Point-to-point response to the reviewers’ comments Report Tibo Gerriets: 1) ..it (the study) cannot provide any data in comparison to malignant MCA stroke patients who received conventional treatment… This is correct. We originally planned to compare a group of DCH patients with a conservatively treated patient group as well as a healthy control group. We simply did not manage to collect enough patients for the conservatively treated group. We now present a description of the cognitive situation of DCH patients. These results are certainly not representative of conservatively treated patients (and are not intended to be so). This study has shown us that a comparable work with conservatively treated patients could require a multi-center design. Nevertheless, to our knowledge there is no other study on a comparable number of DCH patients. We thus consider our work to be new and informative for the medical community. 2) …it (is) possible that this kind of patients had mild cognitive impairment (MCI) even before infarction This is true for all retrospective studies. We cannot rule out such an effect since we were not able to examine the patient before the cerebral infarction. However, in our opinion, the symptoms we observed would have been diagnosed before the disease if they had been present. We had to trust the information from the relatives that before the stroke no obvious abnormality was present. A major point is the delineation of our cognitive findings between MCI and dementia. There is no generally acknowledged, defining z value for “impairment”. The one we applied is described in the methods section. There are several reports in the literature dealing with this definition. 3) A statistical difference in cognitive performance overall (presented as one of the main findings) is just an expectable result when contrasting patients after severe brain lesions with healthy individuals After reading the paper by Leonard et al. on cognition after DCH, we expected much better results and were thus rather surprised at our findings. The group of healthy individuals was chosen because we applied a test battery composed for this study. However, all the tests used were evaluated test by test; a normal population for the total test battery was not available. Therefore, in our opinion it was necessary to compare the patient group not only to the results given in the respective test manuals but also to the test results of a healthy group who performed the same test sequence. In addition, we hope that by comparison with the results of the healthy group we were able to put the patients’ results in the context of more reliable normal values than just with the z values of the test handbook. 4) The selection of patients with non-speech dominant hemisphere stroke should be discussed insistently, since many authors do not exclude aphasic patients from DHC and find quite remarkable recovery of speech during the rehabilitation and acceptable QoL thereafter We have discussed this issue more extensively. However, even after a successful rehabilitation of aphasia, subtle but measurable deficits usually persist. Since there are no rules on how to correct cognitive test results with aphasic symptoms we were not able to include the speech-dominant DCH patients. 5) …modify I would furthermore modify the last sentence of the abstract. The term "should be informed" should be avoided and the second key finding (high incidence of depression) might be emphasized. We changed the paragraph accordingly. 6) How was post-stroke dementia differentiated from MCI? This comment is important. Patients with MCI must fulfil the criteria for MCI defined by the consensus conference in Stockholm in 2003 (Winblad et al., 2004). According to this definition, one affected cognitive domain is sufficient, and the activities of daily living have to be unimpaired. We quantified this impairment of ADL by means of the Nottingham extended activities of daily living scale. The results for the NEADL are given in table 1. All of our patients showed reduced scale values. According to the reviewer’s suggestion, we calculated a reduced form of our applied activities of daily living questionnaire to focus on the cognitive problems (“NEADLred.”). This revealed a patient with impaired cognitive functions whose NEADLred. score was normal. The text was changed accordingly. In agreement with your suggestions, we now have classified this patient as MCI (even though his overall NEADL score was reduced). 7)..z-scores somewhat lower than -1 indicate only mild impairment… We calculated a cut-off for impairment of z < -1.5. Even with this cut off, 16 of 20 patients fell into the group of impaired cognitive functions. 8) Depression - and this is a major issue - was very common in this study group. Cognitive results are severely influenced by depression (“pseudo dementia”), thus cognitive impairment or dementia could be over-estimated. Of course, depression (and other psychiatric diseases) can lead to cognitive impairment. This might be relevant for putative treatment options but still it remains a cognitive impairment caused by depression. However, the term pseudo-dementia is a matter of debatei. Actually, the term is not helpful and often misleading. The current DSM criteria for dementia thus do not use etiological or prognostic factors. This makes sense since nowadays we know that patients with psychiatric diseases such as schizophrenia or depression, which are accompanied by cognitive impairment, still show abnormal cognitive functions during mental symptom-free episodesii. In our patients with severe non-speech dominant brain ischemia we assumed that they realized their cognitive impairments, which in turn could have caused their depressive moods. Thus, we have here a mixture of causes that separated methodologically. However, that cognitive impairment in these patients is only caused by the frequently detected depressive mood is not very probable concerning the lack of significant correlations of the BDI score, the SCL90r score for depression and cognitive functioning. In addition visuo-constructive functions were also impaired (please see table 2). This domain is usually preserved in depressive patients with cognitive problemsiii. The same is true for the AAT (language)iv. We have added these explanations to the discussion. 9) …was depression correlated to the presence of epilepsy? We made a group comparison for the BDI score for depressed and non-depressed patients. The BDI scores were not statistically different. The patients with epilepsy did not perform significantly worse for the cognitive domains than the ones without epilepsy. These results were included into the paper. 10) The results indicate it is not the cognitive outcome that impairs quality of life primarily but depression, although these phenomena might be interrelated. This remark is correct; the phenomena are highly interrelated. Unfortunately, because of this, we are unable to separate the effects and the respective phenomena from each other. However, because of the high inter-correlations between the quality of life scales and the cognitive domain results, we are not sure whether the impairment of quality of life depends more on the presence of depression or cognitive impairment. 11) Detailed information about medical / psychotherapeutic treatment of the depressive symptoms should be provided None of the patients had undergone psychotherapy at the time of examination. Information on anti-depressive medication has been added to the text. 12) The authors do not state what underlying pathophysiology is assumed to play a role in the outcomes like cognitive impairment or depression. A paragraph with some pathophysiological background for the cognitive data has been added to the discussion section. 13) How long did the cognitive assessment take? The test battery is quite extraordinarily extensive. The assessment was very extensive. It took between 3 and 4 hours (with breaks). The time to fill in the questionnaires was approximately 45 min. 14) In Figures 1-2 it is advisable to present groups graphically more distinguishable (e.g. black vs. white). We changed the figures according to the reviewer’s suggestion. Reviewer 2, Dr. Jüttler 1) The authors should explain why not even one third of patients with malignant MCA infarction were operated.. Before 2000 patients with malignant MCA infarctions were only exceptionally treated neurosurgically in our hospital (DESTINY, HAMLET and DECIMAL data were not yet available at this time, and the benefits of this treatment was not yet clear). Originally, our study was designed to compare conservatively treated and neurosurgically treated patients after malignant MCA infarction. Therefore, files of five consecutive years were analyzed. In the years 2000-2003, 40 patients were treated, of whom 21 received a DCH. We have provided more information on the patient group in the methods section. 2) The authors must clearly try to explain this difference and must very clearly state that these results are unexpectedly poor and that therefore their patient population is not at all representative compared with most other centres. The poor Rankin scale of the population has to be attributed to the older mean age as compared to the large DCH studies. This and the fact that our data might not be representative for younger patients (who are at the moment the ones recommended for surgery) are now mentioned in the discussion. 3) QoL questionnaires…the authors must clearly explain why they used these specific instruments for evaluation and not others. When we planned the study, DESTINY and HAMLET were not yet available. WHO aimed to establish a common QoL score. The WHOQoL questionnaire is one of the most often used QoL questionnaires (17 Pubmed hits in conjunction with stroke, whereas the SF36 has 15 hits in the context of stroke). The WHOQoL is well evaluated available in many languages and therefore the data may serve as the basis for future research. To make our data comparable and to give an idea of the severity of QoL impairment, we used a healthy control group and standardized the results for the QoL. Thus, in our opinion, the WHOQoL is one of the best questionnaires in the area of health-related QoL. Meanwhile, recent data show the good comparability of the WHOQoL and the SF36 as to their respective subscalesv. 4) I would strongly recommend not to use a cut-off for age….age should better be used as a continuous variable In agreement with the reviewer, we omitted the group comparisons of younger and older patients derived from a cut-off, and instead included correlative data. 5) NIHSS score must be described as median, not as mean and non-parametric tests should be used. We have used for the group comparison of the NIHSS a non-parametric description. 6) I would strongly recommend to the authors to keep their data merely descriptive.. Multivariate analysis has been omitted from the statistics. We applied only simple group comparisons and used the very conservative non-parametric statistics (U-test), replacing the t-tests even when the data was normally distributed in order. 7) The majority of patients suffered from depression. Were the results correctly interpreted with respect to the presence of depression, because this may influence neuropsychological testing and other tests, quality of life and the decision to retrospectively agree with treatment. Were these patients adequately treated for depression? This question was also asked by reviewer 1. We now have discussed this point in more detail in the discussion section. However, the time we could spend with the patients was too short to ascertain by one interview whether the depression (if present) was treated adequately or sufficiently. Of course, mood influences cognition. However, from the pattern of cognitive changes that we observed, there is solid evidence that depression was not the main cause for the cognitive changes (however, the localisation of the lesion could well have caused depression as well). 8) To me it is unclear what the comparison of these patients to healthy subjects should explain or demonstrate. A comparison to healthy control group must be done when several neuropsychological tests are used since the tests must be validated test per test, never in a larger test battery. Whenever we want to classify neuropsychological results in our coordinate system of healthy and pathological, the healthy result has always to be given for the respective setting in which the study was performed. A comparison made only to the test manuals’ z values is methodologically not acceptable. 9) …more useful if the authors would compare the results to other severely brain injured patients such as patients with SAH We aimed at normalizing the results and providing a well matched control group, thus allowing the reader to compare our findings with other measurements of cognitive functions in any other disease (such as SAH). 10) …discussion is much too long The discussion has been re-structured and focussed on the above mentioned issues. 11) …not so much focussing on aspects such as the influence of age… The comparisons of the younger and older age-groups have all been omitted. 12) …comparing the results of this study with those of other studies on quality of life, retrospective agreement to the procedure.. This has been done. Minor points: 13) The introduction is too long We have shortened the introduction and made the discussion a little bit longer. 14) ..hardly was used as largely. The manuscript would clearly profit from a revision by a professional translator. No, hardly was really meant. The manuscript has been corrected by a native English speaker. Again, after the revision, this native speaker is responsible for the grammatical and orthographical style of the manuscript. 15) …but I do not feel adequately qualified to assess the statistics. According to the reviewer’s suggestion, we omitted all more complex calculations and only used simple group comparisons. This kind of statistical calculations could easily be performed without the help of a statistician (who would clearly be underchallenged by such a task). i McAllister, T.W. &Price, T.R.P. (1982). Severe depressive pseudodementia with and without dementia.. American Journal of Psychiatry, 139, 626-629. ii Crowe, S.F. (1998). Neuropsychological effects of the psychiatric disorders. Amsterdam: Harwood Academic Publishers.. iii Rosenstein, L.D. (1999). Visuoconstructional drawing ability in the differential diagnosis of neurologic compromise versus depression.. Archives of Clinical Neuropsychology, 14, 359-372. iv Theml, T. (2001). Zeitschrift für Neuropsychologie© 2001Verlag Hans HuberNovember Vol. 12, No. 4, 302-313 v Unalan D, Soyuer F, Ozturk A, Mistik S. Comparison of SF-36 and WHOQOL-100 in patients with stroke. Neurol India. 2008 Oct-Dec;56(4):426-32.