There have been some studies investigating blood neurofilament light chain (NfL) levels as predictors of cognitive functions decline in neurological disorders. I want to discuss here the association between blood NfL levels and neuroaxonal damage in patients with brain damages including Alzheimer's disease and stroke by considering the underlying mechanisms.
First, Egle et al. reported that baseline increased serum NfL levels could predict cognitive decline and the risk of converting to dementia in a cerebral small vessel disease (SVD), but there was no change in serum NfL levels over a 5-year follow-up period [1]. The lack of dynamic changes of NfL in stroke stand in contrast to neurodegenerative disease, and serum NfL levels may not be used as a surrogate marker for monitoring cognitive impairment in patients with SVD. In contrast, Stokowskaet et al. examined plasma NfL levels for the prediction of functional improvement in the late phase after stroke [2]. The odds ratios (ORs) (95% confidence intervals [CIs]) of elevated plasma NfL levels for the improvement in balance and gait improvement were 2.34 (1.35-4.27) and 2.27 (1.25-4.32), respectively. In addition, OR (95% CI) of elevated plasma NfL levels for cognitive improvement was 7.54 (1.52-45.66), which was also verified by intervention trial. This study presented the usefulness of plasma NfL levels as a biomarker of physical and psychological function after stroke events. As there is a wide range of 95% CI...
There have been some studies investigating blood neurofilament light chain (NfL) levels as predictors of cognitive functions decline in neurological disorders. I want to discuss here the association between blood NfL levels and neuroaxonal damage in patients with brain damages including Alzheimer's disease and stroke by considering the underlying mechanisms.
First, Egle et al. reported that baseline increased serum NfL levels could predict cognitive decline and the risk of converting to dementia in a cerebral small vessel disease (SVD), but there was no change in serum NfL levels over a 5-year follow-up period [1]. The lack of dynamic changes of NfL in stroke stand in contrast to neurodegenerative disease, and serum NfL levels may not be used as a surrogate marker for monitoring cognitive impairment in patients with SVD. In contrast, Stokowskaet et al. examined plasma NfL levels for the prediction of functional improvement in the late phase after stroke [2]. The odds ratios (ORs) (95% confidence intervals [CIs]) of elevated plasma NfL levels for the improvement in balance and gait improvement were 2.34 (1.35-4.27) and 2.27 (1.25-4.32), respectively. In addition, OR (95% CI) of elevated plasma NfL levels for cognitive improvement was 7.54 (1.52-45.66), which was also verified by intervention trial. This study presented the usefulness of plasma NfL levels as a biomarker of physical and psychological function after stroke events. As there is a wide range of 95% CI of OR for cognitive improvement, unstable risk estimation may be updated by summing-up the events. Anyway, discrepancy in the results from two reports should be specified by further studies.
Second, Santangelo et al. examined predictors of cognitive decline rate to assess the risk of fast Alzheimer's disease (AD) progression [3]. Higher plasma NfL levels, worse scores at semantic verbal fluency and clock drawing test were significant predictors of fast progression in AD. Their regression model could predict 81.2% of patients' progression correctly, if all the three predictors were judged abnormal. Patients with AD present cognitive decline as a major neurological symptom and neuroaxonal damages are progressive. As conclusive results have been made whether blood NfL levels could substitute for information from neuroimaging and NfL levels in cerebrospinal fluids, further studies by using blood samples are needed to verify the association.
Regarding the second query, Lin et al. reported that high plasma NfL correlated with poor cognition in AD, and plasma NfL represented a biomarker of cognitive decline in AD [4]. Although the majority of studies found that blood NfL levels were inversely correlated with cognition, there are also positive relationships in some specific status of the neurological disorders, and individual differences and methodological procedures should be considered for the analysis [5]. Indeed, patients with AD have shown that intra-individual NfL changes were sensitive to detect the disease onset of neurodegenerative diseases [6].
In any case, the association between blood NfL levels and neuroaxonal damage in the brain during neurodegeneration may be mediated by disease-specific factors and fundamental biological factors such as sex and age.
We read with great interest the paper by Yaghi S. et al on the lacunar stroke mechanisms and their therapeutic implications. We would like to highlight that the deficiency of ADA2 (DADA2) is the most common cause of monogenic vasculitis and is also responsible for causing lacunar strokes, but is commonly overlooked [1]. It has an autosomal recessive inheritance and has multi-system involvement: skin, nervous, gastrointestinal and hematological systems being most commonly involved [1]. Children and young adults are most commonly affected with a “polyarteritis nodosa-type” picture with cutaneous involvement, abdominal pains and renal involvement, and mild strokes. The lacunar infarcts are more common in the posterior circulation [2]. Most cases are diagnosed late or go undiagnosed because of lack of knowledge about this disorder [3, 4].
Patients are treated by immunosuppressants with anti-tumour necrosis factor (TNF) agents and usually adalimumab is the first line agent. Early diagnosis and treatment lead to favorable treatment response.
References:
1. Meyts I, Aksentijevich I. Deficiency of Adenosine Deaminase 2 (DADA2): Updates on the Phenotype, Genetics, Pathogenesis, and Treatment. Journal of Clinical Immunology (2018) 38: 569-578
2. Geraldo AF, Carosi R, Tortora D et al. Widening the Neuroimaging features of Adenosine Deaminase 2 Deficiency. American Journal of Neuroradiology. February 2021
3. Sharma A, Agarwal A, Srivastava MVP, et al. Hy...
We read with great interest the paper by Yaghi S. et al on the lacunar stroke mechanisms and their therapeutic implications. We would like to highlight that the deficiency of ADA2 (DADA2) is the most common cause of monogenic vasculitis and is also responsible for causing lacunar strokes, but is commonly overlooked [1]. It has an autosomal recessive inheritance and has multi-system involvement: skin, nervous, gastrointestinal and hematological systems being most commonly involved [1]. Children and young adults are most commonly affected with a “polyarteritis nodosa-type” picture with cutaneous involvement, abdominal pains and renal involvement, and mild strokes. The lacunar infarcts are more common in the posterior circulation [2]. Most cases are diagnosed late or go undiagnosed because of lack of knowledge about this disorder [3, 4].
Patients are treated by immunosuppressants with anti-tumour necrosis factor (TNF) agents and usually adalimumab is the first line agent. Early diagnosis and treatment lead to favorable treatment response.
References:
1. Meyts I, Aksentijevich I. Deficiency of Adenosine Deaminase 2 (DADA2): Updates on the Phenotype, Genetics, Pathogenesis, and Treatment. Journal of Clinical Immunology (2018) 38: 569-578
2. Geraldo AF, Carosi R, Tortora D et al. Widening the Neuroimaging features of Adenosine Deaminase 2 Deficiency. American Journal of Neuroradiology. February 2021
3. Sharma A, Agarwal A, Srivastava MVP, et al. Hypertension with recurrent focal deficits. Pract Neurol 2021;0:1-5
4. Babtiwale S, Vishnu VY, Garg A, et al. Young stroke and systemic manifestations: Deficiency of Adenosine Deaminase-2 (DADA-2). Annals of Indian Academy of Neurology 2020. DOI: 10.4103/aian.AIAN_657_20
We recently published our preliminary case-control study showing that a medical history of hypothyroidism was more prevalent among COVID-19 patients with persistent olfactory dysfunction compared to controls (50% vs 8%; p=0.009) and that hypothyroidism was independently (p=0.021) associated with higher likelihood of persistent hyposmia/anosmia among patients with COVID-19 (OR: 21.1; 95%CI: 2.0 to 219.4) after adjusting for age and sex (1). As previously stated, our results are not -by any means- confirmatory of an etiologic association between hypothyroidism (or preferably chronic autoimmune thyroiditis, CAT, as aptly suggested by Rotondi et al.) and the development of persistent anosmia in COVID-19 patients (1). However, the suggetsed mechanism by Rotondi et al. strengthens our observations by proposing a possible biomolecular explanation behind our clinical observations. Indeed, chemokines that are induced by SARS-CoV-2 infection, and especially CXCL10, could act as effectors of demyelination of the central nervous system (CNS) - including the olfactory apparatus - through attraction and recruitment of T-lymphocytes (2,3). Although the proposed pathogenetic mechanism by Rotondi et al. needs further investigation and laboratory confirmation through experimental studies in COVID-19 patients with persistent olfactory dysfunction, it certainly invigorates our preliminary clinical results and sets the grounds for further research in a clinically significant post-COVID-9 seque...
We recently published our preliminary case-control study showing that a medical history of hypothyroidism was more prevalent among COVID-19 patients with persistent olfactory dysfunction compared to controls (50% vs 8%; p=0.009) and that hypothyroidism was independently (p=0.021) associated with higher likelihood of persistent hyposmia/anosmia among patients with COVID-19 (OR: 21.1; 95%CI: 2.0 to 219.4) after adjusting for age and sex (1). As previously stated, our results are not -by any means- confirmatory of an etiologic association between hypothyroidism (or preferably chronic autoimmune thyroiditis, CAT, as aptly suggested by Rotondi et al.) and the development of persistent anosmia in COVID-19 patients (1). However, the suggetsed mechanism by Rotondi et al. strengthens our observations by proposing a possible biomolecular explanation behind our clinical observations. Indeed, chemokines that are induced by SARS-CoV-2 infection, and especially CXCL10, could act as effectors of demyelination of the central nervous system (CNS) - including the olfactory apparatus - through attraction and recruitment of T-lymphocytes (2,3). Although the proposed pathogenetic mechanism by Rotondi et al. needs further investigation and laboratory confirmation through experimental studies in COVID-19 patients with persistent olfactory dysfunction, it certainly invigorates our preliminary clinical results and sets the grounds for further research in a clinically significant post-COVID-9 sequela. Therefore, we are highly grateful to Rotondi and colleagues for their insightful and constructive comments in our study.
References
1. Tsivgoulis G, Fragkou PC, Karofylakis E, Paneta M, Papathanasiou K, Palaiodimou L, Psarros C, Papathanasiou M, Lachanis S, Sfikakis PP, Tsiodras S. Hypothyroidism is associated with prolonged COVID-19-induced anosmia: a case-control study. J Neurol Neurosurg Psychiatry. 2021.
2. Oliviero A, de Castro F, Coperchini F, Chiovato L, Rotondi M. COVID-19 Pulmonary and Olfactory Dysfunctions: Is the Chemokine CXCL10 the Common Denominator? Neuroscientist. 2020:1073858420939033.
3. Rotondi M, Chiovato L, Romagnani S, Serio M, Romagnani P. Role of chemokines in endocrine autoimmune diseases. Endocr Rev. 2007;28(5):492-520.
Thyroid hormones play a role in the development and function of virtually all human cells, including maturation of olfactory neurons. The clinical observation that patients with hypothyroidism can experience disturbances in their sense of smell was first reported more than 60 years ago, and it was subsequently confirmed in both humans and animal models. In vivo animal studies clearly demonstrated that hypothyroidism induced by anti-thyroid drugs administration in mice was associated to variable degrees of anosmia, which however promptly reverted following restoration of euthyroidism by levothyroxine replacement therapy (1).
This latter finding was regarded as the proof that thyroxine, besides its role for correct development of the nervous system would also be involved in the genesis of new olfactory receptor neurons, a process demonstrated to be maintained also in adulthood.
Since the early phase of the ongoing Sars-CoV-2 pandemic, anosmia was identified as a peculiar clinical symptom of COVID-19 being experienced by nearly 80% of the affected patients (2). It is now known that, at least in some cases, COVID-19 course may encompass protracted olfactory dysfunction and development of olphactory bulb atrophy (3). Thus, attention was paid to potential risk factors predicting this long-term sequela. Interestingly, Tsivgoulis et al., recently performed a prospective case–control study aimed at evaluating whether hypothyroidism could be associated to prolonged COVID...
Thyroid hormones play a role in the development and function of virtually all human cells, including maturation of olfactory neurons. The clinical observation that patients with hypothyroidism can experience disturbances in their sense of smell was first reported more than 60 years ago, and it was subsequently confirmed in both humans and animal models. In vivo animal studies clearly demonstrated that hypothyroidism induced by anti-thyroid drugs administration in mice was associated to variable degrees of anosmia, which however promptly reverted following restoration of euthyroidism by levothyroxine replacement therapy (1).
This latter finding was regarded as the proof that thyroxine, besides its role for correct development of the nervous system would also be involved in the genesis of new olfactory receptor neurons, a process demonstrated to be maintained also in adulthood.
Since the early phase of the ongoing Sars-CoV-2 pandemic, anosmia was identified as a peculiar clinical symptom of COVID-19 being experienced by nearly 80% of the affected patients (2). It is now known that, at least in some cases, COVID-19 course may encompass protracted olfactory dysfunction and development of olphactory bulb atrophy (3). Thus, attention was paid to potential risk factors predicting this long-term sequela. Interestingly, Tsivgoulis et al., recently performed a prospective case–control study aimed at evaluating whether hypothyroidism could be associated to prolonged COVID19-induced hyposmia/anosmia(3). Olfactory function and anosmia were objectively evaluated by the validated Quick Smell Identification Test. Briefly, among patients with a >40days duration of anosmia in the presence of a negative PCR for Sars-CoV-2, a strikingly higher prevalence of hypothyroidism (50% vs 8%; p=0.009) was observed in cases as compared to controls.
More interestingly, hypothyroidism was identified to be significantly and independently associated with higher risk for persistent olfactory dysfunction among patients with COVID-19, even after adjusting for potential confounders such as age and sex. This latter is a relevant point in that it is known that autoimmune thyroid diseases display a strong female gender prevalence, thus the correction for sex further strengthen the findings.
Although the above results were obtained in a rather limited study group, their potential clinical significance should not be neglected in view of their potential utility in the clinical care of the so called “post-COVID-19” syndrome”. However, some considerations should be drawn. Indeed, all of the patients studied by Tsivgoulis et al. were affected by chronic autoimmune thyroiditis (CAT) and were receiving levothyroxine replacement therapy with restoration of euthyroidism as assessed by normal thyroid function tests at study entry.
Thus, a direct role for thyroid hormones on the persistency of olfactory dysfunction would be difficult to be envisaged in these patients. On the other hand, the observation by Tsivgoulis et al. appears to be worth to be further investigated in view of the following aspects.
CAT is the most prevalent human autoimmune disease being the major cause of primary hypothyroidism. Interestingly, among several immune-active molecules, CXCL10 a Th1-oriented chemokine, was identified to play a crucial role in the recruitment and maintenance of lymphocytes sustaining chronic autoimmune inflammation (4). More specifically, patients with CAT either in the hypothyroid phase and in the euthyroid patients under LT4 phase display significantly higher circulating levels of CXCL10 as compared to both healthy controls and non-autoimmune hypothyroid patients (4). As far as COVID-19 is concerned, CXCL10 is currently regarded as a main actor in the so called “immune signature” of COVID-19, which is characterized by increased levels of soluble biomarkers (cytokine and chemokines) involved in the recruitment and activation of several immune cell types (5). Of note, we have previously reported how CXCL10 would play a crucial role in the genesis of olfactory dysfunction in COVID-19 infections. Briefly, following Sars-CoV-2 entrance in the upper respiratory tract, it enters nerve cells, promoting the secretion of CXCL10, which, in turn, recruits immune cells expressing the CXCL10-receptor CXCR3 (2). CXCL10-dependent attraction of T lymphocytes within the CNS would ultimately contribute to the demyelination of the olfactory pathway. Indeed, CXCL10 is a strongly involved chemokine in T cells recruitment within the CNS and T-lymphocytes are crucial effectors in the demyelination process (2). Taking together the above evidences, while highlighting the interesting findings reported by Tsivgoulis et al., we would strongly support the concept that the elevated circulating concentrations of CXCL10 observed in several human autoimmune condition and in particular CAT, rather than hypothyroidism (unless when left untreated) would be the cause of a more prolonged anosmia in COVID-19 patients.
REFERENCES
1. Beard MD, Mackay-Sim A. Loss of sense of smell in adult, hypothyroid mice. Brain Res. 1987;433(2):181-189.
2. Oliviero A, de Castro F, Coperchini F, Chiovato L, Rotondi M. COVID-19 Pulmonary and Olfactory Dysfunctions: Is the Chemokine CXCL10 the Common Denominator? Neuroscientist. 2020:1073858420939033.
3. Tsivgoulis G, Fragkou PC, Karofylakis E, Paneta M, Papathanasiou K, Palaiodimou L, Psarros C, Papathanasiou M, Lachanis S, Sfikakis PP, Tsiodras S. Hypothyroidism is associated with prolonged COVID-19-induced anosmia: a case-control study. J Neurol Neurosurg Psychiatry. 2021.
4. Rotondi M, Chiovato L, Romagnani S, Serio M, Romagnani P. Role of chemokines in endocrine autoimmune diseases. Endocr Rev. 2007;28(5):492-520.
5. Coperchini F, Chiovato L, Ricci G, Croce L, Magri F, Rotondi M. The cytokine storm in COVID-19: Further advances in our understanding the role of specific chemokines involved. Cytokine Growth Factor Rev. 2021.
Dear Editor,
We have read with interest a recent paper by Seiffge and his colleagues published in your journal (1). In their study entitled as “Small vessel disease burden and intracerebral haemorrhage in patients taking oral anticoagulants”, the authors have investigated the role of small vessel disease on intracerebral hemorrhages (ICH) associated with the use of oral anticoagulation therapy. The authors showed that the small vessel disease with medium-to-high severity, detected by either computed tomography (CT) or magnetic resonance imaging (MRI), was significantly more prevalent in patients with ICH taking oral anticoagulants in compared to those without prior anticoagulation therapy (56.1% vs 43.5% on CT, and 78.7% vs 64.5% on MRI, respectively; p<0.001). Leukoaraiosis and atrophy were also reported to be more frequent and severe in patients with ICH related to anticoagulation therapy. We think that the results of the study are considerable emphasizing the importance of small vessel disease for ICH, which should therefore be implemented among the criteria of the risk stratification scores of bleeding.
The use of the scoring systems for the risk stratification of the intracranial bleeding is practically important in patients who are the candidates for the anticoagulation therapy. A recent study investigating the risk factors predicting ICH in patients with atrial fibrillation under anticoagulation therapy demonstrated that the presence of white matter...
Dear Editor,
We have read with interest a recent paper by Seiffge and his colleagues published in your journal (1). In their study entitled as “Small vessel disease burden and intracerebral haemorrhage in patients taking oral anticoagulants”, the authors have investigated the role of small vessel disease on intracerebral hemorrhages (ICH) associated with the use of oral anticoagulation therapy. The authors showed that the small vessel disease with medium-to-high severity, detected by either computed tomography (CT) or magnetic resonance imaging (MRI), was significantly more prevalent in patients with ICH taking oral anticoagulants in compared to those without prior anticoagulation therapy (56.1% vs 43.5% on CT, and 78.7% vs 64.5% on MRI, respectively; p<0.001). Leukoaraiosis and atrophy were also reported to be more frequent and severe in patients with ICH related to anticoagulation therapy. We think that the results of the study are considerable emphasizing the importance of small vessel disease for ICH, which should therefore be implemented among the criteria of the risk stratification scores of bleeding.
The use of the scoring systems for the risk stratification of the intracranial bleeding is practically important in patients who are the candidates for the anticoagulation therapy. A recent study investigating the risk factors predicting ICH in patients with atrial fibrillation under anticoagulation therapy demonstrated that the presence of white matter changes was one of the risk factors being significantly higher in patients having ICH than controls (66.6% versus 32.5% respectively, p=0.0001) (2). On the other hand, the authors concluded that although the presence of white matter changes was one of the risk factors predicting ICH in patients with atrial fibrillation under anticoagulation therapy, it failed to show a significant association with CHA2DS2-VASc or HAS-BLED scores. While the use of validated scoring systems was encouraged in prediction of the ‘risk’ versus ‘benefit’ reasoning when deciding whether or not to start/resume oral anticoagulation therapy in patients with atrial fibrillation, this discrepancy tells us that these scoring systems may benefit from some revisions. Indeed, we have previously discussed the need for the revisions in HAS-BLED, and suggested the incorporation of the presence of white matter abnormalities and leukoaraiosis into the scoring system, in addition with the type of stroke (whether ischemic or hemorrhagic of type), and the localization of previous hemorrhages (whether deep versus lobar in location) (3,4). The latest guideline of the European Society of Cardiology (ESC) for the diagnosis and the management of atrial fibrillation have also emphasized that there is a prominent increase in the occurrence of ICH in parallel with the increase in the numbers of cerebral micro bleeds (5). On the other hand, the effects of cerebral micro bleeds on the treatment strategies were reported to be proven.
In the light of these data, it seems that some revisions are being required for the scoring systems, as supported by the recent study by Seiffge and his colleagues (1), demonstrating the importance of small vessel disease in patients with anticoagulation-associated ICH. The failure to demonstrate a significant association with the risk factors of ICH, including small vessel disease, and the CHA2DS2-VASc or HAS-BLED scores in the study by Paciaroni and his colleagues (2) may be explained, at least to some extent, by the shortcomings of the scoring systems to cover important risk factors of ICH in this group of patients, mainly the white matter abnormalities, leukoaraiosis, the type and the localization of previous strokes and the micro bleeds. In this era, the neuroimaging techniques are easily reachable in the detection of white matter abnormalities or cerebral micro bleeds, and the use of these data should be encouraged before a decision was made for the anticoagulation therapy. On these bases, we would like to emphasize the importance and the need for the revision in scoring systems to better cover the risk factors of ICH, which, we believe, will more adequately aid the (re)institution of the oral anticoagulation treatment.
References
1. Seiffge DJ, Wilson D, Ambler G, Banerjee G, Hostettler IC, Houlden H, et al. Small vessel disease burden and intracerebral haemorrhage in patients taking oral anticoagulants. J Neurol Neurosurg Psychiatry. 2021; jnnp-2020-325299.
2. Paciaroni M, Agnelli G, Giustozzi M, Caso V, Toso E, Angelini F, et al. Risk Factors for Intracerebral Hemorrhage in Patients With Atrial Fibrillation on Non-Vitamin K Antagonist Oral Anticoagulants for Stroke Prevention. Stroke. 2021;52(4):1450-1454.
3. Ince B, Benbir G, Gozubatik-Celik G. Should HAS-BLED scoring be revised for better risk estimation in patients with intracerebral hemorrhage? Expert Rev Cardiovasc Ther. 2014;12(8):929-931.
4. Ince B, Senel G. Deep versus lobar intracerebral hemorrhage on HAS-BLED scoring system. Chest. 2016;149(6):1589-1590.
5. Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C, et al; ESC Scientific Document Group. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. European Heart J. 2021;42(5):373–498.
Malpetti et al. examined neuroinflammation in subcortical regions for predicting clinical progression in patients with progressive supranuclear palsy (PSP) (1). Principal component analysis (PCA) was applied for the analysis, and neuroinflammation and tau burden in the brainstem and cerebellum significantly correlated with the subsequent annual rate of change in the score of Progressive Supranuclear Palsy Rating Scale. Namely, PCA-derived [11C]PK11195 positron emission tomography (PET) markers of neuroinflammation and tau pathology significantly correlated with regional brain volume, but MRI volumes alone did not predict the clinical progression. I present some information with special reference to treatment strategies.
As there are no modifiable lifestyle factors to suppress progression of PSP (2), keeping quality of life by symptom-controlling medications has been recommended. Morgan et al. reported that symptomatic medications, most often for parkinsonism and depression, were prescribed for 87% of patients with PSP, whose satisfaction was poor in most cases (3). Although there have been no effective neuroprotective therapies and/or disease-modifying agents for patients with tauopathies and synucleinopathies, Jabbari et al. recently identified that genetic variation at the leucine-rich repeat kinase 2 (LRRK2) locus was significantly associated with survival in PSP, which might be based on the effect of long noncoding RNA on LRRK2 expression (4). As LRRK2 is associ...
Malpetti et al. examined neuroinflammation in subcortical regions for predicting clinical progression in patients with progressive supranuclear palsy (PSP) (1). Principal component analysis (PCA) was applied for the analysis, and neuroinflammation and tau burden in the brainstem and cerebellum significantly correlated with the subsequent annual rate of change in the score of Progressive Supranuclear Palsy Rating Scale. Namely, PCA-derived [11C]PK11195 positron emission tomography (PET) markers of neuroinflammation and tau pathology significantly correlated with regional brain volume, but MRI volumes alone did not predict the clinical progression. I present some information with special reference to treatment strategies.
As there are no modifiable lifestyle factors to suppress progression of PSP (2), keeping quality of life by symptom-controlling medications has been recommended. Morgan et al. reported that symptomatic medications, most often for parkinsonism and depression, were prescribed for 87% of patients with PSP, whose satisfaction was poor in most cases (3). Although there have been no effective neuroprotective therapies and/or disease-modifying agents for patients with tauopathies and synucleinopathies, Jabbari et al. recently identified that genetic variation at the leucine-rich repeat kinase 2 (LRRK2) locus was significantly associated with survival in PSP, which might be based on the effect of long noncoding RNA on LRRK2 expression (4). As LRRK2 is associated with some forms of Parkinson's disease (PD), the potential effect of LRRK2 modulation should be examined as a disease-modifying therapy for PSP and other related tauopathies, including PD.
VandeVrede et al. reviewed tau-targeted therapies in clinical trials (5), and also presented the history and future directions of disease-modifying therapy (6). Although an effective disease-modifying therapy has not been developed yet, information on some genetic variations might lead to the development of new medications in the future (4).
References
1. Malpetti M, Passamonti L, Jones PS, et al. Neuroinflammation predicts disease progression in progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 2021 Mar 17. doi: 10.1136/jnnp-2020-325549. [Epub ahead of print]
2. Glasmacher SA, Leigh PN, Saha RA. Predictors of survival in progressive supranuclear palsy and multiple system atrophy: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2017;88:402-411.
3. Morgan JC, Ye X, Mellor JA, et al. Disease course and treatment patterns in progressive supranuclear palsy: A real-world study. J Neurol Sci 2021;421:117293.
4. Jabbari E, Koga S, Valentino RR, et al. Genetic determinants of survival in progressive supranuclear palsy: a genome-wide association study. Lancet Neurol 2021;20:107-116.
5. VandeVrede L, Boxer AL, Polydoro M. Targeting tau: Clinical trials and novel therapeutic approaches. Neurosci Lett 2020;731:134919.
6. VandeVrede L, Ljubenkov PA, Rojas JC, et al. Four-Repeat Tauopathies: Current Management and Future Treatments. Neurotherapeutics 2020;17:1563-1581.
We read with great interest the article written by Sofia Doubrovinskaia and colleagues, entitled“Primary CNS lymphoma after CLIPPERS: A case series.”1
CLIPPERS mimics are numerous (e.g. primary angiitis of the central nervous system, autoimmune gliopathies [related to anti-myelin oligodendrocyte glycoprotein or anti-glial fibrillary acidic protein antibodies], Erdheim-Chester disease, systemic lymphoma, and primary central nervous system lymphoma [PCNSL]).2
Among these mimics, only patients who eventually developed a PCNSL (EBV-driven or not) fulfilled initially all CIPPERS criteria, including histological features on brain biopsy (i.e. definite CLIPPERS). In this subset of patients, a question arises: is CLIPPERS a prelymphoma state or a paralymphomatous immune response?
1) Some clues suggest that paralymphomatous immune response seems to be the most likely hypothesis.
1.1) In all reported patients who eventually developed PCNSL, histological findings at the first brainstem attack fulfilled histological criterion for CLIPPERS (i.e. characteristic perivascular lymphohistiocytic infiltrates with predominance of T4-cells) with no evidence of lymphoma (i.e. atypical or large B-cells and absence of EBV in B-cells).
1.2) In these patients, while enhancing lesions predominated initially in the pons, as usually described in CLIPPERS, some of them developed PCNSL remote from the brainstem (i.e. periventricular regions).
1.3) Besides PCNSL, defin...
We read with great interest the article written by Sofia Doubrovinskaia and colleagues, entitled“Primary CNS lymphoma after CLIPPERS: A case series.”1
CLIPPERS mimics are numerous (e.g. primary angiitis of the central nervous system, autoimmune gliopathies [related to anti-myelin oligodendrocyte glycoprotein or anti-glial fibrillary acidic protein antibodies], Erdheim-Chester disease, systemic lymphoma, and primary central nervous system lymphoma [PCNSL]).2
Among these mimics, only patients who eventually developed a PCNSL (EBV-driven or not) fulfilled initially all CIPPERS criteria, including histological features on brain biopsy (i.e. definite CLIPPERS). In this subset of patients, a question arises: is CLIPPERS a prelymphoma state or a paralymphomatous immune response?
1) Some clues suggest that paralymphomatous immune response seems to be the most likely hypothesis.
1.1) In all reported patients who eventually developed PCNSL, histological findings at the first brainstem attack fulfilled histological criterion for CLIPPERS (i.e. characteristic perivascular lymphohistiocytic infiltrates with predominance of T4-cells) with no evidence of lymphoma (i.e. atypical or large B-cells and absence of EBV in B-cells).
1.2) In these patients, while enhancing lesions predominated initially in the pons, as usually described in CLIPPERS, some of them developed PCNSL remote from the brainstem (i.e. periventricular regions).
1.3) Besides PCNSL, definite CLIPPERS have been also diagnosed in the setting of concomitant systemic lymphoma, which strengthens the paralymphomatous hypothesis.
2) If we consider that CLIPPERS could be a paralymphomatous reaction, what could be its underlying pathophysiological mechanism?
2.1) In the setting of lymphoma several immune reactions have been described (non-exhaustive list): parneoplastic syndromes (e.g. paraneoplastic cerebellar degeneration with anti-Tr antibody, granulomatous angiitis), demyelinating lesions (also called “sentinel lesions of PCNSL”), antiphospholipid syndrome, thrombotic microangiopathy, sarcoidosis and hemophagocytic lymphohistiocytosis (HLH). Among these distinct immune reactions, HLH is the only mechanism that can share all histological characteristics of CLIPPERS (i.e. perivascular lymphohistiocytic infiltrates with predominance of T4-cells [and not T8-cells], with no evidence of necrotizing angiitis, demyelinating lesions, endoluminal thrombi, and granulomas). HLH can be acquired or inherited, the latter mostly due to functional defect in T lymphocytes and NK cells cytotoxicity, precluding antigen clearance. The persistence of antigen leads to lymphocyte and macrophage over activation, multiorgan lymphohistiocytic infiltration, systemic inflammatory cytokine release and eventually multi-organ failure. In the setting of systemic HLH, about half of the patients have CNS involvement.3 Conversely, because the diagnosis of HLH requires systemic signs, the existence of CNS-restricted involvement related to HLH remained speculative, until a short time ago.
2.2) As we speculated that HLH restricted to the CNS could be an interesting candidate to explain some CLIPPERS characteristics (i.e. numerous histiocytes in the perivascular infiltrates and striking association with lymphomas), we have recently screened adult CLIPPERS patients for mutations in HLH-associated genes.4 In our cohort of 12 patients with CLIPPERS, mutations involved in HLH were identified in 2 definite and 2 probable CLIPPERS. Biallelic PRF1 mutations were found in 3 of them, with subsequent reduction of perforin expression in natural killer cells. Biallelic UNC13D mutations were found in the remaining patient with subsequent cytotoxic lymphocyte impaired degranulation. Because none of them had systemic signs, none reached criteria for systemic HLH. During follow-up, a systemic non-Hodgkin lymphoma emerged in the patient harboring UNC13D mutations. Thus, in our patients presenting as adult-onset CLIPPERS, one third have HLH gene mutations. As hematopoietic stem cell transplantation is currently the only curative treatment for inherited HLH, genetic screening for these mutations should be performed in all CLIPPERS patients, especially those who developed lymphoma.
2.3) In keeping with these results, it would be interesting to know whether patients described by Sofia Doubrovinskaia and colleagues had HLH gene mutations. The presence of mutations could explain both the CLIPPERS features and the PCNSL. On the other hand, in the absence of mutation, we cannot exclude an acquired form of HLH restricted to the CNS and triggered by a PCNSL.
Although speculative, CLIPPERS could be an acquired or inherited HLH, restricted to the CNS. Although rare, systemic hemophagocytic syndrome and extra neurological involvements in CLIPPERS strengthen this assumption.5 However, further studies are needed in order to assess this hypothesis.
References
1. Doubrovinskaia S, Sahm F, Thier MC, et al. Primary CNS lymphoma after CLIPPERS: a case series. J Neurol Neurosurg Psychiatry. 2021 Mar 31:jnnp-2020-325759. doi: 10.1136/jnnp-2020-325759. Epub ahead of print. PMID: 33789924.
2. Taieb G, Mulero P, Psimaras D, et al. CLIPPERS and its mimics: evaluation of new criteria for the diagnosis of CLIPPERS. Journal of neurology, neurosurgery, and psychiatry 2019; 90(9): 1027-38.
3. Horne A, Trottestam H, Arico M, et al. Frequency and spectrum of central nervous system involvement in 193 children with haemophagocytic lymphohistiocytosis. British journal of haematology 2008; 140(3): 327-35.
4. Taieb G, Kaphan E, Duflos C, et al. Hemophagocytic Lymphohistiocytosis Gene Mutations in Adult Patients Presenting With CLIPPERS-Like Syndrome. Neurol Neuroimmunol Neuroinflamm. 2021 Mar 3;8:e970.
5. Li Z, Jiang Z, Ouyang S, et al. CLIPPERS, a syndrome of lymphohistiocytic disorders. Multiple sclerosis and related disorders 2020; 42: 102063.
We read with great interest the recent article by Mac Grory et al.1 The authors conducted a comprehensive review on the carotid network as a possible chain factor of cryptogenic embolic stroke, particularly in young patients without risk factors. This condition accounts for approximately 25% of ischemic strokes and has less severe sequelae than other forms of strokes, making the topic of the association of stroke and other diseases interesting to open discussion, in order to intervene and prevent serious recurrent strokes that will lead to irreversible sequelae.1
The carotid network is defined as a fibromuscular dysplasia of the intima in the carotid arteries, which causes a deficiency in intraluminal filling along the posterior wall of the carotid bulb, this can be observed through imaging such as ultrasound or CT angiography.2 This pathological entity has been reported as a sub diagnostic,2 because it is little known and does not have the epidemiological impact it should have, even more so because most sufferers are asymptomatic.3 Although there are studies that state that this condition occurs more frequently in a population < 55 years (average 45 - 50 years)4, there are cohorts that report cases near 30 years. In addition, another aspect to highlight is that these studies are carried out mainly in developed countries, so the epidemiological distribution of this condition in low- and middle-income countries is not clearly known, who possess genetic characteris...
We read with great interest the recent article by Mac Grory et al.1 The authors conducted a comprehensive review on the carotid network as a possible chain factor of cryptogenic embolic stroke, particularly in young patients without risk factors. This condition accounts for approximately 25% of ischemic strokes and has less severe sequelae than other forms of strokes, making the topic of the association of stroke and other diseases interesting to open discussion, in order to intervene and prevent serious recurrent strokes that will lead to irreversible sequelae.1
The carotid network is defined as a fibromuscular dysplasia of the intima in the carotid arteries, which causes a deficiency in intraluminal filling along the posterior wall of the carotid bulb, this can be observed through imaging such as ultrasound or CT angiography.2 This pathological entity has been reported as a sub diagnostic,2 because it is little known and does not have the epidemiological impact it should have, even more so because most sufferers are asymptomatic.3 Although there are studies that state that this condition occurs more frequently in a population < 55 years (average 45 - 50 years)4, there are cohorts that report cases near 30 years. In addition, another aspect to highlight is that these studies are carried out mainly in developed countries, so the epidemiological distribution of this condition in low- and middle-income countries is not clearly known, who possess genetic characteristics other than those of the first world.1,2,5
Currently, under the ravages of the pandemic by COVID-19, cases of cryptogenic stroke have been reported in young patients positive for COVID-19 without risk factors, representing the stroke as the debut of this disease, a true mystery when compared to other similar groups.6 Although it is known that the state of hypercoagulability precipitates the presentation of thromboembolic events, the question of why in certain groups of young people with no cardiovascular risk factors this neurological complication develops, compared to other groups quickly arises. 6
We consider that the carotid network may be the risk factor that triggers the presentation of stroke in young patients without cardiovascular factors with COVID-19, which along with the state of hypercoagulability, facilitates the presentation of transient ischemic events, the main form of manifestation of these particular cases.6 Based on the above and what is proposed by Mac Grory et al.1, it is necessary to take into account this association when establishing the therapeutic plan of stroke in young people who develop this complication. Likewise, multicenter studies of the best quality should be carried out to accurately determine the prevalence of carotid fibromuscular dysplasia in young patients, especially in low- and middle-income countries, where there is the greatest number of under-registrations.
REFERENCES
1. Mac Grory B, Emmer BJ, Roosendaal SD, Zagzag D, Yaghi S, Nossek E. Carotid web: an occult mechanism of embolic stroke. Journal of Neurology, Neurosurgery & Psychiatry. 2020; 91(12):1283-9.
2. Ren T, Sun S, Qu X, Gao Y. Carotid Web Misdiagnosis. World Neurosurg. 2020; 140:128-130.
3. Hu H, Zhang X, Zhao J, Li Y, Zhao Y. Transient Ischemic Attack and Carotid Web. AJNR Am J Neuroradiol. 2019; 40(2):313-318.
4. Joux J, Boulanger M, Jeannin S, et al. Association Between Carotid Bulb Diaphragm and Ischemic Stroke in Young Afro-Caribbean Patients. Stroke. 2016; 47(10):2641-4.
5. Yu Y, Wang B, Zheng S, Kou J, Gu X, Liu T. Carotid web and ischemic stroke: a CT angiography study. Clin Imaging. 2020; 67:86-90.
6. Fifi JT, Mocco J. COVID-19 related stroke in young individuals. Lancet Neurol. 2020; 19(9):713-715.
Professor Sinclair and her team1 in Birmingham highlight an urgent issue affecting patients with IIH during the COVID19 pandemic. Their paper elegantly shows that weight gain worsens the severity of papilloedema and puts patients at risk of blindness. They also highlight the risk of worsening papilloedema not picked up with reduced access to hospital appointments.
Here, we report the audit results from our service and share practical actions that have been effective for our service, with wider applicability.
From May – Dec 2020, 58/102 (57%) IIH patients seen for follow up had gained weight compared to weight measured prior to pandemic by median 5.35 (range 0.6,27.3; SD 4.42)kg; with overall weight change of median 1.65 (range -24, 27.3; SD 6.81)kg for the group. 3/58 (5%) patients who gained weight, developed worsening papilloedema.
We agree with the importance of optic disc examination as highlighted by Sinclair and colleagues1, and the need for PPE precautions in the COVID19 pandemic setting. An option we found helpful is fundus photography of the optic disc in the community which the patient then emails their clinician. Fundus photography is now widely available at high-street optometrists. Benefits of doing this include: circumventing patients’ fears of attending hospitals during the pandemic; a patient-held record for future comparison; and the option for clinicians to obtain a colleague’s second opinion on the optic disc photograph.
Professor Sinclair and her team1 in Birmingham highlight an urgent issue affecting patients with IIH during the COVID19 pandemic. Their paper elegantly shows that weight gain worsens the severity of papilloedema and puts patients at risk of blindness. They also highlight the risk of worsening papilloedema not picked up with reduced access to hospital appointments.
Here, we report the audit results from our service and share practical actions that have been effective for our service, with wider applicability.
From May – Dec 2020, 58/102 (57%) IIH patients seen for follow up had gained weight compared to weight measured prior to pandemic by median 5.35 (range 0.6,27.3; SD 4.42)kg; with overall weight change of median 1.65 (range -24, 27.3; SD 6.81)kg for the group. 3/58 (5%) patients who gained weight, developed worsening papilloedema.
We agree with the importance of optic disc examination as highlighted by Sinclair and colleagues1, and the need for PPE precautions in the COVID19 pandemic setting. An option we found helpful is fundus photography of the optic disc in the community which the patient then emails their clinician. Fundus photography is now widely available at high-street optometrists. Benefits of doing this include: circumventing patients’ fears of attending hospitals during the pandemic; a patient-held record for future comparison; and the option for clinicians to obtain a colleague’s second opinion on the optic disc photograph.
In response to the pandemic, we set up technician-led IIH follow-up clinics for vision assessment, optic disc photography and optical coherence tomography (OCT). Patients were sent text message links to symptom questionnaires. Patients were then offered review in a group consultation (GC) setting by video. Those who opted out were offered one-to-one telephone review. The patient feedback for the GC have been overwhelming positive; details of this set up is further described elsewhere2.
A key part of our work with IIH patients is creating community and facilitating peer support, to tackle the sense of isolation from having the diagnosis, exacerbated by the COVID19 pandemic 3. In 2017 we started the IIH weight-loss and wellness (IIH-WoW) workshops on sustainable lifestyle measures for weight loss and wellbeing. Since May 2020 in response to the pandemic, these IIH-WoW workshops have been delivered via video calls. Topics covered included healthy habits and routines, nutrition, physical activity, emotional eating, stress management, goal setting and maintaining motivation. Feedback showed a median rating of 9/10 for ‘how much did you enjoy the workshop” and 8/10 for “how much benefit did you gain from the workshop”. The following patient responses to the question ‘What did you gain from the IIH-WoW workshop?’, illustrate the practical benefits gained from the sense of community, hope, and empowerment:
- “I think one of the challenges I've been experiencing has been - not just sharing my goals but being able to share it with someone who understands my motivation as we'd all ideally like to me free of IIH. That's not really something people in my friend circle can relate to and it's just really nice having that sense of community.”
- “Hearing others struggles. Being able to compare, share compassion, give and receive advice.”
- “Focus not just goals but actioning them and knowing others are doing the same and supporting each other.”
- “I gained two very significant things from this session. The first and most important is seeing and knowing that I'm not alone. I was diagnosed with IIH seven years ago and this event was the first opportunity I've had to meet others with the same condition. In the course of an hour, I went from being terribly isolated, to being part of a sisterhood of diverse, strong, and courageous women... I cannot overstate what a transformative experience that was. The second thing I gained is the sense of possibility. I've had numerous doctors tell me all the things I can't do... Dr Wong has shifted the focus back to what we can do, with small steps, targeted, realistic goals and with the wellbeing of our whole person in mind. In short, I've gained a new initiative.”
Patients valued the sense of peer support from these IIH-WoW and GC sessions, feeling less isolated particularly as IIH is a rare condition and they may feel stigmatised. We facilitate these group sessions using principles from Health Coaching 4 and Motivational Interviewing5, where patients are empowered to act and come up with their solutions.
In summary, we echo the concerns raised by Professor Sinclair and colleagues and highlight additional measures that could further support IIH patients during this pandemic.
Acknowledgements
This work was done at Guys & St Thomas’ (GSTT) NHSFT with the GSTT IIH Team. The IIH-WoW work was shortlisted in 2019 for the King’s Health Partners Education Academy Awards (Mind and Body category) and is only possible with the support from the GSTT IIH Team; the Eye Dept; Deborah Gibson; Dr Denise Ratcliffe; dietetics and physiotherapy teams. The Group Consultation work was awarded top abstract for the British Society of Lifestyle Medicine 2020 conference and shortlisted for the HSJ Acute Sector Innovation Award (2021); supported by Group Consultations Ltd.
Conflicts of interest
None to declare
Funders
None
References
1. Thaller M, Tsermoulas G, Sun R, Mollan SP, Sinclair AJ. Negative impact of COVID-19 lockdown on papilloedema and idiopathic intracranial hypertension. J Neurol Neurosurg Psychiatry. 2020 Dec 24:jnnp-2020-325519. doi: 10.1136/jnnp-2020-325519. Epub ahead of print. PMID: 33361411.
2. Wong SH, Barrow N, Hall K, Gandesha P, Manson M. The effective management of Idiopathic Intracranial Hypertension delivered by group consultations: results and reflections from a Phase One Service Delivery. Neuro-ophthalmology (under review)
3. Miller ED. Loneliness in the Era of COVID-19. Front Psychol. 2020 Sep 18;11:2219. doi: 10.3389/fpsyg.2020.02219. PMID: 33071848; PMCID: PMC7530332.
4. Conn S, Curtain S. Health coaching as a lifestyle medicine process in primary care. Aust J Gen Pract. 2019 Oct;48(10):677-680. doi: 10.31128/AJGP-07-19-4984. PMID: 31569315.
5. Rollnick, S., & Miller, W. What is Motivational Interviewing? Behavioural and Cognitive Psychotherapy 1995, 23(4), 325-334. doi:10.1017/S135246580001643X
We read with great interest the study by Jenkins et al 1. Using dopamine transporter (DAT) 123I- Ioflupane SPECT imaging, the authors provide evidence for different patterns of dopaminergic abnormalities in patients with traumatic brain injury (TBI) and patients with Parkinson’s disease.
We would like to report on the clinical observation of a 35-year-old patient who was admitted at our institution after an aneurysmal subarachnoid haemorrhage (SAH). The patient was initially comatose, and the CT-scan revealed an intraparenchymal haemorrhage associated with an intraventricular haemorrhage. The patient was treated with endovascular treatment and a ventricular catheter was inserted to treat SAH-associated hydrocephalus. There were no ischemic complications. Upon awakening, we observed a bilateral postural tremor affecting the upper limbs, which had already been noticed by the relatives before SAH. The patient’s father is deceased but also had a history of tremor. Our initial conclusion was that this tremor was compatible with essential tremor and required no further investigation.
After ventriculoperitoneal shunting for hydrocephalus (complicated by overdrainage) the patient made a progressive recovery and returned to part-time work as a gardener despite the persistence of cognitive symptoms.
One year after haemorrhage, the amplitude of the postural tremor decreased, and a dystonia affecting the right hand appeared. Upon examination 21 months after haemorr...
We read with great interest the study by Jenkins et al 1. Using dopamine transporter (DAT) 123I- Ioflupane SPECT imaging, the authors provide evidence for different patterns of dopaminergic abnormalities in patients with traumatic brain injury (TBI) and patients with Parkinson’s disease.
We would like to report on the clinical observation of a 35-year-old patient who was admitted at our institution after an aneurysmal subarachnoid haemorrhage (SAH). The patient was initially comatose, and the CT-scan revealed an intraparenchymal haemorrhage associated with an intraventricular haemorrhage. The patient was treated with endovascular treatment and a ventricular catheter was inserted to treat SAH-associated hydrocephalus. There were no ischemic complications. Upon awakening, we observed a bilateral postural tremor affecting the upper limbs, which had already been noticed by the relatives before SAH. The patient’s father is deceased but also had a history of tremor. Our initial conclusion was that this tremor was compatible with essential tremor and required no further investigation.
After ventriculoperitoneal shunting for hydrocephalus (complicated by overdrainage) the patient made a progressive recovery and returned to part-time work as a gardener despite the persistence of cognitive symptoms.
One year after haemorrhage, the amplitude of the postural tremor decreased, and a dystonia affecting the right hand appeared. Upon examination 21 months after haemorrhage, in addition to the bilateral postural tremor, we observed a rest tremor affecting the right hand when the patient was sitting and when the patient was walking. Froment maneuver facilitated rigidity in the right hand. There was no bradykinesia. A discrete cervical dystonia was observed (with right laterocolis). There were no cerebellar syndrome and no oculomotor abnormalities.
An 18F-DOPA-PET/MRI was performed 22 months after haemorrhage. There was a clear asymmetry in striatal uptake which was below normal values in the left caudate and the left putamen. At our institution, normal values for 18F-FDOPA imaging were established in 10 patients with essential tremor. Fixation of the caudate could hardly be seen, and fixation was mostly visible in the anterior left putamen creating a radish-like appearance. Analysis of the susceptibility weighted imaging (SWI) sequence showed an hyposignal of the left substantia nigra.
The interpretation of these clinical findings is not unambiguous. One could argue that the tremor and asymmetry in striatal uptake observed on DAT-scan are directly related to the nigral damage (as evidenced by hypodensity on SWI). A second interpretation, which is not incompatible with the former, is that the subarachnoid haemorrhage worsened a preexisting pathology affecting the nigrostriatal dopaminergic projections. We acknowledge that this observation does not allow to draw definitive conclusions since the dopaminergic system has not been investigated before injury in this patient. However, the progressive worsening of extrapyramidal signs is evocative of a continuous degenerative process affecting the nigrostriatal pathway. These clinical findings are reminiscent of a previously published observation of rest tremor and hemiparkinsonism which occurred seven months after mesencephalic haemorrhage 2. In this observation, the authors also report an asymmetry of 18F-FDOPA striatal uptake. Their conclusion is that the delayed onset of symptoms is compatible with nigrostriatal degeneration caused by nigral damage.
Overall, we believe that our observation is in accordance with the results presented by Jenkins et al. It supports the idea that different patterns of dopaminergic abnormalities can account for some of the neurological signs observed after acute brain injury. The diversity of observed patterns could be the result of a complex interplay between structural damage to the nigrostriatal pathway and patient’s susceptibility to nigrostriatal degeneration. Early detection of dopaminergic abnormalities with nuclear imaging could help identify patients who are likely to benefit from dopaminergic treatment after acute brain injury.
1. Jenkins, P. O. et al. Distinct dopaminergic abnormalities in traumatic brain injury and Parkinson’s disease. J Neurol Neurosurg Psychiatry 91, 631–637 (2020).
2. Defer, G. L. et al. Rest tremor and extrapyramidal symptoms after midbrain haemorrhage: clinical and 18F-dopa PET evaluation. J Neurol Neurosurg Psychiatry 57, 987–989 (1994).
There have been some studies investigating blood neurofilament light chain (NfL) levels as predictors of cognitive functions decline in neurological disorders. I want to discuss here the association between blood NfL levels and neuroaxonal damage in patients with brain damages including Alzheimer's disease and stroke by considering the underlying mechanisms.
First, Egle et al. reported that baseline increased serum NfL levels could predict cognitive decline and the risk of converting to dementia in a cerebral small vessel disease (SVD), but there was no change in serum NfL levels over a 5-year follow-up period [1]. The lack of dynamic changes of NfL in stroke stand in contrast to neurodegenerative disease, and serum NfL levels may not be used as a surrogate marker for monitoring cognitive impairment in patients with SVD. In contrast, Stokowskaet et al. examined plasma NfL levels for the prediction of functional improvement in the late phase after stroke [2]. The odds ratios (ORs) (95% confidence intervals [CIs]) of elevated plasma NfL levels for the improvement in balance and gait improvement were 2.34 (1.35-4.27) and 2.27 (1.25-4.32), respectively. In addition, OR (95% CI) of elevated plasma NfL levels for cognitive improvement was 7.54 (1.52-45.66), which was also verified by intervention trial. This study presented the usefulness of plasma NfL levels as a biomarker of physical and psychological function after stroke events. As there is a wide range of 95% CI...
Show MoreWe read with great interest the paper by Yaghi S. et al on the lacunar stroke mechanisms and their therapeutic implications. We would like to highlight that the deficiency of ADA2 (DADA2) is the most common cause of monogenic vasculitis and is also responsible for causing lacunar strokes, but is commonly overlooked [1]. It has an autosomal recessive inheritance and has multi-system involvement: skin, nervous, gastrointestinal and hematological systems being most commonly involved [1]. Children and young adults are most commonly affected with a “polyarteritis nodosa-type” picture with cutaneous involvement, abdominal pains and renal involvement, and mild strokes. The lacunar infarcts are more common in the posterior circulation [2]. Most cases are diagnosed late or go undiagnosed because of lack of knowledge about this disorder [3, 4].
Patients are treated by immunosuppressants with anti-tumour necrosis factor (TNF) agents and usually adalimumab is the first line agent. Early diagnosis and treatment lead to favorable treatment response.
References:
Show More1. Meyts I, Aksentijevich I. Deficiency of Adenosine Deaminase 2 (DADA2): Updates on the Phenotype, Genetics, Pathogenesis, and Treatment. Journal of Clinical Immunology (2018) 38: 569-578
2. Geraldo AF, Carosi R, Tortora D et al. Widening the Neuroimaging features of Adenosine Deaminase 2 Deficiency. American Journal of Neuroradiology. February 2021
3. Sharma A, Agarwal A, Srivastava MVP, et al. Hy...
We recently published our preliminary case-control study showing that a medical history of hypothyroidism was more prevalent among COVID-19 patients with persistent olfactory dysfunction compared to controls (50% vs 8%; p=0.009) and that hypothyroidism was independently (p=0.021) associated with higher likelihood of persistent hyposmia/anosmia among patients with COVID-19 (OR: 21.1; 95%CI: 2.0 to 219.4) after adjusting for age and sex (1). As previously stated, our results are not -by any means- confirmatory of an etiologic association between hypothyroidism (or preferably chronic autoimmune thyroiditis, CAT, as aptly suggested by Rotondi et al.) and the development of persistent anosmia in COVID-19 patients (1). However, the suggetsed mechanism by Rotondi et al. strengthens our observations by proposing a possible biomolecular explanation behind our clinical observations. Indeed, chemokines that are induced by SARS-CoV-2 infection, and especially CXCL10, could act as effectors of demyelination of the central nervous system (CNS) - including the olfactory apparatus - through attraction and recruitment of T-lymphocytes (2,3). Although the proposed pathogenetic mechanism by Rotondi et al. needs further investigation and laboratory confirmation through experimental studies in COVID-19 patients with persistent olfactory dysfunction, it certainly invigorates our preliminary clinical results and sets the grounds for further research in a clinically significant post-COVID-9 seque...
Show MoreThyroid hormones play a role in the development and function of virtually all human cells, including maturation of olfactory neurons. The clinical observation that patients with hypothyroidism can experience disturbances in their sense of smell was first reported more than 60 years ago, and it was subsequently confirmed in both humans and animal models. In vivo animal studies clearly demonstrated that hypothyroidism induced by anti-thyroid drugs administration in mice was associated to variable degrees of anosmia, which however promptly reverted following restoration of euthyroidism by levothyroxine replacement therapy (1).
Show MoreThis latter finding was regarded as the proof that thyroxine, besides its role for correct development of the nervous system would also be involved in the genesis of new olfactory receptor neurons, a process demonstrated to be maintained also in adulthood.
Since the early phase of the ongoing Sars-CoV-2 pandemic, anosmia was identified as a peculiar clinical symptom of COVID-19 being experienced by nearly 80% of the affected patients (2). It is now known that, at least in some cases, COVID-19 course may encompass protracted olfactory dysfunction and development of olphactory bulb atrophy (3). Thus, attention was paid to potential risk factors predicting this long-term sequela. Interestingly, Tsivgoulis et al., recently performed a prospective case–control study aimed at evaluating whether hypothyroidism could be associated to prolonged COVID...
Dear Editor,
We have read with interest a recent paper by Seiffge and his colleagues published in your journal (1). In their study entitled as “Small vessel disease burden and intracerebral haemorrhage in patients taking oral anticoagulants”, the authors have investigated the role of small vessel disease on intracerebral hemorrhages (ICH) associated with the use of oral anticoagulation therapy. The authors showed that the small vessel disease with medium-to-high severity, detected by either computed tomography (CT) or magnetic resonance imaging (MRI), was significantly more prevalent in patients with ICH taking oral anticoagulants in compared to those without prior anticoagulation therapy (56.1% vs 43.5% on CT, and 78.7% vs 64.5% on MRI, respectively; p<0.001). Leukoaraiosis and atrophy were also reported to be more frequent and severe in patients with ICH related to anticoagulation therapy. We think that the results of the study are considerable emphasizing the importance of small vessel disease for ICH, which should therefore be implemented among the criteria of the risk stratification scores of bleeding.
The use of the scoring systems for the risk stratification of the intracranial bleeding is practically important in patients who are the candidates for the anticoagulation therapy. A recent study investigating the risk factors predicting ICH in patients with atrial fibrillation under anticoagulation therapy demonstrated that the presence of white matter...
Show MoreMalpetti et al. examined neuroinflammation in subcortical regions for predicting clinical progression in patients with progressive supranuclear palsy (PSP) (1). Principal component analysis (PCA) was applied for the analysis, and neuroinflammation and tau burden in the brainstem and cerebellum significantly correlated with the subsequent annual rate of change in the score of Progressive Supranuclear Palsy Rating Scale. Namely, PCA-derived [11C]PK11195 positron emission tomography (PET) markers of neuroinflammation and tau pathology significantly correlated with regional brain volume, but MRI volumes alone did not predict the clinical progression. I present some information with special reference to treatment strategies.
As there are no modifiable lifestyle factors to suppress progression of PSP (2), keeping quality of life by symptom-controlling medications has been recommended. Morgan et al. reported that symptomatic medications, most often for parkinsonism and depression, were prescribed for 87% of patients with PSP, whose satisfaction was poor in most cases (3). Although there have been no effective neuroprotective therapies and/or disease-modifying agents for patients with tauopathies and synucleinopathies, Jabbari et al. recently identified that genetic variation at the leucine-rich repeat kinase 2 (LRRK2) locus was significantly associated with survival in PSP, which might be based on the effect of long noncoding RNA on LRRK2 expression (4). As LRRK2 is associ...
Show MoreWe read with great interest the article written by Sofia Doubrovinskaia and colleagues, entitled“Primary CNS lymphoma after CLIPPERS: A case series.”1
Show MoreCLIPPERS mimics are numerous (e.g. primary angiitis of the central nervous system, autoimmune gliopathies [related to anti-myelin oligodendrocyte glycoprotein or anti-glial fibrillary acidic protein antibodies], Erdheim-Chester disease, systemic lymphoma, and primary central nervous system lymphoma [PCNSL]).2
Among these mimics, only patients who eventually developed a PCNSL (EBV-driven or not) fulfilled initially all CIPPERS criteria, including histological features on brain biopsy (i.e. definite CLIPPERS). In this subset of patients, a question arises: is CLIPPERS a prelymphoma state or a paralymphomatous immune response?
1) Some clues suggest that paralymphomatous immune response seems to be the most likely hypothesis.
1.1) In all reported patients who eventually developed PCNSL, histological findings at the first brainstem attack fulfilled histological criterion for CLIPPERS (i.e. characteristic perivascular lymphohistiocytic infiltrates with predominance of T4-cells) with no evidence of lymphoma (i.e. atypical or large B-cells and absence of EBV in B-cells).
1.2) In these patients, while enhancing lesions predominated initially in the pons, as usually described in CLIPPERS, some of them developed PCNSL remote from the brainstem (i.e. periventricular regions).
1.3) Besides PCNSL, defin...
We read with great interest the recent article by Mac Grory et al.1 The authors conducted a comprehensive review on the carotid network as a possible chain factor of cryptogenic embolic stroke, particularly in young patients without risk factors. This condition accounts for approximately 25% of ischemic strokes and has less severe sequelae than other forms of strokes, making the topic of the association of stroke and other diseases interesting to open discussion, in order to intervene and prevent serious recurrent strokes that will lead to irreversible sequelae.1
The carotid network is defined as a fibromuscular dysplasia of the intima in the carotid arteries, which causes a deficiency in intraluminal filling along the posterior wall of the carotid bulb, this can be observed through imaging such as ultrasound or CT angiography.2 This pathological entity has been reported as a sub diagnostic,2 because it is little known and does not have the epidemiological impact it should have, even more so because most sufferers are asymptomatic.3 Although there are studies that state that this condition occurs more frequently in a population < 55 years (average 45 - 50 years)4, there are cohorts that report cases near 30 years. In addition, another aspect to highlight is that these studies are carried out mainly in developed countries, so the epidemiological distribution of this condition in low- and middle-income countries is not clearly known, who possess genetic characteris...
Show MoreProfessor Sinclair and her team1 in Birmingham highlight an urgent issue affecting patients with IIH during the COVID19 pandemic. Their paper elegantly shows that weight gain worsens the severity of papilloedema and puts patients at risk of blindness. They also highlight the risk of worsening papilloedema not picked up with reduced access to hospital appointments.
Here, we report the audit results from our service and share practical actions that have been effective for our service, with wider applicability.
From May – Dec 2020, 58/102 (57%) IIH patients seen for follow up had gained weight compared to weight measured prior to pandemic by median 5.35 (range 0.6,27.3; SD 4.42)kg; with overall weight change of median 1.65 (range -24, 27.3; SD 6.81)kg for the group. 3/58 (5%) patients who gained weight, developed worsening papilloedema.
We agree with the importance of optic disc examination as highlighted by Sinclair and colleagues1, and the need for PPE precautions in the COVID19 pandemic setting. An option we found helpful is fundus photography of the optic disc in the community which the patient then emails their clinician. Fundus photography is now widely available at high-street optometrists. Benefits of doing this include: circumventing patients’ fears of attending hospitals during the pandemic; a patient-held record for future comparison; and the option for clinicians to obtain a colleague’s second opinion on the optic disc photograph.
I...
Show MoreWe read with great interest the study by Jenkins et al 1. Using dopamine transporter (DAT) 123I- Ioflupane SPECT imaging, the authors provide evidence for different patterns of dopaminergic abnormalities in patients with traumatic brain injury (TBI) and patients with Parkinson’s disease.
Show MoreWe would like to report on the clinical observation of a 35-year-old patient who was admitted at our institution after an aneurysmal subarachnoid haemorrhage (SAH). The patient was initially comatose, and the CT-scan revealed an intraparenchymal haemorrhage associated with an intraventricular haemorrhage. The patient was treated with endovascular treatment and a ventricular catheter was inserted to treat SAH-associated hydrocephalus. There were no ischemic complications. Upon awakening, we observed a bilateral postural tremor affecting the upper limbs, which had already been noticed by the relatives before SAH. The patient’s father is deceased but also had a history of tremor. Our initial conclusion was that this tremor was compatible with essential tremor and required no further investigation.
After ventriculoperitoneal shunting for hydrocephalus (complicated by overdrainage) the patient made a progressive recovery and returned to part-time work as a gardener despite the persistence of cognitive symptoms.
One year after haemorrhage, the amplitude of the postural tremor decreased, and a dystonia affecting the right hand appeared. Upon examination 21 months after haemorr...
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