World Neurosurgery News
REFERENCES 1. Clinicaltrials.gov: Flow Diversion in Intracranial Aneurysm Treatement (FIAT). Available at: http:// clinicaltrials.gov/ct2/show/NCT01349582. Accessed November 26, 2013. 2. Clinicaltrials.gov: LARGE Aneurysm Randomized Trial: Flow Diversion versus Traditional Endovascular Coiling Therapy. Available at: http:// clinicaltrials.gov/ct2/show/NCT01762137. Accessed November 26, 2013. 3. Becske T, Kallmes DF, Saatci I, McDougall CG, Szikora I, Lanzino G, Moran CJ, Woo HH, Lopes DK, Berez AL, Cher DJ, Siddiqui AH, Levy EI, Albuquerque FC, Fiorella DJ, Berentei Z, Marosfoi M, Cekirge SH, Nelson PK: Pipeline for uncoilable or failed aneurysms: results from a multicenter clinical trial. Radiology 267:858-868, 2013. 4. Brinjikji W, Murad MH, Lanzino G, Cloft HJ, Kallmes DF: Endovascular treatment of intracranial aneurysms with flow diverters: a meta-analysis. Stroke 44:442-447, 2013. 5. Chitale R, Gonzalez LF, Randazzo C, Dumont AS, Tjoumakaris S, Rosenwasser R, Chalouhi N, Gordon D, Jabbour P: Single center experience with pipeline stent: feasibility, technique, and complications. Neurosurgery 71:679-691 [discussion 691], 2012. 6. Deutschmann HA, Wehrschuetz M, Augustin M, Niederkorn K, Klein GE: Long-term follow-up after treatment of intracranial aneurysms with the Pipeline embolization device: results from a single center. AJNR Am J Neuroradiol 33:481-486, 2012. 7. Ferns SP, Sprengers ME, van Rooij WJ, Rinkel GJ, van Rijn JC, Bipat S, Sluzewski M, Majoie CB: Coiling of intracranial aneurysms: a systematic review on initial occlusion and reopening and retreatment rates. Stroke 40:e523-e529, 2009. 8. Fischer S, Vajda Z, Aguilar Perez M, Schmid E, Hopf N, Bazner H, Henkes H: Pipeline embolization device (PED) for neurovascular reconstruction: initial experience in the treatment of 101 intracranial aneurysms and dissections. Neuroradiology 54:369-382, 2012. 9. Guglielmi G, Vinuela F, Sepetka I, Macellari V: Electrothrombosis of saccular aneurysms via endovascular approach. Part 1: electrochemical
basis, technique, and experimental results. J Neurosurg 75:1-7, 1991. 10. Kan P, Siddiqui AH, Veznedaroglu E, Liebman KM, Binning MJ, Dumont TM, Ogilvy CS, Gaughen JR Jr, Mocco J, Velat GJ, Ringer AJ, Welch BG, Horowitz MB, Snyder KV, Hopkins LN, Levy EI: Early postmarket results after treatment of intracranial aneurysms with the pipeline embolization device: a U.S. multicenter experience. Neurosurgery 71:1080-1087 [discussion 1087-1088], 2012. 11. Lubicz B, Collignon L, Raphaeli G, De Witte O: Pipeline flow-diverter stent for endovascular treatment of intracranial aneurysms: preliminary experience in 20 patients with 27 aneurysms. World Neurosurg 76:114-119, 2011. 12. Lylyk P, Miranda C, Ceratto R, Ferrario A, Scrivano E, Luna HR, Berez AL, Tran Q, Nelson PK, Fiorella D: Curative endovascular reconstruction of cerebral aneurysms with the pipeline embolization device: the Buenos Aires experience. Neurosurgery 64:632-642 [discussion 642-633; quiz N636], 2009. 13. McAuliffe W, Wycoco V, Rice H, Phatouros C, Singh TJ, Wenderoth J: Immediate and midterm results following treatment of unruptured intracranial aneurysms with the Pipeline embolization device. AJNR Am J Neuroradiol 33:164-170, 2012. 14. Murthy SB, Shah S, Shastri A, Venkatasubba Rao CP, Bershad EM, Suarez JI: The SILK flow diverter in the treatment of intracranial aneurysms. J Clin Neurosci 21:203-206, 2014. 15. Murthy SB, Shah S, Venkatasubba Rao CP, Bershad EM, Suarez JI: Treatment of unruptured intracranial aneurysms with the pipeline embolization device. J Clin Neurosci 21:6-11, 2014. 16. Nelson PK, Lylyk P, Szikora I, Wetzel SG, Wanke I, Fiorella D: The pipeline embolization device for the intracranial treatment of aneurysms trial. AJNR Am J Neuroradiol 32:34-40, 2011. 17. O’Kelly CJ, Spears J, Chow M, Wong J, Boulton M, Weill A, Willinsky RA, Kelly M, Marotta TR: Canadian experience with the pipeline embolization device for repair of unruptured intracranial aneurysms. AJNR Am J Neuroradiol 34:381-387, 2013. 18. Phillips TJ, Wenderoth JD, Phatouros CC, Rice H, Singh TP, Devilliers L, Wycoco V, Meckel S,
McAuliffe W: Safety of the pipeline embolization device in treatment of posterior circulation aneurysms. AJNR Am J Neuroradiol 33:1225-1231, 2012. 19. Saatci I, Yavuz K, Ozer C, Geyik S, Cekirge HS: Treatment of intracranial aneurysms using the pipeline flow-diverter embolization device: a singlecenter experience with long-term follow-up results. AJNR Am J Neuroradiol 33:1436-1446, 2012. 20. Shapiro M, Becske T, Sahlein D, Babb J, Nelson PK: Stent-supported aneurysm coiling: a literature survey of treatment and follow-up. AJNR Am J Neuroradiol 33:159-163, 2012. 21. Siddiqui AH, Abla AA, Kan P, Dumont TM, Jahshan S, Britz GW, Hopkins LN, Levy EI: Panacea or problem: flow diverters in the treatment of symptomatic large or giant fusiform vertebrobasilar aneurysms. J Neurosurg 116:1258-1266, 2012. 22. Szikora I, Berentei Z, Kulcsar Z, Marosfoi M, Vajda ZS, Lee W, Berez A, Nelson PK: Treatment of intracranial aneurysms by functional reconstruction of the parent artery: the Budapest experience with the pipeline embolization device. AJNR Am J Neuroradiol 31:1139-1147, 2010. 23. van Rooij WJ, Sluzewski M: Endovascular treatment of large and giant aneurysms. AJNR Am J Neuroradiol 30:12-18, 2009. 24. Wakhloo AK, Gounis MJ, Sandhu JS, Akkawi N, Schenck AE, Linfante I: Complex-shaped platinum coils for brain aneurysms: higher packing density, improved biomechanical stability, and midterm angiographic outcome. AJNR Am J Neuroradiol 28:1395-1400, 2007. 25. Yu SC, Kwok CK, Cheng PW, Chan KY, Lau SS, Lui WM, Leung KM, Lee R, Cheng HK, Cheung YL, Chan CM, Wong GK, Hui JW, Wong YC, Tan CB, Poon WL, Pang KY, Wong AK, Fung KH: Intracranial aneurysms: midterm outcome of pipeline embolization device—a prospective study in 143 patients with 178 aneurysms. Radiology 265:893-901, 2012.
Department of Neurosurgery, Mayo Clinic, Jacksonville, Florida, USA 1878-8750/$ - see front matter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.wneu.2014.06.046
Vasospasm in Aneurysmal Subarachnoid Hemorrhage Joshua T. Billingsley and Brian L. Hoh
Recent studies have rekindled a controversial issue regarding the contribution of vasospasm to the overall morbidity and mortality associated with aneurysmal subarachnoid hemorrhage (SAH)
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(1, 10, 11). Vasospasm was first angiographically identified and associated with aneurysm rupture in the early 1950s (3). Over the next several decades, a connection was made between aneurysmal
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SAH and vasospasm, condemning it as the primary cause of delayed cerebral ischemia and infarcts leading to poor patient outcomes (5). Many efforts have since been directed at treating vasospasm, opening larger caliber arteries in an attempt ultimately to improve outcomes. About 70% of patients with aneurysmal SAH develop vasospasm, and 20% develop infarcts (2, 4, 9). “Triple H” therapy has been the mainstay of treatment, in which hypertension, hypervolemia, and hemodilution are employed in an attempt to increase cerebral perfusion. More recently, endovascular therapy is commonly being used to access the cerebral vasculature for direct dilation of cerebral arteries with medications or balloons or both before infarcts develop. Despite advances in treatment, little, if any, improvement in patient outcomes is being seen. Is vasospasm responsible for the development of delayed ischemia and infarcts? In a study of 134 patients with aneurysmal SAH, Brown et al. (1) found 25% of patients with delayed infarcts had no vasospasm. In another 28% of infarcts with associated vasospasm, the vasospasm that was present was in a different vascular territory than the infarct (Figure 1). Wagner et al. (11) reviewed imaging of 309 patients with infarcts after aneurysmal SAH and found 27% showed infarcts in the absence of vasospasm. Although the authors were seemingly able to attribute some of these to aneurysm treatment, elevated intracranial pressure, and hypoxia, nearly 20% of infarcts were of uncertain etiology. In a more recent prospective, randomized trial, 114 patients with aneurysmal SAH were treated with cilostazol, a platelet aggregation inhibitor that also has a vasodilatory effect on cerebral arteries (10). Angiographic vasospasm, symptomatic vasospasm, and the occurrence of new infarcts all were significantly lower in the cilostazol group compared with the control group. However, no significant difference was found in patient outcomes, mortality, or hospital length of stay between groups. A platelet aggregation inhibitor reduced the incidence of new infarcts in patients with SAH. In a similar fashion, the CONSCIOUS-2 (Clazosentan to Overcome Neurological iSChemia and Infarct OccUrring after Subarachnoid hemorrhage) trial treated patients with SAH with clazosentan, an endothelin receptor antagonist that had already been shown to reduce moderate and severe vasospasm significantly from 66% to 23% (6, 8). In a group of 764 patients with
REFERENCES 1. Brown RJ, Kumar A, Dhar R, Sampson TR, Diringer MN: The relationship between delayed infarcts and angiographic vasospasm after aneurysmal subarachnoid hemorrhage. Neurosurgery 72:702-707; discussion 707-708, 2013. 2. Crowley RW, Medel R, Dumont AS, Ilodigwe D, Kassell NF, Mayer SA, Ruefenacht D, Schmiedek P, Weidauer S, Pasqualin A, Macdonald RL: Angiographic vasospasm is strongly correlated with cerebral infarction after subarachnoid hemorrhage. Stroke 42:919-923, 2011. 3. Ecker A, Riemenschneider PA: Arteriographic demonstration of spasm of the intracranial arteries, with special reference to saccular arterial aneurysms. J Neurosurg 8:660-667, 1951.
Figure 1. A 61-year-old woman presented with a ruptured basilar trunk aneurysm. Despite developing severe vasospasm of the right anterior circulation, she did not have infarcts in these regions. However, she did have an infarct of the left posterior cerebral artery territory, which did not develop significant vasospasm.
aneurysmal SAH that was secured by clipping, clazosentan failed to reduce vasospasm-related morbidity and mortality and failed to improve functional outcomes compared with placebo. This study was repeated in patients treated with endovascular coiling, and clazosentan significantly reduced vasospasm-related morbidity and mortality from all causes (7). However, no improvement in outcomes was observed. It seems increasingly clear that vasospasm is not the primary contributor in the development of many delayed cerebral infarcts. Infarcts develop in a vascular territory different from the region supplied by the arteries in vasospasm and even in the complete absence of vasospasm. However, angiographic vasospasm is at least a permissible factor in the development of some infarcts and is an important pathology to diagnose and treat. We are just breaching the surface in our understanding of the pathologic processes responsible for delayed infarction. Further studies are needed to delineate these underlying factors and develop treatments that will improve patient outcomes.
4. Fergusen S, Macdonald RL: Predictors of cerebral infarction in patients with aneurysmal subarachnoid hemorrhage. Neurosurgery 60:658-667; discussion 667, 2007. 5. Fisher CM, Roberson GH, Ojemann RG: Cerebral vasospasm with ruptured saccular aneurysm—the clinical manifestations. Neurosurgery 1:245-248, 1977.
Randomized trial of clazosentan in patients with aneurysmal subarachnoid hemorrhage undergoing endovascular coiling. Stroke 43:1463-1469, 2012. 8. Macdonald RL, Kassell NF, Mayer S, Ruefenacht D, Schmiedek P, Weidauer S, Frey A, Roux S, Pasqualin A: Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1): randomized, double-blind, placebo-controlled phase 2 dosefinding trial. Stroke 39:3015-3021, 2008.
6. Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, Vajkoczy P, Wanke I, Bach D, Frey A, Marr A, Roux S, Kassell N: Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2). Lancet Neurol 10:618-625, 2011.
9. Rabinstein AA, Friedman JA, Nichols DA, Pichelmann MA, McClelland RL, Manno EM, Atkinson JL, Wijdicks EF: Predictors of outcome after endovascular treatment of cerebral vasospasm. AJNR Am J Neuroradiol 25:1778-1782, 2004.
7. Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, Vajkoczy P, Wanke I, Bach D, Frey A, Nowbakht P, Roux S, Kassell N:
10. Senbokuya N, Kinouchi H, Kanemaru K, Ohashi Y, Fukamachi A, Yagi S, Shimizu T, Furuya K, Uchida M, Takeuchi N, Nakano S, Koizumi H,
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www.WORLDNEUROSURGERY.org
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Kobayashi C, Fukasawa I, Takahashi T, Kuroda K, Nishiyama Y, Yoshioka H, Horikoshi T: Effects of cilostazol on cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a multicenter prospective, randomized, open-label blinded end point trial. J Neurosurg 118:121-130, 2013.
11. Wagner M, Steinbeis P, Guresir E, Hattingen E, du Mesnil de Rochemont R, Weidauer S, Berkefeld J: Beyond delayed cerebral vasospasm: infarct patterns in patients with subarachnoid hemorrhage. Clin Neuroradiol 23:87-95, 2013.
Department of Neurosurgery, University of Florida, Gainesville, Florida, USA 1878-8750/$ - see front matter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.wneu.2014.06.048
Biomimetic Nanopores: A New Age of DNA Sequencing? Tobias A. Mattei
The discoveries about the central role of ion channels in the dynamics of neuronal excitability (resting membrane potential, depolarization, action potential, repolarization, and hyperpolarization) have been regarded as one of the greatest neuroscience breakthroughs of the 20th century. The English physiologists Hodgkin and Huxley from the University of Cambridge (8) were awarded the Nobel Prize in Physiology and Medicine in 1963 for their pioneering studies on the basic biophysical principles of cell membranes, which established a solid theoretical framework for the next generation of experimental studies on the nature of neuronal conduction. Defective ion channels have been implicated in the pathophysiology of various neurologic diseases. Abnormal sodium channels have been identified in patients with epilepsy (14), multiple sclerosis (3), and neuropathic pain (12). Water channels (so-called aquaporins) have been shown to be involved in the etiology of some demyelinating diseases (e.g., neuromyelitis optica) (15) as well as in the induction of brain edema in several different scenarios (e.g., after traumatic brain injury, stroke, and subarachnoid hemorrhage) (6). Pathologic calcium channels have been regarded as playing a central role in the pathophysiology of different genetic hereditary neurological diseases, such as spinocerebellar ataxia, familial hemiplegic migraine (16), and possibly Alzheimer’s disease (24). In recent decades, the exponential progress in the technology of biocompatible nanomaterials has enabled the emergence of new perspectives for artificial manipulation of channels that regulate neural excitability by modulating the gradient of ions on both sides of the cellular membrane. Based on computational analysis and computational modeling of the basic biomolecular structure of such passageways, it has been possible to design both purely synthetic and synthetically modified biomolecules (the so-called biomimetic nanopores), which are able to closely reproduce the biochemical functions of their original counterparts (10). The first strategies to design artificial ion-selective membrane channels were quite primitive and consisted in ion (or electron)beam sculpting of tiny holes with a diameter of a few nanometers in freestanding silicon nitride or silicon dioxide films (11). Nevertheless, further technical refinements, such as the possibility of coating these rude synthetic membranes with a lipid bilayer, enabled researchers to build laminar structures with properties much more similar to those of natural cellular membranes. Finally, more recent studies have demonstrated that by grafting
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additional bioactive molecules to these artificial nanopores (from polymers to enzymes or single-stranded pieces of DNA), it is possible to modify them so that they become able to perform very selective functions. Using such a paradigm, several different types of “solid-state” nanopores (in opposition to “biological nanopores”), which closely mimic the biochemical properties of natural ion channels, have already been developed, including a zincactivated (20), a potassium-responsive (9), and a proton-reactive channel (25). By employing emerging frontline technologies in material engineering (such as graphene, a new atomic-scale carbon honeycomb lattice with unique electronic, optical, and quantum properties) (13), some groups have also explored the use of such membranes as ionic insulators which are capable of displaying different degrees of electronic conductivity depending on the transmembrane solution potentials (5). More recently, other researchers have shown that graphene sheets can be used to design biomimetic nanopores that display preferential selectivity to Naþ or Kþ depending on the functional groups that are attached to their walls (4 negatively charged carboxylate groups for a Naþselective biomimetic nanopore or 4 carbonyl groups for a Kþ-selective biomimetic nanopore) (7). By employing new emerging fluorescence imaging techniques, such as those developed by optogenetics, other groups have developed new methods for single-molecule, super-resolution microscopy that enable the study of the three-dimensional morphological features of nanopores (e.g., their width dimensions, degree of interchannel heterogeneity, and overall in situ porosity of nanochannel arrays) with an advanced imaging resolution up to 40 nm (4). A different strategy for the creation of biomimetic nanopores involves the design of cyclic peptide nanotubes that form artificial transmembrane channels capable of ion transport. It has already been shown that, depending on the size of such nanotubes, different ions (e.g., Liþ, Naþ, Rbþ, Cl) or ion-water clusters may be inserted in such gateways, generating channels with very specific transportational properties (18). In addition, it has been demonstrated that the transport of ions through nanopores can be controlled by the addition of certain polymers to their walls, which, by exhibiting a temperature-dependent conformational transition, allows the creation of a gating effect (Figure 1) (26). A wide variety of artificial nanopores have already been designed, including nanotube-based biochannels (built either with
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REFERENCES 1. Clinicaltrials.gov: Flow Diversion in Intracranial Aneurysm Treatement (FIAT). Available at: http:// clinicaltrials.gov/ct2/show/NCT01349582. Accessed November 26, 2013. 2. Clinicaltrials.gov: LARGE Aneurysm Randomized Trial: Flow Diversion versus Traditional Endovascular Coiling Therapy. Available at: http:// clinicaltrials.gov/ct2/show/NCT01762137. Accessed November 26, 2013. 3. Becske T, Kallmes DF, Saatci I, McDougall CG, Szikora I, Lanzino G, Moran CJ, Woo HH, Lopes DK, Berez AL, Cher DJ, Siddiqui AH, Levy EI, Albuquerque FC, Fiorella DJ, Berentei Z, Marosfoi M, Cekirge SH, Nelson PK: Pipeline for uncoilable or failed aneurysms: results from a multicenter clinical trial. Radiology 267:858-868, 2013. 4. Brinjikji W, Murad MH, Lanzino G, Cloft HJ, Kallmes DF: Endovascular treatment of intracranial aneurysms with flow diverters: a meta-analysis. Stroke 44:442-447, 2013. 5. Chitale R, Gonzalez LF, Randazzo C, Dumont AS, Tjoumakaris S, Rosenwasser R, Chalouhi N, Gordon D, Jabbour P: Single center experience with pipeline stent: feasibility, technique, and complications. Neurosurgery 71:679-691 [discussion 691], 2012. 6. Deutschmann HA, Wehrschuetz M, Augustin M, Niederkorn K, Klein GE: Long-term follow-up after treatment of intracranial aneurysms with the Pipeline embolization device: results from a single center. AJNR Am J Neuroradiol 33:481-486, 2012. 7. Ferns SP, Sprengers ME, van Rooij WJ, Rinkel GJ, van Rijn JC, Bipat S, Sluzewski M, Majoie CB: Coiling of intracranial aneurysms: a systematic review on initial occlusion and reopening and retreatment rates. Stroke 40:e523-e529, 2009. 8. Fischer S, Vajda Z, Aguilar Perez M, Schmid E, Hopf N, Bazner H, Henkes H: Pipeline embolization device (PED) for neurovascular reconstruction: initial experience in the treatment of 101 intracranial aneurysms and dissections. Neuroradiology 54:369-382, 2012. 9. Guglielmi G, Vinuela F, Sepetka I, Macellari V: Electrothrombosis of saccular aneurysms via endovascular approach. Part 1: electrochemical
basis, technique, and experimental results. J Neurosurg 75:1-7, 1991. 10. Kan P, Siddiqui AH, Veznedaroglu E, Liebman KM, Binning MJ, Dumont TM, Ogilvy CS, Gaughen JR Jr, Mocco J, Velat GJ, Ringer AJ, Welch BG, Horowitz MB, Snyder KV, Hopkins LN, Levy EI: Early postmarket results after treatment of intracranial aneurysms with the pipeline embolization device: a U.S. multicenter experience. Neurosurgery 71:1080-1087 [discussion 1087-1088], 2012. 11. Lubicz B, Collignon L, Raphaeli G, De Witte O: Pipeline flow-diverter stent for endovascular treatment of intracranial aneurysms: preliminary experience in 20 patients with 27 aneurysms. World Neurosurg 76:114-119, 2011. 12. Lylyk P, Miranda C, Ceratto R, Ferrario A, Scrivano E, Luna HR, Berez AL, Tran Q, Nelson PK, Fiorella D: Curative endovascular reconstruction of cerebral aneurysms with the pipeline embolization device: the Buenos Aires experience. Neurosurgery 64:632-642 [discussion 642-633; quiz N636], 2009. 13. McAuliffe W, Wycoco V, Rice H, Phatouros C, Singh TJ, Wenderoth J: Immediate and midterm results following treatment of unruptured intracranial aneurysms with the Pipeline embolization device. AJNR Am J Neuroradiol 33:164-170, 2012. 14. Murthy SB, Shah S, Shastri A, Venkatasubba Rao CP, Bershad EM, Suarez JI: The SILK flow diverter in the treatment of intracranial aneurysms. J Clin Neurosci 21:203-206, 2014. 15. Murthy SB, Shah S, Venkatasubba Rao CP, Bershad EM, Suarez JI: Treatment of unruptured intracranial aneurysms with the pipeline embolization device. J Clin Neurosci 21:6-11, 2014. 16. Nelson PK, Lylyk P, Szikora I, Wetzel SG, Wanke I, Fiorella D: The pipeline embolization device for the intracranial treatment of aneurysms trial. AJNR Am J Neuroradiol 32:34-40, 2011. 17. O’Kelly CJ, Spears J, Chow M, Wong J, Boulton M, Weill A, Willinsky RA, Kelly M, Marotta TR: Canadian experience with the pipeline embolization device for repair of unruptured intracranial aneurysms. AJNR Am J Neuroradiol 34:381-387, 2013. 18. Phillips TJ, Wenderoth JD, Phatouros CC, Rice H, Singh TP, Devilliers L, Wycoco V, Meckel S,
McAuliffe W: Safety of the pipeline embolization device in treatment of posterior circulation aneurysms. AJNR Am J Neuroradiol 33:1225-1231, 2012. 19. Saatci I, Yavuz K, Ozer C, Geyik S, Cekirge HS: Treatment of intracranial aneurysms using the pipeline flow-diverter embolization device: a singlecenter experience with long-term follow-up results. AJNR Am J Neuroradiol 33:1436-1446, 2012. 20. Shapiro M, Becske T, Sahlein D, Babb J, Nelson PK: Stent-supported aneurysm coiling: a literature survey of treatment and follow-up. AJNR Am J Neuroradiol 33:159-163, 2012. 21. Siddiqui AH, Abla AA, Kan P, Dumont TM, Jahshan S, Britz GW, Hopkins LN, Levy EI: Panacea or problem: flow diverters in the treatment of symptomatic large or giant fusiform vertebrobasilar aneurysms. J Neurosurg 116:1258-1266, 2012. 22. Szikora I, Berentei Z, Kulcsar Z, Marosfoi M, Vajda ZS, Lee W, Berez A, Nelson PK: Treatment of intracranial aneurysms by functional reconstruction of the parent artery: the Budapest experience with the pipeline embolization device. AJNR Am J Neuroradiol 31:1139-1147, 2010. 23. van Rooij WJ, Sluzewski M: Endovascular treatment of large and giant aneurysms. AJNR Am J Neuroradiol 30:12-18, 2009. 24. Wakhloo AK, Gounis MJ, Sandhu JS, Akkawi N, Schenck AE, Linfante I: Complex-shaped platinum coils for brain aneurysms: higher packing density, improved biomechanical stability, and midterm angiographic outcome. AJNR Am J Neuroradiol 28:1395-1400, 2007. 25. Yu SC, Kwok CK, Cheng PW, Chan KY, Lau SS, Lui WM, Leung KM, Lee R, Cheng HK, Cheung YL, Chan CM, Wong GK, Hui JW, Wong YC, Tan CB, Poon WL, Pang KY, Wong AK, Fung KH: Intracranial aneurysms: midterm outcome of pipeline embolization device—a prospective study in 143 patients with 178 aneurysms. Radiology 265:893-901, 2012.
Department of Neurosurgery, Mayo Clinic, Jacksonville, Florida, USA 1878-8750/$ - see front matter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.wneu.2014.06.046
Vasospasm in Aneurysmal Subarachnoid Hemorrhage Joshua T. Billingsley and Brian L. Hoh
Recent studies have rekindled a controversial issue regarding the contribution of vasospasm to the overall morbidity and mortality associated with aneurysmal subarachnoid hemorrhage (SAH)
250
www.SCIENCEDIRECT.com
(1, 10, 11). Vasospasm was first angiographically identified and associated with aneurysm rupture in the early 1950s (3). Over the next several decades, a connection was made between aneurysmal
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World Neurosurgery News
SAH and vasospasm, condemning it as the primary cause of delayed cerebral ischemia and infarcts leading to poor patient outcomes (5). Many efforts have since been directed at treating vasospasm, opening larger caliber arteries in an attempt ultimately to improve outcomes. About 70% of patients with aneurysmal SAH develop vasospasm, and 20% develop infarcts (2, 4, 9). “Triple H” therapy has been the mainstay of treatment, in which hypertension, hypervolemia, and hemodilution are employed in an attempt to increase cerebral perfusion. More recently, endovascular therapy is commonly being used to access the cerebral vasculature for direct dilation of cerebral arteries with medications or balloons or both before infarcts develop. Despite advances in treatment, little, if any, improvement in patient outcomes is being seen. Is vasospasm responsible for the development of delayed ischemia and infarcts? In a study of 134 patients with aneurysmal SAH, Brown et al. (1) found 25% of patients with delayed infarcts had no vasospasm. In another 28% of infarcts with associated vasospasm, the vasospasm that was present was in a different vascular territory than the infarct (Figure 1). Wagner et al. (11) reviewed imaging of 309 patients with infarcts after aneurysmal SAH and found 27% showed infarcts in the absence of vasospasm. Although the authors were seemingly able to attribute some of these to aneurysm treatment, elevated intracranial pressure, and hypoxia, nearly 20% of infarcts were of uncertain etiology. In a more recent prospective, randomized trial, 114 patients with aneurysmal SAH were treated with cilostazol, a platelet aggregation inhibitor that also has a vasodilatory effect on cerebral arteries (10). Angiographic vasospasm, symptomatic vasospasm, and the occurrence of new infarcts all were significantly lower in the cilostazol group compared with the control group. However, no significant difference was found in patient outcomes, mortality, or hospital length of stay between groups. A platelet aggregation inhibitor reduced the incidence of new infarcts in patients with SAH. In a similar fashion, the CONSCIOUS-2 (Clazosentan to Overcome Neurological iSChemia and Infarct OccUrring after Subarachnoid hemorrhage) trial treated patients with SAH with clazosentan, an endothelin receptor antagonist that had already been shown to reduce moderate and severe vasospasm significantly from 66% to 23% (6, 8). In a group of 764 patients with
REFERENCES 1. Brown RJ, Kumar A, Dhar R, Sampson TR, Diringer MN: The relationship between delayed infarcts and angiographic vasospasm after aneurysmal subarachnoid hemorrhage. Neurosurgery 72:702-707; discussion 707-708, 2013. 2. Crowley RW, Medel R, Dumont AS, Ilodigwe D, Kassell NF, Mayer SA, Ruefenacht D, Schmiedek P, Weidauer S, Pasqualin A, Macdonald RL: Angiographic vasospasm is strongly correlated with cerebral infarction after subarachnoid hemorrhage. Stroke 42:919-923, 2011. 3. Ecker A, Riemenschneider PA: Arteriographic demonstration of spasm of the intracranial arteries, with special reference to saccular arterial aneurysms. J Neurosurg 8:660-667, 1951.
Figure 1. A 61-year-old woman presented with a ruptured basilar trunk aneurysm. Despite developing severe vasospasm of the right anterior circulation, she did not have infarcts in these regions. However, she did have an infarct of the left posterior cerebral artery territory, which did not develop significant vasospasm.
aneurysmal SAH that was secured by clipping, clazosentan failed to reduce vasospasm-related morbidity and mortality and failed to improve functional outcomes compared with placebo. This study was repeated in patients treated with endovascular coiling, and clazosentan significantly reduced vasospasm-related morbidity and mortality from all causes (7). However, no improvement in outcomes was observed. It seems increasingly clear that vasospasm is not the primary contributor in the development of many delayed cerebral infarcts. Infarcts develop in a vascular territory different from the region supplied by the arteries in vasospasm and even in the complete absence of vasospasm. However, angiographic vasospasm is at least a permissible factor in the development of some infarcts and is an important pathology to diagnose and treat. We are just breaching the surface in our understanding of the pathologic processes responsible for delayed infarction. Further studies are needed to delineate these underlying factors and develop treatments that will improve patient outcomes.
4. Fergusen S, Macdonald RL: Predictors of cerebral infarction in patients with aneurysmal subarachnoid hemorrhage. Neurosurgery 60:658-667; discussion 667, 2007. 5. Fisher CM, Roberson GH, Ojemann RG: Cerebral vasospasm with ruptured saccular aneurysm—the clinical manifestations. Neurosurgery 1:245-248, 1977.
Randomized trial of clazosentan in patients with aneurysmal subarachnoid hemorrhage undergoing endovascular coiling. Stroke 43:1463-1469, 2012. 8. Macdonald RL, Kassell NF, Mayer S, Ruefenacht D, Schmiedek P, Weidauer S, Frey A, Roux S, Pasqualin A: Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1): randomized, double-blind, placebo-controlled phase 2 dosefinding trial. Stroke 39:3015-3021, 2008.
6. Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, Vajkoczy P, Wanke I, Bach D, Frey A, Marr A, Roux S, Kassell N: Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2). Lancet Neurol 10:618-625, 2011.
9. Rabinstein AA, Friedman JA, Nichols DA, Pichelmann MA, McClelland RL, Manno EM, Atkinson JL, Wijdicks EF: Predictors of outcome after endovascular treatment of cerebral vasospasm. AJNR Am J Neuroradiol 25:1778-1782, 2004.
7. Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, Vajkoczy P, Wanke I, Bach D, Frey A, Nowbakht P, Roux S, Kassell N:
10. Senbokuya N, Kinouchi H, Kanemaru K, Ohashi Y, Fukamachi A, Yagi S, Shimizu T, Furuya K, Uchida M, Takeuchi N, Nakano S, Koizumi H,
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Kobayashi C, Fukasawa I, Takahashi T, Kuroda K, Nishiyama Y, Yoshioka H, Horikoshi T: Effects of cilostazol on cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a multicenter prospective, randomized, open-label blinded end point trial. J Neurosurg 118:121-130, 2013.
11. Wagner M, Steinbeis P, Guresir E, Hattingen E, du Mesnil de Rochemont R, Weidauer S, Berkefeld J: Beyond delayed cerebral vasospasm: infarct patterns in patients with subarachnoid hemorrhage. Clin Neuroradiol 23:87-95, 2013.
Department of Neurosurgery, University of Florida, Gainesville, Florida, USA 1878-8750/$ - see front matter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.wneu.2014.06.048
Biomimetic Nanopores: A New Age of DNA Sequencing? Tobias A. Mattei
The discoveries about the central role of ion channels in the dynamics of neuronal excitability (resting membrane potential, depolarization, action potential, repolarization, and hyperpolarization) have been regarded as one of the greatest neuroscience breakthroughs of the 20th century. The English physiologists Hodgkin and Huxley from the University of Cambridge (8) were awarded the Nobel Prize in Physiology and Medicine in 1963 for their pioneering studies on the basic biophysical principles of cell membranes, which established a solid theoretical framework for the next generation of experimental studies on the nature of neuronal conduction. Defective ion channels have been implicated in the pathophysiology of various neurologic diseases. Abnormal sodium channels have been identified in patients with epilepsy (14), multiple sclerosis (3), and neuropathic pain (12). Water channels (so-called aquaporins) have been shown to be involved in the etiology of some demyelinating diseases (e.g., neuromyelitis optica) (15) as well as in the induction of brain edema in several different scenarios (e.g., after traumatic brain injury, stroke, and subarachnoid hemorrhage) (6). Pathologic calcium channels have been regarded as playing a central role in the pathophysiology of different genetic hereditary neurological diseases, such as spinocerebellar ataxia, familial hemiplegic migraine (16), and possibly Alzheimer’s disease (24). In recent decades, the exponential progress in the technology of biocompatible nanomaterials has enabled the emergence of new perspectives for artificial manipulation of channels that regulate neural excitability by modulating the gradient of ions on both sides of the cellular membrane. Based on computational analysis and computational modeling of the basic biomolecular structure of such passageways, it has been possible to design both purely synthetic and synthetically modified biomolecules (the so-called biomimetic nanopores), which are able to closely reproduce the biochemical functions of their original counterparts (10). The first strategies to design artificial ion-selective membrane channels were quite primitive and consisted in ion (or electron)beam sculpting of tiny holes with a diameter of a few nanometers in freestanding silicon nitride or silicon dioxide films (11). Nevertheless, further technical refinements, such as the possibility of coating these rude synthetic membranes with a lipid bilayer, enabled researchers to build laminar structures with properties much more similar to those of natural cellular membranes. Finally, more recent studies have demonstrated that by grafting
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additional bioactive molecules to these artificial nanopores (from polymers to enzymes or single-stranded pieces of DNA), it is possible to modify them so that they become able to perform very selective functions. Using such a paradigm, several different types of “solid-state” nanopores (in opposition to “biological nanopores”), which closely mimic the biochemical properties of natural ion channels, have already been developed, including a zincactivated (20), a potassium-responsive (9), and a proton-reactive channel (25). By employing emerging frontline technologies in material engineering (such as graphene, a new atomic-scale carbon honeycomb lattice with unique electronic, optical, and quantum properties) (13), some groups have also explored the use of such membranes as ionic insulators which are capable of displaying different degrees of electronic conductivity depending on the transmembrane solution potentials (5). More recently, other researchers have shown that graphene sheets can be used to design biomimetic nanopores that display preferential selectivity to Naþ or Kþ depending on the functional groups that are attached to their walls (4 negatively charged carboxylate groups for a Naþselective biomimetic nanopore or 4 carbonyl groups for a Kþ-selective biomimetic nanopore) (7). By employing new emerging fluorescence imaging techniques, such as those developed by optogenetics, other groups have developed new methods for single-molecule, super-resolution microscopy that enable the study of the three-dimensional morphological features of nanopores (e.g., their width dimensions, degree of interchannel heterogeneity, and overall in situ porosity of nanochannel arrays) with an advanced imaging resolution up to 40 nm (4). A different strategy for the creation of biomimetic nanopores involves the design of cyclic peptide nanotubes that form artificial transmembrane channels capable of ion transport. It has already been shown that, depending on the size of such nanotubes, different ions (e.g., Liþ, Naþ, Rbþ, Cl) or ion-water clusters may be inserted in such gateways, generating channels with very specific transportational properties (18). In addition, it has been demonstrated that the transport of ions through nanopores can be controlled by the addition of certain polymers to their walls, which, by exhibiting a temperature-dependent conformational transition, allows the creation of a gating effect (Figure 1) (26). A wide variety of artificial nanopores have already been designed, including nanotube-based biochannels (built either with
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