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The future of neurovascular disease
Surgical Neurology 64 (2005) 189 – 190 www.surgicalneurology-online.com
Editorial
The future of neurovascular disease In this issue of Surgical Neurology, there are articles on the metabolic changes in subarachnoid hemorrhage, the long-term effects of vasospasm on the cerebral circulation and cerebral vascular reserve and of the effects on the vasculature of interventional treatment of vasospasm with angioplasty, interventional approaches to cavernous sinus fistulas with balloons and coils, and intracerebral hemorrhage treatment by ultra-early surgery and control of blood pressure. There is also an article on the parenchymal effects of anterior cerebral artery aneurysms with spasm that produce paraparesis. We would not have seen these articles 20 years ago or even 10 years ago. They are signaling a change that is happening progressively but certainly. Day by day, a neurosurgeon may not notice the changes, but over longer periods, the changes are unstoppable. First of all, the treatment of aneurysms surgically is progressively giving way to coiling regardless of the resistance of neurosurgeons, which is waning. It is a better treatment than surgery for selected cases in the hands of excellent interventionalists [2]. Complex aneurysms will still be treated surgically until better interventional approaches are devised. The use of advanced imaging, bypasses, and interventional approaches to complex aneurysms as used at UCLA by teams of neurosurgeons and interventionalists working together cooperatively is indicative that the complex aneurysm cases will be sent to major centers as the experience with aneurysms of the neurosurgeons in practice becomes more limited [6]. The advances in stent technology and the introduction of nanomanufacturing to stent technology will be astounding. We are only seeing the beginning of this process. Secondly, with the work of Pradilla et al [8], Reilly et al [9], and Yen et al [13], the metabolic and genetic aspects of vasospasm are being discovered. This response can be muted or stopped by antibodies and agents that neutralize the various cytokines released by the affected vessels calling for inflammatory repair [8]. The treatment for vasospasm that had eluded us for 50 years is finally within reach. This successful treatment will alter the entire landscape of this disease and with interventional approaches will convert it from the lethal disease it is to one that is more benign. Thirdly, an understanding of the metabolic changes that occur during ischemia and cell injury are beginning to be understood and reported. There are detailed reports of the 0090-3019/$ – see front matter D 2005 Published by Elsevier Inc. doi:10.1016/j.surneu.2005.05.005
sequential genetic activations that occur as the ischemic process evolves over weeks [12]. These genes are producing proteins that are directing cell repair or signaling cell death. Interventions on this course of events is beginning. The article by Noske et al in this issue uses microdialysis to understand the metabolic changes in a small segment of tissue over time. Similar studies on head injury are also being done at major centers [11]. Positron emission tomography and single photon emission computed tomography scanning are being used to measure blood flow; magnetic resonance (MR) technology will become prominent in measuring flow by phase-contrast MR techniques. Smaller vessels will be visualized as MR becomes more detailed with higher field strengths, as we are seeing with the 3-T MR work. GE Medical Systems research has developed this technology, and Nick Hopkins and his colleagues are pioneering work in this area. MR techniques are revealing venous blood flow as reported by Lee Jong-Myung et al in this issue and are only an example of the potential of MR technology. MR spectroscopy, which is being used in defining brain tumor types, will also be used to measure lactate and pyruvate in ischemia and other metabolites, as is now being done in a more limited area by microdialysis, and as reported in this issue by Noske et al. Ultimately, all of these metabolic changes will need to be monitored repeatedly. Thus, the MRs will have to be located near or in the intensive care units (ICUs) for repeated sampling of the tissue changes. This location will be more efficient for the nurses and personnel because the patient will only be out of the ICU for minutes to obtain this information. As these changes are noted, the importance of managing the dynamically changing metabolic and genetic events in the ischemic tissue will become apparent. The recovery and repair of nervous tissue will become the predominant focus of neuroclinicians. Neurointensivists will become specialists in high demand to manage the injured brain and spinal cord. The operative approaches will become of less importance than the preservation of the neurons and astrocytes. So, our emphasis on ICU care for neurological disease will become primary. Neurological disease will still be cared for in hospitals in the foreseeable future because of the need for all of this technology and specialized personnel. Also in this issue are articles on intracerebral hematomas. We have failed to understand this disease. There is a sudden
190
Editorial / Surgical Neurology 64 (2005) 189 – 190
release of blood, which forms a mass in the brain, compressing the neural and astrocytic tissue. Many studies have shown that surgery does not have significant value in altering the course of this disease. From my personal observations over 40 years, I do not accept this conclusion as valid. I have seen many people who had significant recovery after removal of the hematomas. One of the problems is that there is no good animal model of this disease of which I am aware. In an unpublished work 20 years ago, Dujovny studied monkeys with a stereotactically introduced hematoma in the basal ganglia. One group of 3 monkeys was untreated and another group of 3 had urokinase injected into the hematoma immediately. Those who were injected had much better recovery than those who did not receive the thrombolytic agent. It seems to me that an animal experiment can be done in which a balloon-tipped catheter can be introduced in the same anatomical location in the brain of monkeys. The balloon can be inflated for varying periods and then deflated to determine the effects of immediate and delayed removal of the mass and the respective outcome. Such an experiment is devoid of the elements of blood that may be a crucial factor in this disease process but would go a long way to solving the problem or the large clinical trials that cost far more money with less results. An article in this issue by Hsieh et al on the ultra-early removal of the hematomas is an example of the continuing controversy in this field. Hoff and his colleagues have done superb work showing the damaging effects of iron on the DNA in ICH [7]. Perhaps, this work argues for immediate removal of the hematoma and its toxic agents. Fisher in 1979 [4] wrote an outstanding article on the cause of lenticulostriate hemorrhages or lacunar infarcts. After making thousands of sections in the brains of about 10 patients, he determined that there was hyalinosis in the lenticulostriate vessels about 1 cm after their origin from the middle cerebral artery. Nothing could be done about this discovery, but the technology is here to begin to treat this disease, which accounts for a major part of the strokes in the population. Although we published one article on arteriovenous malformations in this issue, this disease, too, will yield to interventional approaches and gene therapy. Work has already been reported on the genetic changes in arteriovenous malformations [5,10]. It is only a matter of time for genetic treatments to be introduced interventionally [1]. As an aside, in my opinion, our Japanese colleagues have led the world in neurosurgery in the study of neurovascular disease. Their work, which is not read by many outside Japan, is outstanding. So, will these changes happen tomorrow? No. Should the vascular neurosurgeon worry that his/her life will change
immediately? In 1997, I wrote about the changes in aneurysm surgery, predicting that it would be overtaken by interventional approaches [3]. Few wanted to believe it and were very critical of my position. Today, virtually all neurosurgical programs and many practitioners are involved with the interventional approach to aneurysms. Neurosurgeons are even being trained as interventionalists. So, what is the message? I may not be entirely correct, but chances are that I am far more accurate than not. If so, do you want to be a proactive neurosurgeon or a reactive neurosurgeon? For me, I would rather be at the head defining the changes than waiting for others to define them for me. James I. Ausman MD, PhD (Editor) References [1] Abrahams JM, Song C, DeFelice S, et al. Endovascular delivery of genes. Stroke 2002;33:1376 - 82. [2] Ausman JI. Comments on the unruptured aneurysm study from Japan; does this study clarify what to do? J Neurosurg 2005;102(4):593 - 5. [3] Ausman JI. The future of neurovascular surgery part I: intracranial aneurysms. Surg Neurol 1997;48:98 - 100. [4] Fisher CM. Capsular infarcts: the underlying vascular lesions. Arch Neurol 1979;36:65 - 73. [5] Jabbour P, Gault J, Awad IA. What genes can teach us about human cerebrovascular malformations. Clin Neurosurg 2004;51:140 - 52. [6] Martin NA. The combination of endovascular and surgical techniques for the treatment of intracranial aneurysms. Neurosurg Clin N Am 1998;9(4):897. [7] Nakamura T, Keep RF, Hua Y, Hoff JT, Xi G. Oxidative DNA injury after experimental intracerebral hemorrhage. Brain Res 2005; 1039(1-2):30 - 6. [8] Pradilla G, Wang PP, Legnani FG, Ogata L, Dietsch GN, Tamargo RJ. Prevention of vasospasm by anti–CD11/CD18 monoclonal antibody therapy following subarachnoid hemorrhage in rabbits. J Neurosurg 2004;101(1):88 - 92. [9] Reilly C, Amidei C, Tolentino J, Jahromi BS, Macdonald RL. Clot volume and clearance rate as independent predictors of vasospasm after aneurysmal subarachnoid hemorrhage. J Neurosurg 2004;101(2): 255 - 61. [10] Rhoten RLP, Comair YG, Chayette D, Simonson MS. Specific repression of the preproendothelin-1 gene in arteriovenous malformations. J Neurosurg 1999;90:605 - 7. [11] Vespa P, Bergsneider M, Hattori N, Wu HM, Huang SC, Martin NA, Glenn TC, McArthur DL, Hovda DA. Metabolic crisis without brain ischemia is common after traumatic brain injury: a combined microdialysis and positron emission tomography study. J Cereb Blood Flow Metab 2005;25:763 - 4. [12] Wang X, Feuerstein GZ. The Janus face of inflammation in ischemic brain injury. In: Baethmann A, et al, editors. Mechanisms of secondary brain damage from trauma and ischemia. New York7 Springer-Wein; 2004. [13] Yen CP, Chen SC, Lin TK, Wu SC, Chang CY, Lue SI, Jeng AY, Kassell NF, Kwan AL. CGS 26303 upregulates mRNA expression of heme oxygenase-1 in brain tissue of rats subjected to experimental subarachnoid hemorrhage. J Cardiovasc Pharmacol 2004;44:S474 - 8.
If a man takes no thought about what is distant, he will find sorrow near at hand. — Confucius, The Confucian Analects
Editorial
The future of neurovascular disease In this issue of Surgical Neurology, there are articles on the metabolic changes in subarachnoid hemorrhage, the long-term effects of vasospasm on the cerebral circulation and cerebral vascular reserve and of the effects on the vasculature of interventional treatment of vasospasm with angioplasty, interventional approaches to cavernous sinus fistulas with balloons and coils, and intracerebral hemorrhage treatment by ultra-early surgery and control of blood pressure. There is also an article on the parenchymal effects of anterior cerebral artery aneurysms with spasm that produce paraparesis. We would not have seen these articles 20 years ago or even 10 years ago. They are signaling a change that is happening progressively but certainly. Day by day, a neurosurgeon may not notice the changes, but over longer periods, the changes are unstoppable. First of all, the treatment of aneurysms surgically is progressively giving way to coiling regardless of the resistance of neurosurgeons, which is waning. It is a better treatment than surgery for selected cases in the hands of excellent interventionalists [2]. Complex aneurysms will still be treated surgically until better interventional approaches are devised. The use of advanced imaging, bypasses, and interventional approaches to complex aneurysms as used at UCLA by teams of neurosurgeons and interventionalists working together cooperatively is indicative that the complex aneurysm cases will be sent to major centers as the experience with aneurysms of the neurosurgeons in practice becomes more limited [6]. The advances in stent technology and the introduction of nanomanufacturing to stent technology will be astounding. We are only seeing the beginning of this process. Secondly, with the work of Pradilla et al [8], Reilly et al [9], and Yen et al [13], the metabolic and genetic aspects of vasospasm are being discovered. This response can be muted or stopped by antibodies and agents that neutralize the various cytokines released by the affected vessels calling for inflammatory repair [8]. The treatment for vasospasm that had eluded us for 50 years is finally within reach. This successful treatment will alter the entire landscape of this disease and with interventional approaches will convert it from the lethal disease it is to one that is more benign. Thirdly, an understanding of the metabolic changes that occur during ischemia and cell injury are beginning to be understood and reported. There are detailed reports of the 0090-3019/$ – see front matter D 2005 Published by Elsevier Inc. doi:10.1016/j.surneu.2005.05.005
sequential genetic activations that occur as the ischemic process evolves over weeks [12]. These genes are producing proteins that are directing cell repair or signaling cell death. Interventions on this course of events is beginning. The article by Noske et al in this issue uses microdialysis to understand the metabolic changes in a small segment of tissue over time. Similar studies on head injury are also being done at major centers [11]. Positron emission tomography and single photon emission computed tomography scanning are being used to measure blood flow; magnetic resonance (MR) technology will become prominent in measuring flow by phase-contrast MR techniques. Smaller vessels will be visualized as MR becomes more detailed with higher field strengths, as we are seeing with the 3-T MR work. GE Medical Systems research has developed this technology, and Nick Hopkins and his colleagues are pioneering work in this area. MR techniques are revealing venous blood flow as reported by Lee Jong-Myung et al in this issue and are only an example of the potential of MR technology. MR spectroscopy, which is being used in defining brain tumor types, will also be used to measure lactate and pyruvate in ischemia and other metabolites, as is now being done in a more limited area by microdialysis, and as reported in this issue by Noske et al. Ultimately, all of these metabolic changes will need to be monitored repeatedly. Thus, the MRs will have to be located near or in the intensive care units (ICUs) for repeated sampling of the tissue changes. This location will be more efficient for the nurses and personnel because the patient will only be out of the ICU for minutes to obtain this information. As these changes are noted, the importance of managing the dynamically changing metabolic and genetic events in the ischemic tissue will become apparent. The recovery and repair of nervous tissue will become the predominant focus of neuroclinicians. Neurointensivists will become specialists in high demand to manage the injured brain and spinal cord. The operative approaches will become of less importance than the preservation of the neurons and astrocytes. So, our emphasis on ICU care for neurological disease will become primary. Neurological disease will still be cared for in hospitals in the foreseeable future because of the need for all of this technology and specialized personnel. Also in this issue are articles on intracerebral hematomas. We have failed to understand this disease. There is a sudden
190
Editorial / Surgical Neurology 64 (2005) 189 – 190
release of blood, which forms a mass in the brain, compressing the neural and astrocytic tissue. Many studies have shown that surgery does not have significant value in altering the course of this disease. From my personal observations over 40 years, I do not accept this conclusion as valid. I have seen many people who had significant recovery after removal of the hematomas. One of the problems is that there is no good animal model of this disease of which I am aware. In an unpublished work 20 years ago, Dujovny studied monkeys with a stereotactically introduced hematoma in the basal ganglia. One group of 3 monkeys was untreated and another group of 3 had urokinase injected into the hematoma immediately. Those who were injected had much better recovery than those who did not receive the thrombolytic agent. It seems to me that an animal experiment can be done in which a balloon-tipped catheter can be introduced in the same anatomical location in the brain of monkeys. The balloon can be inflated for varying periods and then deflated to determine the effects of immediate and delayed removal of the mass and the respective outcome. Such an experiment is devoid of the elements of blood that may be a crucial factor in this disease process but would go a long way to solving the problem or the large clinical trials that cost far more money with less results. An article in this issue by Hsieh et al on the ultra-early removal of the hematomas is an example of the continuing controversy in this field. Hoff and his colleagues have done superb work showing the damaging effects of iron on the DNA in ICH [7]. Perhaps, this work argues for immediate removal of the hematoma and its toxic agents. Fisher in 1979 [4] wrote an outstanding article on the cause of lenticulostriate hemorrhages or lacunar infarcts. After making thousands of sections in the brains of about 10 patients, he determined that there was hyalinosis in the lenticulostriate vessels about 1 cm after their origin from the middle cerebral artery. Nothing could be done about this discovery, but the technology is here to begin to treat this disease, which accounts for a major part of the strokes in the population. Although we published one article on arteriovenous malformations in this issue, this disease, too, will yield to interventional approaches and gene therapy. Work has already been reported on the genetic changes in arteriovenous malformations [5,10]. It is only a matter of time for genetic treatments to be introduced interventionally [1]. As an aside, in my opinion, our Japanese colleagues have led the world in neurosurgery in the study of neurovascular disease. Their work, which is not read by many outside Japan, is outstanding. So, will these changes happen tomorrow? No. Should the vascular neurosurgeon worry that his/her life will change
immediately? In 1997, I wrote about the changes in aneurysm surgery, predicting that it would be overtaken by interventional approaches [3]. Few wanted to believe it and were very critical of my position. Today, virtually all neurosurgical programs and many practitioners are involved with the interventional approach to aneurysms. Neurosurgeons are even being trained as interventionalists. So, what is the message? I may not be entirely correct, but chances are that I am far more accurate than not. If so, do you want to be a proactive neurosurgeon or a reactive neurosurgeon? For me, I would rather be at the head defining the changes than waiting for others to define them for me. James I. Ausman MD, PhD (Editor) References [1] Abrahams JM, Song C, DeFelice S, et al. Endovascular delivery of genes. Stroke 2002;33:1376 - 82. [2] Ausman JI. Comments on the unruptured aneurysm study from Japan; does this study clarify what to do? J Neurosurg 2005;102(4):593 - 5. [3] Ausman JI. The future of neurovascular surgery part I: intracranial aneurysms. Surg Neurol 1997;48:98 - 100. [4] Fisher CM. Capsular infarcts: the underlying vascular lesions. Arch Neurol 1979;36:65 - 73. [5] Jabbour P, Gault J, Awad IA. What genes can teach us about human cerebrovascular malformations. Clin Neurosurg 2004;51:140 - 52. [6] Martin NA. The combination of endovascular and surgical techniques for the treatment of intracranial aneurysms. Neurosurg Clin N Am 1998;9(4):897. [7] Nakamura T, Keep RF, Hua Y, Hoff JT, Xi G. Oxidative DNA injury after experimental intracerebral hemorrhage. Brain Res 2005; 1039(1-2):30 - 6. [8] Pradilla G, Wang PP, Legnani FG, Ogata L, Dietsch GN, Tamargo RJ. Prevention of vasospasm by anti–CD11/CD18 monoclonal antibody therapy following subarachnoid hemorrhage in rabbits. J Neurosurg 2004;101(1):88 - 92. [9] Reilly C, Amidei C, Tolentino J, Jahromi BS, Macdonald RL. Clot volume and clearance rate as independent predictors of vasospasm after aneurysmal subarachnoid hemorrhage. J Neurosurg 2004;101(2): 255 - 61. [10] Rhoten RLP, Comair YG, Chayette D, Simonson MS. Specific repression of the preproendothelin-1 gene in arteriovenous malformations. J Neurosurg 1999;90:605 - 7. [11] Vespa P, Bergsneider M, Hattori N, Wu HM, Huang SC, Martin NA, Glenn TC, McArthur DL, Hovda DA. Metabolic crisis without brain ischemia is common after traumatic brain injury: a combined microdialysis and positron emission tomography study. J Cereb Blood Flow Metab 2005;25:763 - 4. [12] Wang X, Feuerstein GZ. The Janus face of inflammation in ischemic brain injury. In: Baethmann A, et al, editors. Mechanisms of secondary brain damage from trauma and ischemia. New York7 Springer-Wein; 2004. [13] Yen CP, Chen SC, Lin TK, Wu SC, Chang CY, Lue SI, Jeng AY, Kassell NF, Kwan AL. CGS 26303 upregulates mRNA expression of heme oxygenase-1 in brain tissue of rats subjected to experimental subarachnoid hemorrhage. J Cardiovasc Pharmacol 2004;44:S474 - 8.
If a man takes no thought about what is distant, he will find sorrow near at hand. — Confucius, The Confucian Analects