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 applaud Suichi et al.[1] for proposing new diagnostic criteria for POEMS syndrome. There is clearly a need for simplified validated criteria that permit early diagnosis of this rare, elusive and devastating paraneoplastic disorder, especially because early local or systemic treatment of the underlying plasma cell malignancy can dramatically improve prognosis.[2] Our recent clinical experience[3] is in full agreement with the three proposed cardinal features of POEMS syndrome, namely polyneuropathy, vascular endothelial growth factor (VEGF) level elevation, and the presence of monoclonal protein. The authors argue that the triad alone may be insufficiently specific; therefore they propose the additional requirement of two of four secondary features, namely extravascular fluid accumulation, skin changes, organomegaly, and sclerotic bone lesion.
We would like to draw attention to clinical and methodological aspects that could further enhance or refine the diagnosis of POEMS syndrome. First, the process of diagnosis starts with clinical suspicion. Polyneuropathy is usually the earliest symptom of POEMS syndrome. POEMS syndrome should be considered in any patient with a severely progressive polyneuropathy of acute to subacute onset that is not otherwise explained, and VEGF level measurement should be offered. Routine screening for monoclonal protein (with immunofixation) and skeletal survey may be negative initially, and could remain negative for a long duration into...
We applaud Suichi et al.[1] for proposing new diagnostic criteria for POEMS syndrome. There is clearly a need for simplified validated criteria that permit early diagnosis of this rare, elusive and devastating paraneoplastic disorder, especially because early local or systemic treatment of the underlying plasma cell malignancy can dramatically improve prognosis.[2] Our recent clinical experience[3] is in full agreement with the three proposed cardinal features of POEMS syndrome, namely polyneuropathy, vascular endothelial growth factor (VEGF) level elevation, and the presence of monoclonal protein. The authors argue that the triad alone may be insufficiently specific; therefore they propose the additional requirement of two of four secondary features, namely extravascular fluid accumulation, skin changes, organomegaly, and sclerotic bone lesion.
We would like to draw attention to clinical and methodological aspects that could further enhance or refine the diagnosis of POEMS syndrome. First, the process of diagnosis starts with clinical suspicion. Polyneuropathy is usually the earliest symptom of POEMS syndrome. POEMS syndrome should be considered in any patient with a severely progressive polyneuropathy of acute to subacute onset that is not otherwise explained, and VEGF level measurement should be offered. Routine screening for monoclonal protein (with immunofixation) and skeletal survey may be negative initially, and could remain negative for a long duration into the disease course. In fact, in many patients with POEMS, the concentration of monoclonal protein in the serum or urine is conspicuously low. Lack of abnormality on one or these two tests is insufficient to exclude a diagnosis of POEMS syndrome.[3,4] It is important to emphasize that any patient with a severe polyneuropathy and a significantly elevated VEGF level (usually >200 pg/ml) should be subjected to an aggressive search for plasma cell malignancy with CT or CT-PET and possibly image-directed bone marrow biopsy. Second, searching for characteristics of the polyneuropathy may improve the specificity of the POEMS diagnosis and differentiate it from mimics, even in the absence of secondary features: sensorimotor polyneuropathy with mixed axonal and demyelinating features, notably a prior diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) refractory to intravenous immunoglobulin and corticosteroids, severe axon loss in distal leg muscles together with diffuse demyelinating features on nerve conduction studies of the upper extremity, and evidence of proximal involvement in the form of root enhancement on imaging and elevated cerebrospinal protein.[3,5] Third, secondary features of edema, skin changes, and organomegaly develop as the disease advances, and may not be manifest in the earliest stages. As it is desirable to make an early diagnosis and prevent accumulation of impairment from this treatable condition, there should not be a delay in diagnosing due to a lack of secondary features.
Validation exercises of diagnostic criteria of clinical syndromes (that lack an objective diagnostic criterion) are by definition circular arguments that inflate the accuracy of criteria that match prevalent practice. It is possible that the reported 100% sensitivity and specificity are overestimates, and may be more applicable for patients in later stages.
Therefore we propose a designation of "possible POEMS" for any progressive/severe or "red flags" polyneuropathy with elevated VEGF level. The probability of POEMS syndrome in this group is sufficiently high that a rapid and aggressive diagnostic evaluation for plasma cell malignancy is warranted. Only after completion of such an evaluation and careful neurological and hematological follow-up can POEMS syndrome be excluded.
1 Suichi T, Misawa S, Sato Y, et al. Proposal of new clinical diagnostic criteria for POEMS syndrome. J Neurol Neurosurg Psychiatry 2019;90:133–7. doi:10.1136/jnnp-2018-318514
2 Dispenzieri A. POEMS syndrome: 2017 Update on diagnosis, risk stratification, and management. Am J Hematol 2017;92:814–29. doi:10.1002/ajh.24802
3 Li Y, Valent J, Soltanzadeh P, et al. Diagnostic challenges in POEMS syndrome presenting with polyneuropathy: A case series. J Neurol Sci 2017;378:170–4. doi:10.1016/j.jns.2017.05.019
4 He T, Zhao A, Zhao H, et al. Clinical characteristics and the long-term outcome of patients with atypical POEMS syndrome variant with undetectable monoclonal gammopathy. Ann Hematol 2019;98:735–43. doi:10.1007/s00277-018-03589-4
5 Mauermann ML, Sorenson EJ, Dispenzieri A, et al. Uniform demyelination and more severe axonal loss distinguish POEMS syndrome from CIDP. J Neurol Neurosurg Psychiatry 2012;83:480–6. doi:10.1136/jnnp-2011-301472
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 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.
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
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.
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.
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 were interested to read the study of Filosto et al [1] concluding a significant link between Guillain-Barre Syndrome (GBS) and COVID-19 infection in Northern Italy at the peak of the 1st wave SARS-CoV2 pandemic. We urge caution in accepting such a causative conclusion using a retrospective observational study; causation is not conclusively proven and is drawn from potentially biased data and small case numbers of a rare condition, and a rate calculation without confidence intervals to infer uncertainty.
Only 34 cases of GBS, of whom 30 were COVID-19 positive, are reported over a 2-month period, with a denominator population of 8,400,107. We calculated the 95% confidence intervals of the incidence rates as 0.08 per 100,000 per month (95% C.I.: 0.04-0.15) in 2019 and 0.2 per 100,000 per month (95% C.I.: 0.14-0.28) in 2020. The overlapping confidence intervals do not support a statistically significant increase in GBS rates from 2019 to 2020. Furthermore, the simple multiplication of the monthly rate by 12 to create an approximate annualised incidence potentially amplifies the inaccuracy. We suggest that the 2.6-fold difference in GBS incidence from 2019 to 2019 is prone to meaningful statistical error.
During the initial stages of the pandemic the denominator of COVID-19 positive cases will have been under-reported because testing was limited to the symptomatic and presenting populations. We are told that 62,679 inhabitants of the regi...
We were interested to read the study of Filosto et al [1] concluding a significant link between Guillain-Barre Syndrome (GBS) and COVID-19 infection in Northern Italy at the peak of the 1st wave SARS-CoV2 pandemic. We urge caution in accepting such a causative conclusion using a retrospective observational study; causation is not conclusively proven and is drawn from potentially biased data and small case numbers of a rare condition, and a rate calculation without confidence intervals to infer uncertainty.
Only 34 cases of GBS, of whom 30 were COVID-19 positive, are reported over a 2-month period, with a denominator population of 8,400,107. We calculated the 95% confidence intervals of the incidence rates as 0.08 per 100,000 per month (95% C.I.: 0.04-0.15) in 2019 and 0.2 per 100,000 per month (95% C.I.: 0.14-0.28) in 2020. The overlapping confidence intervals do not support a statistically significant increase in GBS rates from 2019 to 2020. Furthermore, the simple multiplication of the monthly rate by 12 to create an approximate annualised incidence potentially amplifies the inaccuracy. We suggest that the 2.6-fold difference in GBS incidence from 2019 to 2019 is prone to meaningful statistical error.
During the initial stages of the pandemic the denominator of COVID-19 positive cases will have been under-reported because testing was limited to the symptomatic and presenting populations. We are told that 62,679 inhabitants of the region had positive COVID-19 swabs during the study, but this is unlikely to provide an accurate population-based rate of COVID-19 infection. More specifically, given that hospital admissions were the only ascertainment source for GBS cases in this study, we are not given comparative information on the rate of COVID-19 positivity in the hospital population, which was likely to have been very high as the Northern Italy healthcare system was reportedly overwhelmed. It is possible, or probable, that a large proportion of the hospitalised population were COVID-19 positive independent of other factors. It is thus likely that these data report a coincidental association between COVID-19 and GBS rather than a causative one.
The COVID-19 seroprevalence rate in the Italian Instituto Nazionale di Statistica (ISTAT) study for Lombardy was the highest in Italy at 7.5%. [2] From this rate, the estimated number of COVID-19 cases would be approximately 630,000 across the seven cities, compared to the 62 679 reported from swabs in the Filosto study. Using seroprevalence as the denominator, we believe the reported calculated incidence reduces from 47.9 to approximately 4.76 per 100,000 COVID-19 infections. The 7.5% seroprevalence may also be an underestimate because of selection bias (under half the planned sample size were tested) or imperfect sensitivity of the assay. It is striking that the seroprevalence reported in London from the NHS Blood Transfusion Service at a similar time was 17.5%;[3] Northern Italy, recognised as one of the hardest hit populations worldwide, seemingly had a seroprevalence of less than half that. Without major differences in health care structure and economic status of these two European countries it is difficult to explain the discrepancy other than the recorded seroprevalence figures were lower than actual infection rates.
Importantly, no account is given for the dramatic 3.3-fold decline in non-COVID GBS to 0.29/100000 per year either. One potential reason for the apparent decline is the mis-attribution of GBS causation, where COVID-19 causation is applied to every COVID-19 positive GBS case. The authors do not explore the possibility of alternative causes of GBS and incidental COVID-19 infection. For example, four of the COVID-19 cases had gastrointestinal symptoms but causation was still attributed to COVID-19 despite a gastroenteritis being the commonest precursor of GBS and occurring less frequently as a COVID-19 specific feature. The authors have presented no data on the exclusion of other causes of GBS such as Campylobacter serology etc. and this is of relevance, as without excluding other causes as far as possible the possibility of misattribution again exists.
Part of the justification Filosto et al make for the causative link is published data to support an interaction of the SarCoV2 spike protein with ganglioside GM1, referencing in silico modelling studies. [4] These studies model shape and energy efficient interactions of the Receptor Binding Domain (RBD) of the spike (S-)protein of SARS-CoV2 with the ACE2 Receptor. Convincing in silico predictive data of the subsequent available N-Terminal Domain of the S-Protein also indicate energy efficient potential binding sites for two GM1 molecules. However, these are models and interactions have not been shown to occur in or ex-vivo. Furthermore, there are no data to suggest that ACE2 receptors are present in peripheral nerve axons or myelin to provide the basis of binding to a colocalised ganglioside.
GBS is a para- or more likely post-infectious autoimmune neuropathy, although acute polyradiculoneuropathies indistinguishable from classical Campylobacter jejuni enteritis associated GBS may occur by direct infection in Zika- and West Nile viruses and others. These cases of GBS occur with short latency whereas classical GBS occurs one to three (and possibly up to six) weeks after infection after an immune response induction. In the series of Filosto et al their median time from infection to GBS was 23 days (IQR 16-34), almost all within the COVID-19 symptom period (5 cases started after COVID symptoms resolved and thus are most consistent with a post-infectious timing). Thus, if it proposed that covalent binding to gangliosides is a mechanism for direct infection of peripheral nerves this would be considered too long a latency, and if an immune response is the key, then COVID-19 spike protein binding to a ganglioside is possibly irrelevant to the pathogenesis. Clearly more work is required to establish whether a definitive temporal relationship exists between COVID-19 and GBS, and more so the pathogenic mechanism which links infection to neuropathy.
The Witebsky Postulates, with some minor modifications, have stood the test of time to provide support for autoimmune linkage of a pathogen to a disease.[5] None are really fulfilled here and we should be very cautious about drawing causative conclusions from observational studies of small numbers of patients where the prevalence of COVID-19 in the population is so high as to have affected very many people who may have been presenting to hospital anyway.
Lastly, it is reassuring that the treatment and outcomes of patients are no different between COVID-19 positive and negative GBS patients and that given the lack of any spike in GBS presentations in Northern Italy (with the total incidence rate being 2.43/100000) we do not expect an additional pandemic of acute neuromuscular paralysis.
Stephen Keddie, Julia Pakpoor, Aisling Carr, Michael P Lunn
References
1. Filosto M, Cotti Piccinelli S, Gazzina S, et al. Guillain-Barré syndrome and COVID-19: an observational multicentre study from two Italian hotspot regions. J Neurol Neurosurg Psychiatry 2020;0:jnnp-2020-324837. doi:10.1136/jnnp-2020-324837
2. ISTAT, Ministero della Salute. Primi risultati dell’indagine di sieroprevalenza sul SARS-CoV-2. 2020;:10.
3. Public Health England. Sero-surveillance of COVID-19. 2020.https://www.gov.uk/government/publications/national-covid-19-surveillanc... (accessed 13 Jul 2020).
4. Fantini J, Di Scala C, Chahinian H, et al. Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection. Int J Antimicrob Agents 2020;55. doi:10.1016/j.ijantimicag.2020.105960
5. Witebsky E, Rose NR, Terplan K, et al. Chronic thyroiditis and autoimmunization. J Am Med Assoc 1957;164:1439–47. doi:10.1001/jama.1957.02980130015004
We read with interest the comments of Keddie and Colleagues who suggested caution in accepting a causation link between SARS-CoV-2 infection and Guillain-Barré syndrome (GBS) and in interpreting results from our study “Guillain-Barrè syndrome and COVID-19: an observational multicentre study from two Italian hotspot regions" (1).
We believe they have misinterpreted the message of our paper and have drawn conclusions that was not our intention to draw.
Their first consideration is that our paper cannot demonstrate a causation link between COVID-19 and GBS. Of course, we agree. In fact, we did not talk about any causal nexus. It is well known that, in statistics, “causation” indicates a relationship between two events where one event is affected by the other. In order to demonstrate “causation”, prospective studies are needed. Our study is based on retrospective findings and identified an increased rate of GBS cases concomitantly with the COVID-19 spread in our regions. On this basis, we could not (and indeed we did not) conclude for a definite causative relationship but we suggested a pathogenic link for which COVID-19 could represent a trigger for GBS, as already suggested by other authors (2).
Keddie et al. claimed some possible methodological biases. Part of them is obviously related to the retrospective nature of the study and have been listed as limitations of the study at the end of our paper. They calculated the 95% confidence intervals of the...
We read with interest the comments of Keddie and Colleagues who suggested caution in accepting a causation link between SARS-CoV-2 infection and Guillain-Barré syndrome (GBS) and in interpreting results from our study “Guillain-Barrè syndrome and COVID-19: an observational multicentre study from two Italian hotspot regions" (1).
We believe they have misinterpreted the message of our paper and have drawn conclusions that was not our intention to draw.
Their first consideration is that our paper cannot demonstrate a causation link between COVID-19 and GBS. Of course, we agree. In fact, we did not talk about any causal nexus. It is well known that, in statistics, “causation” indicates a relationship between two events where one event is affected by the other. In order to demonstrate “causation”, prospective studies are needed. Our study is based on retrospective findings and identified an increased rate of GBS cases concomitantly with the COVID-19 spread in our regions. On this basis, we could not (and indeed we did not) conclude for a definite causative relationship but we suggested a pathogenic link for which COVID-19 could represent a trigger for GBS, as already suggested by other authors (2).
Keddie et al. claimed some possible methodological biases. Part of them is obviously related to the retrospective nature of the study and have been listed as limitations of the study at the end of our paper. They calculated the 95% confidence intervals of the incidence rates as 0.08 per 100,000 per month in 2019 (95% C.I.: 0.04-0.15) and 0.2 per 100,000 per month in 2020 (C.I.: 0.14-0.28) and concluded for an overlap between confidence intervals. Actually the 95% confidence intervals based on the numbers of cases and population we reported in our study were 0.077 per 100,000 per month in 2019 (C.I.: 0.041-0.132) and 0.202 per 100,000 per month in 2020 (C.I. 0.140-0.282) (MedCalc, MedCalc Software Ltd, Belgium). Thus, there is no overlap of confidence intervals. Moreover, judging the significance of differences by examining the overlap between two confidence intervals has been debated and discouraged by the statistical community (3).
As a second point, Keddie et al. suggested that the denominator (COVID-19 positive cases) could be underestimated because testing was limited to symptomatic subjects. We clearly acknowledged in the paper that the real number of COVID-19-positive patients was likely higher than that in the official data and this could cause an overestimation of the GBS incidence in the COVID-19-positive population. On the other hand, it should be stressed that also the numerator can be biased. During the Italian outbreak, many Neurological Units were closed in order to provide medical staff for COVID-19 Units and many neurological patients (COVID-19 positive and negative) could not be admitted. Thus, it is likely that GBS cases (either COVID-19 positive or negative) were not recognized. This might also justify the lower number of COVID-19 negative GBS observed in 2020.
Similar problems arose in evaluating the incidence of GBS in Latin America and Caribbean countries during the 2015-20216 Zika virus epidemic because only about 25% of subjects infected by Zika virus showed clinical manifestations and difficulties were encountered in certainty of laboratory diagnosis in regions where other flavivirus are endemic. Nonetheless, a recent meta-analysis of observational studies concluded that GBS increased 2.6 times over background rates during Zika outbreak (4).
Keddie et al. claimed that the denominator for rate calculation of GBS in COVID-19 patients should be substituted with the seroprevalence in the same population (630,000, based on a 7.5% prevalence in Lombardy reported by ISTAT) (5). Again, we agree that the real denominator is difficult to obtain, as we reported in the limitations of the study. However, it should be noted that the reported SARS-CoV-2 seroprevalence tests were performed from May 25, 2020 to July 15, 2020, i.e., in a period subsequent to the months considered in our study and disclosed in August 2020 (6). We do not know and cannot enucleate the seroprevalence in the months of March and April and, for this reason, we preferred to work on the real data of nasopharyngeal swabs rather than on estimated data referring to a period subsequent to that considered in our study.
Findings about duration of seropositivity are discordant (7,8) and whether levels of IgG specific for SARS-CoV-2 antigen persist or decay remains a debated issue (7). We also want to point out that many asymptomatic subjects are seropositive and this raises further questions: 1) Is it correct to investigate a COVID-19/GBS relationship in seropositive patients without active or recent infectious signs? 2) Do we know if asymptomatic patients with positive nasopharyngeal swab are prone to develop para- or post-infectious complications? To date, our answers are no.
Obviously, we cannot exclude that some COVID-19 positive GBS patients represented a casual association and we never excluded this possibility. However, the fact remains that GBS was 2.6 time increased in the same hospitals between 2019 and 2020 and that the incidence of GBS in March and April 2019 (0.077/100 000/month; estimated rate 0.93/100 000/year) was consistent with a previous epidemiological study showing a GBS incidence of 0.75–1.09/100 000/year in Lombardy (9), therefore suggesting a true increased incidence of GBS during the pandemic peak in Northern Italy.
We acknowledge as a limitation of the study the fact that, in many cases, was not possible to exclude other infective antecedents and this is true also for most of reported cases of GBS associated with SARS-CoV2 infection from all over the world (10). Again, this was due to the severe and exceptional health emergency we suffered in Northern Italy during the first epidemic wave.
About the pathogenesis of COVID-19 related GBS, it is untrue that we used data from modelling studies suggesting interaction of the SARS-CoV-2 spike protein with ganglioside GM1 to support a causative link (11). Actually, in our discussion we just mentioned this hypothesis as a “possibility” (“an immune cross-reaction between epitopes within the spike-bearing gangliosides and sugar residues of surface peripheral nerve glycolipids is also possible”) without claiming any causative link.
We also were far from wanting to prove that GBS associated with SARS-CoV-2 infection fulfilled the Witebsky’s criteria for autoimmune disease, that as far as we know in the field of GBS, have been fulfilled only for the acute motor axonal neuropathy variant with anti-GM1 antibodies (12).
In conclusion, isolated or small series of GBS cases associated with SARS-CoV 2 infection were described from all over the world in the first pandemic months (10) and have reached to November 19th 2020 a total of 139 cases especially reported from Italy (38.1%). Our study showed an increased incidence of GBS during COVID-19 outbreak in Northern Italy. Despite the limitations mentioned in the paper and inherent to a retrospective study we deem that these results suggest a relationship.
Keddie et al. reported in their disclosures that they have a similar paper due to be published in a larger cohort and reaching different conclusion. We do not have any detail about their study but different reasons can be hypothesized to explain the differences in results including that the circulating SARS-CoV-2 in Northern Italy and England during the first pandemic wave might have been genetically different with eventually a different capability to trigger GBS (13).
Anyway, currently we are conducting a follow-up analysis on GBS incidence for the months following April 2020 and ISTAT data will be certainly taken into account and evaluated in order to obtain further findings on this debated area.
References
1. Filosto M, Cotti Piccinelli S, Gazzina S, et al. Guillain-Barré syndrome and COVID-19: an observational multicentre study from two Italian hotspot regions. J Neurol Neurosurg Psychiatry 2020; jnnp-2020-324837
2. Rahimi K. Guillain-Barre syndrome during COVID-19 pandemic: an overview of the reports. Neurol Sci 2020; 41: 3149-3156
3. Schenker N, Gentleman JF. On judging the significance of differences by examining the overlap between confidence intervals. The American Statistician 2001; 55:3, 182-186
4. Capasso A, Ompad DC, Vieira DL, Wilder-Smith A, Tozan Y. Incidence of Guillain-Barre´ Syndrome (GBS) in Latin America and the Caribbean before and during the 2015–2016 Zika virus epidemic: A systematic review and meta-analysis. PLoS Negl Trop Dis 2019; 13: e0007622
5. ISTAT, Ministero della Salute. Primi risultati dell’indagine di sieroprevalenza sul SARS-CoV-2. 2020; https://www.istat.it/it/files/2020/08/ReportPrimiRisultatiIndagineSiero.pdf
6.Ministero della Salute, http://www.salute.gov.it/portale/news/p3_2_1_1_1.jsp?lingua=italiano&men...
7.Isho B, Abe KT, Zuo M et al. Persistence of serum and saliva antibody responses to SARS-CoV-2 spike antigens in COVID-19 patients. Science Immunology 2020; 52: eabe5511
8. Escribano P, Álvarez-Uría A, Alonso R, Catalán P, Alcalá L, Muñoz P, Guinea J. Detection of SARS-CoV-2 antibodies is insufficient for the diagnosis of active or cured COVID-19. Sci Rep 2020; 10: 19893
9. Beghi E, Bogliun G. The Guillain-Barrè syndrome (GBS). implementation of a register of the disease on a nationwide basis. Italian GBS Study Group. Ital J Neurol Sci 1996; 17 :355–6
10. Uncini A, Vallat J-M, Jacobs BC. Guillain-Barré syndrome in SARS-CoV-2 infection: an instant systematic review of the first six months of pandemic. J Neurol Neurosurg Psychiatry 2020; 91:1105–10
11. Fantini J, Di Scala C, Chahinian H, et al. Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection. Int J Antimicrob Agents 2020; 55: 105960
12. Yuki N. Ganglioside mimicry and peripheral nerve disease Muscle Nerve 2007; 35: 691-711
13. Pachetti M., Marini B., Benedetti F., Giudici F., Mauro E., Storici P. et al. Emerging SARS-CoV-2 mutation hot spots include a novel RNA-dependent-RNA polymerase variant. J Transl Med 2020; 18: 17
We 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 applaud Suichi et al.[1] for proposing new diagnostic criteria for POEMS syndrome. There is clearly a need for simplified validated criteria that permit early diagnosis of this rare, elusive and devastating paraneoplastic disorder, especially because early local or systemic treatment of the underlying plasma cell malignancy can dramatically improve prognosis.[2] Our recent clinical experience[3] is in full agreement with the three proposed cardinal features of POEMS syndrome, namely polyneuropathy, vascular endothelial growth factor (VEGF) level elevation, and the presence of monoclonal protein. The authors argue that the triad alone may be insufficiently specific; therefore they propose the additional requirement of two of four secondary features, namely extravascular fluid accumulation, skin changes, organomegaly, and sclerotic bone lesion.
We would like to draw attention to clinical and methodological aspects that could further enhance or refine the diagnosis of POEMS syndrome. First, the process of diagnosis starts with clinical suspicion. Polyneuropathy is usually the earliest symptom of POEMS syndrome. POEMS syndrome should be considered in any patient with a severely progressive polyneuropathy of acute to subacute onset that is not otherwise explained, and VEGF level measurement should be offered. Routine screening for monoclonal protein (with immunofixation) and skeletal survey may be negative initially, and could remain negative for a long duration into...
Show MoreThere 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 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 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...
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 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...
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...
Show MoreTo the Editor
We were interested to read the study of Filosto et al [1] concluding a significant link between Guillain-Barre Syndrome (GBS) and COVID-19 infection in Northern Italy at the peak of the 1st wave SARS-CoV2 pandemic. We urge caution in accepting such a causative conclusion using a retrospective observational study; causation is not conclusively proven and is drawn from potentially biased data and small case numbers of a rare condition, and a rate calculation without confidence intervals to infer uncertainty.
Only 34 cases of GBS, of whom 30 were COVID-19 positive, are reported over a 2-month period, with a denominator population of 8,400,107. We calculated the 95% confidence intervals of the incidence rates as 0.08 per 100,000 per month (95% C.I.: 0.04-0.15) in 2019 and 0.2 per 100,000 per month (95% C.I.: 0.14-0.28) in 2020. The overlapping confidence intervals do not support a statistically significant increase in GBS rates from 2019 to 2020. Furthermore, the simple multiplication of the monthly rate by 12 to create an approximate annualised incidence potentially amplifies the inaccuracy. We suggest that the 2.6-fold difference in GBS incidence from 2019 to 2019 is prone to meaningful statistical error.
During the initial stages of the pandemic the denominator of COVID-19 positive cases will have been under-reported because testing was limited to the symptomatic and presenting populations. We are told that 62,679 inhabitants of the regi...
Show MoreWe read with interest the comments of Keddie and Colleagues who suggested caution in accepting a causation link between SARS-CoV-2 infection and Guillain-Barré syndrome (GBS) and in interpreting results from our study “Guillain-Barrè syndrome and COVID-19: an observational multicentre study from two Italian hotspot regions" (1).
Show MoreWe believe they have misinterpreted the message of our paper and have drawn conclusions that was not our intention to draw.
Their first consideration is that our paper cannot demonstrate a causation link between COVID-19 and GBS. Of course, we agree. In fact, we did not talk about any causal nexus. It is well known that, in statistics, “causation” indicates a relationship between two events where one event is affected by the other. In order to demonstrate “causation”, prospective studies are needed. Our study is based on retrospective findings and identified an increased rate of GBS cases concomitantly with the COVID-19 spread in our regions. On this basis, we could not (and indeed we did not) conclude for a definite causative relationship but we suggested a pathogenic link for which COVID-19 could represent a trigger for GBS, as already suggested by other authors (2).
Keddie et al. claimed some possible methodological biases. Part of them is obviously related to the retrospective nature of the study and have been listed as limitations of the study at the end of our paper. They calculated the 95% confidence intervals of the...
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