We read with interest the work by Kim et al that shows relationship between radiological characteristics and molecular signatures in a group of 49 patients with anaplastic oligodendroglioma (AO) and 7 patients with anaplastic oligoastrocytoma (AOAs). Frontal lobe location, indistinct tumor borders and heterogeneous intratumoral signal intensity were significantly correlated with the 1p19q codeletion. It has been previously published the existence of molecular heterogeneity associated to location in oligodendroglial tumors showing an increased frequency of 1p19q codeletion in frontal lobe location whereas temporal lobe location associated greater number of patients lacking 1p19q codeletion. Previous works also describe decreased chemosensibility of AO located in temporal lobe, insula and diencephalus. The authors try to conclude that high-grade oligodendroglial tumors (AO/AOAs) share a similar relationship between radiological characteristics and molecular signatures as in oligodendroglial tumors. We would like to add further comments to these issues. First, the limited number of patients and doubtful tumoral anatomical location (eleven tumor cases were located in multiple lobes) should make see the results cautiously. Previous published experiences report loss of heterozygosity for 1p and 19q to be significantly associated with a bilateral pattern of growth [1], but Kim et al do not refer to bilateral pattern in their paper, nor clearly define multiple location, and only report 4 patients with parieto-occipital lesion and 11 with temporoinsular location. Second, we would like also to raise the question of patient selection: management of low grade glioma is very heterogeneous including total/subtotal removal of the lesion with functional boundaries, biopsy and even "wait and see" attitude. In our opinion, only complete or near complete removal of low grade glioma can give complete information of the histological diagnosis, since it is our experience that anaplastic transformation loci, and astrocytic component can be seen after expanded removal in a previously so called low grade lesion or oligodendroglial lesion without astrocytic component. Third, the authors report intratumoral heterogeneous to be favorable sign for patient survival and also that this signal may result from intratumoral haemorrhage, necrosis or calcification. The 2009 EORTC prospective randomized study on molecular analysis of anaplastic oligodendroglial tumors [2], report both necrosis, and 1p(loss)19q(loss) to be independent prognostic factors. Since necrosis has a profound impact on survival, a more refined description of intratumoral heterogeneity could help to establish the association between both radiological and molecular characteristics. Fourth, we read with surprise that no significant relationship between 1p19q codeletion and tumor enhancement is found in the present series. Around 20% of AO have the enhancement pattern, which is statistically correlated with frequent recurrence, indeed, some series report not to have found combined 1p/19 loss in any of the cases with anaplastic oligodendrogliomas with enhancement pattern [3]. Although quite interesting, the study has several limitations, particularly its retrospective nature. Further prospective studies including larger numbers of cases and standardized evaluation of 1p19q codeletion in conjunction with other relevant prognostic parameters are needed to draw definitive conclusions on the issue of radiological markers for molecular signatures in grade III oligodendroglial tumors 1. Zlatescu MC, TehraniYazdi A, Sasaki H, et al. Tumor location and growth pattern correlate with genetic signature in oligodendroglial neoplasms. Cancer Res 2001; 61:6713-15. 2. Kouwenhoven MC, Gorlia T, Kros JM, et al. Molecular analysis of anaplastic oligodendroglial tumors in a prospective randomized study: A report from EORTC study 26951. Neuro Oncol 2009; 11:737-46. 3. Young Choi, Tae-Young Jung, Shin Jung, et al. Prognosis of oligodendroglial tumor with ring enhancement showing central necrotic portion. J Neurooncol 2011; 103:103-110

Conflict of Interest:

None declared

Response to letter regarding article, "The prognosis of acute subdural haematoma from intracranial aneurysm rupture."

J. Matthijs Biesbroek1, MD; Jan Willem Berkelbach van der Sprenkel1, MD, PhD; Ale Algra1,2, MD; Gabriel J.E. Rinkel1, MD.

1. Utrecht Stroke Centre, Department of Neurology and Neurosurgery, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands. 2. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.

Corresponding author J. Matthijs Biesbroek, MD. University Medical Center Utrecht Department of Neurology Heidelberglaan 100 Room G03.323 3508 GA Utrecht The Netherlands Tel. +31 88 755 5555 Fax. +31 30 254 2100 E-mail: J.M.Biesbroek@umcutrecht.nl

Word count: 512 References: 4

RESPONSE

We thank Dr Gelabert-Gonz?lez and co-workers for their interest in our study, in which we concluded that the presence of acute subdural hematoma (aSDH) in patients with aneurysmal subarachnoid haemorrhage (SAH) is an independent risk factor for poor outcome. These findings were based on 713 patients with SAH admitted from 1986 through 2009, of whom 53 had aSDH.1

Dr Gelabert-Gonz?lez and co-workers raised two questions regarding our treatment protocol for patients with SAH. Firstly, they wondered why a large number of patients were not subjected to arteriography and stated that arteriography is important in identifying the exact location of aneurysms as well as any possible anatomical variation in brain arteries. Until 1995 the policy in our hospital was to perform arteriography only in case aneurysm surgery was considered. Surgery was until then mostly performed in the late phase. In patients who were (initially) not in a good clinical condition, arteriography was not performed until patients had recovered. Thus, those patients who did not recover did not undergo arteriography. From 1995 onwards, all patients with SAH undergo CT angiography (CTA) on admission and most patients are operated upon in the early phase. In our experience this CTA often provides sufficient information for surgical planning of the operation, thus obviating the need for arteriography in many of these patients.2,3

Secondly, the authors wondered why the majority of patients with aSDH and poor clinical condition on admission did not undergo decompressive surgery and noted that in their experience urgent surgical decompression and immediate aneurysm clipping results in better outcomes than delayed treatment or non-treatment. They refer to their retrospective study on four patients with aneurysmal aSDH who underwent decompressive surgery and clipping of the aneurysm.4 Despite this aggressive approach, 2 patients died, 1 was disabled and dependent and 1 patient had good clinical outcome at discharge. In our series, 13 out of 53 patients with aSDH underwent decompressive surgery (eight of whom within 24 hours), which was combined with clipping of the aneurysm in 11 cases. Out of 53 patients with aSDH, 79% had poor outcome at discharge and 75% had poor outcome at 3 months. Thus, clinical outcome of patients with aSDH was essentially the same in both series. We favour a tailored approach in patients with aSDH after aneurysmal rupture. In patients in whom we consider the aSDH to be (partially) the cause of the poor condition, we advocate surgery; in case it is highly unlikely that the aSDH contributes to the poor clinical condition, we are reluctant to perform decompressive surgery. We do agree with the authors that in case of an aSDH after aneurysmal rupture not all is lost and an aggressive approach is needed. Patients with an aSDH after aneurysmal rupture should always be transferred to a tertiary referral centre where the pros and cons of decompressive surgery should be decided on an individual basis. We hope that our study and the letter from Dr Gelabert-Gonz?lez and co-workers contribute to a more aggressive approach and thereby to a higher chance of good outcome for patients with aSDH after aneurysmal rupture.

REFERENCES 1. Biesbroek JM, Berkelbach van der Sprenkel JW, Algra A, et al. Prognosis of acute subdural haematoma from intracranial aneurysm rupture. J Neurol Neurosurg Psychiatry. doi: 10.1136/jnnp-2011-302139. Published Online First: 31 October 2012 2. Velthuis BK, Van Leeuwen MS, Witkamp TD, et al. Computerized tomography angiography in patients with subarachnoid hemorrhage: from aneurysm detection to treatment without conventional angiography. J Neurosurg 1999;91:761-7. 3. Velthuis BK, Rinkel GJ, Ramos LM, et al. Subarachnoid hemorrhage: aneurysm detection and preoperative evaluation with CT angiography. Radiology 1998;208:423-30. 4. Gelabert-Gonz?lez M, Iglesias-Pais M, Fernandez-Villa JM. Acute subdural haematoma due to ruptured intracranial aneurysms. Neurosurg Rev 2004;27: 256-62.

Conflict of Interest:

None declared

Dear Sir, We are pleased with the interest of Weerkamp in our work and are grateful for his comments, giving us the chance to comment the results of our study [1]. We would like to further thank him for having raised the issue of several scales which have been developed to assess the non-motor symptoms (NMS), but include such motor symptoms as morning dystonia and tremor on awakening. However, this is not the case here. Indeed, the NMS-Quest does not include such symptoms (nor they are discussed in our paper) and is likely to reflect a "pure" non-motor involvement [2]. With regard of the possible confounding interaction between the motor fluctuations and the NMS, it should be stressed that the NMS-Quest assesses the presence of NMS which patients might have experienced in the previous month. It is thereby very unlikely that the NMS-Quest may be severely affected by the pharmacological state. Nevertheless, it has been suggested that NMS may also fluctuate in more advanced stages of the disease. However, our patients were all evaluated in the on-state when assessed at follow-up and none of them had experienced motor fluctuations, as we have stated in our work. On the other hand, the reliability of the NMS-Quest in different pharmacological states has not been tested yet, and it may be interesting to further compare it with different scales, such as the Wearing-Off Questionnaires, which have been specifically developed for the non-motor fluctuations [3]. With regard of the study's design and the aim to assess the NMS progression, it should be noticed that, due to the efficacy of pharmacological treatment, evaluation of the natural progression of both motor and non-motor features of PD is nowadays impossible. Data on the natural short-term worsening of motor symptoms have been indeed obtained from patients in the placebo arms of controlled studies. To our knowledge, no placebo-controlled study has been developed so far regarding the whole NMS complex and its progression over the disease course and the dopaminergic therapy introduction. The work which has been mentioned by Weerkamp (the RECOVER study), neither included drug-naive PD patients at enrollment nor provided long-term outcomes regarding the NMS. It only showed the efficacy of 3-month lasting therapy with rotigotine on a few NMS (i.e. sleep disturbances, which in our opinion may partially reflect motor disturbances). This setting is far away from the clinical practice and from our first aim, which was to evaluate the NMS burden in the first 4 years of the disease over the dopaminergic therapy introduction. A control group of untreated patients would have given of course more informations to discuss, but this kind of study's design is impossible at present due to ethical issues. Assessment of the natural long-term progression of NMS over the whole disease course is indeed possible only by mean of comparisons of patients with and without L-Dopa and/or dopamine agonists. We finally want to thank Weerkamp for having brought to our attention the recently published article focusing on NMS progression [4], which unfortunately had not been published by the time of our submission. Antonini and colleagues attempted to evaluated the NMS progression and its relationship with quality of life in a large cohort PD patients. Although they used a different scale for the assessment of NMS and included more advanced (also fluctuating) patients with no informations regarding the dopaminergic therapy (for details, see the PRIAMO study), their findings are in line with our results and highlight the concept that NMS progression pursues different patterns and that the relationship between the dopaminergic therapy and the NMS improvement is not straightforward. This is further supported by the results of other studies evaluating the short-term effects of dopaminergic treatment on NMS in de novo PD patients [5]. Assessing the non-motor progression is currently one of the most exciting challenge of the research on PD: our results should serve as an incentive for planning future studies targeting the non motor disturbances. Given the absence of a reliable bio-marker which may be able to measure the underlying pathological progression, further clinical studies are needed to prospectively evaluate both NMS occurrence and severity and how they are modified by specific therapies.

Roberto Erro, Paolo Barone.

Reference [1] Erro R, Picillo M, Vitale C, et al. Non-motor symptoms in early Parkinson's disease: a 2-year follow-up study on previously untreated patients. J Neurol Neurosurg Psychiatry. 2013;84(1):14-7 [2] Martinez-Martin P, Schapira AH, Stocchi F, et al. Prevalence of nonmotor symptoms in Parkinson's disease in an international Setting; study using Nonmotor symptoms questionnaire in 545 patients. Mov Disord 2007;22:1623-9. [3] Stacy M. The wearing-off phenomenon and the use of questionnaires to facilitate its recognition in Parkinson's disease. J Neural Transm. 2010;117:837-46. [4] Antonini A, Barone P, Marconi R, et al. The progression of non-motor symptoms in Parkinson's disease and their contribution to motor disability and quality of life. J Neurol. 2012;259:2621-31. [5] Kim HJ, Park SY, Cho YJ, et al. Nonmotor symptoms in de novo Parkinson disease before and after dopaminergic treatment. J Neurol Sci 2009;287:200 -4.

Conflict of Interest:

None declared

We would like to share several observations that we made on Ammirati et al. recently published meta-analysis. The authors reviewed the available English-language literature from 1990 to the present, comparing microsurgery versus endoscopy for treatment of pituitary adenomas, and conducted a systematic review and meta-analysis of the data obtained. The authors concluded that the two treatment methods produced similar outcomes for all of the variables analyzed, except for a statistically significant higher rate of vascular complications with endoscopy. We want to point out that endoscopy-assisted studies were included in the microsurgery cohort, including most notably a study by Mortini et al.1 involving 1140 patients, which represented 32.4% of all of the microsurgery cases and thus was weighted heavily in the analysis. The use of intraoperative endoscopy after microscopic resection provides the advantages of endoscopic procedures, such as better visualization of structures and of lateral and suprasellar limits, as well as differentiation between normal and diseased tissue. Inclusion of these patients introduces significant bias, strongly favoring microsurgery by giving it the advantages of endoscopy, and complicating a comparison between the two methods. Additionally, the variety of complications that were grouped together as vascular complications was highly heterogeneous, encompassing carotid lesions, lesions in less important vessels like the sphenopalatine artery, intracranial or sellar hemorrhages, ischemic infarcts, and cavernous sinus bleeding. While all of these complications are of a vascular nature, their characteristics and the resulting morbidity/mortality can be quite different. The limitations of microsurgery for treatment of significant invasions into the cavernous sinus are well known. Thus, when approaching an invasive cavernous sinus adenoma endoscopically for treatment, as in the study by Zhang et al.2, consideration of vascular complications from cavernous sinus bleeding is not comparable to microsurgical approach cases where there was no initial intention to treat invasive cavernous sinus tumors. Moreover, based on available data, we can only be certain that 57,6% (2027/3518) of the microscopic patients were macroadenomas, whereas 77% (1453/1887) of the cases were macroadenomas in the endoscopic cohort. This heterogeneous distribution of patients for something as fundamental as differentiation between micro and macroadenomas could have influenced the meta-analysis results, especially the observed rates of complete resection, vascular complications and csf leak. It is also worth noting that of the 22 microsurgery studies included, only 12 had data on vascular complications, whereas 17/24 endoscopic studies had such data. Meta- analysis variable data are collected more frequently, in general, in endoscopic studies than in microsurgery studies.As for the meta-analysis methodology, depending on the heterogeneity between studies, fixed effect models or randomized models were applied. Randomized models provide more conservative estimates than fixed effect models, and therefore are more apt to miss existing differences. These methods were used to compare rates of diabetes insipidus, hypopituitarism, and complete resection. All trended toward favoring the endoscopy group, but without statistical significance. Death rates for the microsurgery and endoscopy cohorts were 0.23% and 0.49%, csf leak 6.34 vs 7%, meningitis 2,08 vs 1.11%, vascular complication 0.5 vs 1.58%, visual loss 0.60 vs 0.72%, diabetes insipidus temporary 10.23 vs 9.10% and permanent 4.25 vs 2.31%, hypopituitarism 11,64 vs 8.51%, nerve injury 0.53 vs 0.28% and complete resection 64.44 vs 68.77% respectively. When we evaluated surgeons with more than 500 microsurgeries from the study by Ciric et al.3, the death rate was 0.2%, csf leak 1.5%, meningitis 0.5%, vascular complication (carotid artery injury + hemorrhage residual tumor) 1.2%, visual loss 0.5%, diabetes insipidus 7.6%, hypopituitarism 7.2%. Thus, with respect to vascular complications, death, diabetes insipidus, and hypopituitarism, the microsurgery group turned out to be a select group of patients with results superior to those obtained by highly experienced microsurgery specialists. This result could be due to many reasons, such as those suggested above, including: a series of patients with a high incidence of microadenomas; inclusion of endoscopy-assisted cases in the microsurgery group; the long tradition and evolution of microsurgery since the 1950s versus the recent history of purely endoscopic techniques (first series reported in 1997); and the significant experience of microscopic surgeons whose numerous studies populated the meta-analysis. There were two microsurgery studies, which described sets of 1140 and 638 patients; meanwhile, eight microsurgery studies described the treatment of only functional tumors, and six of the reviewed studies included more than 50 acromegalies or Cushing's syndrome cases, implying that the surgeons in question treated a significant number of adenomas. On the other hand, only one endoscopic study had more than 200 patients. If we compare the group of surgeons with less than 200 microscopic surgeries from the study by Ciric et al. (results: death rate 1.2%, csf leak 4.2%, meningitis 1.9%, vascular complication 4.2%, visual loss 2.4%, diabetes insipidus 19%, hypopituitarism 20,6%), with the metaanalisis endoscopic group, results strongly favor endoscopy. Nevertheless, the rates of complete resection, hypopituitarism, diabetes insipidus, meningitis, and nerve damage were all better for patients treated purely endoscopically, although without statistical significance. The authors of the review study criticize prior meta-analyses for being biased toward endoscopy based solely on the argument of fewer included patients; but they did not take into account their own inclusion criteria, which were more restrictive, considering only studies comparing both techniques, but not those using endoscopy- assisted microsurgery or those without complete outcomes that would enable better data ?interpretation and more solid and reliable results. In short, reading this study in isolation can lead to erroneous conclusions given the aforementioned biases and limitations.

Reference

1. Ciric I, Ragin A, Baumgartner C, et al. Complications of transsphenoidal surgery: results of a national survey, review of the literature, and personal experience. Neurosurgery 1997;40:225-37.

2. Mortini P, Losa M, Barzaghi R, et al. Results of transsphenoidal surgery in a large series of patients with pituitary adenoma. Neurosurgery 2005;56:1222-33.

3. Zhang X, Fei Z, Zhang W, et al. Endoscopic endonasal transsphenoidal surgery for invasive pituitary adenoma. J Clin Neurosci 2008;15:241-5.

Conflict of Interest:

None declared