Komatsu et al. presented an interesting clinicopathological case of anti-myelin oligodendrocyte glycoprotein (MOG) demyelinating disease of the CNS. (1) Their patient had a rather unusual subacute encephalopathic presentation with extensive supratentorial fluid-attenuation inversion recovery white matter hyperintensities. The authors focused mainly on the conspicuous MRI punctuate and curvilinear enhancement pattern within the hemispheric lesions.
It is well established that intraparenchymal punctuate and curvilinear gadolinium enhancement may arise in the context of Moyamoya syndrome, various endotheliopathies and most commonly, in disorders causing small vessels blood-brain barrier disruption. (2)These entities are associated histologically with perivascular cellular infiltrates and include inflammatory autoimmune diseases (i.e. primary or secondary angiitis of the CNS, neurosarcoidosis, histiocytosis and demyelinating diseases of the CNS), pre-lymphoma states (i.e. sentinel lesions of primary CNS lymphoma), non-Hodgkin lymphoma (i.e. intravascular lymphoma) and CLIPPERS syndrome. (2) Notably, among demyelinating disorders, multiple sclerosis and aquaporin-4 antibody (AQP4-Ab) neuromyelitis optica spectrum disorders (NMOSD) manifest this specific neuroimaging pattern in rare cases. (2,3)
We agree with Komatsu et al. that their case is the first report of the perivascular enhancement in anti-MOG antibody disease. Indeed, gadolinium enhancement was observed in...
Komatsu et al. presented an interesting clinicopathological case of anti-myelin oligodendrocyte glycoprotein (MOG) demyelinating disease of the CNS. (1) Their patient had a rather unusual subacute encephalopathic presentation with extensive supratentorial fluid-attenuation inversion recovery white matter hyperintensities. The authors focused mainly on the conspicuous MRI punctuate and curvilinear enhancement pattern within the hemispheric lesions.
It is well established that intraparenchymal punctuate and curvilinear gadolinium enhancement may arise in the context of Moyamoya syndrome, various endotheliopathies and most commonly, in disorders causing small vessels blood-brain barrier disruption. (2)These entities are associated histologically with perivascular cellular infiltrates and include inflammatory autoimmune diseases (i.e. primary or secondary angiitis of the CNS, neurosarcoidosis, histiocytosis and demyelinating diseases of the CNS), pre-lymphoma states (i.e. sentinel lesions of primary CNS lymphoma), non-Hodgkin lymphoma (i.e. intravascular lymphoma) and CLIPPERS syndrome. (2) Notably, among demyelinating disorders, multiple sclerosis and aquaporin-4 antibody (AQP4-Ab) neuromyelitis optica spectrum disorders (NMOSD) manifest this specific neuroimaging pattern in rare cases. (2,3)
We agree with Komatsu et al. that their case is the first report of the perivascular enhancement in anti-MOG antibody disease. Indeed, gadolinium enhancement was observed in 6 out of 108 MRIs among adult patients with CNS MOG autoimmunity in a large French natiowide cohort. (4) Leptomeningeal enhancement, thought to indicate cortical encephalitis, was detected in only 3 scans. Most importantly, none of the patients in this study or other related publications, demonstrated punctuate or fine, linear-shaped enhancing lesions.
Intriguingly, the enhancement pattern in the case of Komatsu et al. shares many similarities with the imaging abnormalities seen in a recently described disorder, namely autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy. This is a novel form of a steroid-responsive meningoencephalomyelitis associated with IgG binding to GFAP. A characteristic pattern on neuroimaging of brain linear, perivascular enhancement, oriented radially to the ventricles was identified in the seminal paper by Fang et al. (5) This striking abnormality was also observed in a substantial proportion of patients with the disorder in subsequent cohorts. (6)
Therefore, it would be useful to know the CSF status of GFAP-Ab of the forementioned patient. Besides, about 40% of individuals with GFAP antibody-positive meningoencephalomyelitis had coexisting neural autoantibodies. (5, 6)
Many questions regarding GFAP autoimmunity and, to a lesser extent, MOG-Ab–associated diseases remain to be answered in future studies. Overall, it seems that in the right clinical context, when perivascular enhancement on MRI is observed, one should be alert in making a differential diagnosis of GFAP astrocytopathy rather than anti-MOG antibody demyelinating disease.
1. Komatsu T, Matsushima S, Kaneko K, et al. Perivascular enhancement in anti-MOG antibody demyelinating disease of the CNS. J Neurol Neurosurg Psychiatry 2019;90:111-112.
2. Taieb, G., Duran-Peña, A., de Chamfleur, N.M. et al. Neuroradiology 2016; 58: 221-235 https://doi.org/10.1007/s00234-015-1629-y
3. Pekcevik Y, Izbudak I. Perivascular enhancement in a patient with neuromyelitis optica spectrum disease during an optic neuritis attack. J Neuroimaging 2015; 25:686–687
4. Cobo-Calvo I, Ruiz A, Maillart E, et al. Clinical spectrum and prognostic value of CNS MOG autoimmunity in adults. The MOGADOR study. Neurology 2018; 90 (21) e1858-e1869; DOI: 10.1212/WNL.0000000000005560
5. Fang B, McKeon A, Hinson SR, et al. Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy: A Novel Meningoencephalomyelitis. JAMA Neurol. 2016;73(11):1297–1307. doi:10.1001/jamaneurol.2016.2549
6. Zarkali A, Cousins O, Athauda D, et al. Glial fibrillary acidic protein antibody-positive meningoencephalomyelitis. Practical Neurology 2018;18:315-319
Re: A unifying theory for cognitive abnormalities in functional neurological disorders, fibromyalgia and chronic fatigue syndrome
Viraj Bharambe Specialist registrar in neurology
John C Williamson Specialist registrar in neurology
Andrew J Larner Consultant Neurologist
Cognitive Function Clinic
Walton Centre for Neurology and Neurosurgery
Lower Lane
Fazakerley
Liverpool
L9 7LJ
UK
e-mail: a.larner@thewaltoncentre.nhs.uk
Teodoro et al. present evidence for shared cognitive symptoms in fibromyalgia, chronic fatigue syndrome, and functional neurological disorders, and hypothesize that functional cognitive disorders (FCD) may share similar symptoms.1 We present data which speak to this issue.
We have previously reported preliminary data examining performance on the mini-Addenbrooke’s Cognitive Examination (MACE) by patients diagnosed with fibromyalgia2 as part of a larger study of MACE.3 Here, we update these data for fibromyalgia patients (n = 17; F:M = 17:0; age range 33-56 years, median 49) and compare them to MACE performance by patients diagnosed with FCD (n = 43; F:M = 18:25; age range 28-82 years, median 58).4
There was no statistical difference (p > 0.1) in the proportions of patients scoring below the two cut-off scores (≤21/30, ≤25/30) defined in the index MACE report.5 Looking at MACE subscores (Attention, Registration,...
Re: A unifying theory for cognitive abnormalities in functional neurological disorders, fibromyalgia and chronic fatigue syndrome
Viraj Bharambe Specialist registrar in neurology
John C Williamson Specialist registrar in neurology
Andrew J Larner Consultant Neurologist
Cognitive Function Clinic
Walton Centre for Neurology and Neurosurgery
Lower Lane
Fazakerley
Liverpool
L9 7LJ
UK
e-mail: a.larner@thewaltoncentre.nhs.uk
Teodoro et al. present evidence for shared cognitive symptoms in fibromyalgia, chronic fatigue syndrome, and functional neurological disorders, and hypothesize that functional cognitive disorders (FCD) may share similar symptoms.1 We present data which speak to this issue.
We have previously reported preliminary data examining performance on the mini-Addenbrooke’s Cognitive Examination (MACE) by patients diagnosed with fibromyalgia2 as part of a larger study of MACE.3 Here, we update these data for fibromyalgia patients (n = 17; F:M = 17:0; age range 33-56 years, median 49) and compare them to MACE performance by patients diagnosed with FCD (n = 43; F:M = 18:25; age range 28-82 years, median 58).4
There was no statistical difference (p > 0.1) in the proportions of patients scoring below the two cut-off scores (≤21/30, ≤25/30) defined in the index MACE report.5 Looking at MACE subscores (Attention, Registration, Verbal fluency, Clock Drawing, Memory recall), the proportions scoring at ceiling were not statistically different (p > 0.1) in the fibromyalgia and FCD groups. Ranking performance in cognitive domains from worst to best showed the same pattern in both patient groups, namely Verbal fluency, Memory recall, Registration, Attention, and Clock drawing.
Although numbers are small and the cognitive testing relatively simple, and the group demographics differ (both gender and age p < 0.05), nevertheless we suggest this evidence supports the hypothesis of Teodoro et al. of shared cognitive symptoms in fibromyalgia and FCD.
References
1. Teodoro T, Edwards MJ, Isaacs JD. A unifying theory for cognitive abnormalities in functional neurological disorders, fibromyalgia and chronic fatigue syndrome: systematic review. J Neurol Neurosurg Psychiatry 2018; 89: 1308-19. doi: 10.1136/jnnp-2017-317823.
2. Williamson J, Larner AJ. Cognitive dysfunction in patients with fibromyalgia. Br J Hosp Med 2016; 77: 116. doi: 10.12968/hmed.2016.77.2.116.
3. Williamson J, Larner AJ. MACE for the diagnosis of dementia and MCI: 3-year pragmatic diagnostic test accuracy study. Dement Geriatr Cogn Disord 2018; 45: 300-7. doi: 10.1159/000484438.
4. Bharambe V, Larner AJ. Functional cognitive disorders: demographic and clinical features contribute to a positive diagnosis. Neurodegener Dis Manag 2018; 8: 377-83. doi: 10.2217/nmt-2018-0025.
5. Hsieh S, McGrory S, Leslie F, et al. The Mini-Addenbrooke’s Cognitive Examination: a new assessment tool for dementia. Dement Geriatr Cogn Disord 2015; 39: 1-11. doi: 10.1159/000366040.
Conflicts of interest
The authors declare no conflict of interest
Dear Editor,
We have read with great interest the work by Scarpazza et al that provided a longitudinal MRI evaluation of natalizumab-related Progressive Multifocal Leukoencephalopathy (NTZ-PML) lesions in Multiple Sclerosis (MS) patients (1).
Their central finding was the high percentage (78.1%) of patients, who eventually developed NTZ-PML, in whom highly suggestive lesions were already retrospectively detectable on pre-diagnostic MRI exams. Furthermore, the pre-diagnostic phase proved to be relatively long (150.8±74.9 days), with an estimated percentage increase of the lesions’ volume of 62.8% per month (1).
Given the widely recognized crucial role of a timely NTZ-PML identification in reducing mortality and residual disability (1), these results present the neurological and neuroradiological communities with an important clinical challenge, prompting a major effort to ensure an early diagnosis of this condition.
Although redefining the timing of MRI surveillance, with up to one brain MRI exam every 3-4 months for high-risk patients, appears as a justified strategy, we think that improving the accuracy of early identification of NTZ-PML is also mandatory.
In our opinion, such achievement should be pursued using two complementary approaches: (i) a specific training addressed to neuroradiologists working in the field of MS, who should be aware of the relevance of even very small asymptomatic PML lesions and how to differentiate them from new M...
Dear Editor,
We have read with great interest the work by Scarpazza et al that provided a longitudinal MRI evaluation of natalizumab-related Progressive Multifocal Leukoencephalopathy (NTZ-PML) lesions in Multiple Sclerosis (MS) patients (1).
Their central finding was the high percentage (78.1%) of patients, who eventually developed NTZ-PML, in whom highly suggestive lesions were already retrospectively detectable on pre-diagnostic MRI exams. Furthermore, the pre-diagnostic phase proved to be relatively long (150.8±74.9 days), with an estimated percentage increase of the lesions’ volume of 62.8% per month (1).
Given the widely recognized crucial role of a timely NTZ-PML identification in reducing mortality and residual disability (1), these results present the neurological and neuroradiological communities with an important clinical challenge, prompting a major effort to ensure an early diagnosis of this condition.
Although redefining the timing of MRI surveillance, with up to one brain MRI exam every 3-4 months for high-risk patients, appears as a justified strategy, we think that improving the accuracy of early identification of NTZ-PML is also mandatory.
In our opinion, such achievement should be pursued using two complementary approaches: (i) a specific training addressed to neuroradiologists working in the field of MS, who should be aware of the relevance of even very small asymptomatic PML lesions and how to differentiate them from new MS lesions on conventional brain MRI scans (2), and (ii) the identification of new MRI markers that could help in an early neuroradiological identification of PML.
It is noteworthy to mention that recent works described the presence of significant magnetic susceptibility changes, revealing a paramagnetic dipole, at the level of the subcortical U-fibers adjacent to PML lesions (3, 4). This paramagnetic effect, which has been speculatively attributed to iron accumulation inside macrophages and microglial cells following myelin degeneration, has been reported as an early and constant finding in this condition (3, 4).
Given the known absence of significant paramagnetic effects within new MS plaques (5), this sign, which still needs validation studies on larger patient cohorts, could potentially improve the accuracy of an early neuroradiological differential diagnosis between these two conditions, eventually leading to the implementation of susceptibility-weighted sequences in routine brain MRI exams of high-risk patients.
References
1. Scarpazza C, Signori A, Prosperini L, et al. Early diagnosis of progressive multifocal leucoencephalopathy: longitudinal lesion evolution. Journal of neurology, neurosurgery, and psychiatry 2018.
2. Wijburg MT, Witte BI, Vennegoor A, et al. MRI criteria differentiating asymptomatic PML from new MS lesions during natalizumab pharmacovigilance. Journal of neurology, neurosurgery, and psychiatry 2016;87(10):1138-45.
3. Hodel J, Outteryck O, Verclytte S, et al. Brain Magnetic Susceptibility Changes in Patients with Natalizumab-Associated Progressive Multifocal Leukoencephalopathy. AJNR American journal of neuroradiology 2015;36(12):2296-302.
4. Pontillo G, Cocozza S, Lanzillo R, et al. Brain Susceptibility Changes in a Patient with Natalizumab-Related Progressive Multifocal Leukoencephalopathy: A Longitudinal Quantitative Susceptibility Mapping and Relaxometry Study. Frontiers in neurology 2017;8:294.
5. Zhang Y, Gauthier SA, Gupta A, et al. Quantitative Susceptibility Mapping and R2* Measured Changes during White Matter Lesion Development in Multiple Sclerosis: Myelin Breakdown, Myelin Debris Degradation and Removal, and Iron Accumulation. AJNR American journal of neuroradiology 2016;37(9):1629-35.
Corresponding Author:
Giuseppe Pontillo, MD
Department of Advanced Biomedical Sciences
University “Federico II”, Via Pansini, 5, 80131 - Naples - Italy
E-mail: giuseppe.pon@gmail.com
We thank Abat et al. for re-emphasizing an important interpretation of our work, namely that sex-differences in life-expectancy likely influenced the presented lifetime risks [1]. Indeed, in our paper we repeatedly discussed in several sections (for instance in the methods) that differences in life-expectancy between men and women could differentially affect their lifetime risk. It was for this reason that we consequently decided to analyze the data in a sex-specific manner while taking the competing risk of death into account in order to prevent potential overestimation.
Abat et al. unfortunately also allege that we attributed the observed sex-differences in disease risk to sex-specific effects on a biological level. The authors have seemingly missed our discussion at length arguing that observed differences in lifetime risk may be primarily attributed to the effects of differences in life-expectancy between men and women: “Apart from a longer life-expectancy in general, these findings may be explained by smaller differences in life-expectancy between men and women in the Netherlands (1.8 years), compared with the USA (4.8 years). With longer life-expectancy, individuals in this study simply had more time to develop these diseases in a timeframe with high age-specific incidence rates.”
It seems thus that ours and Abat and co-authors’ interpretation of our findings is pretty much congruent, i.e. age, irrespective of sex, should be consid...
We thank Abat et al. for re-emphasizing an important interpretation of our work, namely that sex-differences in life-expectancy likely influenced the presented lifetime risks [1]. Indeed, in our paper we repeatedly discussed in several sections (for instance in the methods) that differences in life-expectancy between men and women could differentially affect their lifetime risk. It was for this reason that we consequently decided to analyze the data in a sex-specific manner while taking the competing risk of death into account in order to prevent potential overestimation.
Abat et al. unfortunately also allege that we attributed the observed sex-differences in disease risk to sex-specific effects on a biological level. The authors have seemingly missed our discussion at length arguing that observed differences in lifetime risk may be primarily attributed to the effects of differences in life-expectancy between men and women: “Apart from a longer life-expectancy in general, these findings may be explained by smaller differences in life-expectancy between men and women in the Netherlands (1.8 years), compared with the USA (4.8 years). With longer life-expectancy, individuals in this study simply had more time to develop these diseases in a timeframe with high age-specific incidence rates.”
It seems thus that ours and Abat and co-authors’ interpretation of our findings is pretty much congruent, i.e. age, irrespective of sex, should be considered as the main driver for the observed differences in lifetime risks of these diseases. Yet, in order not to rule out other interpretations prematurely, we also indicate that consideration should be given to potential sex-specific risk factors. For example, we observed a lower educational level for women compared to men which may have led to a lower resilience for dementia in women.
Reference
1 Licher S, Darweesh SKL, Wolters FJ, et al. Lifetime risk of common neurological diseases in the elderly population. J Neurol Neurosurg Psychiatry 2018;:jnnp-2018-318650.
To the Editor,
We read with interest the work from Licher et al. [1] in which the authors tried to quantify the burden of common neurological diseases (i.e. dementia, stroke and parkinsonism) in 12 102 individuals (6 982 women and 5 120 men) aged ≥ 45 years and free from these diseases at baseline. All these individuals were recruited between 1990 and 2016 into the prospective population-based Rotterdam Study. At the end of their analyzes, the authors concluded that one in two women and one in three men will develop dementia, stroke or parkinsonism during their lifetime, and that the risk for women to develop both stroke and dementia during their life is almost twice that of men [1].
By reading the article from Licher et al. [1], we were extremely surprised by the fact that the authors did not consider the impact of the difference in life expectancies between men and women on their results and conclusions. This is particularly well underlined by the fact that the authors did not clearly precise the age structures of the two populations they studied [1]. In our view, this information is critical as, although the reasons for this difference are still debated and may probably be multi-factorial [2], it is well known that women live longer than men. This trend is confirmed by the 2018 World Health Statistics report [3] that estimates that in 2016, the life expectancies of men and women at birth were respectively 69.8 and 74.2 years at the international level. The...
To the Editor,
We read with interest the work from Licher et al. [1] in which the authors tried to quantify the burden of common neurological diseases (i.e. dementia, stroke and parkinsonism) in 12 102 individuals (6 982 women and 5 120 men) aged ≥ 45 years and free from these diseases at baseline. All these individuals were recruited between 1990 and 2016 into the prospective population-based Rotterdam Study. At the end of their analyzes, the authors concluded that one in two women and one in three men will develop dementia, stroke or parkinsonism during their lifetime, and that the risk for women to develop both stroke and dementia during their life is almost twice that of men [1].
By reading the article from Licher et al. [1], we were extremely surprised by the fact that the authors did not consider the impact of the difference in life expectancies between men and women on their results and conclusions. This is particularly well underlined by the fact that the authors did not clearly precise the age structures of the two populations they studied [1]. In our view, this information is critical as, although the reasons for this difference are still debated and may probably be multi-factorial [2], it is well known that women live longer than men. This trend is confirmed by the 2018 World Health Statistics report [3] that estimates that in 2016, the life expectancies of men and women at birth were respectively 69.8 and 74.2 years at the international level. Therefore, knowing that stroke, dementia and parkinsonism are more prevalent in the elderly than in younger people [4], it is clear for us that what the authors attributed to sex is in fact the direct consequence of ageing, an aspect that was not studied by the authors. By not highlighting this factor, they led readers to misinterpretations, including general newspapers journalists that assume that this difference is a gender gap that should be filled.
To conclude, by not considering the impact of the difference in life expectancies between men and women on their study, the authors introduced an important bias in their study, leading them to draw erroneous conclusions. Age is the real culprit, not gender!
References
1 Licher S, Darweesh SKL, Wolters FJ, et al. Lifetime risk of common neurological diseases in the elderly population. J Neurol Neurosurg Psychiatry 2018;:jnnp-2018-318650.
2 Marais GAB, Gaillard J-M, Vieira C, et al. Sex gap in aging and longevity: can sex chromosomes play a role? Biol Sex Differ 2018;9:33.
3 World Health Organization. World Health Statistics 2018- Monitoring health for the Sustainable Development Goals. Available from http://apps.who.int/iris/bitstream/handle/10665/272596/9789241565585-eng.... Accessed on 2018/10/22.
4 GBD 2015 Neurological Disorders Collaborator Group. Global, regional, and national
burden of neurological disorders during 1990-2015: a systematic analysis for the
Global Burden of Disease Study 2015. Lancet Neurol 2017;16:877–97.
We thoroughly enjoyed reading the comment on our paper which analysed expert ratings of the movement disorder associated with NMDAR antibody-encephalitis.1 Thompson et al’s elegant pathophysiological explanation provides an excellent framework of the most plausible neural structures involved in NMDAR-antibody encephalitis. Further, they note these movements can occur in semi-conscious patients, and this concurs well with the previous description of anti-gravity movements in the context of ‘status dissociatus’.2 A review of our 76 videos, revealed Thompson et al’s account of “variable, complex jerky semi-rhythmic movements….in the obtunded state” in 45 (59%) of cases. Therefore, this complex description was not present in almost half of patients. Furthermore, our recent clinical experiences note some NMDAR-antibody patients with abnormal movements but without obtundation: perhaps, given the known stepwise progression of many cases, this is a function of increasingly early disease recognition.3
By contrast to Thompson et al, our published study design intentionally used conventional phenomenological terms to define the movement disorder associated with NMDAR antibody-encephalitis.1 This approach aimed to define a pragmatic method, available to all clinicians, which could identify and faithfully communicate this complex movement disorder, with the important aim of earlier disease recognition. The results identified a dominant set of recognised classifications – dyston...
We thoroughly enjoyed reading the comment on our paper which analysed expert ratings of the movement disorder associated with NMDAR antibody-encephalitis.1 Thompson et al’s elegant pathophysiological explanation provides an excellent framework of the most plausible neural structures involved in NMDAR-antibody encephalitis. Further, they note these movements can occur in semi-conscious patients, and this concurs well with the previous description of anti-gravity movements in the context of ‘status dissociatus’.2 A review of our 76 videos, revealed Thompson et al’s account of “variable, complex jerky semi-rhythmic movements….in the obtunded state” in 45 (59%) of cases. Therefore, this complex description was not present in almost half of patients. Furthermore, our recent clinical experiences note some NMDAR-antibody patients with abnormal movements but without obtundation: perhaps, given the known stepwise progression of many cases, this is a function of increasingly early disease recognition.3
By contrast to Thompson et al, our published study design intentionally used conventional phenomenological terms to define the movement disorder associated with NMDAR antibody-encephalitis.1 This approach aimed to define a pragmatic method, available to all clinicians, which could identify and faithfully communicate this complex movement disorder, with the important aim of earlier disease recognition. The results identified a dominant set of recognised classifications – dystonia, stererotypies and chorea – with a paucity of tremor. In agreement with Thompson et al’s observations, it revealed some additional under-represented features. These were within our ‘other’ classification category (Figure 1D), and included mutism, stupor, myorhythmia, myokymia, tics, opisthotonus, ataxia, dyskinesias, waxy flexibility, oculogyric crises, athetosis, agitation, startle and vocal perseveration. However, we noted in our discussion that even the expert raters found it difficult to accurately describe this movement disorder within the predictable constraints of preconceived and established categorisations, and much of their feedback reflected a dissatisfaction with the final category chosen. Quantitatively, and by comparison to the other mixed movement disorders they rated, this limitation was strikingly reflected by the appreciably poorer inter-rater variability and the significantly more descriptive terms used to capture the essence of this movement disorder (P<0.0001).
Indeed, our findings are best interpreted within the intrinsic framework of movement disorder nomenclature. By extension, and particularly to the expert eye, we agree with Thompson et al that the disorder is often even more distinctive than this rare combination would suggest. In fact, in some cases, it may be unique. Interestingly, use of the term ‘unique’ may only be inaccurate given some of the closest mimics include ketamine / phencyclidine use and GRIN1A mutations. Of course, all of these imply the targeted specific-NMDAR modulation is at the core of this network-based pathophysiology.
Overall, within inevitable contemporary nomenclature constraints, we anticipate that the constellation of dystonia, stereotypies and chorea, with limited tremor, will provide a comprehensive, clear and concise message to clinicians and alert them to the possibility of this highly-treatable disorder. Yet, in future, perhaps this multifaceted movement disorder merits its own nomenclature to better emphasise the distinctive nature of the clinical observations. However, a term such as NMDAR-antibody associated movement disorder would be self-fulfilling and perhaps divert from the aim of its accurate recognition. Therefore, a reliance on conventional terms will yet be necessary to communicate this entity.
References
1. Varley JA, Webb AJS, Balint B, et al. The Movement disorder associated with NMDAR antibody-encephalitis is complex and characteristic: an expert video-rating study. J Neuro Neurosurg Psychiatry 2018;
2. Stamelou M, Plazzi G, Lugaresi E, et al. The distinct movement disorder in anti‐NMDA receptor encephalitis may be related to status dissociatus: A hypothesis. Mov Disord. 2012;27(11):1360–1363.
3. Irani SR, Bera K, Waters P, et al. N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain 2010;133(Pt 6):1655–1667.
We read with interest the description of the movement disorder manifestations in patients with N-methyl-D-aspartate receptor antibody mediated encephalitis (NMDAR-AbE) by a panel of movement disorders experts (1). The authors conclude that the co-existence of dystonia, chorea and stereotypies within the same patient, variability in phenomenology within the course of a single day and evolution over time, are helpful pointers to the diagnosis of NMDAR-AbE and therefore early treatment. We agree with this conclusion. However, this analysis overlooks consideration of the distinctive, if not unique, phenomenology of the “classical” movement disorder of NMDAR-AbE (2).
In our earlier description of this complex movement disorder we reported the presence of variable, complex, jerky semi-rhythmic bulbar and limb movements, associated with posturing and oculogyric crises, but in summarising the overall clinical syndrome we deliberately avoided conventional movement disorder terms because none captured the entire clinical picture (2). Classification of a movement disorder, particularly when complex, is guided by the most obvious, dominant or overwhelming clinical feature. The ‘classical’ movement disorder in NMDAR-AbE is complex but as acknowledged by the expert reviewers, is not typical of any of the movement disorder categories (1). Stereotypies are purposeless repetitive motor behaviours that occur when awake and are interrupted by a shift in attention or distraction. Dy...
We read with interest the description of the movement disorder manifestations in patients with N-methyl-D-aspartate receptor antibody mediated encephalitis (NMDAR-AbE) by a panel of movement disorders experts (1). The authors conclude that the co-existence of dystonia, chorea and stereotypies within the same patient, variability in phenomenology within the course of a single day and evolution over time, are helpful pointers to the diagnosis of NMDAR-AbE and therefore early treatment. We agree with this conclusion. However, this analysis overlooks consideration of the distinctive, if not unique, phenomenology of the “classical” movement disorder of NMDAR-AbE (2).
In our earlier description of this complex movement disorder we reported the presence of variable, complex, jerky semi-rhythmic bulbar and limb movements, associated with posturing and oculogyric crises, but in summarising the overall clinical syndrome we deliberately avoided conventional movement disorder terms because none captured the entire clinical picture (2). Classification of a movement disorder, particularly when complex, is guided by the most obvious, dominant or overwhelming clinical feature. The ‘classical’ movement disorder in NMDAR-AbE is complex but as acknowledged by the expert reviewers, is not typical of any of the movement disorder categories (1). Stereotypies are purposeless repetitive motor behaviours that occur when awake and are interrupted by a shift in attention or distraction. Dystonia and chorea characteristically accompany voluntary or postural movements, subsiding with rest and disappearing during sleep. We drew attention to the occurrence of the movement disorder in the obtunded state, ‘awake unresponsiveness’ or coma, the disappearance of the movements following recovery of consciousness, and highlighted the modulation of movements with sensory stimuli. These features are not typical of stereotypies, dystonia or chorea. Mutism, waxy flexibility, catatonia, oculogyric crises, opisthotonus and other signs occur as elements of the clinical picture but are not dominant features of the syndrome.
We suggested the occurrence of these movements in obtunded states provided an important clue to the pathophysiology (2) and drew attention to similar movements in phencyclidine and ketamine intoxication associated with “dissociative anaesthesia” (ie, loss of responsiveness to external stimuli, also referred to as akinetic mutism, coma vigil or wakeful unresponsiveness in the neurological literature), stupor or coma. The initial neuropsychiatric and behavioural abnormalities suggest frontal-limbic involvement but this does not account for the altered conscious state and movement disorder. In order to explain this we postulated progression to diffuse cortical NMDA receptor blockade, interrupting glutamate transmission and suspending or “silencing” supratentorial descending tonic GABAergic inhibitory input to brainstem reticular systems, releasing patterned rhythmic movements such as chewing, bruxism, facial grimacing, frowning, lip smacking, tongue movements and rudimentary limb movements from pattern generators within pontomesencephalic locomotor regions or the pontomedullary reticular formation. These movements are analogous to primitive motor synergies such as undulatory gill and fin motion in fish, chewing and stepping. Decerebrate posturing, opisthotonus and oculogyric crises may be generated by similar mechanisms releasing the brainstem reticular systems from supratentorial control. As conscious state, awareness and responsiveness improve the movements subside, indicating return of the normal hierarchical descending hemispheric control over the brainstem centres. This model therefore explains the observed correlation between level of consciousness and movement severity.
References
1. Varley JA, Webb AJS, Balint B, et al. The movement disorder associated with NMDAR antibody encephalitis is complex and characteristic: an expert video rating study. J Neurol Neurosurg Psychiatry doi:10.1136/jnnp-2018-318584.
2. Kleinig TJ, Thompson PD, Matar W, et al. The distinctive movement disorder of ovarian teratoma associated encephalitis. Mov Disord 2008, 23: 1256-1261.
The interplay among statins, serum cholesterol, and spontaneous intracerebral hemorrhage (ICH) with and without prior history of ischemic stroke is controversial.
Studies over the last decade, like the GERFHS study,[1] have concluded that increasing serum cholesterol levels may decrease the risk of ICH. This finding was confirmed in one of the largest observational studies[2] which estimated an adjusted hazard ratio (HR) of 0.94 (0.92-0.96) with every 10 mg increase in baseline serum total cholesterol level. Similar interaction was observed with increasing LDL cholesterol quartiles (LDL > 168 mg/dL; HR 0.53 [0.45-0.63]).[2]
However, the evidence on the effect of statins in ICH is less clear. Studies ranging from the SPARCL trial[3] which showed an increased risk of recurrent ICH with high dose statins to the recent meta-analysis by Ziff et al.,[4] which described no significant increase of the risk of ICH with statins, are few examples. Similar non-significant trends were seen in the risk of ICH after prior ischemic stroke and prior ICH.[3] Prior retrospective studies also described a neutral effect of statins on recurrent ICH. Interestingly, analysis from the largest administrative database in Israel[2] showed a surprising result; statin use might be associated with decreased ICH risk. Furthermore, an indirect, albeit unique measurement of dose-response using average atorvastatin equivalent daily dose (AAEDD) churned out interesting figures – a HR of 0....
The interplay among statins, serum cholesterol, and spontaneous intracerebral hemorrhage (ICH) with and without prior history of ischemic stroke is controversial.
Studies over the last decade, like the GERFHS study,[1] have concluded that increasing serum cholesterol levels may decrease the risk of ICH. This finding was confirmed in one of the largest observational studies[2] which estimated an adjusted hazard ratio (HR) of 0.94 (0.92-0.96) with every 10 mg increase in baseline serum total cholesterol level. Similar interaction was observed with increasing LDL cholesterol quartiles (LDL > 168 mg/dL; HR 0.53 [0.45-0.63]).[2]
However, the evidence on the effect of statins in ICH is less clear. Studies ranging from the SPARCL trial[3] which showed an increased risk of recurrent ICH with high dose statins to the recent meta-analysis by Ziff et al.,[4] which described no significant increase of the risk of ICH with statins, are few examples. Similar non-significant trends were seen in the risk of ICH after prior ischemic stroke and prior ICH.[3] Prior retrospective studies also described a neutral effect of statins on recurrent ICH. Interestingly, analysis from the largest administrative database in Israel[2] showed a surprising result; statin use might be associated with decreased ICH risk. Furthermore, an indirect, albeit unique measurement of dose-response using average atorvastatin equivalent daily dose (AAEDD) churned out interesting figures – a HR of 0.86 (0.79-0.94) for every 10mg/d increase of AAEDD. This dose-dependent effect of statins in reducing the risk of ICH is yet to be thoroughly investigated. Choice of statin might also be of significance, as it has been suggested that lipophilic statins (like atorvastatin and simvastatin) are associated with a much higher risk of recurrent ICH as compared to rosuvastatin and pravastatin (hydrophilic compounds). One would assume that the statin-mediated decrease in serum cholesterol would contribute to decreased vascular integrity and stability, and an elevated risk of bleeding.
How small vessel hemorrhagic risk factors like cerebral microbleeds (CMBs), a ‘surrogate marker’ for ICH contributes to the risk of ICH in the setting of hypercholesterolemia and statin use is unknown. Current evidence points towards statin use and increased risk of CMBs. While reports of patients on statins having twice the burden CMBs as compared to those not on statins seem conclusive, recent evidence suggests a clinical equipoise of CMBs, pointing to a novel biological mechanism.[5] These complex interactions stress the importance of exploring new pathological pathways and effective treatments for ICH.
The confounding elements of using administrative databases, as large as they may be, and non-uniform retrospective study groups, fail to answer these questions:
1. Do statins independently increase the true risk of ICH (spontaneous and recurrent)?
2. Do statins play a similar role after adjusting to the prevalence of small vessel disease?
3. Is there an ideal statin and an ideal serum cholesterol range?
4. Is there an optimal time window to start statins for prevention of ischemic stroke keeping in mind the risk of hemorrhagic transformation?
Only future randomized controlled trials can answer, and help elucidate the complex relationship among statins, cholesterol, and ICH.
References
1. Martini SR, Flaherty ML, Brown WM, et al. Risk factors for intracerebral hemorrhage differ according to hemorrhage location. Neurology 2012;79:2275-2282.
2. Saliba W, Rennert HS, Barnett-Griness O, et al. Association of statin use with spontaneous intracerebral hemorrhage. A cohort study. Neurology 2018;91:e400-e409.
3. Goldstein LB, Amarenco P, Szarek M, Callahan A, Hennerici M, Sillesen H, Zivin JA, Welch KMA. Hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels study. Neurology 2008;70:2364-2370.
4. Ziff OJ, Banerjee G, Ambler G, et al. Statins and the risk of intracerebral haemorrhage inpatients withstroke:systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2018. Published Online First: 27 August 2018. doi: 10.1136/jnnp-2018-318483.
5. Martí-Fàbregas J, Medrano-Martorell S, Merino E, et al. Statins do not increase Markers of Cerebral Angiopathies in patients with Cardioembolic Stroke. Sci Rep 2018;8:1492.
Dear Editor,
Re: A response from Noble et al. to e-letter by Psychology Task Force of the International League Against Epilepsy
Cognitive behavioural therapy (CBT) has been recommended for treating depression in people with epilepsy (PWE).[1, 2] The clinical significance of the effects of CBT for PWE has though, not been considered. We therefore systematically searched the literature for randomised controlled trials of CBT for PWE [3] and used Jacobson’s criteria [4] to empirically determine whether PWE made clinically reliable improvement. We compared this to that seen in the control arms of these trials.
Our main findings were that the likelihood of statistically reliable improvement in symptoms of depression was significantly higher for those PWE randomised to CBT compared to control conditions. The overall proportion of PWE achieving reliable improvement was low – 30% compared to 10% in the control arms. For most PWE, symptoms were unchanged.
The proportion of PWE who improve following CBT is limited. It should serve as a clarion call for the development of more effective treatments. Indeed, our review may have inflated CBT’s benefit since some trials included PWE without clinical distress at baseline and so it was not possible to apply Jacobson’s second, more stringent criterion and calculate for what proportion CBT also resulted in recovery.
The Psychology Task Force of the International League Against Epilepsy submitted a response to ou...
Dear Editor,
Re: A response from Noble et al. to e-letter by Psychology Task Force of the International League Against Epilepsy
Cognitive behavioural therapy (CBT) has been recommended for treating depression in people with epilepsy (PWE).[1, 2] The clinical significance of the effects of CBT for PWE has though, not been considered. We therefore systematically searched the literature for randomised controlled trials of CBT for PWE [3] and used Jacobson’s criteria [4] to empirically determine whether PWE made clinically reliable improvement. We compared this to that seen in the control arms of these trials.
Our main findings were that the likelihood of statistically reliable improvement in symptoms of depression was significantly higher for those PWE randomised to CBT compared to control conditions. The overall proportion of PWE achieving reliable improvement was low – 30% compared to 10% in the control arms. For most PWE, symptoms were unchanged.
The proportion of PWE who improve following CBT is limited. It should serve as a clarion call for the development of more effective treatments. Indeed, our review may have inflated CBT’s benefit since some trials included PWE without clinical distress at baseline and so it was not possible to apply Jacobson’s second, more stringent criterion and calculate for what proportion CBT also resulted in recovery.
The Psychology Task Force of the International League Against Epilepsy submitted a response to our article. [5] We are pleased that our article has drawn attention to the issue of what currently available treatments are able to offer PWE and that is has stimulated a needed discussion on the topic. Our paper agreed with many of the points raised by the Task Force:
1. More well conducted trials of psychological interventions are needed. Methodologically weak trials are known to overestimate treatment effects;
2. CBT can alleviate depression for some PWE in clinical practice, but substantial room for improvement exists;
3. Participant samples need to be better described and standardised criteria should be used to do this. Evaluations of sample representativeness can then be made, and potential treatment moderators identified;
4. Trials need to test the benefit of treatments for the full range of clinical depression. Trials have so far tended to exclude those with severe levels of depression, and some have included PWE without depression at baseline;
5. Trials should use measures of depression that are valid and reliable for the epilepsy population and for the context in which they are used.
However, there were several comments in the Task Force’s response which misrepresented our position. The Task Force also presented some reasons that they felt might explain the low rate of improvement in depression detected by our review. Below we clarify our position and address the explanations forwarded by the Task Force.
MISREPRESENTATIONS
Comment 1 by Task Force: “...we hope to encourage health professionals to continue to refer patients for psychotherapy... 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... the ILAE Psychology Task Force believes that it is inaccurate to label CBT as ‘ineffective’.”
Nowhere in our article did we recommend not referring PWE who are distressed for CBT or psychotherapy. Our review explicitly states that CBT does lead to statistically reliable improvement for some PWE and is preferable to offering no treatment. Depression has many deleterious effects and should not be left unmanaged.
Our review indicates that substantial room for treatment improvement exists. Consequently, we said “that it seems reasonable to conclude that when only 30% of treated patients make an improvement that highly effective CBT treatments for distress in epilepsy do not exist.” We did not, as asserted, label CBT as ineffective. Rather, we said the approach was “largely ineffective”.
Comment 2 by Task Force: “the authors suggest CBT... could even lead to lower ‘self–esteem’ and ‘helplessness’... the latter conclusions were based on hypothetical reactions to treatment, rather than empirically supported outcomes.”
Here a discussion point is mistaken for a conclusion. In our discussion we appropriately considered what implications our results have for what therapists should tell PWE considering CBT and related this to ethical and professional guidelines. We questioned how patients might feel if they were not informed about likely treatment response and went on to experience no benefit. Based on clinical experience amongst our team, and evidence from the literature,[6] we suggested possible reactions might include increased feelings of helplessness and hopelessness and lower expectations of therapy being successful in the future.
REASONS PRESENTED BY TASK FORCE TO ACCOUNT FOR LOW RATE OF IMPROVEMENT:
Comment 3 by Task Force: “we offer alternative interpretations of the findings...we would like to highlight the heterogeneity of the studies pooled and how this impacts the findings... First, the interventions were very diverse... Interestingly, one trial that utilised a standardised CBT protocol, resulted in 50% reliable change reductions in depressive symptoms... Second, over 10% of patients in the analyses had depressive symptoms within the non-clinical ranges.”
The pooled risk difference (RD) across the trials in our review was 0.20 – meaning 20% more PWE randomised to the CBT treatment arms reliably improved compared to the control arms. The trials in our review used different modes of treatment delivery and had samples with different levels of pre-treatment distress. We acknowledged this in our article and to explore whether this heterogeneity obscured higher rates of improvement in some trials, we presented RDs for the individual trials and also pooled RDs for trials using similar treatments and/or samples.
Unfortunately, regardless of how one approached the dataset (i.e., just looking at change in individuals who received face to face treatments or focusing on change in just participants who were distressed at baseline) only around 20% more patients in the CBT groups reliably improved compared to the control arms (see supplementary Figures 1-2 of our review [3]).
The Task Force highlighted the rate of reliable change reported by one trial in our review and implied that it’s results better reflect the potential of CBT for PWE. The trial in question was by Ciechanowski et al.[7]. Unfortunately, the benefit of CBT in that trial was actually not much better than indicated by the pooled RD. The Task Force correctly point out that the proportion of reliable change in the treatment arm of Ciechanowski et al.’s trial was 50%. They neglected to consider though that the proportion who reliably improved in that trial’s (treatment as usual) control arm was 24%. Thus, the RD for Ciechanowski et al.’s trial is 0.26 – not that much different to the pooled RD of 0.20.
Comment 4 by Task Force: “One important limitation of previous trials is the relatively short duration of psychotherapy offered to PWE, a factor that Noble et al. [1] acknowledge... it is very likely that participants did not receive a sufficient dosage of CBT... many PWE experience cognitive difficulties, including memory impairment, which may require more intensive and tailored CBT [5].”
Our review could only comment on the extent of change elicited by CBT treatments so far evaluated for PWE by trials. On average, the treatments offered by the trials in our review lasted 8.8 sessions. The Task Force suggest more treatment sessions may be required for PWE due to the presence of cognitive impairment. Whilst some PWE do experience such difficulties, this explanation does not appear to be able to account for the low rate of improvement seen in the trials in our review since most of them excluded patients with such difficulties.
Comment 5 by Task Force: “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... which Noble et al. did not consider.”
We focused on trials for which the primary outcome measure was depression and examined the degree of change achieved
We thank you for the opportunity to respond to the Task Force’s letter. We trust that we have clarified our position on a range of points, including the need at present to continue to refer PWE who are distressed for CBT. We stand by our position though that there remains an urgent need for more effective treatments to be developed.
Yours sincerely,
Adam J. Noble
James Temple
James Reilly
Peter L. Fisher.
REFERENCES
[1] Kerr MP, Mensah S, Besag F, de Toffol B, Ettinger A, Kanemoto K, Kanner A, Kemp S, Krishnamoorthy E, LaFrance WJ, Mula M, Schmitz B, van Elst LT, Trollor J, Wilson SJ. International consensus clinical practice statements for the treatment of neuropsychiatric conditions associated with epilepsy. Epilepsia 2011;52: 2133-2138.
[2] Barry JJ, Ettinger AB, Friel P, Gilliam FG, Harden CL, Hermann B, Kanner AM, Caplan R, Plioplys S, Salpekar J, Dunn D, Austin J, Jones J, Advisory Group of the Epilepsy Foundation as part of its Mood Disorder. Consensus statement: the evaluation and treatment of people with epilepsy and affective disorders. Epilepsy & Behavior 2008 13: S1-29.
[3] Noble AJ, Reilly J, Temple J, Fisher PL. 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: 10.1136/jnnp-2018-317997.
[4] Jacobson NS, Truax P. Clinical significance: a statistical approach to defining meaningful change in psychotherapy research. Journal of Consulting and Clinical Psychology 1991;59: 12-19.
[5] Gandy M, Reuber M, LaFrance Jr WC, Modi A, Wagner JL, Goldstein LH, Tang V, Donald KA, Valente KD, Michaelis R. Why it’s still important to consider referring patients with epilepsy (PWE) with depression for psychotherapy – including Cognitive Behaviour Therapy. Response from the Psychology Task Force of the International League Against Epilepsy. Journal of Neurology, Neurosurgery & Psychiatry 2018; Published on: 11 July 2018.
[6] Crawford MJ, Thana L, Farquharson L, Palmer L, Hancock E, Bassett P, Clarke J, Parry GD. Patient experience of negative effects of psychological treatment: results of a national survey. The British Journal of Psychiatry 2016;208: 260-265.
[7] Ciechanowski P, Chaytor N, Miller J, Fraser R, Russo J, Unutzer J, Gilliam F. PEARLS depression treatment for individuals with epilepsy: a randomized controlled trial. Epilepsy & Behavior 2010;19: 225-231.
We read with great interest the recent report of Banerjee and colleagues of three cases of minimally symptomatic cerebral amyloid angiopathy-related inflammation (CAA-ri) cases, drawing attention to the possibility of a wider spectrum of clinical manifestations in patients with CAA-ri than previously described1.
Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a rare form of meningoencephalitis, presenting acutely with cognitive decline, seizures, headache and /or encephalopathy in most patients. The prognosis is poor even in patients under immunosuppressive treatment, with a mortality rate of 30% and only a minority of patients making a full recovery2-3. However, in the three cases reported by Banerjee and colleagues, patients presented with mild symptoms despite the magnitude of the MRI findings and made a full clinical and radiologic recovery in 2 of the cases with immunosuppressant treatment and in the remaining without any treatment.
We have recently evaluated a similar patient, that presented with mild transient symptoms in whom the diagnosis was made following the finding of characteristic CAA-ri changes in brain MRI.
He was a 62 year-old-man with a past history of hypertension, who was referred to the Emergency Department (ER) due to moderate frontal headache followed by left hemisensory numbness with Jacksonian march lasting a few minutes. He was asymptomatic on arrival at the ER and his neurological examination was normal. He perfor...
We read with great interest the recent report of Banerjee and colleagues of three cases of minimally symptomatic cerebral amyloid angiopathy-related inflammation (CAA-ri) cases, drawing attention to the possibility of a wider spectrum of clinical manifestations in patients with CAA-ri than previously described1.
Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a rare form of meningoencephalitis, presenting acutely with cognitive decline, seizures, headache and /or encephalopathy in most patients. The prognosis is poor even in patients under immunosuppressive treatment, with a mortality rate of 30% and only a minority of patients making a full recovery2-3. However, in the three cases reported by Banerjee and colleagues, patients presented with mild symptoms despite the magnitude of the MRI findings and made a full clinical and radiologic recovery in 2 of the cases with immunosuppressant treatment and in the remaining without any treatment.
We have recently evaluated a similar patient, that presented with mild transient symptoms in whom the diagnosis was made following the finding of characteristic CAA-ri changes in brain MRI.
He was a 62 year-old-man with a past history of hypertension, who was referred to the Emergency Department (ER) due to moderate frontal headache followed by left hemisensory numbness with Jacksonian march lasting a few minutes. He was asymptomatic on arrival at the ER and his neurological examination was normal. He performed a cranial CT scan that revealed a right subcortical temporoparietal hypodensity which led to the request of a brain MRI that showed a right pseudotumoral temporoparietal white matter lesion, hyperintense on T2-weighted sequences without gadolinium enhancement, and multiple corticosubcortical microbleeds in T2* co-localized with the T2-lesion. CSF evaluation disclosed a mild elevation of proteins (53mg/dl) with a normal white cell count and no oligoclonal bands. Alzheimer disease (AD) biomarkers in CSF were consistent with a DA-related pathophysiology Aβ1-42: 494 pg/mL (normal range (NR) >542), total-tau: 252 pg/mL (NR <212), phospho-tau: 126 pg/mL (NR < 32). We further evaluated the presence of antibodies against Aβ which were positive (48.17 ng/mL). Neuropsychological evaluation and EEG were normal. At this point, a diagnosis of probable CAA-ri was made, according to the clinicoradiological criteria of CAA-ri4. The Apo-E genotype was ɛ4/ɛ4 further supporting the CAA-ri diagnosis. Given the benign course of the disease, a conservative approach was adopted, and steroid therapy and biopsy were deferred. The patient has been followed for 2 years and remains asymptomatic. A 3-month and 1-year follow up MRI showed complete reversion of the temporoparietal T2-hyperintense lesion and stabilization of the number of microbleeds.
Given the findings reported by Banerjee and colleagues and our own, we agree that CAA-ri might be underdiagnosed, its clinical spectrum might be wider than previously thought, and the entity might be underdiagnosed in patients with mild clinical symptoms. We also believe that the increasing availability of brain MRI will probably keep expanding the clinical spectrum of manifestations associated with CAA-ri.
Dr. Banerjee and colleagues suggested that milder phenotypes of CAA-ri might relate to a genotype of ApoE other than ɛ4/ɛ4, which is known to associate with a higher risk of developing the classic form of CAA-ri. However, in our patient, the genotype of Apo E was ɛ4/ɛ4, and previous reports could not find a relation between the ApoE genotype and the clinical course of CAA-ri5. Still, information regarding the relationship between ApoE genotype and the CAA-ri clinical course is scarce, and further studies will be needed to evaluate this hypothesis.
Finally, in our patient, we identify antibodies against Aβ in the CSF. Although their precise role remains to be established we can speculate a possible implication in the overlap described by Banerjee and colleagues, between the entity of minimal symptomatic amyloid angiopathy and amyloid-related imaging abnormalities (ARIA) found in patients with AD under anti-amyloid immunotherapy
To conclude our case reinforces the existence of a variant of minimal symptomatic CAA-ri described by Dr. Banerjee and colleagues. A high index of suspicion is key to identifying these patients. In the cases described so far, patients’ demographic characteristics and radiologic findings resembled those with a classic form of CAA-ri (the majority were men, with a mean age of 63 years). Further studies are needed to characterize this different phenotype, including CSF findings, ApoE genotype as well as the role of antibodies against Aβ in the CSF.
Acknowledgments
The authors thank Dr. Fabrizio Piazza for the evaluation of antibodies against Aβ in the CSF.
References
1. Banerjee G, Alvares D, Bowen J, et al. J Neurol Neurosurg Psychiatry. Epub ahead of print: [March 13, 2018]. doi:10.1136/jnnp-2017-317347
2. Corovic A, Kelly S, Markus HS. Int J Stroke. 2018: 13(3): 257-267. doi.org/10.1177/1747493017741569
3. M, Caetano A, Pinto M, et al. Stroke-Like Episodes Heralding a Reversible Encephalopathy: Microbleeds as the Key to the Diagnosis of Cerebral Amyloid Angiopathy–Related Inflammation—A Case Report and Literature Review J Stroke Cerebrovasc Dis. 2015 24(9), e245-e250. 10.1016/j.jstrokecerebrovasdis.2015.04.042
4. Auriel E, Charidimou A, Gurol E, et al. Validation of Clinicoradiological Criteria for the Diagnosis of Cerebral Amyloid Angiopathy-Related Inflammation. JAMA Neurol. 2016; 73 (2):197-292. doi: 10.1001/jamaneurol.2015.4078
5. Kinnecom MS, Lev MH, Wendell L, et al. Neurology. 2007:68 (17): 1411-6. doi: 10.1212/01.wnl.0000260066.98681.2e
Komatsu et al. presented an interesting clinicopathological case of anti-myelin oligodendrocyte glycoprotein (MOG) demyelinating disease of the CNS. (1) Their patient had a rather unusual subacute encephalopathic presentation with extensive supratentorial fluid-attenuation inversion recovery white matter hyperintensities. The authors focused mainly on the conspicuous MRI punctuate and curvilinear enhancement pattern within the hemispheric lesions.
Show MoreIt is well established that intraparenchymal punctuate and curvilinear gadolinium enhancement may arise in the context of Moyamoya syndrome, various endotheliopathies and most commonly, in disorders causing small vessels blood-brain barrier disruption. (2)These entities are associated histologically with perivascular cellular infiltrates and include inflammatory autoimmune diseases (i.e. primary or secondary angiitis of the CNS, neurosarcoidosis, histiocytosis and demyelinating diseases of the CNS), pre-lymphoma states (i.e. sentinel lesions of primary CNS lymphoma), non-Hodgkin lymphoma (i.e. intravascular lymphoma) and CLIPPERS syndrome. (2) Notably, among demyelinating disorders, multiple sclerosis and aquaporin-4 antibody (AQP4-Ab) neuromyelitis optica spectrum disorders (NMOSD) manifest this specific neuroimaging pattern in rare cases. (2,3)
We agree with Komatsu et al. that their case is the first report of the perivascular enhancement in anti-MOG antibody disease. Indeed, gadolinium enhancement was observed in...
Re: A unifying theory for cognitive abnormalities in functional neurological disorders, fibromyalgia and chronic fatigue syndrome
Viraj Bharambe Specialist registrar in neurology
John C Williamson Specialist registrar in neurology
Andrew J Larner Consultant Neurologist
Cognitive Function Clinic
Walton Centre for Neurology and Neurosurgery
Lower Lane
Fazakerley
Liverpool
L9 7LJ
UK
e-mail: a.larner@thewaltoncentre.nhs.uk
Teodoro et al. present evidence for shared cognitive symptoms in fibromyalgia, chronic fatigue syndrome, and functional neurological disorders, and hypothesize that functional cognitive disorders (FCD) may share similar symptoms.1 We present data which speak to this issue.
We have previously reported preliminary data examining performance on the mini-Addenbrooke’s Cognitive Examination (MACE) by patients diagnosed with fibromyalgia2 as part of a larger study of MACE.3 Here, we update these data for fibromyalgia patients (n = 17; F:M = 17:0; age range 33-56 years, median 49) and compare them to MACE performance by patients diagnosed with FCD (n = 43; F:M = 18:25; age range 28-82 years, median 58).4
There was no statistical difference (p > 0.1) in the proportions of patients scoring below the two cut-off scores (≤21/30, ≤25/30) defined in the index MACE report.5 Looking at MACE subscores (Attention, Registration,...
Show MoreDear Editor,
Show MoreWe have read with great interest the work by Scarpazza et al that provided a longitudinal MRI evaluation of natalizumab-related Progressive Multifocal Leukoencephalopathy (NTZ-PML) lesions in Multiple Sclerosis (MS) patients (1).
Their central finding was the high percentage (78.1%) of patients, who eventually developed NTZ-PML, in whom highly suggestive lesions were already retrospectively detectable on pre-diagnostic MRI exams. Furthermore, the pre-diagnostic phase proved to be relatively long (150.8±74.9 days), with an estimated percentage increase of the lesions’ volume of 62.8% per month (1).
Given the widely recognized crucial role of a timely NTZ-PML identification in reducing mortality and residual disability (1), these results present the neurological and neuroradiological communities with an important clinical challenge, prompting a major effort to ensure an early diagnosis of this condition.
Although redefining the timing of MRI surveillance, with up to one brain MRI exam every 3-4 months for high-risk patients, appears as a justified strategy, we think that improving the accuracy of early identification of NTZ-PML is also mandatory.
In our opinion, such achievement should be pursued using two complementary approaches: (i) a specific training addressed to neuroradiologists working in the field of MS, who should be aware of the relevance of even very small asymptomatic PML lesions and how to differentiate them from new M...
Dear Editor,
We thank Abat et al. for re-emphasizing an important interpretation of our work, namely that sex-differences in life-expectancy likely influenced the presented lifetime risks [1]. Indeed, in our paper we repeatedly discussed in several sections (for instance in the methods) that differences in life-expectancy between men and women could differentially affect their lifetime risk. It was for this reason that we consequently decided to analyze the data in a sex-specific manner while taking the competing risk of death into account in order to prevent potential overestimation.
Abat et al. unfortunately also allege that we attributed the observed sex-differences in disease risk to sex-specific effects on a biological level. The authors have seemingly missed our discussion at length arguing that observed differences in lifetime risk may be primarily attributed to the effects of differences in life-expectancy between men and women: “Apart from a longer life-expectancy in general, these findings may be explained by smaller differences in life-expectancy between men and women in the Netherlands (1.8 years), compared with the USA (4.8 years). With longer life-expectancy, individuals in this study simply had more time to develop these diseases in a timeframe with high age-specific incidence rates.”
It seems thus that ours and Abat and co-authors’ interpretation of our findings is pretty much congruent, i.e. age, irrespective of sex, should be consid...
Show MoreTo the Editor,
Show MoreWe read with interest the work from Licher et al. [1] in which the authors tried to quantify the burden of common neurological diseases (i.e. dementia, stroke and parkinsonism) in 12 102 individuals (6 982 women and 5 120 men) aged ≥ 45 years and free from these diseases at baseline. All these individuals were recruited between 1990 and 2016 into the prospective population-based Rotterdam Study. At the end of their analyzes, the authors concluded that one in two women and one in three men will develop dementia, stroke or parkinsonism during their lifetime, and that the risk for women to develop both stroke and dementia during their life is almost twice that of men [1].
By reading the article from Licher et al. [1], we were extremely surprised by the fact that the authors did not consider the impact of the difference in life expectancies between men and women on their results and conclusions. This is particularly well underlined by the fact that the authors did not clearly precise the age structures of the two populations they studied [1]. In our view, this information is critical as, although the reasons for this difference are still debated and may probably be multi-factorial [2], it is well known that women live longer than men. This trend is confirmed by the 2018 World Health Statistics report [3] that estimates that in 2016, the life expectancies of men and women at birth were respectively 69.8 and 74.2 years at the international level. The...
We thoroughly enjoyed reading the comment on our paper which analysed expert ratings of the movement disorder associated with NMDAR antibody-encephalitis.1 Thompson et al’s elegant pathophysiological explanation provides an excellent framework of the most plausible neural structures involved in NMDAR-antibody encephalitis. Further, they note these movements can occur in semi-conscious patients, and this concurs well with the previous description of anti-gravity movements in the context of ‘status dissociatus’.2 A review of our 76 videos, revealed Thompson et al’s account of “variable, complex jerky semi-rhythmic movements….in the obtunded state” in 45 (59%) of cases. Therefore, this complex description was not present in almost half of patients. Furthermore, our recent clinical experiences note some NMDAR-antibody patients with abnormal movements but without obtundation: perhaps, given the known stepwise progression of many cases, this is a function of increasingly early disease recognition.3
By contrast to Thompson et al, our published study design intentionally used conventional phenomenological terms to define the movement disorder associated with NMDAR antibody-encephalitis.1 This approach aimed to define a pragmatic method, available to all clinicians, which could identify and faithfully communicate this complex movement disorder, with the important aim of earlier disease recognition. The results identified a dominant set of recognised classifications – dyston...
Show MoreWe read with interest the description of the movement disorder manifestations in patients with N-methyl-D-aspartate receptor antibody mediated encephalitis (NMDAR-AbE) by a panel of movement disorders experts (1). The authors conclude that the co-existence of dystonia, chorea and stereotypies within the same patient, variability in phenomenology within the course of a single day and evolution over time, are helpful pointers to the diagnosis of NMDAR-AbE and therefore early treatment. We agree with this conclusion. However, this analysis overlooks consideration of the distinctive, if not unique, phenomenology of the “classical” movement disorder of NMDAR-AbE (2).
In our earlier description of this complex movement disorder we reported the presence of variable, complex, jerky semi-rhythmic bulbar and limb movements, associated with posturing and oculogyric crises, but in summarising the overall clinical syndrome we deliberately avoided conventional movement disorder terms because none captured the entire clinical picture (2). Classification of a movement disorder, particularly when complex, is guided by the most obvious, dominant or overwhelming clinical feature. The ‘classical’ movement disorder in NMDAR-AbE is complex but as acknowledged by the expert reviewers, is not typical of any of the movement disorder categories (1). Stereotypies are purposeless repetitive motor behaviours that occur when awake and are interrupted by a shift in attention or distraction. Dy...
Show MoreThe interplay among statins, serum cholesterol, and spontaneous intracerebral hemorrhage (ICH) with and without prior history of ischemic stroke is controversial.
Studies over the last decade, like the GERFHS study,[1] have concluded that increasing serum cholesterol levels may decrease the risk of ICH. This finding was confirmed in one of the largest observational studies[2] which estimated an adjusted hazard ratio (HR) of 0.94 (0.92-0.96) with every 10 mg increase in baseline serum total cholesterol level. Similar interaction was observed with increasing LDL cholesterol quartiles (LDL > 168 mg/dL; HR 0.53 [0.45-0.63]).[2]
However, the evidence on the effect of statins in ICH is less clear. Studies ranging from the SPARCL trial[3] which showed an increased risk of recurrent ICH with high dose statins to the recent meta-analysis by Ziff et al.,[4] which described no significant increase of the risk of ICH with statins, are few examples. Similar non-significant trends were seen in the risk of ICH after prior ischemic stroke and prior ICH.[3] Prior retrospective studies also described a neutral effect of statins on recurrent ICH. Interestingly, analysis from the largest administrative database in Israel[2] showed a surprising result; statin use might be associated with decreased ICH risk. Furthermore, an indirect, albeit unique measurement of dose-response using average atorvastatin equivalent daily dose (AAEDD) churned out interesting figures – a HR of 0....
Show MoreDear Editor,
Show MoreRe: A response from Noble et al. to e-letter by Psychology Task Force of the International League Against Epilepsy
Cognitive behavioural therapy (CBT) has been recommended for treating depression in people with epilepsy (PWE).[1, 2] The clinical significance of the effects of CBT for PWE has though, not been considered. We therefore systematically searched the literature for randomised controlled trials of CBT for PWE [3] and used Jacobson’s criteria [4] to empirically determine whether PWE made clinically reliable improvement. We compared this to that seen in the control arms of these trials.
Our main findings were that the likelihood of statistically reliable improvement in symptoms of depression was significantly higher for those PWE randomised to CBT compared to control conditions. The overall proportion of PWE achieving reliable improvement was low – 30% compared to 10% in the control arms. For most PWE, symptoms were unchanged.
The proportion of PWE who improve following CBT is limited. It should serve as a clarion call for the development of more effective treatments. Indeed, our review may have inflated CBT’s benefit since some trials included PWE without clinical distress at baseline and so it was not possible to apply Jacobson’s second, more stringent criterion and calculate for what proportion CBT also resulted in recovery.
The Psychology Task Force of the International League Against Epilepsy submitted a response to ou...
We read with great interest the recent report of Banerjee and colleagues of three cases of minimally symptomatic cerebral amyloid angiopathy-related inflammation (CAA-ri) cases, drawing attention to the possibility of a wider spectrum of clinical manifestations in patients with CAA-ri than previously described1.
Show MoreCerebral amyloid angiopathy-related inflammation (CAA-ri) is a rare form of meningoencephalitis, presenting acutely with cognitive decline, seizures, headache and /or encephalopathy in most patients. The prognosis is poor even in patients under immunosuppressive treatment, with a mortality rate of 30% and only a minority of patients making a full recovery2-3. However, in the three cases reported by Banerjee and colleagues, patients presented with mild symptoms despite the magnitude of the MRI findings and made a full clinical and radiologic recovery in 2 of the cases with immunosuppressant treatment and in the remaining without any treatment.
We have recently evaluated a similar patient, that presented with mild transient symptoms in whom the diagnosis was made following the finding of characteristic CAA-ri changes in brain MRI.
He was a 62 year-old-man with a past history of hypertension, who was referred to the Emergency Department (ER) due to moderate frontal headache followed by left hemisensory numbness with Jacksonian march lasting a few minutes. He was asymptomatic on arrival at the ER and his neurological examination was normal. He perfor...
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