621 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.

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

    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...

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  • Letter to the Editor regarding "Small vessel disease burden and intracerebral haemorrhage in patients taking oral anticoagulants"

    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...

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