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Recent eLetters

Displaying 1-10 letters out of 500 published

  1. Response to "Incident dementia and cognitive decline in patients with stroke/TIA" by Professor Tomoyuki Kawada

    Professor Kawada expresses three concerns regarding the outcomes of our study into how cognitive deficits progress in the years following a stroke [1]. Firstly, he cites Rajan et al. [2] as finding that cognitive decline was greater after stroke than before stroke, and suggests that our study should have considered pre-stroke cognitive decline. How doing so would have affected our outcomes or their interpretation is unclear. We found greater decline in MMSE scores for stroke patients than for a well- matched healthy control group. This complements the findings of Rajan et al., whose cognitive measure was a composite of four tests that included the MMSE. We also found that 23% of our patients had a further stroke during follow-up, and which was associated with accelerated cognitive decline. This is also in keeping with the findings of Rajan et al., but goes further to highlight a need to consider how overall outcomes are affected by including patients with repeat strokes in analyses of post- stroke cognitive decline. The second concern of Professor Kawada involves a recommendation that we conduct sensitivity analyses in light of a report of warfarin being associated with higher rates of haemorrhagic stroke than dabigatran etexilate, particularly in Asians as compared with non-Asians [3]. This seems beyond the scope or aims of our study. Professor Kawada's third concern involves our observation of increased rates of dementia in stroke patients, and he seems to suggest that pre- stroke cognitive functioning must be considered when making such claims. This is despite his further reference to studies reporting an independent effect of stroke on dementia, including one we also cite [4], and our exclusion of patients with a diagnosis of dementia prior to their stroke. The purpose of our study was to examine how cognitive deficits progress in the years following a stroke, which we did by comparing stroke patients, either with or without a further stroke, against a suitable control group. We believe that extending our analyses to include pre-stroke cognitive functioning and effects of incident stroke rates would be additional purposes, and that not including these should not alter the interpretation of our results.

    References

    1 Sachdev PS, Lipnicki DM, Crawford JD, et al. Progression of cognitive impairment in stroke/TIA patients over 3 years. J Neurol Neurosurg Psychiatry 2014 Mar 21 [Epub ahead of print].

    2 Rajan KB, Aggarwal NT, Wilson RS, et al. Association of cognitive functioning, incident stroke, and mortality in older adults. Stroke 2014;45:2563-7.

    3 Hori M, Connolly SJ, Zhu J, et al. Dabigatran versus warfarin: effects on ischemic and hemorrhagic strokes and bleeding in Asians and non -Asians with atrial fibrillation. Stroke 2013;44:1891-6.

    4 Savva GM, Stephan BC. Epidemiological studies of the effect of stroke on incident dementia: a systematic review. Stroke 2010;41:e41-6.

    Conflict of Interest:

    None declared

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  2. Incident dementia and cognitive decline in patients with stroke/TIA

    Sachdev et al. conducted a 3-year follow-up study to know the progress of cognitive deficits after stroke or transient ischemic attack (TIA) (1). The authors gathered 183 stroke/TIA patients and 97 healthy controls, and concluded that cognitive decline in post-stroke patients was not greater than in controls, except for verbal memory, although rates of incident dementia were 5.9% per year in patients and 0.4% in controls, respectively. I have some queries on their study outcome.

    First, Rajan et al. conducted a cohort study to check bidirectional causality of the association between incident stroke and cognitive function in 7217 older adults with 3-year intervals (2). They concluded that baseline cognitive function was associated with incident stroke, and the level of cognitive decline was 1.9-fold higher after stroke, compared with periods before stroke. This study shows that the level of cognitive decline should also be compared in stroke/TIA patients before and after events.

    As the second concern, there is a report that effects of different types of anticoagulant medication for stroke subtype differ and they are affected by races (3). I recommend the authors conducting sensitivity analysis with use of stroke subtype such as ischemic and hemorrhagic stroke, by considering medication, which would be possible by the enough number of incident strokes.

    As the third concern, Savva et al. reported a systematic review of the effect of stroke on incident dementia (4). In their study, stroke increased 2-folds risk of incident dementia in the older population, and the increase could not be explained by demographic or cardiovascular risk factors or by pre-stroke cognitive decline. Relating to their study, Dregan et al. estimated the occurrence in post-stroke dementia as a function of pre-stroke cognitive status and incident stroke, and concluded that stroke and pre-stroke cognitive impairment were independently associated with increased risk of post-stroke dementia (5). These reports show that the level of cognitive function should be checked in stroke/TIA patients before and after events. I understand that the study design by Sachdev et al. can also evaluate the progress of cognitive impairment in stroke/TIA patients with adjustment of confounders. My recommendation would be achieved by a follow-up study in large number of subjects without stroke or TIA as a baseline study.

    References

    1 Sachdev PS, Lipnicki DM, Crawford JD, et al. Progression of cognitive impairment in stroke/TIA patients over 3 years. J Neurol Neurosurg Psychiatry 2014 Mar 21. doi: 10.1136/jnnp-2013-306776

    2 Rajan KB, Aggarwal NT, Wilson RS, et al. Association of cognitive functioning, incident stroke, and mortality in older adults. Stroke 2014;45:2563-7.

    3 Hori M, Connolly SJ, Zhu J, et al. Dabigatran versus warfarin: effects on ischemic and hemorrhagic strokes and bleeding in Asians and non -Asians with atrial fibrillation. Stroke 2013;44:1891-6.

    4 Savva GM, Stephan BC; Alzheimer's Society Vascular Dementia Systematic Review Group. Epidemiological studies of the effect of stroke on incident dementia: a systematic review. Stroke 2010;41:e41-6.

    5 Dregan A, Wolfe CD, Gulliford MC. Does the influence of stroke on dementia vary by different levels of prestroke cognitive functioning?: a cohort study. Stroke 2013;44:3445-51.

    Conflict of Interest:

    None declared

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  3. Rapid cognitive decline in attention, executive function and memory: the gold standard for delirium?

    I endorse the authors' use of multiple information sources to identify prevalent delirium in medical and surgical inpatients 1-2: family and other informants, junior and senior physicians, medical case notes and nurses. Although the authors did not use the model I developed, I suggest that their paper is about distinguishing rapid cognitive decline (RCD, one form being delirium) from slow cognitive decline (SCD) in dementia and mild cognitive impairment (Diagnostic and Statistical Manual of Mental Disorders or DSM-V major minor neurocognitive disorder). Until each cognitive domain is measured in RCD patients by a 6-minute battery of non- copyrighted paper and pencil neuropsychological tests, I prefer the umbrella term rapid cognitive decline (RCD) over RCD subtypes such as delirium. My prospective randomised controlled trial, Central Coast Australia Delirium Intervention Study (CADIS), examined a new RCD phenotype. CADIS enrolled 130 Confusion Assessment Method (CAM) positive elderly who had at least 25% relative decline in attention or executive function and stringent measures to exclude behavioral and psychological symptoms of dementia (BPSD) 3-5. RCD is classified by cognitive domain into five main subtypes: 1) Delirium: RCD involving mainly attention, executive function, word-list memory; 2) Transient global amnesia: RCD involving memory and orientation with sparing of other domains; 3) Dysphasia: RCD involving mainly language, often from acute ischemic stroke (AIS); 4) Executive dysfunction RCD due to AIS; 5) Visuospatial impairment RCD from AIS. RCD in CADIS was associated with rapid cognitive recovery (RCR). I wish to focus on seven issues in the author's methods, results and conclusions which lead to false positive delirium diagnosis in severe hearing impairment, dementia and behavioral and psychological symptoms of dementia (BPSD). 1) While spatial span forward (SSF) is an excellent test for inattention, months of the year backwards (MOTYB) reflects both attention and executive function. If MOTYB resolved from say 2 / 12 months accurate on admission to 12 / 12 months at discharge this rapid recovery this would prove that abnormal MOTYB was due to delirium rather than dementia. If MOTYB did not change then an abnormal score on admission should not be used as evidence of delirium; 2) Digit span forward (DSF) in CADIS proved highly robust and sensitive to change: 6-DSF fell by 54% prior to admission and improved by 54% from admission to recovery. DSF is quicker and easier to measure than SSF and MOTYB. 3) Investigators did not exclude severely deaf subjects or use amplifiers with headphones (cost US$120) for the deaf to ameliorate hearing deficits, leading to false positive attribution to delirium. 4) The opening sentence of the discussion section decries underdetection of delirium, which I agree is a major problem. The greater problem of overdiagnosis, however, receives almost no attention in the medical literature - false positive diagnosis of delirium in dementia with or without BPSD. Behavioral decline is counted falsely as disorganized thinking. In many countries with national health services if a GP wishes to admit a dementia patient with behavioral problems she or he will insist on acute onset and new confusion knowing that if the patient were labelled as BPSD the hospital physicians would recommend management in the community. Furthermore there is a certain prestige in diagnosing delirium which is absent with BPSD. 5) The questions used by geriatricians to identify disorganised thinking such as "Would a stone float on water?" or interpreting a proverb are impaired in moderate to severe dementia and not specific for delirium. 6) The authors state in the last paragraph of the introduction that their aim was to determine if SSF and MOTYB would predict delirium by DSM-IV. While their findings confirmed this, the data they present is silent on reversibility and magnitude / rate of cognitive decline and cognitive recovery. 7) CAM item 4 in table 1, altered level of consciousness during the interview could have arisen from factors other than delirium such as sedative or antipsychotics for BPSD, sleep deprivation from acute symptoms or tests after midnight or temporary lack of CPAP in obstructive sleep apnoea (CPAP often not taken in ambulance to emergency department). In conclusion I believe that the speed of cognitive decline (25% per 24 hours) and the speed of cognitive recovery are the gold standards for delirium and other forms of RCD. This parallels the time course of many disease pairs: acute kidney injury compared to chronic kidney disease or asthma compared to chronic obstructive pulmonary disease. The suggestion that certainty in diagnosis wait 2-3 days after hospital admission to measure recovery is no different than the waiting period to confirm blood stream infection or to wait for tests not available in medium or small hospitals after midnight such as MRI imaging to show a new cerebral infarct on T2 or FLAIR when initial CT scan shows no acute changes. It is time for logic-based medicine to correct evidence-based medicine (EBM) when EBM started on an imperfect delirium phenotype from DSM which was perpetuated in 1990 with CAM. References 1. O'Regan NA, Ryan DJ, Boland E et al Meagher D. Attention! A good bedside test for delirium? J Neurol Neurosurg Psychiatry 2014;85:1122-1131 2. Ryan DJ, O'Regan NA, Caoimh RO et al, Paula T Trzepacz, David Meagher. Delirium in an adult acute hospital population: predictors, prevalence and detection. BMJ Open 2013;3:e001772 3. Regal P. Delirium Reversibility and Instrumental Activities of Daily Living. Geriatrics and Gerontology International October 2014;14:in press 4. Regal, P. Serial Montreal Cognitive Assessments demonstrate reversible cognitive impairment in patients with acute transient ischemic attack and minor stroke. Stroke 2014;45:e193 5. Regal P. Need for new methods to study delirium. Internal Medicine Journal 2013;43:1053-4

    Conflict of Interest:

    None declared

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  4. Control arms in brain stimulation trials and experiments

    The JNNP recently published an interesting study which used magnetic stimulation to the spine of people with Parkinson's disease, and showed a promising improvement in camptocormia compared to a group receiving 'sham' stimulation [1]. In an Editorial Comment, Caslake [2] argued that the participants in this particular study may not have been sufficiently blinded as to the group to which they had been assigned. Although the stimulation used by Arii and colleagues was delivered to the spine and not to the head (trans-spinal magnetic stimulation, TSMS, rather than transcranial magnetic stimulation, TMS), we believe there are general principles of experimental design that are of relevance to studies using these technologies.

    We have previously argued that it is almost impossible to create a convincing placebo control for experiments using stimulation such as TMS or transcranial current stimulation (tCS) [3]. TMS by its nature is a multisensory experience: driving a current through the hand-held coil creates the intended magnetic pulse, but as a side-effect creates a clicking sound and, depending on the stimulation target, a muscular twitch or an illusory flash of light in the participant's vision. One option for creating a sham condition is to use a "sham coil" which reproduces the clicking sound but does not reproduce the side-effects. If an individual, na?ve participant does not participate in both active and control arms of the study, it can usually be argued that the presence or absence of side-effects does not give the participant enough information to know which treatment they had received. However in the study by Arii et al. [1], and in many other reported in the literature, the participants crossed over so that each person experienced both conditions. This means that each participant was able to compare their second treatment to their first, so reducing the blinding. In the case of the study by Arii et al., we note first that their Table 2 suggests a tell-tale additional improvement in the group that received real stimulation after sham, and second that the authors do not report subjective comments from the participants except that two participants experienced discomfort.

    The poverty of the control arm in stimulation therefore introduces a challenge when designing experiments and trials to use these techniques. One solution, as we mentioned, might be to divide participants into groups who separately receive either real or sham stimulation. Another solution could be to introduce an alternative stimulation target which is hypothesised not to be involved in the behaviour of interest, although we note that this is a difficult and somewhat subjective alternative [3]. At a more philosophical level it could also be argued that so-called 'non- invasive' [4] techniques such as TMS and tCS are inherently imperfect for creating control and blinding conditions in awake and aware participants, and therefore to qualify any reported results by adding participants' comments and other observations so the degree of unblinding can be assessed.

    In conclusion, we agree with the comments of Caslake [2] that proper experimental science requires a proper experimental control, however it is important to acknowledge that proper blinding is very difficult to achieve in many situations. Our use of non-invasive stimulation requires an ethical balance between the need to preserve the scientific integrity of an experiment or trial, and the desire to advance treatments for debilitating conditions. We therefore advocate a culture of open reporting of all relevant circumstances in an experiment.

    Dr Nick Davis, Swansea University, UK Dr Martyn Bracewell, Bangor University, UK.

    References

    1. Arii Y, Sawada Y, Kawamura K, et al. Immediate effect of spinal magnetic stimulation on camptocormia in Parkinson's disease. Journal of Neurology Neurosurgery and Psychiatry 2014;85:1221-26 doi: 10.1136/jnnp- 2014-307651 . 2. Caslake R. Dif?culties with control arms in repetitive magnetic stimulation studies. Journal of Neurology Neurosurgery and Psychiatry 2014;85:1182 doi: 10.1136/jnnp-2014-307906.

    3. Davis N, Gold E, Pascual-Leone A, et al. Challenges of proper placebo control for noninvasive brain stimulation in clinical and experimental applications. European Journal of Neuroscience 2013;38(7):2973-77

    4. Davis N, van Koningsbruggen M. 'Non-invasive' brain stimulation is not non-invasive. Frontiers in Systems Neuroscience 2013;7:76 doi: 10.3389/fnsys.2013.00076.

    Conflict of Interest:

    None declared

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  5. Reply to Letter: Which target is best for patients with Parkinson's disease? A meta-analysis of pallidal and subthalamic stimulation

    We are pleased that Dr. Cyron agrees with our statement. Although our meta-analysis revealed that depression was more frequent in STN DBS relative to GPi DBS, additional randomized trials which investigate long- term outcome including UPDRS, quality of life and adverse events are required to determine which target is more appropriate for patients with PD. We hope our findings and suggestions would be useful for future studies which provide valuable evidence as meta-analyses helped to establish various treatment options historically.

    Conflict of Interest:

    None declared

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  6. STN revisted

    This is a timely contribution to an issue overdue. STN-stimulation has been the undisputed mainstay of DBS for Pakinson's disease more than a decade. Reports on deleterious side effects mainly in the field of cognition and emotion however accumulate. While the rather subtle effects on cognitive abilities have been the subject of a plethora of publications, changes in personality and behavior remain underreported. Yet it is these changes that can have catastrophic impacts on the wellbeing of patients and their relatives. In my experience with GPI stimulation behavior and mood are by far less affected or even improved. In the light of these complications the advantage of greater reductions in medication with STN stimulation appears less relevant. Depleting patients of badly needed dopamin may even worsen axial symptoms, emotional state and incentive. I therefore strongly agree with the author's statement, that it is now time to clarify this issue involving an appropriate number of patients.

    Conflict of Interest:

    None declared

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  7. Temozolomide for seizure control in low-grade gliomas: role of malignant degeneration

    We were particularly appreciated the paper by Koekkoek and colleagues1 on temozolomide (TMZ) and seizure frequency after low-grade gliomas (LGG) in a retrospective study. Interestingly, seizure frequency in patients with LGG was remarkably reduced after 6-month TMZ therapy, which was also "an independent prognostic factor for progression-free survival and overall survival",1 indicating associations between seizure reduction and tumor response. However, no significant objective responses were detected on MRI in patients with and without seizure reduction.1 We offered an alternative explanation for this paradox.

    Tumor progression of LGG was composed of at least two types, recurrence and malignant degeneration, with definitions of tumor recurrence or progressive growth on MRI for recurrence and either a significant increase in tumor contrast enhancement and/or malignant degeneration of a histological diagnosis for malignant degeneration, respectively.2 Regarding on the latter scenario, driver mutations of recurrent tumor were usually distinct from those of the initial ones, and nearly 50% of the mutations in the initial LGG were undetected in the same patient at recurrence, which occurred in 43% of all patients consecutively suffering from initial LGG and malignant degeneration. 3With an exomes sequence study of 23 objects who underwent both initial LGG and malignant degeneration, Johnson and colleagues3 demonstrated that patient receiving TMZ treatment had an incredible increase in mutations from 0.2 to 4.5 per megabase (Mb) at up-front to 31.9 to 90.9 per Mb at recurrence. The TMZ- induced hypermutations covered many tumor driver mutations, including dysregulation of RB and activation of AKT-mTOR signaling pathways.3 Recently, AKT-mTOR signaling pathway was reported to be involved in the controlling of epileptogenesis, and mTOR inhibition might contribute to antiseizure and antiepileptogenic effect in the WAG/Rij rat model.4 In terms of TMZ initiation either LGG up-front or at tumor progression in Koekkoek and colleagues's study 1, the underlying molecular signal pathways could be of significant heterogeneity, which may imply inherent differences in seizure frequency. Furthermore, although there were 21 out of 26 second histological diagnosis of malignant transformation before TMZ initiation2, there was no declaration of progression type distribution in each cohort. Let alone the declared absences of the relative molecular markers in the final diagnosis. In summary, these little flaws made such beautiful study kinds of imperfect.

    Therefore, we suggest that the confounding role of malignant degeneration should be clarified in the elegant work described by Koekkoek and colleagues, which showed beneficial effects of TMZ on reduction of seizure frequency after LGG1.

    Reference

    1. Koekkoek JA, Dirven L, Heimans JJ, et al. Seizure reduction in a low-grade glioma: more than a beneficial side effect of temozolomide. J Neurol Neurosurg Psychiatry 2014;0:1-8.doi:10.1136/jnnp-2014-308136

    2. Chaichana KL, McGirt MJ, Laterra J, et al. Recurrence and malignant degeneration after resection of adult hemispheric low-grade gliomas. J Neurosurg 2010;112:10-17.

    3. Johnson BE, Mazor T, Hong C, et al. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science 2014;343:189-193.

    4. Russo E, Andreozzi F, Iuliano R, et al. Early molecular and behavioral response to lipopolysaccharide in the WAG/Rij rat model of absence epilepsy and depressive-like behavior, involves interplay between AMPK, AKT/mTOR pathways and neuroinflammatory cytokine release. Brain Behav Immun 2014; http://dx.doi.org/10.1016/j.bbi.2014.06.016

    Conflict of Interest:

    None declared

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  8. Serial electrophysiology in Guillain-Barre syndrome: how crucial and of how much clinical relevance?

    We thank Kokubun et al. [1], for their interest in our study. First, as we stated in our paper [2], our new proposed criteria provided, with a single study, globally, similar proportions and diagnostic shifts, to those found with older criteria and serial studies [3, 4]. There could be no indication from our study that in each and every single individual patient, similar diagnoses would be reached.

    Uncini et al. have however very recently, in a editorial on our paper in this journal, reported the results of the application of our criteria to their cohort of 55 patients [5]. This provided an albeit retrospective, validation of our criteria in another European population. They precisely used as gold-standard the serial studies available to them. For acute inflammatory demyelinating polyradiculoneuropathy (AIDP), they found that our criteria had a 70% sensitivity and 96% specificity with one study, versus 94% and 72% respectively obtained with Hadden et al.'s criteria [6]. For axonal GBS, our criteria had a sensitivity of 81% and a specificity of 94% with one study, versus 47% and 100% respectively with Hadden et al.'s criteria. Hence, diagnostic accuracy was equivalent with our criteria to that of Hadden et al.'s criteria for AIDP (83.6% for both) and substantially higher with our criteria for axonal GBS (89.1% vs. 80%), considering a single electrophysiological evaluation.

    Patient 1 presented by Kokubun et al. illustrates the superior accuracy of our criteria which allowed early identification of axonal GBS, with a single study, in keeping with the serological data provided. Kokubun et al.'s Patient 2, for her part, illustrates the fact that delayed appearance of electrophysiological abnormalities may, in a proportion of cases, result in late diagnostic confirmation of GBS subtype, irrespective of criteria utilized.

    As we also mentioned in our paper, our analysis otherwise demonstrated a sensitivity of 91.3% for a definite, i.e. unequivocal, diagnosis of GBS, irrespective of subtype. This level of sensitivity is, for a diagnostic test in the acute setting of this disease, and in comparison to other neuropathies such as chronic inflammatory demyelinating polyneuropathy [7], very high, and unambiguously shows, the practical usefulness of electrophysiology with our criteria with a single test.

    We are grateful to Kokubun et al. who state that our criteria may be more appropriate than previous criteria [1]. We fully agree that in a minority of cases, accurate diagnosis of GBS subtype may require a repeat set of nerve conductions. However, how relevant this may be from a purely clinical and diagnostic perspective, weeks after onset and treatment, remains very debatable in our opinion, particularly given the high accuracy of our criteria for GBS subtype, already achieved with a single study.

    References.

    1.Kokubun N, Nagashima T, Odamura M, Hirata K, Yuki N. Timing is crucial for electrodiagnosis of Guillain-Barré syndrome. J Neurol Neurosurg Psychiatry 2014, EPub before print.

    2. Rajabally YA, Durand MC, Mitchell J, et al. Electrophysiological diagnosis of Guillain-Barré syndrome subtype: could a single study suffice? J Neurol Neurosurg Psychiatry 2014 May 9 EPub ahead of print.

    3. Uncini A, Manzoli C, Notturno F, Capasso M. Pitfalls in electrodiagnosis of Guillain- Barré syndrome subtypes. J Neurol Neurosurg Psychiatry 2010;81:1157-1163.

    4. Shahrizaila N, Goh KJ, Abdullah S, Kuppusamy R, Yuki N. Two sets of nerve conduction studies may suffice in reaching a reliable electrodiagnosis in Guillain-Barré syndrome. Clin Neurophysiol 2013;124:1456-1459.

    5. Uncini A, Zappasodi F, Notturno F. Electrodiagnosis of GBS subtypes by a single study: not yet the squaring of the circle. J Neurol Neurosurg Psychiatry 2014 June 5 EPub ahead of print.

    6. Hadden RD, Cornblath DR, Hughes RA, et al. Electrophysiological classification of Guillain-Barré syndrome: clinical associations and outcome. Ann Neurol 1998;44:780-788.

    7. Rajabally YA, Nicolas G, Piéret F, et al. Validity of diagnostic criteria for chronic inflammatory demyelinating polyneuropathy: a multicentre European study. J Neurol Neurosurg Psychiatry 2009;80:1364- 1368.

    Conflict of Interest:

    Y.A.R. has received speaker/consultancy honoraria from LfB France, Griffols, and BPL and has received educational sponsorships from LfB France, CSL Behring and Baxter. G.N. has received deparmental research support/honoraria from Debiopharm, GSK, LfB France, Ipsen and Novartis.

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  9. Appropriate baseline setting for the evaluation of treatment

    Troussiere et al. conducted an interesting survey to prevent the progress of Alzheimer's disease in patients with sleep apnoea syndrome (SAS) by continuous positive airway pressure (CPAP) therapy (1). I fundamentally agree with their study outcome. I have a query on the setting of CPAP and non-CPAP groups.

    The cut-off point of 23 for Mini Mental State Examination (MMSE) is widely accepted. The authors mentioned that there was no significant difference in median value MMSE at baseline between two groups, but the max value of MMSE in 9 patients without treatment of CPAP was 24. On this point, I cannot ignore the 3.5 difference of median value. MMSE is one of the screening questionnaires and it reflects the progress of cognitive function in each patients.

    Vos et al. investigated the prevalence and long-term outcome of preclinical Alzheimer's disease according to the following criteria: cognitively normal individuals with abnormal amyloid markers (stage 1), abnormal amyloid and neuronal injury markers (stage 2), or abnormal amyloid and neuronal injury markers and subtle cognitive changes (stage 3), by follow-up 311 participants, aged 65 or older, with clinical dementia rating of 0 (2). The 5-year progression rate to clinical dementia rating at least 0.5 was calculated, according to the baseline stages. As a result, a symptomatic Alzheimer's disease was 2% for participants classed as normal, 11% for stage 1, 26% for stage 2, and 56% for stage 3, respectively.

    I suppose that baseline allocation of patients into CPAP and non-CPAP groups should be paid with caution, especially in MMSE. If not so, the net effect of CPAP treatment on the progress of cognitive function cannot determine. In addition, during the 3-year follow-up period, there is a possibility in the progress of preclinical Alzheimer's disease. I understand that SAS is not only the factor, but baseline setting is important to know the effect of CPAP therapy in patients with SAS for the progress of cognitive function.

    I also recommend the authors to check the MMSE values more frequently during the 3-year follow-up study.

    References

    1 Troussiere AC, Monaca Charley C, Salleron J, et al. Treatment of sleep apnoea syndrome decreases cognitive decline in patients with Alzheimer's disease. J Neurol Neurosurg Psychiatry 2014 May 14. doi: 10.1136/jnnp-2013-307544

    2 Vos SJ, Xiong C, Visser PJ, et al. Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study. Lancet Neurol 2013;12:957- 65.

    Conflict of Interest:

    None declared

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  10. CT-negative, lumbar puncture-positive and CTA-negative patients have a low risk of aneurysms.

    Dear Editor,

    We are grateful to Bakker et al. for their prospective study in this area.[1]

    Two months prior to this, we published on the topic of CT-negative, lumbar puncture-positive and CT-angiography (CTA) negative patients.[2] Such patients had been reported in 98 published cases. No causative aneurysms were found in neither these nor in the 9 cases which we identified.

    Bakker et al report 37 additional patients in the section 'Imaging' on page 3 of their article. These 37 patients had digital subtraction angiography (DSA) within 48 hours and no vascular lesions were found. This brings the number of published cases to 144.

    We recommend double-reporting of the CT angiogram in these apparently normal scans. The risk:benefit ratio of proceeding to DSA in such patients is debatable due to the relatively small number of published cases.

    Arnab K. Rana[a], Helen E. Turner[b] and Kevin A. Deans[b]

    a Aberdeen Biomedical Imaging Centre, University of Aberdeen, Lilian Sutton Building, Foresterhill, Aberdeen, AB25 2ZD, UK

    b Department of Clinical Biochemistry, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, AB25 2ZN, UK

    References:

    [1] Bakker NA, Groen RJM, Foumani M et al. Appreciation of CT- negative, lumbar puncture-positive subarachnoid haemorrhage: risk factors for presence of aneurysms and diagnostic yield of imaging. J Neurol Neurosurg Psychiatry doi:10.1136/jnnp-2013-305955.

    [2] Rana AK, Turner HE and Deans KA. Likelihood of aneurysmal subarachnoid haemorrhage in patients with normal unenhanced CT, CSF xanthochromia on spectrophotometry and negative CT angiography. J R Coll Physicans Edinburgh 2013; 43: 200-6.

    Conflict of Interest:

    None declared

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