoing public health concerns with brain health in contact sports specifically, accuracy is paramount. We urge the authors to clarify the sporting backgrounds of their participants so the scientific community, policy makers, the public and the media can be better placed to evaluate these findings.
To the Editor,
I am writing to commend and engage with the recently published study, "Cognition in patients with myelin oligodendrocyte glycoprotein antibody-associated disease: a prospective, longitudinal, multicentre study of 113 patients (CogniMOG-Study)." (1). This pioneering work addresses a crucial yet underexplored aspect of MOGAD, namely its impact on cognitive function. The study represents a significant advancement in understanding cognitive impairments associated with this rare but impactful condition.
Significance of Findings: The CogniMOG-Study provides a comprehensive assessment of cognitive function in MOGAD patients, revealing that while cognitive deficits are present, they are relatively limited compared to other neuroinflammatory conditions. The observed impairments in semantic fluency and processing speed are particularly noteworthy. These findings suggest that cognitive deficits in MOGAD primarily affect verbal and information processing domains, which are critical for daily functioning and quality of life.
The study’s longitudinal design is a particular strength, allowing for the observation of cognitive changes over time. The absence of significant cognitive decline over the follow-up periods is an encouraging finding, suggesting stability in cognitive function among MOGAD patients. However, it also raises questions about the factors contributing to cognitive stability and the potential for practice effects, which merit fur...
To the Editor,
I am writing to commend and engage with the recently published study, "Cognition in patients with myelin oligodendrocyte glycoprotein antibody-associated disease: a prospective, longitudinal, multicentre study of 113 patients (CogniMOG-Study)." (1). This pioneering work addresses a crucial yet underexplored aspect of MOGAD, namely its impact on cognitive function. The study represents a significant advancement in understanding cognitive impairments associated with this rare but impactful condition.
Significance of Findings: The CogniMOG-Study provides a comprehensive assessment of cognitive function in MOGAD patients, revealing that while cognitive deficits are present, they are relatively limited compared to other neuroinflammatory conditions. The observed impairments in semantic fluency and processing speed are particularly noteworthy. These findings suggest that cognitive deficits in MOGAD primarily affect verbal and information processing domains, which are critical for daily functioning and quality of life.
The study’s longitudinal design is a particular strength, allowing for the observation of cognitive changes over time. The absence of significant cognitive decline over the follow-up periods is an encouraging finding, suggesting stability in cognitive function among MOGAD patients. However, it also raises questions about the factors contributing to cognitive stability and the potential for practice effects, which merit further investigation.
Clinical and Research Implications: The identification of cerebral lesions as a predictor of cognitive deficits is a critical insight. This association underscores the importance of considering cerebral involvement when evaluating cognitive function in MOGAD patients. It also highlights the need for further research into the specific neurobiological mechanisms that link cerebral lesions with cognitive impairment.
The study’s findings have important implications for clinical practice. Understanding that MOGAD patients may experience specific cognitive challenges can inform the development of targeted cognitive rehabilitation strategies. Moreover, recognizing the relatively mild nature of cognitive impairments compared to conditions like NMOSD can guide more nuanced patient assessments and management plans.
Limitations and Future Directions: While the study is a valuable contribution, several limitations should be acknowledged. The use of normative data that may not reflect current population characteristics could impact the interpretation of cognitive test results. Additionally, the exclusion of severely affected patients from neuropsychological testing may limit the generalizability of the findings. Future research should address these limitations by incorporating updated normative data and including a broader range of patients.
Furthermore, the study highlights the need for ongoing longitudinal research to explore cognitive changes beyond the 2-year follow-up. Longer-term studies could provide deeper insights into the trajectory of cognitive function in MOGAD and help distinguish between genuine cognitive changes and methodological artifacts such as practice effects.
Conclusion: In conclusion, the CogniMOG-Study is a significant step forward in understanding the cognitive profile of MOGAD patients. It provides valuable insights into the nature and extent of cognitive impairments associated with this condition and sets the stage for future research and clinical advancements. I applaud the authors for their meticulous work and look forward to continued exploration in this vital area of research.
References
1. Passoke S, Stern C, Häußler V, et alCognition in patients with myelin oligodendrocyte glycoprotein antibody-associated disease: a prospective, longitudinal, multicentre study of 113 patients (CogniMOG-Study)Journal of Neurology, Neurosurgery & Psychiatry Published Online First: 30 July 2024. doi: 10.1136/jnnp-2024-333994
Dear Editor,
I am writing to express my thoughts on the thought-provoking article titled, "Poor long-term outcomes and abnormal neurodegeneration biomarkers after military traumatic brain injury: the ADVANCE study." This comprehensive study delves into the long-term impacts of traumatic brain injury (TBI) on UK military personnel, focusing on the prevalence, psychological consequences, functional impairments, and the role of fluid biomarkers in elucidating the ongoing neurodegenerative processes associated with these injuries.
One of the critical aspects of this study is its detailed examination of plasma biomarkers, including neurofilament light (NfL) and glial fibrillar acidic protein (GFAP), which serve as indicators of axonal damage and astrocytic activation, respectively. The sustained elevation of GFAP levels, detected even 8 years post-injury, suggests a prolonged neuroinflammatory response and astrocytic reactivity that could contribute to chronic neurodegeneration. This aligns with existing literature on the role of GFAP in central nervous system injury, where it is often linked to the activation and proliferation of astrocytes as part of the neuroinflammatory response. The finding of a 47% higher concentration of GFAP in moderate-to-severe TBI cases compared to mild cases indicates a dose-response relationship that highlights the progressive nature of astroglial activation in severe injuries.
It is particularly intriguing that while GF...
Dear Editor,
I am writing to express my thoughts on the thought-provoking article titled, "Poor long-term outcomes and abnormal neurodegeneration biomarkers after military traumatic brain injury: the ADVANCE study." This comprehensive study delves into the long-term impacts of traumatic brain injury (TBI) on UK military personnel, focusing on the prevalence, psychological consequences, functional impairments, and the role of fluid biomarkers in elucidating the ongoing neurodegenerative processes associated with these injuries.
One of the critical aspects of this study is its detailed examination of plasma biomarkers, including neurofilament light (NfL) and glial fibrillar acidic protein (GFAP), which serve as indicators of axonal damage and astrocytic activation, respectively. The sustained elevation of GFAP levels, detected even 8 years post-injury, suggests a prolonged neuroinflammatory response and astrocytic reactivity that could contribute to chronic neurodegeneration. This aligns with existing literature on the role of GFAP in central nervous system injury, where it is often linked to the activation and proliferation of astrocytes as part of the neuroinflammatory response. The finding of a 47% higher concentration of GFAP in moderate-to-severe TBI cases compared to mild cases indicates a dose-response relationship that highlights the progressive nature of astroglial activation in severe injuries.
It is particularly intriguing that while GFAP levels were elevated, amyloid-β42 (Aβ42) levels showed a reduction over time post-injury in the ADVANCE cohort. This reduction contrasts with the increased amyloid deposition often observed on positron emission tomography (PET) scans in the chronic phase of moderate-to-severe TBI. The decline in Aβ42 could suggest a complex interaction between injury-induced mechanisms and amyloid processing pathways that might differ from the patterns observed in classical AD, highlighting the need for further research to decipher these relationships in the context of TBI.
The ADVANCE study's strength lies in its robust design, including a large extracranial trauma comparison group, which allows for a more precise delineation of TBI-specific outcomes. This comparative analysis provides compelling evidence that poor neuropsychiatric, motor, and quality of life outcomes are indeed linked to TBI rather than to the effects of trauma in general. Nonetheless, the study also acknowledges several limitations, such as the lack of cognitive data to correlate with biomarker concentrations, and the reliance on historical data for TBI diagnosis, which could potentially miss cases of undiagnosed or mild repetitive injuries. The focus on a male-only cohort also necessitates future studies to examine the generalizability of these findings to female service members and the broader veteran population.
In conclusion, the ADVANCE study offers a comprehensive look at the enduring consequences of TBI among military personnel, linking these injuries to chronic neuroinflammation and poor long-term functional and psychological outcomes. The elevated GFAP levels observed in this study indicate a continued astrocytic response, which may have profound implications for neurodegenerative disease risk within this cohort. These findings highlight the need for ongoing surveillance of veterans with TBI and the development of targeted therapeutic strategies aimed at mitigating chronic neuroinflammation and improving quality of life outcomes. The incorporation of advanced proteomic and neuroimaging techniques in future studies could further unravel the pathophysiological processes underlying TBI-related neurodegeneration and lead to more precise interventions for those affected.
Reference
1. Graham NS, Blissitt G, Zimmerman K, et alPoor long-term outcomes and abnormal neurodegeneration biomarkers after military traumatic brain injury: the ADVANCE studyJournal of Neurology, Neurosurgery & Psychiatry Published Online First: 11 October 2024. doi: 10.1136/jnnp-2024-333777
I read with great interest the article by Schwake et al, in which the authors performed a retrospective observational study evaluating clinical outcomes in 117 myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD) attacks treated with apheresis.[1]
One of the main findings and conclusions of the paper was that “apheresis was revealed to be most effective if started within 2 days of attack onset, with complete remission rates dropping radically afterwards”. Critically however, this finding may largely be due to selection bias (i.e., confounding by indication) rather than a true causal effect of apheresis timing.[2] As this was a retrospective study, assignment to first-line, second-line or third-line apheresis treatment was not random. Escalation to use of apheresis in the second-line or third-line groups would reasonably be expected to have occurred mainly due to persistent or worsening clinical deficits following treatment with high-dose corticosteroids. Conversely, in the early/first-line apheresis treatment, since the apheresis treatment was initiated as a first-line treatment (presumably concurrently with high-dose corticosteroids, though this is not explicitly stated by the authors in the article), it is quite possible that these attacks would have achieved complete remission even without the use of apheresis, either due to the effects of concomitant high-dose corticosteroids or due to the natural history of such attacks. Notably, demyelinati...
I read with great interest the article by Schwake et al, in which the authors performed a retrospective observational study evaluating clinical outcomes in 117 myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD) attacks treated with apheresis.[1]
One of the main findings and conclusions of the paper was that “apheresis was revealed to be most effective if started within 2 days of attack onset, with complete remission rates dropping radically afterwards”. Critically however, this finding may largely be due to selection bias (i.e., confounding by indication) rather than a true causal effect of apheresis timing.[2] As this was a retrospective study, assignment to first-line, second-line or third-line apheresis treatment was not random. Escalation to use of apheresis in the second-line or third-line groups would reasonably be expected to have occurred mainly due to persistent or worsening clinical deficits following treatment with high-dose corticosteroids. Conversely, in the early/first-line apheresis treatment, since the apheresis treatment was initiated as a first-line treatment (presumably concurrently with high-dose corticosteroids, though this is not explicitly stated by the authors in the article), it is quite possible that these attacks would have achieved complete remission even without the use of apheresis, either due to the effects of concomitant high-dose corticosteroids or due to the natural history of such attacks. Notably, demyelinating attacks of the central nervous system typically exhibit at least some spontaneous improvement, even in the absence of acute therapy, and the Optic Neuritis Treatment Trial (ONTT) failed to show a benefit of high-dose corticosteroids vs placebo on long-term clinical outcomes after acute optic neuritis, including in participants with severe attacks (visual acuity of 20/200 or worse at baseline), although the number of MOGAD participants in the ONTT was low.[3,4]
This is a clear example of confounding by indication, and notably this bias is not isolated to this specific study, but has also been present in other studies that are cited as evidence that early apheresis influences clinical outcomes in neuromyelitis optica spectrum disorder (NMOSD).[5,6] This selection bias is further highlighted by the fact that in the present study disability outcomes (as determined by use of the Expanded Disability Status Scale) at last follow-up were better in those who did not receive apheresis compared to those who did, despite having similar demographic characteristics, annualized relapse rate, and disease duration. Interpreting this result in a consistent manner with the authors’ interpretation of their findings regarding early apheresis treatment would mean concluding that apheresis treatment is actually harmful, a conclusion that would be dismissed as being illogical and due to selection bias. However, the finding regarding early apheresis is not similarly scrutinized since it is consistent with a pre-conceived notion regarding the effectiveness of early apheresis, which is in turn based on similarly biased studies.
Since the authors have information regarding attacks treated without apheresis, it would be very helpful to perform a comparison between outcomes of attacks treated with early apheresis and attacks treated without apheresis (accounting/matching for key variables, including time from attack onset to initial treatment, attack severity, use of disease-modifying therapy at the time of the attack, as well as demographic and other clinical characteristics), in order to assess whether early apheresis improved outcomes compared to high-dose corticosteroids alone. Use of appropriate causal inference methods, such as propensity score matching, can increase the robustness of such analyses.[7] Furthermore, no information is given in the article regarding the characteristics of the first-line, second-line, and third-line apheresis groups (such as attack phenotype, demographic and clinical characteristics). Presenting this information in a tabular format (similar to Table 1 that compares the characteristics of those who did vs did not receive apheresis) is critical for the reader to understand how comparable these groups are.
Given the above issues, a randomized clinical trial of early (first-line) vs rescue (second-line) apheresis is warranted to assess whether early apheresis leads to better clinical outcomes in acute demyelinating attacks of the central nervous system. In this context, a multi-center, randomized-controlled, open-label, rater-blinded, pragmatic trial “Treatment of Inflammatory Myelitis and Optic Neuritis with Early vs Rescue Plasma Exchange (TIMELY-PLEX)”is planned to commence in the United States in 2025, comparing these two treatment approaches in severe optic neuritis and transverse myelitis.[8]
References:
1 Schwake C, Ladopoulos T, Häußler V, et al. Apheresis therapies in MOGAD: a retrospective study of 117 therapeutic interventions in 571 attacks. J Neurol Neurosurg Psychiatry. 2024;jnnp-2024-334863. doi: 10.1136/jnnp-2024-334863
2 Kyriacou DN, Lewis RJ. Confounding by Indication in Clinical Research. JAMA. 2016;316:1818–9. doi: 10.1001/jama.2016.16435
3 Beck RW, Cleary PA. Optic neuritis treatment trial. One-year follow-up results. Arch Ophthalmol. 1993;111:773–5. doi: 10.1001/archopht.1993.01090060061023
4 Chen JJ, Tobin WO, Majed M, et al. Prevalence of Myelin Oligodendrocyte Glycoprotein and Aquaporin-4-IgG in Patients in the Optic Neuritis Treatment Trial. JAMA Ophthalmol. 2018;136:419–22. doi: 10.1001/jamaophthalmol.2017.6757
5 Bonnan M, Valentino R, Debeugny S, et al. Short delay to initiate plasma exchange is the strongest predictor of outcome in severe attacks of NMO spectrum disorders. J Neurol Neurosurg Psychiatry. 2018;89:346–51. doi: 10.1136/jnnp-2017-316286
6 Kleiter I, Gahlen A, Borisow N, et al. Apheresis therapies for NMOSD attacks. Neurol Neuroimmunol Neuroinflamm. 2018;5:e504. doi: 10.1212/NXI.0000000000000504
7 Austin PC. An Introduction to Propensity Score Methods for Reducing the Effects of Confounding in Observational Studies. Multivariate Behav Res. 2011;46:399–424. doi: 10.1080/00273171.2011.568786
8 Treatment of Inflammatory Myelitis and Optic Neuritis with Early Plasma Exchange (TIMELY-PLEX) | PCORI. 2024. https://www.pcori.org/research-results/2024/treatment-inflammatory-myeli... (accessed 12 November 2024)
I read the recent meta-analysis from Pozzilli et al in Journal of Neurology, Neurosurgery and Psychiatry on seizure risk in multiple sclerosis (MS), which found a higher risk of seizures in patients with MS compared with the general population and a 2.45-fold higher risk in patients treated with sphingosine 1-phosphate (S1P) receptor modulators.1 I would like to address this claim with regards to the selective S1P receptor modulator ozanimod.
The methodology behind this meta-analysis captured reports of seizures reported as common adverse events (AEs), serious AEs, or AEs of interest, but did not capture reports of seizures failing to meet the criteria for serious AEs or those that were not reported based on a small number of patients, a limitation noted by the authors. Another noted limitation was AE coding in the different trials, as a standardized framework for AE reporting was not developed until 2010. Since S1P receptor modulators were not developed until after 2010, the comparison with earlier trials is inconclusive. Also, as none of the trials included were designed to explore seizure risk, and event rates were very low, the results of this meta-analysis are at most hypothesis-generating.
The methodology led to the erroneous representation that seizures occurred more frequently with ozanimod than with the active comparator interferon β-1a (IFN) in the RADIANCE (NCT02047734) trial. In the key publication from RADIANCE, AEs were reported if they were se...
I read the recent meta-analysis from Pozzilli et al in Journal of Neurology, Neurosurgery and Psychiatry on seizure risk in multiple sclerosis (MS), which found a higher risk of seizures in patients with MS compared with the general population and a 2.45-fold higher risk in patients treated with sphingosine 1-phosphate (S1P) receptor modulators.1 I would like to address this claim with regards to the selective S1P receptor modulator ozanimod.
The methodology behind this meta-analysis captured reports of seizures reported as common adverse events (AEs), serious AEs, or AEs of interest, but did not capture reports of seizures failing to meet the criteria for serious AEs or those that were not reported based on a small number of patients, a limitation noted by the authors. Another noted limitation was AE coding in the different trials, as a standardized framework for AE reporting was not developed until 2010. Since S1P receptor modulators were not developed until after 2010, the comparison with earlier trials is inconclusive. Also, as none of the trials included were designed to explore seizure risk, and event rates were very low, the results of this meta-analysis are at most hypothesis-generating.
The methodology led to the erroneous representation that seizures occurred more frequently with ozanimod than with the active comparator interferon β-1a (IFN) in the RADIANCE (NCT02047734) trial. In the key publication from RADIANCE, AEs were reported if they were serious or occurred in at least 2% of ozanimod-treated patients, but only if that incidence was at least 1% higher than what occurred in the IFN treatment group.2 The seizure incidences from RADIANCE published in Pozzilli et al only represent serious AEs and are not representative of the overall incidence of seizures.
When looking at the total incidence of seizure-related AEs in the phase 3 SUNBEAM (NCT02294058) and RADIANCE ozanimod trials combined, the incidence of seizures was numerically lower with ozanimod (5/1774, 0.3%) versus IFN (4/885, 0.5%). Through 7 years of the DAYBREAK long-term extension trial (NCT02576717), the incidence of seizures remained low (20/2494, 0.8%).3 Analyses of seizure incidence in DAYBREAK were transmitted to the United States Food and Drug Administration, and these did not support an association between seizures and treatment.
A methodological issue contributing to the unwarranted conclusion that all S1P receptor modulators increase seizure risk is the subanalysis that grouped all S1P receptor modulator trials. While Pozzilli et al mention that the rationale for this subanalysis was that nearly half of the seizure events were noted in these trials, this fails to account for the various patient populations. For example, the EXPAND trial included only patients with secondary progressive MS and had a relatively higher incidence of seizures overall.1,4 Indeed, Pozzilli et al identified progressive MS, longer disease duration, and higher Expanded Disability Status Scale scores as risk factors for seizure.1
The grouping of S1P receptor modulators was noted in an accompanying editorial to be mechanistically problematic.5 S1P receptor modulators have different pharmacological profiles and act on different S1P receptor subtypes.4 While the general mechanisms of action are similar, safety profiles differ, and numerically different trends in seizure incidence may be related to pharmacological properties.4
In conclusion, it is the opinion of this author that Pozzilli et al's assertion that all S1P receptor modulators lead to an increased risk of seizure is incorrect. In the ozanimod phase 3 trials, the overall incidence of seizures was low and not higher with ozanimod versus IFN, and incidence remained low throughout a long-term extension trial. Future investigations on the topic of seizures and MS therapies should include full data sets and ensure appropriate trial combining when subgroup analyses are performed.
References
1. Pozzilli V, Haggiag S, Di Filippo M, et al. Incidence and determinants of seizures
in multiple sclerosis: a meta-analysis of randomised clinical trials. J Neurol
Neurosurg Psychiatry. 2024;95:612-619.
2. Cohen JA, Comi G, Selmaj KW, et al. Safety and efficacy of ozanimod versus
interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre,
randomised, 24-month, phase 3 trial. Lancet Neurol. 2019;18:1021-1033.
3. Cree BA, Selmaj KW, Steinman L, et al. Long-term safety and efficacy of
ozanimod in relapsing multiple sclerosis: Up to 5 years of follow-up in the
DAYBREAK open-label extension trial. Mult Scler. 2022;28:1944-1962.
4. Coyle PK, Freedman MS, Cohen BA, Cree BAC, Markowitz CE. Sphingosine 1-
phosphate receptor modulators in multiple sclerosis treatment: A practical review.
Ann Clin Transl Neurol. 2024;11:842-855.
5. Ioannidis JP. Therapeutic interventions increasing seizure risk in multiple
sclerosis: resolving discordant meta-analyses. J Neurol Neurosurg Psychiatry.
2024;95:594.
People with ME/CFS have a serious condition with high symptom burden and impaired function. They deserve guidelines that favour good care and effective treatment supported by the best research evidence of efficacy and safety. Unfortunately, that is not what 2021 NICE guidelines have achieved.
The 2007 NICE guidance recommended cognitive behaviour therapy (CBT) and graded exercise therapy (GET) “…as these interventions show clearest evidence of benefit.”(1) In spite of the strengthening of the evidence supporting these two treatments, the new 2021 guidance restricted the use of CBT to helping patients cope with illness related distress, and recommended that GET should not be used at all.(2)
In response, 51 international clinicians and academics joined together to offer an alternative perspective, being particularly critical of the methods used to produce the guideline. (3)
In response NICE advisors and staff have rejected this argument and have referred to the process as “robust” and “thorough”. (4) We are not convinced. We do not have space here to address every error but simply outline some of the most major areas of disagreement.
Defining ME/CFS
----------------------
Barry and colleagues state they appraised criteria to diagnose ME/CFS with the AGREE II instrument. This is a misuse of AGREE II, which is a tool to assess the robustness of procedures for developing guidelines: this is not a tool that can be used to examine the criter...
People with ME/CFS have a serious condition with high symptom burden and impaired function. They deserve guidelines that favour good care and effective treatment supported by the best research evidence of efficacy and safety. Unfortunately, that is not what 2021 NICE guidelines have achieved.
The 2007 NICE guidance recommended cognitive behaviour therapy (CBT) and graded exercise therapy (GET) “…as these interventions show clearest evidence of benefit.”(1) In spite of the strengthening of the evidence supporting these two treatments, the new 2021 guidance restricted the use of CBT to helping patients cope with illness related distress, and recommended that GET should not be used at all.(2)
In response, 51 international clinicians and academics joined together to offer an alternative perspective, being particularly critical of the methods used to produce the guideline. (3)
In response NICE advisors and staff have rejected this argument and have referred to the process as “robust” and “thorough”. (4) We are not convinced. We do not have space here to address every error but simply outline some of the most major areas of disagreement.
Defining ME/CFS
----------------------
Barry and colleagues state they appraised criteria to diagnose ME/CFS with the AGREE II instrument. This is a misuse of AGREE II, which is a tool to assess the robustness of procedures for developing guidelines: this is not a tool that can be used to examine the criteria for diagnosis from individual studies. (5) They misrepresent the Oxford criteria as including healthy subjects with mild fatigue whereas the definition is “the fatigue is disabling”. They used their adopted definition of ME/CFS to downgrade all previous trials that did not mandate the symptom of “post-exertional malaise” (PEM). Yet, a systematic review of trials of CBT showed that the presence or absence of PEM made no difference to the positive results of this treatment. (6)
Choosing the wrong trial end-points
-----------------------------------------------
A major concern is selective reporting. For example, data from trial primary end-points at 12 months follow-up was left out. This led to the incorrect conclusion that neither CBT nor GET are effective treatments. We re-analysed the data, using Cochrane methods. We compared GET with usual medical care at 12 months, and found there were double the number of people feeling “much better” or “very much better” after GET (RR 2.29, 95%CI 1.69 to 3.10; 3 trials, 464 participants); (paper submitted for publication.)
Ignoring trial safety outcomes
---------------------------------------
A further methodological weakness was the prioritisation of qualitative study assessments of treatment harm over trial evidence that found these treatments to be safe.(7)
Misrepresenting graded exercise therapy
------------------------------------------------------
The authors described GET wrongly by suggesting it involves fixed increments of exercise, no matter how a patient reacts. We have given numerous examples to show that this is not the case. (3)
Pacing is recommended despite evidence of its lack of efficacy
----------------------------------------------------------------------------------
Proposing the only management strategy is pacing (“energy management”), that is, staying within perceived energy limits, is not supported by the data. RCT evidence from the PACE trial showed pacing, on average, was inferior to both GET and CBT. Indeed, deterioration was observed in physical function in 25% of participants after pacing, compared to 9% after CBT and 11% after GET.(8, 9)
Conclusion
----------------
We once again argue that the process by which NICE revised a sound original guideline was flawed. The errors are important because they discourage people with ME/CFS and healthcare professionals to consider rehabilitation treatments that may improve their symptoms. We conclude by calling for these guidelines to be withdrawn, the analyses of data to be redone, and the guideline recommendations to be re-formulated.
References
---------------
1. Baker, R, and E J Shaw. "Diagnosis and Management of Chronic Fatigue Syndrome or Myalgic Encephalomyelitis (or Encephalopathy): Summary of Nice Guidance." BMJ 335, no. 7617 (2007): 446-48. https://doi.org/10.1136/bmj.39302.509005.AE.
2. National Institute for Health and Care Excellence. Myalgic Encephalomyelitis (or Encephalopathy)/Chronic fatigue syndrome: diagnosis and management. NICE guideline [NG206], 2021. Available: https://www.nice.org.uk/guidance/ng206
3. White P, Abbey S, Angus B, et al. Anomalies in the review process and interpretation of the evidence in the NICE guideline for chronic fatigue syndrome and myalgic encephalomyelitis. J Neurol Neurosurg Psychiatry 2023;94:1056–63.
4. Barry PW, Kelley K, Tan T, Finlay I. NICE guideline on ME/CFS: robust advice based on a thorough review of the evidence. J Neurol Neurosurg Psychiatry. 2024;95(7):671-4.
5. Brouwers MC, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, et al. AGREE II: advancing guideline development, reporting and evaluation in health care. CMAJ. 2010;182(18):E839-42.
6. Kuut TA, Buffart LM, Braamse AMJ, Csorba I, Bleijenberg G, Nieuwkerk P, et al. Does the effect of cognitive behavior therapy for chronic fatigue syndrome (ME/CFS) vary by patient characteristics? A systematic review and individual patient data meta-analysis. Psychol Med. 2024;54(3):447-56.
7. White PD, Etherington J. Adverse outcomes in trials of graded exercise therapy for adult patients with chronic fatigue syndrome. Journal of Psychosomatic Research. 2021;147:110533.
8. White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011;377(9768):823-36.
9. Dougall D, Johnson A, Goldsmith K, Sharpe M, Angus B, Chalder T, et al. Adverse events and deterioration reported by participants in the PACE trial of therapies for chronic fatigue syndrome. J Psychosom Res. 2014;77(1):20-6.
Dear Editor,
I am writing to offer a comprehensive analysis and reflection on the manuscript titled "Oral corticosteroid dosage and taper duration at onset in myelin oligodendrocyte glycoprotein antibody-associated disease influences time to first relapse" (1). This study, which delves into the intricate nuances of managing MOGAD, presents crucial findings that could significantly impact clinical practice and patient outcomes.
The complexity of MOGAD lies not only in its diverse clinical presentations but also in its variable response to treatment modalities. As highlighted in the manuscript's introduction, MOGAD encompasses a spectrum of neurological manifestations, ranging from optic neuritis and transverse myelitis to acute disseminated encephalomyelitis. The recent establishment of consensus diagnostic criteria marks a pivotal advancement in early recognition and intervention, underscoring the urgency for evidence-based therapeutic strategies.
One of the most compelling aspects of the study is its exploration of the optimal corticosteroid regimen at MOGAD onset, aiming to delay the time to first relapse (TTFR) while minimizing cumulative corticosteroid exposure. By retrospectively analyzing data from a multicenter cohort comprising 109 patients, the authors meticulously assessed the relationship between corticosteroid dosage and taper duration and the subsequent risk of relapse. The utilization of Cox proportional hazards models, along...
Dear Editor,
I am writing to offer a comprehensive analysis and reflection on the manuscript titled "Oral corticosteroid dosage and taper duration at onset in myelin oligodendrocyte glycoprotein antibody-associated disease influences time to first relapse" (1). This study, which delves into the intricate nuances of managing MOGAD, presents crucial findings that could significantly impact clinical practice and patient outcomes.
The complexity of MOGAD lies not only in its diverse clinical presentations but also in its variable response to treatment modalities. As highlighted in the manuscript's introduction, MOGAD encompasses a spectrum of neurological manifestations, ranging from optic neuritis and transverse myelitis to acute disseminated encephalomyelitis. The recent establishment of consensus diagnostic criteria marks a pivotal advancement in early recognition and intervention, underscoring the urgency for evidence-based therapeutic strategies.
One of the most compelling aspects of the study is its exploration of the optimal corticosteroid regimen at MOGAD onset, aiming to delay the time to first relapse (TTFR) while minimizing cumulative corticosteroid exposure. By retrospectively analyzing data from a multicenter cohort comprising 109 patients, the authors meticulously assessed the relationship between corticosteroid dosage and taper duration and the subsequent risk of relapse. The utilization of Cox proportional hazards models, along with Simon-Makuch and Kaplan-Meier plots, provided a robust framework for elucidating these intricate dynamics.
The key findings of the study underscore the critical role of corticosteroids in modulating disease activity at MOGAD onset. Notably, the recommendation of initiating a prednisone dose of 12.5 mg/day (0.16 mg/kg/day for children) for a minimum duration of 3 months yielded a remarkable 88% reduction in the risk of relapse compared to alternative regimens. Moreover, the absence of severe adverse events among patients receiving this dosage further accentuates its safety profile, reassuring clinicians of its therapeutic viability.
However, amidst the optimism surrounding these findings, it is imperative to acknowledge the inherent limitations of retrospective studies, including potential selection biases and variability in clinical practices across centers. The authors' candid acknowledgment of these limitations underscores the need for further prospective studies to validate and refine the proposed therapeutic approach.
Beyond its immediate clinical implications, the study prompts broader contemplation on the intricacies of balancing therapeutic efficacy with long-term safety considerations. The delicate interplay between relapse prevention and corticosteroid-related adverse effects necessitates a nuanced and patient-centered approach to treatment decision-making. The proposed regimen represents a commendable stride towards achieving this equilibrium, offering a pragmatic framework for optimizing patient outcomes while mitigating potential risks.
In conclusion, the manuscript makes a significant contribution to the evolving landscape of MOGAD management, offering evidence-based insights that have the potential to revolutionize clinical practice. By delineating a clear roadmap for corticosteroid optimization at disease onset, the study empowers clinicians with valuable tools to navigate the complexities of MOGAD management effectively.
References
1. Trewin BP, Dale RC, Qiu J, et alOral corticosteroid dosage and taper duration at onset in myelin oligodendrocyte glycoprotein antibody-associated disease influences time to first relapseJournal of Neurology, Neurosurgery & Psychiatry Published Online First: 14 May 2024. doi: 10.1136/jnnp-2024-333463
Imagine you are an epilepsy health professional seeing a patient with clinical symptoms of depression. What should you do? If you have read Noble et al.’s [1] recent JNNP review, entitled ‘Cognitive-behavioural therapy does not meaningfully reduce depression in most people with epilepsy…’ you may have become sceptical about the potential of CBT, or psychotherapy in general, to alleviate depression in people with epilepsy (PWE). This recent systematic review pooled data from five small randomised controlled trials (RCTs), with some elements of CBT for PWE, and performed an analysis of reliable change. ‘Pooled risk difference indicated likelihood of reliable improvement in depression symptoms was significantly higher for those randomised to CBT’, but the authors focused on the finding that ‘only’ 30% of patients receiving interventions, compared to 10% of controls, could be considered ‘reliably improved’. Emphasising the fact that over 2/3 of patients did not meet this criterion for improvement, the authors suggest CBT is ‘ineffective’, has ‘limited benefit’ and could even lead to lower ‘self–esteem’ and ‘helplessness’. Notably, the latter conclusions were based on hypothetical reactions to treatment, rather than empirically supported outcomes.
Therefore, the purpose of this letter, written by the Psychology Task Force of the International League Against...
Show MoreDear Editor,
Show MoreI am writing to commend the authors of the article, MYH7-related myopathies: clinical, myopathological and genotypic spectrum in a multicentre French cohort [1], for their meticulous analysis of MYH7-related myopathies (MYH7-RMs). Their study significantly enhances our understanding of the diverse clinical, genetic, and myopathological manifestations associated with pathogenic variants in MYH7, which encodes the slow/beta-cardiac myosin heavy chain. By examining a multicenter cohort of 57 individuals, this study offers critical insights into phenotype variability, imaging features, and mutation-specific implications, contributing to more precise diagnostic and management strategies for this heterogeneous group of myopathies.
The study’s focus on muscle MRI findings, particularly the early and severe involvement of tibialis anterior and the concentric fibro-fatty replacement pattern, is of significant diagnostic value. The consistent and symmetrical fibro-fatty degeneration of distal muscles, coupled with the sparing of rectus femoris and adductor longus muscles in thigh regions, offers clinicians important imaging markers that can help differentiate MYH7-RMs from other myopathies, especially distal hereditary motor neuropathy (dHMN) and Pompe disease. This emphasis on early imaging features complements clinical assessments and may aid in reducing diagnostic delays, particularly in cases where high-amplitude MUPs and reduced interference patterns co...
Lennon and colleagues report on the associations between sport-related concussion (SRC), non-sports-related concussion (nSRC) and long-term cognitive and behavioural outcomes in a longitudinal cohort of community-dwelling adults. Findings suggest that those with SRC showed no long-term cognitive or behavioural deficits compared with those with no concussions. Moreover, it is suggested those with SRC showed better performance in working memory and verbal reasoning at the study baseline which is hypothesized to be due to the ‘benefits of sport’ in the form of physical, social and economic benefits. The authors suggest these findings will help inform physicians and public health authorities when communicating the risks and benefits of community sports to patients and the public.
As the authors note, their findings are “at odds with much of the SRC literature”. This is likely a contributing factor to the media coverage of this research. At the time of writing, The Times, The Telegraph and the Guardian have all reported on the studies finding with variations on the benefits of ‘amateur sport’ outweighing the risk of concussion. The NIHR Applied Health Research and Care South West Peninsula, that supported the research, has also hosted a press release titled ‘Sports concussions in non-athletes not linked to long-term brain problems’. There is a common feature to all the press coverage so far: all have used images of adults or children playing what appears to be contact ru...
Show MoreTo the Editor,
Show MoreI am writing to commend and engage with the recently published study, "Cognition in patients with myelin oligodendrocyte glycoprotein antibody-associated disease: a prospective, longitudinal, multicentre study of 113 patients (CogniMOG-Study)." (1). This pioneering work addresses a crucial yet underexplored aspect of MOGAD, namely its impact on cognitive function. The study represents a significant advancement in understanding cognitive impairments associated with this rare but impactful condition.
Significance of Findings: The CogniMOG-Study provides a comprehensive assessment of cognitive function in MOGAD patients, revealing that while cognitive deficits are present, they are relatively limited compared to other neuroinflammatory conditions. The observed impairments in semantic fluency and processing speed are particularly noteworthy. These findings suggest that cognitive deficits in MOGAD primarily affect verbal and information processing domains, which are critical for daily functioning and quality of life.
The study’s longitudinal design is a particular strength, allowing for the observation of cognitive changes over time. The absence of significant cognitive decline over the follow-up periods is an encouraging finding, suggesting stability in cognitive function among MOGAD patients. However, it also raises questions about the factors contributing to cognitive stability and the potential for practice effects, which merit fur...
Dear Editor,
Show MoreI am writing to express my thoughts on the thought-provoking article titled, "Poor long-term outcomes and abnormal neurodegeneration biomarkers after military traumatic brain injury: the ADVANCE study." This comprehensive study delves into the long-term impacts of traumatic brain injury (TBI) on UK military personnel, focusing on the prevalence, psychological consequences, functional impairments, and the role of fluid biomarkers in elucidating the ongoing neurodegenerative processes associated with these injuries.
One of the critical aspects of this study is its detailed examination of plasma biomarkers, including neurofilament light (NfL) and glial fibrillar acidic protein (GFAP), which serve as indicators of axonal damage and astrocytic activation, respectively. The sustained elevation of GFAP levels, detected even 8 years post-injury, suggests a prolonged neuroinflammatory response and astrocytic reactivity that could contribute to chronic neurodegeneration. This aligns with existing literature on the role of GFAP in central nervous system injury, where it is often linked to the activation and proliferation of astrocytes as part of the neuroinflammatory response. The finding of a 47% higher concentration of GFAP in moderate-to-severe TBI cases compared to mild cases indicates a dose-response relationship that highlights the progressive nature of astroglial activation in severe injuries.
It is particularly intriguing that while GF...
I read with great interest the article by Schwake et al, in which the authors performed a retrospective observational study evaluating clinical outcomes in 117 myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD) attacks treated with apheresis.[1]
One of the main findings and conclusions of the paper was that “apheresis was revealed to be most effective if started within 2 days of attack onset, with complete remission rates dropping radically afterwards”. Critically however, this finding may largely be due to selection bias (i.e., confounding by indication) rather than a true causal effect of apheresis timing.[2] As this was a retrospective study, assignment to first-line, second-line or third-line apheresis treatment was not random. Escalation to use of apheresis in the second-line or third-line groups would reasonably be expected to have occurred mainly due to persistent or worsening clinical deficits following treatment with high-dose corticosteroids. Conversely, in the early/first-line apheresis treatment, since the apheresis treatment was initiated as a first-line treatment (presumably concurrently with high-dose corticosteroids, though this is not explicitly stated by the authors in the article), it is quite possible that these attacks would have achieved complete remission even without the use of apheresis, either due to the effects of concomitant high-dose corticosteroids or due to the natural history of such attacks. Notably, demyelinati...
Show MoreI read the recent meta-analysis from Pozzilli et al in Journal of Neurology, Neurosurgery and Psychiatry on seizure risk in multiple sclerosis (MS), which found a higher risk of seizures in patients with MS compared with the general population and a 2.45-fold higher risk in patients treated with sphingosine 1-phosphate (S1P) receptor modulators.1 I would like to address this claim with regards to the selective S1P receptor modulator ozanimod.
The methodology behind this meta-analysis captured reports of seizures reported as common adverse events (AEs), serious AEs, or AEs of interest, but did not capture reports of seizures failing to meet the criteria for serious AEs or those that were not reported based on a small number of patients, a limitation noted by the authors. Another noted limitation was AE coding in the different trials, as a standardized framework for AE reporting was not developed until 2010. Since S1P receptor modulators were not developed until after 2010, the comparison with earlier trials is inconclusive. Also, as none of the trials included were designed to explore seizure risk, and event rates were very low, the results of this meta-analysis are at most hypothesis-generating.
The methodology led to the erroneous representation that seizures occurred more frequently with ozanimod than with the active comparator interferon β-1a (IFN) in the RADIANCE (NCT02047734) trial. In the key publication from RADIANCE, AEs were reported if they were se...
Show MorePeople with ME/CFS have a serious condition with high symptom burden and impaired function. They deserve guidelines that favour good care and effective treatment supported by the best research evidence of efficacy and safety. Unfortunately, that is not what 2021 NICE guidelines have achieved.
The 2007 NICE guidance recommended cognitive behaviour therapy (CBT) and graded exercise therapy (GET) “…as these interventions show clearest evidence of benefit.”(1) In spite of the strengthening of the evidence supporting these two treatments, the new 2021 guidance restricted the use of CBT to helping patients cope with illness related distress, and recommended that GET should not be used at all.(2)
In response, 51 international clinicians and academics joined together to offer an alternative perspective, being particularly critical of the methods used to produce the guideline. (3)
In response NICE advisors and staff have rejected this argument and have referred to the process as “robust” and “thorough”. (4) We are not convinced. We do not have space here to address every error but simply outline some of the most major areas of disagreement.
Defining ME/CFS
Show More----------------------
Barry and colleagues state they appraised criteria to diagnose ME/CFS with the AGREE II instrument. This is a misuse of AGREE II, which is a tool to assess the robustness of procedures for developing guidelines: this is not a tool that can be used to examine the criter...
Dear Editor,
Show MoreI am writing to offer a comprehensive analysis and reflection on the manuscript titled "Oral corticosteroid dosage and taper duration at onset in myelin oligodendrocyte glycoprotein antibody-associated disease influences time to first relapse" (1). This study, which delves into the intricate nuances of managing MOGAD, presents crucial findings that could significantly impact clinical practice and patient outcomes.
The complexity of MOGAD lies not only in its diverse clinical presentations but also in its variable response to treatment modalities. As highlighted in the manuscript's introduction, MOGAD encompasses a spectrum of neurological manifestations, ranging from optic neuritis and transverse myelitis to acute disseminated encephalomyelitis. The recent establishment of consensus diagnostic criteria marks a pivotal advancement in early recognition and intervention, underscoring the urgency for evidence-based therapeutic strategies.
One of the most compelling aspects of the study is its exploration of the optimal corticosteroid regimen at MOGAD onset, aiming to delay the time to first relapse (TTFR) while minimizing cumulative corticosteroid exposure. By retrospectively analyzing data from a multicenter cohort comprising 109 patients, the authors meticulously assessed the relationship between corticosteroid dosage and taper duration and the subsequent risk of relapse. The utilization of Cox proportional hazards models, along...
Pages