639 e-Letters

  • Doxycycline use, duration and side effect

    Doxycycline is an important drug used in many disease conditions like Brucellosis, Lyme disease, malaria etc. One important side effect with it's use is raised intracranial pressure i.e. idiopathic intracranial pressure. So this study is a nice development as lesser duration of treatment will reduce cost of therapy, and a psychological well being because of less drug, less duration and less cost.
    1. J Lochhead, and J S Elston.Doxycycline induced intracranial hypertension BMJ. 2003 Mar 22; 326(7390): 641–642.
    doi: 10.1136/bmj.326.7390.641.

  • Ophthalmoplegia, sensorineural hearing loss, and bilateral vestibulopathy secondary to presumed VEXAS-related polycranial neuritis

    We read with interest the letter by Bert-Marcaz et al., reporting on a 74-year-old man with vacuole, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome and chronic inflammatory demyelinating polyneuropathy [1]. We agree with the authors’ postulation that the simultaneous onset of the two diseases suggests a potentially causal link between VEXAS and the demyelinating abnormalities they observed on nerve conduction studies and nerve biopsy. We have previously reported a case of a 68-year-old man with VEXAS associated with neurological features, including ophthalmoplegia, sensorineural hearing loss and bilateral vestibulopathy [2]. Our hypothesis for the mechanism of neurological involvement was polycranial neuritis, given that there was no evidence of orbital inflammation on MRI and there was significant improvement with corticosteroids. Neurologists should consider the diagnosis of VEXAS (and other autoinflammatory syndromes of innate immunity) in patients with neurological problems who have (i) unexplained fever and elevated acute phase reactants, especially when there is a remitting and relapsing course, (ii) unexplained multisystem disease, and (iii) no evidence of infection, malignancy or autoimmune (i.e., antibody-mediated) disease.

    [1] Bert-Marcaz C, Briantais A, Faucher B, Corazza G, Ebbo M, Attarian S, Delmont E, Fortanier E. Expanding the spectrum of VEXAS syndrome: association with acute-onset CIDP. J Neurol Neurosurg Psychiat...

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  • Concerns regarding methodology in the purview of definitions and reference intervals

    The research study conducted by Ward et al., [1] has effectively marked an understandable association between frailty, lifestyle and genetics as factors of dementia in adults aged 60 and above. The findings of this study could potentially have major implications in the field of neuropsychiatric research in the field of geriatric studies.

    One of the concerns regarding the methodology of classification of a healthy lifestyle score was that participants who were currently non-smokers were identified as a valid classification in the healthy subgroup. This is questionable due to the fact that, for this classification, no reference was cited to accept non current smokers as a valid factor in the healthy lifestyle score. According to several studies, smoking was indicated as one of the major risk factors for dementia among the elderly. [2] A 2019 Lancet commission identified that smoking was the third among nine modifiable risk factors for dementia. Furthermore a review of 37 studies in the field of association of smoking as a risk factor for dementia identified that compared to never smokers, smokers had a 30% higher chance of developing dementia in general along with a 40% higher chance of developing Alzheimers. [3] So to associate non-current smokers into a healthy lifestyle category is concerning but instead, the classification should have been rather as never-smokers and smokers (both current and non-current). An appropriate classification of smokers and non-smokers...

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  • Re: Frailty, lifestyle, genetics and dementia risk

    Ward et al. reported the relationships between frailty index, healthy lifestyle and polygenic risk scores, and incident all-cause dementia (1). The adjusted hazard ratio (HR) (95% CI) of participants with high frailty for incident dementia was 3.68 (3.11 to 4.35). In addition, the adjusted HR (95% CI) of participants with high genetic risk and high frailty for incident dementia was 5.81 (4.01 to 8.42).The authors emphasized of controlling frailty for dementia prevention strategies, even among subjects at high genetic risk. I have two comments about their study.

    First, Lourida et al. investigated the association between healthy lifestyles and risk of dementia by considering genetic risk (2). The adjusted HR (95% CI) of participants with high genetic risk and unfavorable lifestyle for incident dementia was 2.83 (2.09 to 3.83). In addition, a favorable lifestyle was associated with a lower dementia risk among participants with high genetic risk. There was no significant interaction between genetic risk and lifestyle factors, and I suppose that unfavorable lifestyles and genetic factors independently contribute to the risk of dementia. The level of frailty may be related to lifestyles and contribute to subsequent progression of cognitive impairment.

    Second, Kojima et al. conducted a meta-analysis regarding the effect of frailty on the incident dementia among community-dwelling older people (3). Th pooled HRs (95% CIs) of frailty for the incident Alzheimer disease...

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  • Frailty, genetics, and dementia risk: why stop at lifestyle?

    Ward et al.'s recent study on frailty, lifestyle, genetics and dementia risk (1) is a major contribution to the growing multimorbidity approach towards dementia. But it is not clear why the authors exclusively frame their discussion on practical steps to reduce dementia risk around healthy lifestyle. They paradoxically argue that "adherence to national guidelines for healthy lifestyle behaviours is central to dementia risk reduction recommendations," while also recognising that multi-domain lifestyle interventions have a weak evidence base in favour of them. An exclusive focus on lifestyle to achieve reduction of frailty and dementia overlooks social gradients of health, particularly the unequal distribution of access to the kind of safe and stimulating living and working environments in which risk reduction can take place through high-quality stimulation and the absence of stressors like noise and air pollution (2). The authors make no mention of social determinants. People with higher income are more likely to part in lifestyle interventions (3), and focusing exclusively on conscious behavioural change to achieve dementia risk reduction may therefore worsen inequalities in dementia risk (4). Therefore, to address not only dementia risk reduction but also the reduction of health inequities, as well as promoting lifestyle changes, the research community ought to stress the need for action against the social determinants of frailty and dementia (5).


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  • The link between CLIPPERS and lymphoma might be not fortuitous

    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...

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  • Refining diagnosis of early POEMS syndrome

    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...

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  • Blood neurofilament light chain and cognitive progression in neurological disorders

    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...

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  • Response to "Persistent COVID-19 related anosmia in patients with chronic autoimmune thyroiditis: What’s behind hypothyroidism?"

    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...

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  • DADA2: An under-diagnosed monogenic cause of lacunar stroke

    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.

    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...

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