Recent eLetters

I have read, with great interest, the paper by Stemer et al. titled 'Acute embolization of ruptured brain arteriovenous malformations' [1]. The authors describe a cohort of 21 patients with ruptured intracranial arteriovenous malformations (AVM) who were treated with endovascular Onyx (ev3, Irvine, California, USA) embolization in the acute phase following hemorrhage. The median interval from hemorrhagic presentation to treatment was 4 days (range 0-19 days). Thirteen patients received a single treatment (62%), and eight patients were treated in more than one stage (38%). Complete occlusion was achieved in 11 patients (52%) including seven in one stage and four in multiple stages. There were two asymptomatic intraprocedural complications (10%) as well as two mortalities unrelated to treatment (10%).

Excluding three patients lost to follow-up and six patients who underwent post-embolization surgical resection, 12 patients had angiographic follow-up at a mean interval of 7.5 months. It would be interesting to know the number of AVMs, if any, which had post- embolization recanalization at follow-up as this is known to occur at varying time intervals following endovascular treatment. Despite high levels of initial enthusiasm for complete AVM cure with standalone endovascular embolization following the advent and subsequent widespread therapeutic use of permanent liquid embolic agents, especially Onyx, the role of embolization in the overall management of AVMs remains largely adjunctive.

Studies reporting high rates of complete AVM obliteration with embolization alone, approaching 50%, were subject to significant selection biases [2]. Total obliteration rates of 10-20% with embolization alone are more reflective of less selected AVM cohorts [3]. The effect of partial AVM treatment on the subsequent hemorrhage risk is still controversial with conflicting studies reporting improved and worsened outcomes of incompletely obliterated AVMs. With increasing evidence that embolization reduces AVM obliteration rates following radiosurgery, judicious use of endovascular therapy for AVMs is crucial to the optimal long-term management of these complex vascular lesions [4-6].

Early natural history studies of AVMs did not distinguish ruptured from unruptured lesions. However, several recent studies in the past decade have repeatedly demonstrated that the hemorrhage risk of ruptured AVMs is significantly higher than the hemorrhage risk of unruptured ones [7]. Unlike intracranial aneurysms, for which the risk of acute repeat hemorrhage following initial rupture is well described, the acute rehemorrhage rate of ruptured AVMs is poorly defined. In a recent meta- analysis of over 3900 patients, Gross et al. reported an annual hemorrhage risk of 4.5% for ruptured AVMs compared to 2.2% for unruptured lesions [8]. A follow-up duration of less than one year, such as in this study, is inadequate to compare treatment outcomes to the natural history.

In summary, the authors should be congratulated for demonstrating the feasibility and safety of endovascular Onyx embolization for the treatment of acutely ruptured AVMs. As the authors note, the study is significantly limited by the relatively small number of patients with angiographic follow-up and the relatively short duration of follow-up. Therefore it remains to be determined in larger cohorts with longer follow-up whether the strategy of acute embolization for ruptured AVMs is superior to current approaches which are largely conservative in the acute post- hemorrhage phase.

References

1. Stemer, A.B., W.O. Bank, R.A. Armonda, A.H. Liu, D.W. Herzig, and R.S. Bell, Acute embolization of ruptured brain arteriovenous malformations. J Neurointerv Surg, 2013. 5(3): p. 196-200. 2. Saatci, I., S. Geyik, K. Yavuz, and H.S. Cekirge, Endovascular treatment of brain arteriovenous malformations with prolonged intranidal Onyx injection technique: long-term results in 350 consecutive patients with completed endovascular treatment course. J Neurosurg, 2011. 115(1): p. 78-88. 3. van Rooij, W.J., M. Sluzewski, and G.N. Beute, Brain AVM embolization with Onyx. AJNR Am J Neuroradiol, 2007. 28(1): p. 172-7; discussion 178. 4. Schwyzer, L., C.P. Yen, A. Evans, S. Zavoian, and L. Steiner, Long-term Results of Gamma Knife Surgery for Partially Embolized Arteriovenous Malformations. Neurosurgery, 2012. 71(6): p. 1139-48. 5. Ding, D., C.P. Yen, Z. Xu, R.M. Starke, and J.P. Sheehan, Radiosurgery for patients with unruptured intracranial arteriovenous malformations. J Neurosurg, 2013. 6. Andrade-Souza, Y.M., M. Ramani, D. Scora, M.N. Tsao, K. terBrugge, and M.L. Schwartz, Embolization before radiosurgery reduces the obliteration rate of arteriovenous malformations. Neurosurgery, 2007. 60(3): p. 443-51; discussion 451-2. 7. Stapf, C., H. Mast, R.R. Sciacca, J.H. Choi, A.V. Khaw, E.S. Connolly, J. Pile-Spellman, and J.P. Mohr, Predictors of hemorrhage in patients with untreated brain arteriovenous malformation. Neurology, 2006. 66(9): p. 1350-5. 8. Gross, B.A. and R. Du, Natural history of cerebral arteriovenous malformations: a meta-analysis. J Neurosurg, 2013. 118(2): p. 437-43.

Conflict of Interest:

None declared

Nohra Chalouhi M.D., Stavropoula Tjoumakaris M.D.,and Pascal Jabbour M.D.

We read with great interest the article by Turk et al[1] assessing the safety and efficacy of endovascular stroke intervention based on CT perfusion (CTP) criteria. The authors are to be congratulated for this excellent report and for achieving remarkably high rates of favorable outcomes (42%) in stroke patients with poor neurological status (mean NIHSS, 18.2). They further categorize their patient population based on time from symptom onset and clearly show that patients treated after 8 h had no difference in outcomes or mortality than those treated before 8 h. The fact that time from symptom onset to intervention was as long as 16.4 h in the late group (>8h) lends further credence to their findings because the extent of salvageable brain tissue and the prospect of improvement significantly decrease with delayed recanalization.[2-4] This report adds substantially to the growing body of literature supporting the use of CTP in stroke patients and reinforces what we have always believed; specifically, CTP can optimize and guide patient selection for intraarterial therapy based on an individual's physiological parameters namely the extent of salvageable ischemic penumbra.

Although we agree with the authors about the merits of CTP and stress the importance of their results, we would like to bring to their attention that their conclusion may not be totally supported by the presented data. The authors have compared functional outcomes in patients treated <8 h and >8 h after symptom onset. Although all patients were selected for endovascular stroke intervention based on CTP criteria, they conclude that "physiologic imaging-guided patient selection rather than time for endovascular reperfusion in ischemic stroke may be effective and safe". We believe the only way to reach such a conclusion is to compare two groups of patients, one selected based on CTP criteria and the other based on time from symptom onset. Indeed, the authors do not discuss the study by Hassan et al[5] published in 2010 that retrospectively compared 69 patients undergoing CTP-guided and 127 patients undergoing time-guided endovascular treatment. The authors of this study found no incremental benefit with the use of CTP, with similar rates of recanalization, intracranial hemorrhage, favorable outcomes, and in-hospital mortality in both groups. It should be noted, however, that only 40% of patients in their study underwent mechanical thrombectomy and that CTP-guided treatment at the primary author's institution was compared to time-guided treatment at a different institution, which could have influenced their results. Still, this is to our knowledge the only study that has compared time-guided to CTP-guide patient selection for acute stroke intervention. Randomized controlled trials comparing the 2 strategies are needed especially that many prominent centers still have not adopted CTP as a screening tool in this setting.

We would also like to highlight some of the potential shortcomings associated with CTP that were not discussed in this study. The inter- observer variability remains a great concern with CTP.[6] Additionally, the optimal post-processing algorithm for defining penumbra and core infarct have yet to be determined, and thresholds for guiding therapy are still under investigation.[7] The variation in reconstruction of CTP images and qualitative interpretation of salvageable tissue may lead to selection of a relatively heterogeneous population, leading to the inclusion of patients with limited salvageable tissue. False negatives and non interpretable imaging can occur with CTP due to low cardiac output, inappropriate slow rate of bolus administration, contrast extravasation in the subcutaneous tissue, patient movement, and operator inexperience.

Finally, despite the potential caveats of CTP imaging , Turk et al[1] have clearly demonstrated that CTP allows effective treatment of many patients who otherwise would be destined for supportive management or end of life care due to presentation outside of the therapeutic window. We commend the authors for their rigorous work and await similar contributions that will help us determine the best approach for patient selection for acute stroke intervention.

References 1. Turk AS, Magarick JA, Frei D, et al. CT perfusion-guided patient selection for endovascular recanalization in acute ischemic stroke: a multicenter study. J Neurointerv Surg 2012 doi: neurintsurg-2012-010491 [pii] 10.1136/neurintsurg-2012-010491[published Online First: Epub Date]|. 2. Wardlaw JM, Murray V, Berge E, et al. Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis. Lancet 2012;379(9834):2364-72 doi: S0140-6736(12)60738-7 [pii] 10.1016/S0140-6736(12)60738-7[published Online First: Epub Date]|. 3. Hesselmann V, Niederstadt T, Dziewas R, et al. Reperfusion by combined thrombolysis and mechanical thrombectomy in acute stroke: effect of collateralization, mismatch, and time to and grade of recanalization on clinical and tissue outcome. AJNR Am J Neuroradiol 2012;33(2):336-42 doi: ajnr.A2746 [pii] 10.3174/ajnr.A2746[published Online First: Epub Date]|. 4. Vergouwen MD, Algra A, Pfefferkorn T, et al. Time Is Brain(stem) in Basilar Artery Occlusion. Stroke 2012 doi: STROKEAHA.112.666867 [pii] 10.1161/STROKEAHA.112.666867[published Online First: Epub Date]|. 5. Hassan AE, Zacharatos H, Rodriguez GJ, et al. A comparison of Computed Tomography perfusion-guided and time-guided endovascular treatments for patients with acute ischemic stroke. Stroke 2010;41(8):1673-8 doi: STROKEAHA.110.586685 [pii] 10.1161/STROKEAHA.110.586685[published Online First: Epub Date]|. 6. Hassan AE, Zacharatos H, Chaudhry SA, et al. Agreement in endovascular thrombolysis patient selection based on interpretation of presenting CT and CT-P changes in ischemic stroke patients. Neurocrit Care 2012;16(1):88 -94 doi: 10.1007/s12028-011-9577-9[published Online First: Epub Date]|. 7. Amenta PS, Ali MS, Dumont AS, et al. Computed tomography perfusion- based selection of patients for endovascular recanalization. Neurosurg Focus 2011;30(6):E6 doi: 10.3171/2011.4.FOCUS10296[published Online First: Epub Date]|.

Conflict of Interest:

None declared

Hirsh and Meyers espouse that same party line of the many private non -governmental agencies (and academics who will personally benefit from this program) who wish to impose private interest group-unproven corporate interests upon practicing physicians. They continue to state MOC is "voluntary" and then describe the many ways these "non-profit" corporations (who earn handsomely and have over $400 million in assets and as great yearly gross receipts!) will see this product forced on physicians. HOWEVER, Working physicians do not want or even see any value in this unproven imposition:

The American Medical Association (AMA) developed the Physician's Recognition Award (PRA) in the late 1960's as the validation program for Continuing Medical Education (CME), embraced by most, but not all states, to validate physician "lifelong learning" as the educational component of re-licensure. Recently, the Federation of State Medical Boards (FSMB), Inc., a multimillion dollar, non-profit and non-governmental corporation, targeted the State of Ohio as the first of 11 pilot states to implement their corporate brand of MOL (Ohio., Calif., Colo., Del., Iowa, Mass., Mississippi, Okla., Ore., Va., Wis.). On May 19, 2012, the Ohio State Medical Association, as the first Ohio physician organization, formally resolved at the state meeting to oppose the FSMB MOL program. (1) OSMA recognized early that FSMB MOL was the unwarranted regulatory capture of physician licensure: the act of securing corporate income through legislation. (2) An intense battle over FSMB MOL ensued within the State Medical Board of Ohio (SMBO), zealously led by two FSMB board members, who also occupied the SMBO Executive Director and one senior Board member positions. On October 5, 2012, the OSMA drafted with 10 other state medical associations, representing over 15,000 physicians, a formal resolution of opposition directed to the SMBO. (3) The defeat of the FSMB MOL proposal by SMBO vote followed on October 11, 2012. In the aftermath, the two FSMB board members serving on the SMBO were formally reviewed. The Executive Director of the SMBO was ousted October 12th and formal investigations regarding violations of conflict of interests continue regarding the senior SMBO member. (4) Subsequent communications with legal offices of the SMBO and OSMA concluded that: 1) FSMB MOL was not advocated by any other corporate, government or consumer groups, no deficiency of AMA PRA CME programs or physician competency issues were identified in Ohio and 2) FSMB MOL initiative appeared solely promulgated by the FSMB as a corporate mandate. It continues to be actively advocated by FSMB in 9 states and must be either fought or approved in each state. FSMB MOL serves primarily corporate coffers and false reassurance through testing vs CME. Effective physician opposition is primarily possible via grass-roots resolutions at state level. We must inform and support all state organizations at this time regarding FSMB MOL, using this "Ohio experience" as evidence and instruction in opposing this regulatory capture of physicians, solely for corporate profits. (5) The assertions by the Certification industrial complex including the ABMS that MOC and MOL are "Done deals" is simple propaganda-nothing more!

References: 1) Ohio State Medical Association Statement on MOL. Available at: http://www.osma.org/files/pdf/facts-maintenance-of-licensure-final-.pdf Accessed 10/27/12

2)Kempen PM: Maintenance of Certification (MOC), Maintenance of Licensure (MOL), and Continuing Medical Education (CME):the Regulatory Capture of Medicine. Journal of American Physicians and Surgeons 2012; 17:72-5. Available at: http://www.jpands.org/vol17no3/kempen.pdf Accessed 10/27/12 3) Kumar D et al: Joint letter from 11 medical societies to the SMBO. Available at: http://www.itraumaohio.org/aws/OACEP/asset_manager/get_file/54757/2012.10.5_joint_mol_letter_to_medical_board.pdf Accessed 10/27/12 4) Alan Johnson In The Columbus Dispatch Thursday October 18, 2012 6:07 AM: State medical board ousts chief Available at: http://www.dispatch.com/content/stories/local/2012/10/18/state-medical- board-ousts-chief.html Accessed 10/27/12 5)Kempen PM: What to do about MOC and MOL? Available at: http://www.youtube.com/watch?v=WRS15Dmsk7E Accessed Nov 1, 2012

Conflict of Interest:

None declared

Dear Sir,

We thank the authors for their letter entitled, "Caution during use of DDAVP in IPSS," by Drs. Pecori Giraldi, Federici, and Cavagnini. The authors suggest that because of the hypercoagulable state that characterizes Cushing disease, DDAVP may not be safe since it has been shown to increase the level of von Willebrand factor (vWF) and could therefore lead to platelet adhesion and cause thromboembolism. The authors point to their own published work suggesting this effect (1). In this paper, the authors show that not only vWF levels increase, but also t-PA, likely to achieve a balance by activating fibrinolytic pathways. Therefore, increased risk of thromboembolic events in Cushing disease patients in the context of DDAVP administration is a theoretical consideration.

Thromboembolism is a rare complication of BIPSS and when reported, has been linked to lack of prophylaxis with IV heparin (2, 3). In our practice, we routinely heparinize patients undergoing BIPSS, whether they receive CRH or DDAVP to stimulate the pituitary (4). The case series previously reported where DDAVP was used rather than CRH do not indicate an increased risk of thromboembolic events (5-8). As the increased risk of thromboembolism is only a theoretical consideration, we can only use this available clinical data. Because the sensitivity of BIPSS is significantly increased by the use of CRH or DDAVP, the benefits of using DDAVP appear at this point to outweigh the theoretical risks. One possible positive outcome of the CRH shortage is that more data will be accumulated to determine whether there are unexpected negative effects of using DDAVP.

1. Pecori Giraldi F, Ambrogio AG, Fatti LM, Rubini V, Cozzi G, Scacchi M et al. Von Willebrand factor and fibrinolytic parameters during the desmopressin test in patients with Cushing's disease. Br.J.Pharmacol. 2011;71:132-6.

2. Blevins LS Jr, Clark RV, Owens DS. Thromboembolic complications after inferior petrosal sinus sampling in patients with Cushing's syndrome. Endocr Pract 1998; 4:365-367.

3. Obuobie K, Davies JS, Ogunko A, Scanlon MF. Venous thrombo- embolism following inferior petrosal sinus sampling in Cushing's disease. J Endocrinol Invest 2000; 23:542-544.

4. Deipolyi...Oklu et al. The role of bilateral inferior petrosal sinus sampling in the diagnostic evaluation of Cushing syndrome. Diagn Interv Radiol 2012; 18:132-138

5. Castinetti F, Morange I, Dufour H, et al. Desmopressin test during petrosal sinus sampling: a valuable tool to discriminate pituitary or ectopic ACTH-dependent Cushing's syndrome. Eur J Endocrinol 2007;157:271- 7.

6. Machado MC, de Sa SV, Domenice S, et al. The role of desmopressin in bilateral and simultaneous inferior petrosal sinus sampling for differential diagnosis of ACTH-dependent Cushing's syndrome. Clin Endocrinol (Oxf) 2007;66:136-42.

7. Malerbi DA, Mendonca BB, Liberman B, et al. The desmopressin stimulation test in the differential diagnosis of Cushing's syndrome. Clin Endocrinol (Oxf) 1993;38:463-72.

8. Salgado LR, Mendon??a BB, Pereira MAA, et al. Use of Desmopressin in Bilateral and Simultaneous Inferior Petrosal Sinus Sampling for Differential Diagnosis of ACTH-Dependent Cushing's Syndrome. The Endocrinologist 1997;7:135-40.

Conflict of Interest:

None declared

The reply from Perez et al to my letter of March 2012 is misleading and wrong in two important regards.1 First, they state that their report of the use of the solitaire stent for thrombectomy was just a case report, "nothing else". 2 This is not true. In fact, they explicitly use this report, both in the abstract and conclusion to lay claim for developing the stentreiever concept for thrombectomy: "This was the first .. use of the Solitaire stent for this purpose and the ignition spark for the development of a whole new generation of devices". In addition, this report was titled a "Historical Vignette". This report was written to take credit for the development of stentreivers for acute stroke. To state, as they do in their response to my letter, that their paper makes no claims is clearly disingenuous.

Second, they dismiss the idea that the prior publication by Kelly et al -- reporting the use of an Enterprise stent (Codman Neurovascular, Rayhnam, MA) as a temporary endovascular bypass to achieve successful revascularization in a patient with an acute ischemic stroke and large vessel occlusion -- had any influence on their work. This claim is disingenuous as well. In their response, they state that " ... temporary bypass might have been a local and ephemeral phenomenon; however it did not cause to much commotion, at least in Europe." However, the technique of stent-retrieval, or any kind of temporary stenting for acute stroke is, in fact, part and parcel of "temporary endovascular bypass". The best evidence of this is that the authors presented their own original experience with the Solitaire at the 2010 International Stroke Conference in an abstract entitled "Temporary Endovascular Bypass for the treatment of ischemic stroke: Experience After 50 Patients". Clearly their work with the Solitaire stent in acute stroke was influenced by this prior report.

In summary, despite their claims, the concept of temporary stenting for acute stroke treatment preceded the authors' 2008 case. In their Historical Vignette and subsequent response to my prior letter, the authors are attempting to rewrite history. They do deserve credit for taking this concept and rapidly moving it forward in clinical practice, however. References: 1. Re: Perez et al 'Intracranial thrombectomy using the Solitaire stent: a historical vignette'. Derdeyn CP. J Neurointerv Surg. 2012 Mar;4(2):153-4; Author Response 154 2. Intracranial thrombectomy using the Solitaire stent: a historical vignette. P?rez MA, Miloslavski E, Fischer S, B?zner H, Henkes H. J Neurointerv Surg. 2011 Dec 14. 3. Kelly ME, Furlan AJ, Fiorella D. Recanalization of an acute middle cerebral artery occlusion using a self-expanding, reconstrainable, intracranial microstent as a temporary endovascular bypass. Stroke 2008;39:1770-3. 4. Liebig T, Lockau H, Stehle S, Dorn F, Prothmann S, Henkes HH. Temporary Endovascular Bypass in Acute Stroke: Experience After 50 Patients. Stroke 2010 Vol 41,1:e259-260.

Conflict of Interest:

None declared