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Ryuji Kaji MD, PhD
Department of Neurology, Tokushima University
I appreciate Dr Popkirov’s unique and interesting views and comments related to our paper [1]. This reminds me of the gating of sensory inputs at various levels of the nervous system, and their perception is not a passive but is a very active process. In addition to the fact that it is not possible to tickle oneself, other sensory phenomena associated with abnormal movements deserve mention. Restless legs syndrome is characterized by constant urge to move legs, and is successfully managed by dopamine agonists. Tics are also preceded by sensory symptoms. These could be examples of aberrant sensory inputs coming to the conscious level, which would normally be handled at subconscious pathways. At this moment, the exact role of the cerebellar pathway in these conditions is not clear, but should be investigated in the future aside from dystonia.
1. Kaji R, Bhatia K, Graybiel AM. Pathogenesis of dystonia: is it of cerebellar or basal ganglia origin? J Neurol Neurosurg Psychiatry. 2017 Oct 31. pii: jnnp-2017-316250. doi: 10.1136/jnnp-2017-316250. [Epub ahead of print]
No conflict of interest declared
Dear Editor,
We read with great interest the article of Boentert et al.1 recently published on this journal. In their paper, the authors describe polysomnographic findings in a large series of non-ventilated patients with amyotrophic lateral sclerosis (ALS). One of the points the authors underscore is that in their patients most respiratory events during sleep were of the obstructive, and not of the central type. This finding is in agreement with what described by Kimura,2 but not by several other authors who found that most respiratory events were of the central type.3 Furthermore, the authors of this paper did not find that obstructive apneas were preferentially associated with bulbar ALS, similarly to David et al.4 but unlike what described by Santos et al.5 However, the tables in the article show that most of the respiratory events were hypopneas, whose type was not specified.
Criteria for scoring sleep disordered breathing events have changed over time, especially as regards hypopneas. Only recently a general rule for type of hypopnea, central or obstructive has been proposed. Obstructive hypopneas are those where at least one of three criteria is met during the event: presence of snoring, flow limitation demonstrated by a flattening of the nasal pressure derived flow signal, opposing thoracic and abdominal movements. Absence of all these criteria characterizes central hypopneas.6 However, standard criteria for apneas and hypopneas fit well to patients wi...
Dear Editor,
We read with great interest the article of Boentert et al.1 recently published on this journal. In their paper, the authors describe polysomnographic findings in a large series of non-ventilated patients with amyotrophic lateral sclerosis (ALS). One of the points the authors underscore is that in their patients most respiratory events during sleep were of the obstructive, and not of the central type. This finding is in agreement with what described by Kimura,2 but not by several other authors who found that most respiratory events were of the central type.3 Furthermore, the authors of this paper did not find that obstructive apneas were preferentially associated with bulbar ALS, similarly to David et al.4 but unlike what described by Santos et al.5 However, the tables in the article show that most of the respiratory events were hypopneas, whose type was not specified.
Criteria for scoring sleep disordered breathing events have changed over time, especially as regards hypopneas. Only recently a general rule for type of hypopnea, central or obstructive has been proposed. Obstructive hypopneas are those where at least one of three criteria is met during the event: presence of snoring, flow limitation demonstrated by a flattening of the nasal pressure derived flow signal, opposing thoracic and abdominal movements. Absence of all these criteria characterizes central hypopneas.6 However, standard criteria for apneas and hypopneas fit well to patients with sleep apnea syndromes, but may be difficult to use in patients with other disorders, and in particular in those with neuromuscular diseases.
The separate occurrence of central and obstructive hypopneas was reported in some ALS studies, although standard criteria were not applied. However, a sharp separation of obstructive and central hypopneas in patients with ALS may be difficult, either using standard criteria or not, and often factitious. A clear flattening of the flow signal may not be clearly identified with a weak flow signal. Paradoxical thoraco-abdominal movements may be the effect not only of upper airway narrowing but also of respiratory muscle weakness. Finally, perhaps most importantly, presence of obstruction during a hypopnea does not exclude a simultaneous reduction of respiratory drive, thus a concomitant central genesis of the event.
Even when dealing with apneas, the precise nature of an event in neuromuscular patients is often dubious based on its polygraphic appearance. In the International Classification of Sleep Disorders, central apneas are indicated as the result of a failure of ventilatory control centers to initiate ventilatory effort.7 However, in common practice central apneas are identified by the absence of respiratory movements on polygraphic recordings, although it may not be always easy to precisely identify the pathogenesis of an event based on its polygraphic expression. In neuromuscular patients, many apneas are associated with very small movements. That may lead different scorers to classify them as either central or obstructive. Some authors suggested to introduce the new category of “pseudocentral apneas” to indicate events occurring when the contraction of respiratory muscles is too weak to maintain breathing, which may be more often seen in phasic REM sleep.8 During these events, deflections in the traces of the respiratory movements are very small. Despite their polygraphic aspect resembles apneas more often of the central type, their pathogenesis depends more on peripheral that on central causes. This category of events is not taken in consideration by most authors studying neuromuscular patients. Probably, a non-uniform way to score respiratory events in ALS is one reason for some discrepancies among studies.
We are aware that a correct identification of central and obstructive events is important, because they require different ventilatory approaches that may have a strong influence on sleep quality, therapy acceptance and, in the long-term, disease evolution and survival. Use of positive expiratory pressure, which is mandatory when obstructive events are present, is not only useless, but also questionable in case of absence of upper airway obstruction, as it enhances patient-ventilator asynchronies and sympathetic nervous system tone during sleep.9
Possibly, criteria for scoring sleep disordered breathing events in non-ventilated patients with neuromuscular diseases should be better standardized. They could be useful to have a better agreement among physicians who evaluate polysomnographic recordings, and to better guide in the choice of an appropriate therapeutic strategy.
REFERENCES
1 Boentert M, Glatz C, Helmle C, et al. Prevalence of sleep apnoea and capnographic detection of nocturnal hypoventilation in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2017 doi: 10.1136/jnnp-2017-316515.
2 Kimura K, Tachibana N, Kimura J, et al. Sleep-disordered breathing at an early stage of amyotrophic lateral sclerosis. J Neurol Sci 1999;164:37-43.
3 Aboussouan LS, Mireles-Cabodevila E. Sleep-Disordered Breathing in Neuromuscular Disease: Diagnostic and Therapeutic Challenges. Chest 2017;152:880-892.
4 David WS, Bundlie SR, Mahdavi Z. Polysomnographic studies in amyotrophic lateral sclerosis. J Neurol Sci 1997;152:29-35
5 Santos C, Braghiroli A, Mazzini L, et al. Sleep-related breathing disorders in amyotrophic lateral sclerosis. Monaldi Arch Chest Dis 2003;59:160-5.
6 Berry RB, Budhiraja R, Gottlieb DJ, et al. American Academy of Sleep Medicine. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med 2012;8:597-619
7 American Academy of Sleep Medicine . International Classification of Sleep Disorders . 3rd ed. Darien, IL : American Academy of Sleep Medicine; 2014.
8 Gould GA, Gugger M, Molloy J, et al. Breathing pattern and eye movement density during REM sleep in humans. Am Rev Respir Dis 1988;138:874-7
9 Crescimanno G, Greco F, Arrisicato S, et al. Effects of positive end expiratory pressure administration during non-invasive ventilation inpatients affected by amyotrophic lateral sclerosis: A randomized crossover study. Respirology 2016;21:1307-13
In their recent article on the pathogenesis of dystonia, Kaji and colleagues argue that aberrant cerebellar inputs can induce dystonic movement mediated by the basal ganglia.[1] In this framework, the sensory trick (geste antagoniste) leads to a realignment between predicted and actual sensory information, thus reduces (or overrides) the sensorimotor mismatch forwarded to the basal ganglia, and in turn alleviates dystonic contractions.
A similar model of sensorimotor mismatch response has been implicated in the physiology of being tickled[2]. Specifically, it has been proposed that the inability to tickle oneself is related to a sensory attenuation mediated by the cerebellum during self-generated tactile sensation[3]. This attenuation is proportional to the precision of the sensory prediction[4]. Whether the same cerebellar processes are responsible for the alleviation of dystonia during a sensory trick would be an interesting question to explore experimentally. At the risk of straining the analogy, one could even describe the postures and movements one produces when being tickled as dystonic-like. Neurologists are reminded of this when interpreting ambiguous plantar responses in very ticklish patients -- a problem that can be avoided by employing the patient's cerebellar sensory attentuation[5].
1. Kaji R, Bhatia K, Graybiel AM. Pathogenesis of dystonia: is it of cerebellar or basal ganglia origin? J Neurol Neurosurg Psychiatry. 2017 Oct 31. pii: jnnp-20...
In their recent article on the pathogenesis of dystonia, Kaji and colleagues argue that aberrant cerebellar inputs can induce dystonic movement mediated by the basal ganglia.[1] In this framework, the sensory trick (geste antagoniste) leads to a realignment between predicted and actual sensory information, thus reduces (or overrides) the sensorimotor mismatch forwarded to the basal ganglia, and in turn alleviates dystonic contractions.
A similar model of sensorimotor mismatch response has been implicated in the physiology of being tickled[2]. Specifically, it has been proposed that the inability to tickle oneself is related to a sensory attenuation mediated by the cerebellum during self-generated tactile sensation[3]. This attenuation is proportional to the precision of the sensory prediction[4]. Whether the same cerebellar processes are responsible for the alleviation of dystonia during a sensory trick would be an interesting question to explore experimentally. At the risk of straining the analogy, one could even describe the postures and movements one produces when being tickled as dystonic-like. Neurologists are reminded of this when interpreting ambiguous plantar responses in very ticklish patients -- a problem that can be avoided by employing the patient's cerebellar sensory attentuation[5].
1. Kaji R, Bhatia K, Graybiel AM. Pathogenesis of dystonia: is it of cerebellar or basal ganglia origin? J Neurol Neurosurg Psychiatry. 2017 Oct 31. pii: jnnp-2017-316250. doi: 10.1136/jnnp-2017-316250. [Epub ahead of print]
2. Blakemore SJ, Wolpert D, Frith C. Why can't you tickle yourself? Neuroreport. 2000;11(11):R11-6.
3. Blakemore SJ, Wolpert DM, Frith CD. Central cancellation of self-produced tickle sensation. Nat Neurosci. 1998 Nov;1(7):635-40.
4. Blakemore SJ, Frith CD, Wolpert DM. Spatio-temporal prediction modulates the perception of self-produced stimuli. J Cogn Neurosci. 1999 Sep;11(5):551-9.
5. Sohrab SA, Gelb D. Value of self-induced plantar reflex in distinguishing Babinski from withdrawal. Neurology. 2016 Mar 8;86(10):977.
In our previous meta-analysis of cerebellar atrophy in seven major neurodegenerative conditions (Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Huntington’s disease (HD), Parkinson’s disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP)) we investigated studies that reported grey matter (GM) loss in the cerebellum [1]. Consistent regions of atrophy were found in AD, ALS, FTD, MSA, and PSP but not HD or PD. In their comment on our meta-analysis, Sheng and Pan have argued that our method of selectively investigating studies that found cerebellar atrophy, rather than adopting a whole-brain approach, is “not optimal in a coordinate-based meta-analysis” [2]. They further cite previous whole-brain meta-analyses that did not identify clusters of cerebellar grey matter loss in patients [3-6].
Here, we argue that our approach was justified given our aim, which was to focus on cases where cerebellar atrophy was found in the respective disease groups in order to determine 1) if such atrophy followed a consistent, robust pattern, and 2) if atrophy patterns were disease-specific or generic, where possible relating them to symptomatology.
There are several reasons why we chose to focus on the cerebellum rather than adopting a whole-brain approach. First, the cerebellum is hardly a “region of interest” in the classical sense given its marked heterogeneity in terms of function and connectivity as we...
In our previous meta-analysis of cerebellar atrophy in seven major neurodegenerative conditions (Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Huntington’s disease (HD), Parkinson’s disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP)) we investigated studies that reported grey matter (GM) loss in the cerebellum [1]. Consistent regions of atrophy were found in AD, ALS, FTD, MSA, and PSP but not HD or PD. In their comment on our meta-analysis, Sheng and Pan have argued that our method of selectively investigating studies that found cerebellar atrophy, rather than adopting a whole-brain approach, is “not optimal in a coordinate-based meta-analysis” [2]. They further cite previous whole-brain meta-analyses that did not identify clusters of cerebellar grey matter loss in patients [3-6].
Here, we argue that our approach was justified given our aim, which was to focus on cases where cerebellar atrophy was found in the respective disease groups in order to determine 1) if such atrophy followed a consistent, robust pattern, and 2) if atrophy patterns were disease-specific or generic, where possible relating them to symptomatology.
There are several reasons why we chose to focus on the cerebellum rather than adopting a whole-brain approach. First, the cerebellum is hardly a “region of interest” in the classical sense given its marked heterogeneity in terms of function and connectivity as well as its large cell count [7,8]. Using an ROI approach on the cerebellum is therefore not vastly different from conducting an analysis restricted to the neocortex, a practice that is abundant and well accepted. The vast majority of coordinates used in our analysis stemmed from whole-brain analyses and omitting the few studies with an ROI approach for the cerebellum is highly unlikely to affect the main clusters we identified.
Second, there is an abundance of coordinate-based meta-analyses using ROI approaches (see http://www.brainmap.org/pubs/), including one of the most influential papers into the functions of the cerebellum [8].
Third, the systematic literature search of papers investigating the diseases in question has revealed that many analyses were inherently biased against the cerebellum. As shown in our PRISMA flowchart, there was a tendency towards excluding the cerebellum (n=64) or not reporting or discussing cerebellar findings in text even when figures indicated the cerebellum was affected (n=13 for which we could not obtain data even after contacting authors). Twenty-seven studies further indicated potential cerebellar effects but did not report coordinates. These numbers made it clear that this bias in investigating the diseases of interest and in reporting results would inadvertently be translated into a bias in the meta-analytic results when choosing a whole-brain approach.
Given this abundance of studies excluding the cerebellum and underreporting cerebellar findings, it is not surprising that previous meta-analyses did not find robust clusters of cerebellar atrophy. Furthermore, there are additional factors that can explain the apparent lack of GM loss in the cerebellum in the AD, ALS, and FTD meta-analyses.
First, the majority of studies in AD and ALS investigated early stages, during which cerebellar atrophy may not yet be apparent. This tendency to investigate early structural changes may contribute to the belief that the cerebellum is typically spared. Given that clinical assessment using magnetic resonance imaging is carried out early in disease progression and that follow-up scans in clinical practice are rare, later GM loss often remains unexplored. However, neuropathological investigations have found the cerebellum to be affected in AD, ALS, and PSP [9-11]. Second, in our systematic literature search, we contacted authors to obtain additional coordinate data, which was not done in most of the other meta-analyses. The following should emphasize these arguments:
• AD meta-analysis [3]: did not include seven studies present in our analysis; of the 46 AD studies listed in Table 1, n=23 included exclusively early-stage/mild AD, and n=9 studies mild to moderate AD. One study with preclinical AD cases and another with a sample of MSA with dementia would not have met our inclusion criteria [12,13].
• FTD meta-analysis [4]: did not include nine studies from our analysis. 3/9 studies in the whole-brain analysis showed cerebellar atrophy; of the remaining six, n=3 included only patients with mild FTD severity, while n=1 included mild to moderate.
• ALS meta-analysis [5]: did not include two of the studies in our paper. 5/20 studies reported disease-related cerebellar grey matter (GM) or white matter integrity loss; of the other 15, n=10 focussed on patients with mild symptom severity. Interestingly, Minnerop et al. showed a correlation of cerebellar GM loss and disease duration, suggesting that the cerebellum is affected later in the course of ALS [14].
• We would like to point out that the PSP meta-analysis [6], which was cited by Sheng and Pan as not having detected cerebellar GM loss, did find a cluster of atrophy in right declive (see Table 2). This meta-analysis also did not include two of the studies incorporated in our investigation. Cerebellar GM loss was found in 5/12 studies in this meta-analysis, while n=4 of the remaining seven found white matter loss in cerebellar peduncles in the absence of GM differences. Of the three studies with no cerebellar findings, n=2 were in mild PSP.
Finally, we would like to emphasise that we are not claiming that cerebellar atrophy is necessarily present in the majority of patients in all of the investigated diseases. Given that we only selected studies with findings in the cerebellum, we did not seek to determine the likelihood of the cerebellum being affected in a given disease. For our purpose, a focus on studies with cerebellar findings is justified. We conclude that if cerebellar atrophy is present, it follows a disease-specific pattern that tends to correlate with symptomatology in many of the included studies. Our findings demonstrate the importance of future research into the role of the cerebellum in neurodegeneration given the two major issues in the literature which are the tendency to disregard the cerebellum and the vast heterogeneity of patient groups regarding disease stages and subtypes.
References
1. Gellersen HM, Guo CC, O’Callaghan C, et al. Cerebellar atrophy in neurodegeneration—a meta-analysis. J Neurol, Neurosurg Psychiatry 2017, in press.
2. Sheng L-Q, Pan P-L. Does Cerebellar Atrophy in Neurodegeneration? J Neurol, Neurosurg Psychiatry 2017. http://jnnp.bmj.com/content/early/2017/05/27/jnnp-2017-315607.responses
3. Chapleau M, Aldebert J, Montembeault M, Brambati SM. Atrophy in Alzheimer's Disease and Semantic Dementia: An ALE Meta-Analysis of Voxel-Based Morphometry Studies. J Alzheimers Dis 2016;54(3):941-55.
4. Schroeter ML, Laird AR, Chwiesko C, et al. Conceptualizing neuropsychiatric diseases with multimodal data-driven meta-analyses - the case of behavioral variant frontotemporal dementia. Cortex 2014;57:22-37.
5. Sheng L, Ma H, Zhong J, et al. Motor and extra-motor gray matter atrophy in amyotrophic lateral sclerosis: quantitative meta-analyses of voxel-based morphometry studies. Neurobiol Aging 2015;36(12):3288-99.
6. Yu F, Barron DS, Tantiwongkosi B, Fox P. Patterns of gray matter atrophy in atypical parkinsonism syndromes: a VBM meta-analysis. Brain Behav 2015;5(6):e00329.
7. Balsters JH, Laird AR, Fox PT, Eickhoff SB. Bridging the gap between functional and anatomical features of cortico-cerebellar circuits using meta-analytic connectivity modeling. Hum Brain Mapp 2014;35(7):3152-69.
8. Stoodley CJ, Schmahmann JD. Functional topography in the human cerebellum: A meta-analysis of neuroimaging studies. NeuroImage 2009;44(2):489-501.
9. Kanazawa M, Shimohata T, Toyoshima Y, et al. Cerebellar involvement in progressive supranuclear palsy: A clinicopathological study. Mov Disord 2009;24(9):1312-8.
10. Larner AJ. The Cerebellum in Alzheimer's Disease. Dement Geriatr Cogn Disord 1997;8(4):203-9.
11. Prell T, Grosskreutz J. The involvement of the cerebellum in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degen 2013;14(7-8):507-15.
12. Hämäläinen A, Pihlajamäki M, Tanila H, et al. Increased fMRI responses during encoding in mild cognitive impairment. Neurobiol Aging 2007;28(12):1889-903.
13. Tondelli M, Wilcock GK, Nichelli P, et al. Structural MRI changes detectable up to ten years before clinical Alzheimer's disease. Neurobiol Aging 2012;33(4):825.e25-36.
14. Minnerop M, Specht K, Ruhlmann J, et al. In vivo voxel-based relaxometry in amyotrophic lateral sclerosis. J Neurol 2009;256(1):28-34.
Li-Qin Sheng1, Ping-Lei Pan2
1 Department of Neurology, Traditional Chinese Medicine Hospital of Kunshan, Kunshan, PR China
2 Department of Neurology, Affiliated Yancheng Hospital, School of Medicine, Southeast University, Yancheng, PR China
Correspondence:
PingLei Pan, Department of Neurology, Affiliated Yancheng Hospital, School of Medicine, Southeast University, West Xindu Road 2#, Yancheng, Jiangsu Province, 224001, PR China. E-mail: panpinglei@163.com, Telephone: +8618361146977
Coordinate-based meta-analysis is a powerful way for neuroimaging studies to identify the most consistent and replicable differences in brain activity or structure in neurodegenerative disorders. In their JNNP publication, Gellersen et al 1 conducted coordinate-based meta-analyses of 54 voxel-based morphometry (VBM) studies in Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), behavioral variant frontotemporal dementia (bvFTD), amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). In this study, they solely focused on cerebellar grey matter (GM) atrophy.1 Marked cerebellar atrophy in AD, ALS, bvFTD, PSP and MSA, but not in PD or HD, was identified in the meta-analyses.1
These findings are of interest.1 However, the procedure of the meta-analyses had a major limitation. Coordin...
Li-Qin Sheng1, Ping-Lei Pan2
1 Department of Neurology, Traditional Chinese Medicine Hospital of Kunshan, Kunshan, PR China
2 Department of Neurology, Affiliated Yancheng Hospital, School of Medicine, Southeast University, Yancheng, PR China
Correspondence:
PingLei Pan, Department of Neurology, Affiliated Yancheng Hospital, School of Medicine, Southeast University, West Xindu Road 2#, Yancheng, Jiangsu Province, 224001, PR China. E-mail: panpinglei@163.com, Telephone: +8618361146977
Coordinate-based meta-analysis is a powerful way for neuroimaging studies to identify the most consistent and replicable differences in brain activity or structure in neurodegenerative disorders. In their JNNP publication, Gellersen et al 1 conducted coordinate-based meta-analyses of 54 voxel-based morphometry (VBM) studies in Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), behavioral variant frontotemporal dementia (bvFTD), amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). In this study, they solely focused on cerebellar grey matter (GM) atrophy.1 Marked cerebellar atrophy in AD, ALS, bvFTD, PSP and MSA, but not in PD or HD, was identified in the meta-analyses.1
These findings are of interest.1 However, the procedure of the meta-analyses had a major limitation. Coordinate-based meta-analysis is usually used for whole-brain imaging findings. Gellersen et al1 only included the studies that reported coordinates of the cerebellar regions, which resulted in study selection bias in the analyses. This bias may increase the statistical power and the risk of false positive findings in their study. The view is supported by previous meta-analyses in these disorders. Robust cerebellar atrophy was not detected in AD 2, ALS 3, bvFTD 4, PSP 5, PD 6, or HD 7 by previous meta-analyses that included many more whole-brain VBM studies. In contrast, cerebellar atrophy was consistently identified in MSA 5, which was accordant with the meta-analysis by Gellersen et al.1 Thus, selective use of a paticular brain region is not optimal in a coordinate-based meta-analysis.
Based on the current conflicting imaging evidence, it is debatable to consider the existence of cerebellar atrophy in AD, ALS, bvFTD and PSP in VBM studies. As clinical heterogeneity in these disorders and limited by the imaging techniques, further research is warranted to validate cerebellar atrophy in neurodegeneration.
Funding: This work was supported in part by the National Natural Science Foundation of China (Grant No. 81601161).
Competing interests: None.
Contributors: LQS wrote the draft. PLP revised the manuscript.
References:
1. Gellersen HM, Guo CC, O'Callaghan C, et al. Cerebellar atrophy in neurodegeneration-a meta-analysis. J Neurol Neurosurg Psychiatry 2017, in press.
2. Chapleau M, Aldebert J, Montembeault M, et al. Atrophy in Alzheimer's Disease and Semantic Dementia: An ALE Meta-Analysis of Voxel-Based Morphometry Studies. J Alzheimers Dis 2016;54(3):941-55.
3. Sheng L, Ma H, Zhong J, et al. Motor and extra-motor gray matter atrophy in amyotrophic lateral sclerosis: quantitative meta-analyses of voxel-based morphometry studies. Neurobiol Aging 2015;36(12):3288-99.
4. Schroeter ML, Laird AR, Chwiesko C, et al. Conceptualizing neuropsychiatric diseases with multimodal data-driven meta-analyses - the case of behavioral variant frontotemporal dementia. Cortex 2014;57:22-37.
5. Yu F, Barron DS, Tantiwongkosi B, et al. Patterns of gray matter atrophy in atypical parkinsonism syndromes: a VBM meta-analysis. Brain Behav 2015;5(6):e00329.
6. Shao N, Yang J, Shang H. Voxelwise meta-analysis of gray matter anomalies in Parkinson variant of multiple system atrophy and Parkinson's disease using anatomic likelihood estimation. Neurosci Lett 2015;587:79-86.
7. Dogan I, Eickhoff SB, Schulz JB, et al. Consistent neurodegeneration and its association with clinical progression in Huntington's disease: a coordinate-based meta-analysis. Neurodegener Dis 2013;12(1):23-35.
We thank dr. Coebergh and colleagues for their interest in our study. We agree that(a) there are many differences between the health care systems of the UK and the Netherlands, (b) the results of our study do not apply to excluded patients, and (c) the management of new neurological symptoms, relapses of previous FNS and relevant neurological and other co-morbidities remain very important in order to prevent inappropriate re-referrals and investigations of patients. However, in the absence of sound evidence from appropriate clinical studies,we disagree with the authors’ conclusion that neurological follow-up of these patients is often beneficial.
We wish to emphasize that in our study, firstly a neurologist established the diagnosis and briefly explained the diagnosis to the patient. Secondly, the first neurologist referred the patient to a specially trained second neurologist, who scheduled half an hour to discuss the diagnosis with the patient. This approach is clearly different from immediate referral to a GP after the diagnosis.
It is good to see that trials are being done to answer the critical question of how best to provide care for those patients with functional neurological symptoms (FNS). The research paper, ‘Management of patients with functional neurological symptoms: a single-centre randomised controlled trial’, by Pleizier, de Haan and Vermeulen, randomizes outpatients with functional neurological symptoms after diagnosis, to either two outpatient appointments with a neurologist, or referral back to a GP. Intriguingly, it finds no difference in outcome, that is quality of life scores, between the two groups.[1] While this study attempts to address an important question, namely the role of the neurologist in the care of patients with functional neurological disorders, we feel it has a number of problems that limit its generalizability, particularly to UK neurology practice.
The Netherlands is a country that compared to the UK, has approximately four times as many neurologists per head of the population, and many more GPs with higher levels of job satisfaction,[2] and often have mental health nurse support in the practice itself. Neurology outpatient waiting times are shorter in the Netherlands, and in-patient neurology review happens routinely and is quicker, unlike in the UK where it may not occur at all.[3] Because of this lack of prompt neurological review in the UK, it is common for patients to receive erroneous diagnoses, often necessitating an “undiagnosis” at the eventual neu...
It is good to see that trials are being done to answer the critical question of how best to provide care for those patients with functional neurological symptoms (FNS). The research paper, ‘Management of patients with functional neurological symptoms: a single-centre randomised controlled trial’, by Pleizier, de Haan and Vermeulen, randomizes outpatients with functional neurological symptoms after diagnosis, to either two outpatient appointments with a neurologist, or referral back to a GP. Intriguingly, it finds no difference in outcome, that is quality of life scores, between the two groups.[1] While this study attempts to address an important question, namely the role of the neurologist in the care of patients with functional neurological disorders, we feel it has a number of problems that limit its generalizability, particularly to UK neurology practice.
The Netherlands is a country that compared to the UK, has approximately four times as many neurologists per head of the population, and many more GPs with higher levels of job satisfaction,[2] and often have mental health nurse support in the practice itself. Neurology outpatient waiting times are shorter in the Netherlands, and in-patient neurology review happens routinely and is quicker, unlike in the UK where it may not occur at all.[3] Because of this lack of prompt neurological review in the UK, it is common for patients to receive erroneous diagnoses, often necessitating an “undiagnosis” at the eventual neurology review.[4] Given these starkly different clinical contexts, we believe that a single neurology appointment in the UK, as compared to neurological follow-up for patients with FNS, would not lead to similar outcomes as published in this study.
Not withstanding these cultural differences, there is also significant, multi-faceted selection bias in this study, which limits the interpretation of the results. Firstly, the authors only include patients referred by GPs in this study. In our experience, patients that come via A&E or have been recently discharged from hospital are different to those referred by GPs, having had more investigations, and have more severe symptoms and a poorer prognosis if there is
no improvement in hospital.[5] The authors also exclude patients who have been symptomatic for over a year. In reality, this would mean the exclusion of large numbers of patients. Indeed in this study 923/1147 patients are excluded for this very reason,[1] and the proportion of patients is likely to be higher in the UK for the reasons of delayed diagnosis explained above. It is likely that the longer patients are symptomatic with FNS, the poorer their prognosis.[6] These strict criteria therefore exclude the very patients who need treatment and follow-up care most, and are likely to bias the results of this study, and limit its interpretability when applied to the broader population of patients with FNS.
Lastly, a single neurologist accounted for treatment of 90% of the patients in the intervention arm of the study. It is therefore conceivable that the (high) standard of care received by patients from this neurologist who had a specific interest in FNS reduced any additional benefit from further neurology follow-up appointments. Indeed 34% of the patients who were supposed to receive at least 2 follow-up appointments failed to do so either because they thought it was unnecessary, or because they did not attend the follow-up appointments. The generalizability of these findings must therefore be in question.
The authors suggest many useful ideas for future studies. However, the variability present in their approach to follow up appointments and the use of physiotherapy and psychotherapy, demonstrates that ultimately, individualized treatment and follow up plans remain the gold standard in this complex group of patients with competing biological, psychological and social factors relevant to their FNS. Furthermore, the management of new neurological symptoms, relapses of previous FNS and relevant neurological and other co-morbidities remains very important in order to prevent inappropriate re-referrals and investigations of patients.[7] For these reasons and those discussed above, we believe that neurological follow-up of these patients is often beneficial.
Reference list
1. Pleizier M, de Haan RJ, Vermeulen M. Management of patients with functional neurological symptoms: a single-centre randomised controlled trial. J Neurol Neurosurg Psychiatry. 2017;88(5):430-436.
2. Arie S. Why are Dutch GPs so much happier? BMJ. 2015;351:h6870.
3. Gregory R, Nicholl D, Lawrence J, et al. Association of British Neurologists (ABN) 2017 Acute Neurology Survey. March 2017.
4. Coebergh JA, Wren DR, Mumford CJ. ‘Undiagnosing’ neurological disease: how to do it, and when not to. Practical Neurology. 2014;14:436-439.
5. Couprie W, Wijdicks EF, Rooijmans HG, et al. Outcome in conversion disorder: a follow up study. J Neurol Neurosurg Psychiatry. 1995;58(6):750-2.
6. Gelauff J, Stone J, Edwards M, et al. The prognosis of functional (psychogenic) motor symptoms: a systematic review. J Neurol Neurosurg Psychiatry. 2014;85(2):220-6.
7. Crimlisk HL, Bhatia KP, Cope H, et al. Patterns of referral in patients with medically unexplained motor symptoms. J Psychosom Res. 2000;49(3):217-9.
We agree that an evaluation of the total cerebrovascular disease
(CeVD) burden is important to understand the effect of brain structural
abnormalities on clinical outcomes such as cognitive impairment and
neuropsychiatric disorders. Recently, integrated measures of total brain
MRI burden have been employed to understand neuropathological changes in
elderly. However, global CeVD burden may not be best measured by the
sim...
We agree that an evaluation of the total cerebrovascular disease
(CeVD) burden is important to understand the effect of brain structural
abnormalities on clinical outcomes such as cognitive impairment and
neuropsychiatric disorders. Recently, integrated measures of total brain
MRI burden have been employed to understand neuropathological changes in
elderly. However, global CeVD burden may not be best measured by the
simple ordinal addition of individual markers, as not all MRI markers
contribute equally to clinical outcomes. Hence we have argued that it is
essential to take into consideration differential weighting of individual
MRI markers when constructing a composite scale. In a previously published
paper (Xu et al, 2015), a weighted composite score of CeVD encompassing
both small vessel and large vessel disease markers was constructed and its
association with cognitive function was reported in a clinic population.
This scale was subsequently validated in a community sample and found
useful in differentiating between elderly at various clinical and
preclinical stages of dementia (Xu et al, 2016). We are currently
examining whether such associations are also found with global
neuropsychiatric burden and individual neuropsychiatric symptoms.
Reference:
1. Xu X, Hilal S, Collinson SL, Yi Chong EJ, Ikram MK,
Venketasubramanian N, Chen CLH (2015). Association of magnetic resonance
imaging markers of cerebrovascular disease burden and cognition. Stroke
46: 2808-2814
2. Xu X, Hilal S, Collinson SL, Chan QL, Chong EJY, Ikram MK,
Venketasubramanian N, Cheng CY, Wong TY, Chen C(2016). Validation of the
total cerebrovascular disease burden scale in a community sample. Journal
of Alzheimer's Disease 52:1021-1028
Transthyretin-related familial amyloid polyneuropathy (TTR-FAP) is an
autosomal dominant disorder caused by the mutations of the transthyretin
(TTR) gene. The mutant amyloidogenic TTR protein causes systemic
accumulation of amyloid fibrils that result in organ dysfunction [1]. Over
100 mutations in TTR gene are associated with the disease but still, the
first identified Val30Met mutation make up 50% of the cases worldwide....
Transthyretin-related familial amyloid polyneuropathy (TTR-FAP) is an
autosomal dominant disorder caused by the mutations of the transthyretin
(TTR) gene. The mutant amyloidogenic TTR protein causes systemic
accumulation of amyloid fibrils that result in organ dysfunction [1]. Over
100 mutations in TTR gene are associated with the disease but still, the
first identified Val30Met mutation make up 50% of the cases worldwide. In
the three main regions in which TTR-FAP is endemic (Portugal, Sweden and
Japan), the Val30Met mutation is the predominant genetic cause. However,
in non-endemic regions genetic features are more heterogeneous [2].
Clinical presentation is highly variable due to the interplay between
several factors consisting of genotype, geographical origin of the
patient, regional variation, penetrance of gene mutation and age at onset
of symptoms [2]. Length dependent axonal sensory-motor and autonomic
polyneuropathy is the hallmark feature of TTR-FAP hence, lower limb
sensory symptoms are generally the initial manifestations. Yet, Koike et
al reported that 5 of 50 patients presented with upper limb sensory
symptoms [3]. Herein, we describe a patient with Val30Met mutation
presented with asymmetrical upper limb symptoms which was not previously
reported in non-endemic regions. A 66-year-old male patient was admitted
with 3-year history of progressive numbness and pain in right hand. He
progressively deteriorated and his symptoms have spread to his left hand
in several months. He was diagnosed as bilateral carpal tunnel syndrome
and underwent bilateral surgical carpal tunnel ligament release. However,
he gradually worsened with tingling and numbness spreading to his forearms
followed by weakness in both hands without any significant lower limb
symptoms. He has had recurrent constipation, orthostatism and impotence,
which are suggestive of autonomic involvement, for three years. Two years
after the onset of the upper limb symptoms he developed numbness in
footpad, followed by pain and weakness in both legs. He was diagnosed
chronic inflammatory demyelinating polyneuropathy two years ago and
treated with prednisolone for six months. His past medical history was
significant for systemic hypertension and a myocardial infarction four
years prior. His grandfather, father and uncle had died from unknown
cardiac cause. In his initial examination, he had bilateral miosis, distal
muscle weakness predominantly in upper and left-side with absent deep
tendon reflexes, stocking and glove type hypoaesthesia and hypoalgesia,
diminished vibration sensation. Nerve conduction studies revealed a
demyelinating sensory and motor polyneuropathy syndrome accompanied by the
signs of axonal loss. These findings were accompanied by sympathetic
autonomic involvement. His cerebrospinal fluid (CSF) examination revealed
increased protein level (75 mg/dl) with normal cytological examination.
Urinalysis results showed microalbuminuria but urinary tract
ultrasonography was normal. Because of the positive family history of
unknown cardiac deaths, echocardiograpy was performed which revealed
secondary changes in the myocardium associated with amyloid deposition.
His cardiac magnetic resonance imaging results correlated with the
findings of echocardiogram. In his rhythm holter monitoring, baseline
rhythm was sinus with the average heart rate of 62/min (lowest heart rate:
47/min, highest heart rate: 78/min). No signs of arrythmia or conduction
blocks were detected. With those findings, we assumed that the patient had
amyloid associated neuropathy. Minor salivary gland biopsy was performed
and amyloid infiltration of the blood vessel wall and periductal field was
observed. Molecular analysis of TTR gene revealed heterozygous Val30Met
(c.148G>A) mutation in exon 2. Tafamidis 20 mg/day treatment was
initiated right after the patient was diagnosed. TTR-FAP is a
multisystemic and increasingly popular disease but still very difficult to
recognize especially in non-endemic regions. Various clinic presentations,
negative family history and the clinicians' lack of awareness are most
common causes of misdiagnosis. Upper limb onset axonal polyneuropathy is a
rare presentation in general practice and was not reported in TTR-FAP
patients in non-endemic regions [4]. Based on the natural course of the
disease, a duration of 4 to 5 years is expected before the upper limb
symptoms would start [5]. On the other hand, in a previous analysis of
late-onset cases with Val30Met mutation, 10% of the patients had upper
limb symptoms as the initial presentation. Among those patients, the mean
age at upper limb onset was 66.3 ? 5.8 whereas lower limb symptoms occured
at 66.5 ? 6.2 years of age. Although age at disease onset was nearly
similar in our case, duration between the upper limb and the lower limb
symptoms was slightly longer than the latter report. In conclusion, we
emphasize the heterogenous clinical presentation of late -onset FAP in non
-endemic regions. Careful examination and clinical suspicion is mandatory
for reducing the misdiagnosis of the atypical cases.
References
1. Andrade, C., A peculiar form of peripheral neuropathy; familiar
atypical generalized amyloidosis with special involvement of the
peripheral nerves. Brain, 1952. 75(3): p. 408-27.
2. Parman, Y., et al., Sixty years of transthyretin familial amyloid
polyneuropathy (TTR-FAP) in Europe: where are we now? A European network
approach to defining the epidemiology and management patterns for TTR-FAP.
Curr Opin Neurol, 2016. 29 Suppl 1: p. S3-13. 3.
3. Koike, H., et al., Natural history of transthyretin Val30Met
familial amyloid polyneuropathy: analysis of late-onset cases from non-
endemic areas. J Neurol Neurosurg Psychiatry, 2012. 83(2): p. 152-8. 4.
4. Durmus-Tekce, H., et al., Genotypic and phenotypic presentation of
transthyretin-related familial amyloid polyneuropathy (TTR-FAP) in Turkey.
Neuromuscul Disord, 2016. 26(7): p. 441-6. 5.
5. Conceicao, I., et al., "Red-flag" symptom clusters in
transthyretin familial amyloid polyneuropathy. J Peripher Nerv Syst, 2016.
21(1): p. 5- 9.
In a study published in J Neurol Neurosurg Psychiatry, Xu et al.1
aimed to investigate the relation between microbleeds (CMBs) and
Neuropsychiatric symptoms (NPS) in an elderly population, through a cross-
sectional study related to 802 participants. Interestingly, they found a
statistically significant increment of the incidence of depression, with
the presence of multiple CMBs, in particular lobar CMBs. This finding is...
In a study published in J Neurol Neurosurg Psychiatry, Xu et al.1
aimed to investigate the relation between microbleeds (CMBs) and
Neuropsychiatric symptoms (NPS) in an elderly population, through a cross-
sectional study related to 802 participants. Interestingly, they found a
statistically significant increment of the incidence of depression, with
the presence of multiple CMBs, in particular lobar CMBs. This finding is
in line with the previous research by Tang et al..2 However, a recent
study by Zhang et al.3 did not find the similar increment trend in deep
CMBs in patients with post-stroke depression, indicating that the presence
of lobar CMBs, not deep CMBs, was a potential predictor maker of
depression. While CMBs is one of the MRI biomarkers of cerebral small
vessel disease (cSVD) and was often accompanied by other cSVD-related
brain changes, such as lacunar infarcts, white matter lesions, and
enlarged perivascular spaces.
The available evidence suggests that cSVD was a principal determinant
in the pathogenesis and development of post-stroke depression,4 and
depression in patients with a prevalence of cerebrovascular disease burden
may be related more to cumulative vascular pathology than to the location
and severity of a single risk factor. Investigating the role of a total
MRI burden of cSVD in its pathogenesis may help to understand this disease
better. As the previously mentioned, Zhang et al. found that higher total
MRI burden of cSVD was an independent predictor of depression, even
without detecting an apparent association between deep CMBs and
depression. Similar to the study by Zhang et al., a recent research
investigated total MRI burden of cSVD in cerebral amyloid angiopathy
(CAA), in univariable analysis, total cSVD score was associated with the
presence of CAA-related changes on pathologic analysis and CAA
presentation with ICH, but none of the different MRI markers comprising
the score were individually linked to vasculopathic changes in univariable
or multivariable logistic regression analyses.5 These suggest that an
assessment of total MRI burden of cSVD has several potential advantages
because it avoids overreliance on any one individual marker of small
vessel disease.5 Hence, a complete evaluation of the total MRI burden of
cSVD may be important to understand the effect of cSVD on clinical
outcomes, such as depression.
Conflict of Interest Disclosures: None.
Reference:
1. Xu X, Chan QL, Hilal S, et al. Cerebral microbleeds and
neuropsychiatric symptoms in an elderly Asian cohort. Journal of
neurology, neurosurgery, and psychiatry 2017;88(1):7-11. doi: 10.1136/jnnp
-2016-313271
2. Tang WK, Chen Y, Liang H, et al. Cerebral microbleeds as a predictor of
1-year outcome of poststroke depression. Stroke; a journal of cerebral
circulation 2014;45(1):77-81. doi: 10.1161/STROKEAHA.113.002686
3. Zhang X, Tang Y, Xie Y, et al. Total magnetic resonance imaging burden
of cerebral small-vessel disease is associated with post-stroke depression
in patients with acute lacunar stroke. Eur J Neurol 2016 doi:
10.1111/ene.13213
4. Pavlovic AM, Pekmezovic T, Zidverc Trajkovic J, et al. Baseline
characteristic of patients presenting with lacunar stroke and cerebral
small vessel disease may predict future development of depression. Int J
Geriatr Psychiatry 2016;31(1):58-65. doi: 10.1002/gps.4289
5. Charidimou A, Martinez-Ramirez S, Reijmer YD, et al. Total Magnetic
Resonance Imaging Burden of Small Vessel Disease in Cerebral Amyloid
Angiopathy: An Imaging-Pathologic Study of Concept Validation. JAMA
neurology 2016;73(8):994-1001. doi: 10.1001/jamaneurol.2016.0832
Ryuji Kaji MD, PhD
Department of Neurology, Tokushima University
I appreciate Dr Popkirov’s unique and interesting views and comments related to our paper [1]. This reminds me of the gating of sensory inputs at various levels of the nervous system, and their perception is not a passive but is a very active process. In addition to the fact that it is not possible to tickle oneself, other sensory phenomena associated with abnormal movements deserve mention. Restless legs syndrome is characterized by constant urge to move legs, and is successfully managed by dopamine agonists. Tics are also preceded by sensory symptoms. These could be examples of aberrant sensory inputs coming to the conscious level, which would normally be handled at subconscious pathways. At this moment, the exact role of the cerebellar pathway in these conditions is not clear, but should be investigated in the future aside from dystonia.
1. Kaji R, Bhatia K, Graybiel AM. Pathogenesis of dystonia: is it of cerebellar or basal ganglia origin? J Neurol Neurosurg Psychiatry. 2017 Oct 31. pii: jnnp-2017-316250. doi: 10.1136/jnnp-2017-316250. [Epub ahead of print]
No conflict of interest declared
Dear Editor,
Show MoreWe read with great interest the article of Boentert et al.1 recently published on this journal. In their paper, the authors describe polysomnographic findings in a large series of non-ventilated patients with amyotrophic lateral sclerosis (ALS). One of the points the authors underscore is that in their patients most respiratory events during sleep were of the obstructive, and not of the central type. This finding is in agreement with what described by Kimura,2 but not by several other authors who found that most respiratory events were of the central type.3 Furthermore, the authors of this paper did not find that obstructive apneas were preferentially associated with bulbar ALS, similarly to David et al.4 but unlike what described by Santos et al.5 However, the tables in the article show that most of the respiratory events were hypopneas, whose type was not specified.
Criteria for scoring sleep disordered breathing events have changed over time, especially as regards hypopneas. Only recently a general rule for type of hypopnea, central or obstructive has been proposed. Obstructive hypopneas are those where at least one of three criteria is met during the event: presence of snoring, flow limitation demonstrated by a flattening of the nasal pressure derived flow signal, opposing thoracic and abdominal movements. Absence of all these criteria characterizes central hypopneas.6 However, standard criteria for apneas and hypopneas fit well to patients wi...
In their recent article on the pathogenesis of dystonia, Kaji and colleagues argue that aberrant cerebellar inputs can induce dystonic movement mediated by the basal ganglia.[1] In this framework, the sensory trick (geste antagoniste) leads to a realignment between predicted and actual sensory information, thus reduces (or overrides) the sensorimotor mismatch forwarded to the basal ganglia, and in turn alleviates dystonic contractions.
A similar model of sensorimotor mismatch response has been implicated in the physiology of being tickled[2]. Specifically, it has been proposed that the inability to tickle oneself is related to a sensory attenuation mediated by the cerebellum during self-generated tactile sensation[3]. This attenuation is proportional to the precision of the sensory prediction[4]. Whether the same cerebellar processes are responsible for the alleviation of dystonia during a sensory trick would be an interesting question to explore experimentally. At the risk of straining the analogy, one could even describe the postures and movements one produces when being tickled as dystonic-like. Neurologists are reminded of this when interpreting ambiguous plantar responses in very ticklish patients -- a problem that can be avoided by employing the patient's cerebellar sensory attentuation[5].
1. Kaji R, Bhatia K, Graybiel AM. Pathogenesis of dystonia: is it of cerebellar or basal ganglia origin? J Neurol Neurosurg Psychiatry. 2017 Oct 31. pii: jnnp-20...
Show MoreIn our previous meta-analysis of cerebellar atrophy in seven major neurodegenerative conditions (Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Huntington’s disease (HD), Parkinson’s disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP)) we investigated studies that reported grey matter (GM) loss in the cerebellum [1]. Consistent regions of atrophy were found in AD, ALS, FTD, MSA, and PSP but not HD or PD. In their comment on our meta-analysis, Sheng and Pan have argued that our method of selectively investigating studies that found cerebellar atrophy, rather than adopting a whole-brain approach, is “not optimal in a coordinate-based meta-analysis” [2]. They further cite previous whole-brain meta-analyses that did not identify clusters of cerebellar grey matter loss in patients [3-6].
Show MoreHere, we argue that our approach was justified given our aim, which was to focus on cases where cerebellar atrophy was found in the respective disease groups in order to determine 1) if such atrophy followed a consistent, robust pattern, and 2) if atrophy patterns were disease-specific or generic, where possible relating them to symptomatology.
There are several reasons why we chose to focus on the cerebellum rather than adopting a whole-brain approach. First, the cerebellum is hardly a “region of interest” in the classical sense given its marked heterogeneity in terms of function and connectivity as we...
Does Cerebellar Atrophy in Neurodegeneration?
Li-Qin Sheng1, Ping-Lei Pan2
1 Department of Neurology, Traditional Chinese Medicine Hospital of Kunshan, Kunshan, PR China
2 Department of Neurology, Affiliated Yancheng Hospital, School of Medicine, Southeast University, Yancheng, PR China
Correspondence:
Show MorePingLei Pan, Department of Neurology, Affiliated Yancheng Hospital, School of Medicine, Southeast University, West Xindu Road 2#, Yancheng, Jiangsu Province, 224001, PR China. E-mail: panpinglei@163.com, Telephone: +8618361146977
Coordinate-based meta-analysis is a powerful way for neuroimaging studies to identify the most consistent and replicable differences in brain activity or structure in neurodegenerative disorders. In their JNNP publication, Gellersen et al 1 conducted coordinate-based meta-analyses of 54 voxel-based morphometry (VBM) studies in Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), behavioral variant frontotemporal dementia (bvFTD), amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). In this study, they solely focused on cerebellar grey matter (GM) atrophy.1 Marked cerebellar atrophy in AD, ALS, bvFTD, PSP and MSA, but not in PD or HD, was identified in the meta-analyses.1
These findings are of interest.1 However, the procedure of the meta-analyses had a major limitation. Coordin...
We thank dr. Coebergh and colleagues for their interest in our study. We agree that(a) there are many differences between the health care systems of the UK and the Netherlands, (b) the results of our study do not apply to excluded patients, and (c) the management of new neurological symptoms, relapses of previous FNS and relevant neurological and other co-morbidities remain very important in order to prevent inappropriate re-referrals and investigations of patients. However, in the absence of sound evidence from appropriate clinical studies,we disagree with the authors’ conclusion that neurological follow-up of these patients is often beneficial.
We wish to emphasize that in our study, firstly a neurologist established the diagnosis and briefly explained the diagnosis to the patient. Secondly, the first neurologist referred the patient to a specially trained second neurologist, who scheduled half an hour to discuss the diagnosis with the patient. This approach is clearly different from immediate referral to a GP after the diagnosis.
It is good to see that trials are being done to answer the critical question of how best to provide care for those patients with functional neurological symptoms (FNS). The research paper, ‘Management of patients with functional neurological symptoms: a single-centre randomised controlled trial’, by Pleizier, de Haan and Vermeulen, randomizes outpatients with functional neurological symptoms after diagnosis, to either two outpatient appointments with a neurologist, or referral back to a GP. Intriguingly, it finds no difference in outcome, that is quality of life scores, between the two groups.[1] While this study attempts to address an important question, namely the role of the neurologist in the care of patients with functional neurological disorders, we feel it has a number of problems that limit its generalizability, particularly to UK neurology practice.
Show MoreThe Netherlands is a country that compared to the UK, has approximately four times as many neurologists per head of the population, and many more GPs with higher levels of job satisfaction,[2] and often have mental health nurse support in the practice itself. Neurology outpatient waiting times are shorter in the Netherlands, and in-patient neurology review happens routinely and is quicker, unlike in the UK where it may not occur at all.[3] Because of this lack of prompt neurological review in the UK, it is common for patients to receive erroneous diagnoses, often necessitating an “undiagnosis” at the eventual neu...
We agree that an evaluation of the total cerebrovascular disease (CeVD) burden is important to understand the effect of brain structural abnormalities on clinical outcomes such as cognitive impairment and neuropsychiatric disorders. Recently, integrated measures of total brain MRI burden have been employed to understand neuropathological changes in elderly. However, global CeVD burden may not be best measured by the sim...
Transthyretin-related familial amyloid polyneuropathy (TTR-FAP) is an autosomal dominant disorder caused by the mutations of the transthyretin (TTR) gene. The mutant amyloidogenic TTR protein causes systemic accumulation of amyloid fibrils that result in organ dysfunction [1]. Over 100 mutations in TTR gene are associated with the disease but still, the first identified Val30Met mutation make up 50% of the cases worldwide....
In a study published in J Neurol Neurosurg Psychiatry, Xu et al.1 aimed to investigate the relation between microbleeds (CMBs) and Neuropsychiatric symptoms (NPS) in an elderly population, through a cross- sectional study related to 802 participants. Interestingly, they found a statistically significant increment of the incidence of depression, with the presence of multiple CMBs, in particular lobar CMBs. This finding is...
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