From aneurysm to aneurysmal vasculopathies

From Aneurysm to Aneurysmal Vasculopathies Pierre Lasjaunias, MD, PhD

Today, aneurysms raise a number of challenges. Medical challenge: The emergency and severity of the pathology have led to passionate debates that unfortunately stall progress in our knowledge of the underlying disease (or diseases). Indeed we can suppose that some measure of bleeding, perhaps even early recurring hemorrhage, has gone undiscovered and that some patients have bled several times before ever reaching the hospital. Decision-making challenge: Far from emergency and immediate action, this is a challenge of knowledge versus superstition. The decision concerns the therapeutic objective and the choice of a specific technique in a given place, whether surgical or endovascular. The choice of the treatment should first take into consideration the patient's needs, and second, the quality of the treatment available. Ethical challenge: Preventing rupture has a cost in terms of public finances, ethics, and outcomes. The former is a choice of society, while the latter is a result of the invasiveness of the treatment, regardless of the location of the aneurysm. Permanent self-assessment is not a recent suggestion, but today it has become more relevant than ever on account of the publication of medical data considered as universally applicable because it is internationally available. Academic and nosologic challenge: It is difficult to refrain from thinking that aneurysms, though they may be discovered in a variety of contexts (bacterial or viral infection, traumatic or spontaneous dissection, dysplasia, familial or isolated aneurysms, flow-related in cerebral arteriovenous malformations or in cases of anastomoses for revascularization, giant basilar fusiform aneurysms or smaller aneurysms of the P2 segment of the posterior cerebral artery, giant carotid aneurysms or serpentine aneurysms of the distal cerebral arteries, multifocal unilateral or mirror aneurysms, multiple, supra- or infratentorial aneurysms, etc) do not result from entirely different diseases. Therefore, diagnosed aneurysms should be considered the result of 2 simultaneous processes: the production of aneurysms and the failure to repair them. Age and life of aneurysms should be thought of as having a symptomatic clinical stage, an asymptomatic stage, a biological stage, and a prepathological stage (applying to somatic mutations). Copyright 9 2000 by W.B. Saunders Company

T

oday, aneurysms raise a number of challenges.

Medical Challenge. Aneurysms raise complex technical and therapeutic problems, including preventing recurrences and treating complications resulting from hemorrhage, especially in subarachnoid hemorrhage caused by ruptured aneurysms. Aneurysmal hemorrhage causes high morbidity and mortality From Neuroradiologie, H6pital Bic6tre, Cedex, France. Address reprint requests to E Lasjaunias, MD, PhD, Neuroradiologie, H6pital Bic6tre, 78 rue du Gen6ral Leclerc, 94275 Kremlin Bicetre, Cedex, France. Copyright 9 2000 by W.B. Saunders Company 1092-440X/00/0303-0001 $10.00/0 doi: 10.1053/otns.2000.16259

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rates. The emergency and severity of the pathology have led to passionate debates that stall progress in acquiring knowledge of the underlying disease. Although ruptures are symptomatic, the question of whether subclinical hemorrhage already has occurred should not be eluded. Careful grading according to Hunt and Hess, Fisher, and the World Federation of Neurosurgical Societies (WFNS) 1 on admission of the patient does not hide the limited extent of knowledge as to how hemorrhage occurred. It can be supposed that some measure of bleeding, perhaps early recurring hemorrhage, has gone undiscovered and that some patients have bled several times before reaching the hospital. Another possibility is that periods of bleeding may have occurred at such close intervals that they were not identified, despite modern imaging techniques. Cisternal flooding may result from repeated bleeding or poorly controlled bleeding of the aneurysm over time, whether hours or days. tn other cases, a single, sudden rupture into an undivided cavity floods the cistern. Decision-Making Challenge. Decision-making challenges arise in case of unruptured aneurysms. Unruptured does not mean silent; it means that the aneurysm has not been associated with clinical hemorrhage. The challenge does not lie in the intensive care management, prevention of early rupture, or management of the spasm; this challenge confronts knowledge against superstition. The decision concerns the therapeutic objective and following the choice of a specific technique in a given place, whether surgical or endovascular. 2 Despite the dramatic context surrounding the diagnosis of aneurysms, the decision not to intervene should be considered an appropriate one. Such a decision can be made even though the same aneurysm may be operated or embolized, according to the case, in a different environment, with no contradiction in the coherence of decision making. The choice of the treatment should take into consideration first the patient's needs and, second, the quality of the treatment available. The point is to adapt one's decision to one's means. Ethical Challenge. The ethical challenge lies in informing the patient of his or her medical condition, what physicians know about it, what can be done about it, and what can be recommended. How does one recognize the subgroups of patients and aneurysms that may or should be treated? There must be indicators of imminent rupture, but as of now we do not know how to read them. There are probably signs of stability as well, but they may not be long-lasting. Preventing rupture has a cost, in terms of public finances, ethics, and outcomes: The first is a choice of society, whereas the latter two costs are due to the invasiveness of the treatment, regardless of the location of the aneurysm. That is why teams that are ready to manage unruptured aneurysms should most likely list their means to achieve this so as to recognize the different subgroups of patients. Teams also should compute and monitor constantly the quality of their results. Permanent self-assessment is not a recent suggestion, but today it has become more relevant

Operative Techniquesin Neurosurge~ Vol 3, No 3 (September), 2000: pp 160-165

TABLE 1. Aneurysms as Symptoms? Aneurysmal Vasculopathies I Lumen Herniation & Lumen Repair 9 Hemodynamic triggers: flow, velocity, turbulence, pressure, jet effect, valve effect 9 Mechanical treatment: balloons, coils, remodelling, stents, liquids, bags 9 Morphological assessment: 3D images, virtual arterioscopy, vessel lumen models 9 Future: telenavigation,telereconstruction Selectivity of the delivery system and accuracy of the reconstruction 9 Specialists involved: surgeons, neuroradiologist, anatomists, pathologists, engineers

Aneurysmal Vasculopathies II Vessel Wall Herniation & Vessel Watt Repair 9 Disorders: infectious, immune, inflammatory, constitutional remodelling defect, familial or nonfamilial, embryonic or postnatal program defects,

proliferative 9 Therapeutic agents: antibiotics, growth factors, gene therapy 9 Functional assessment: endothelial and wall physiology, phenotypic characteristics, mutations, molecular biology 9 Goal: selective recognition of the diagnosis and focal effect of the therapeutic agent 9 Specialists involved: geneticians, physiologists, pharmacologists, molecular biologists, immunologists

on account of the publication of medical data considered universally applicable because it is internationally available. Academic and Nosologic Challenge. Morphology and disease are two separate entities: Different-shaped aneurysms often reflect different pathologies. Similar ones can reflect different situations; however, a saccular aneurysm of the basilar trunk that developed on the P1 segment may be isolated or associated with muhifocal aneurysms, whether or not familial. Associations with Ehlers-Danlos syndrome, Marfan syndrome, polycystic kidney disease, or an arteriovenous malformation of the occipital lobe differentiate aneurysms from each other beyond their appearance. Aneurysms are symptoms, just as most other types of vascular malformations are all symptoms of a more subtle form of an intracellular and regionally contained disorder, establishing narrow connections with the neighboring tissues through endoluminal and extravascular signals. We should shift the focus from aneurysmal vasculopathy to mural vasculopathy (Table 1), and this shift in focus changes the objectives of treatment and the underlying physiopathologic approach from mechanistic to biologic. As a result of that dual approach, therapeutic research, although it may be compatible in both approaches, has been growing increasingly apart, involving various specialists. This new mindset does not cast out the current mechanistic management of ruptured aneurysms because in this case the point is not so much to analyze the underlying disease but to manage the rupture itself and prevent hemorrhage. Treatment of the complication should never be confused with the preventive treatment of the rupture or that of the underlying disorder, which is probably entirely different.

Physiopathogenesis and Risks The physiopathogenesis of aneurysms is a complex one, just as it is for other vascular disorders. This complexity is due to the fact that we have no knowledge of the life span or regeneration frequency of arteries, whether in the normal or pathologic ANEURYSM AND ANEURYSMAL VASCULOPATHIES

state. In vitro studies provide only a crude model because they isolate blood vessels from their perivascular environment, a key element in the maintenance and renewal of arterial walls. Are aneurysms simply due to aging arterial walls or to the progression of a more specific disorder? Is physiopathogenesis morphologic, biologic, or clinical? Do clinical examinations collect enough information? Is physiopathogenesis an ongoing process? Is it linear? Is it reversible? Is it random or predictable? Can it be modeled? Is it made of events or of a lack of events? Can it feed itself? Can it induce a series of events independent from the disease itself? The history of diseases we diagnose is always retrospective. There is no prospective physiopathogenesis of a disorder, only an order of events. As a result, there is a time gap: Through physiopathogenesis, we collect and attempt to understand a fragment of th e past but do not know its beginning. History always is incomplete because we focus on events rather than on mechanisms. The danger of physiopathogenesis lies in its possible extrapolation to the future in an attempt to anticipate possible events, while forgetting to check if the underlying mechanisms are still present. A model of the future is a temporary model. It is the projection of a past time interval, but it does not take into account the fact that its contents may have changed. Answers provided by models are never completely true, but they are not entirely wrong. A predictive physiopathologic model creates an unclear atmosphere, and the (unclear) management thereof calls for caution. Minute differences at the time of diagnosis carry within them major differences in the development. Future physiopathogenesis is isomeric: Its course most likely changes after a sequence of outside events that shift the real history of the disease from one theoretic curve to another. One of the major stakes in the preventive treatment of aneurysms is probably finding factors that stabilize or destabilize the disorder. Because of its variability, physiopathogenesis is difficult to determine. The notion of individual data must be introduced before making a decision for a patient. Among which history of the physiopathogenesis of aneurysms is it a part--the patient's or the disease's? The projected history of a patient differs from that of the population used to model the future, regardless of its homogeneity. The retrospective analysis of a patient's life; of medical events and resulting clinical signs; and of their connection with indicators of shape and flow, with hormonal, biologic, or genetic activity, all place the patient on a matrix of possible physiopathogeneses. The physiopathogenesis as estab-

TABLE 2. Arterial Aneurysm (AA) Types Infectious--bacterial, viral Dissecting--traumatic, spontaneous Dysplastic--familial, nonfamilial Flow---cerebral AVMs Fusiform--basilar, P2 of PCA Giant--carotid, vertebral, distal cerebral Multifocal--mirror, unilateral, supra- and infratentorial Berry

False Questions MirrorAA PKD1 AA is diagnosed at adult age HBP AA, flow-related AA, and berry AA are not involvingthe same arteries In children, high-flow lesions are not associated with AA Berry AA becomes large, but not giant or fusiform AA Giant AA may keep on growing albeit excluded from the circulation Flow-related AA does not rupture after AVM embolization

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lished from a more or less homogeneous population tends to average out the information, the decision, and ultimately the results. Patient numbers, the attention given to morphology, the visibility of symptoms, the clinical excellence of physicians, physicians' medical knowledge, and empiricism, among other criteria, all have an impact on a team's experience and publications. Using another's figures related to physiopathogenesis proves delicate. Figures should remain an indication but should not become dogmatic or used to justify a decision made for a corporate sort of personal interest or that of a local team.

Classification Traditionally, physiopathology begins with the discovery of a constituted aneurysm. The single (mechanistic) treatment proposed should not hide the diversity of targets (Table 2). It is difficult to refrain from thinking that aneurysms, although they may be discovered in a variety of contexts (eg, bacterial or viral infection; traumatic or spontaneous dissection; dysplasia; familial or isolated aneurysms; flow related in cerebral arteriovenous malformations or in cases of anastomoses for revascularization; giant basilar fusiform aneurysms or smaller aneurysms of the P2 segment of the posterior cerebral artery; giant carotid aneurysms or serpentine aneurysms of the distal cerebral arteries; multifocal, unilateral, or mirror aneurysms; multiple, supratentorial, or infratentorial aneurysms), do not result from entirely different diseases. Crude as this list of dissimilar disorders may appear, aneurysms often are discussed as if they were of a single type before deciding on a treatment or a technique. The differences in pathologies are often smoothed out to present results. Meanwhile, the goal of treatment cannot be identical for each type of aneurysm. Physiopathologies may not be pooled and subsequently applied to each case. Other questions remain, such as what should we think of mirror aneurysms? Why aren't aneurysms diagnosed in children with polycystic kidney disease but only at an adult age 10 years younger than populations without the disease? Other unanswered questions concern the location of aneurysms in

arterial hypertension, flow-related aneurysms, and isolated saccular aneurysms; that aneurysms are never found in highflow lesions in children with arteriovenous fistula; that saccular aneurysms have never been known to become giant or fusiform aneurysms; that flow-related aneurysms do not rupture once an arteriovenous malformation has been treated, they even regress; and that in some areas aneurysms develop and may enlarge, but never rupture, such as on the branches of the splenic artery in portal hypertension. The regression of flowrelated aneurysms also raises the question of whether the body develops aneurysms frequently and may be able to repair them before rupture occurs. Diagnosed aneurysms should be considered as the result of two simultaneous processes: the production of aneurysms and the failure to repair them. All these questions reflect clinicians' ignorance and the need to act. As was the case in genetics, the ability to classify each type of aneurysm in a given disease class requires the in-depth study of the morphologic, 3,4 clinical, biologic, and genetic context in which the aneurysm occurs. As a result, population homogeneity improves, and the analytic study of retrospective physiopathology becomes more useful. Associations with certain aneurysms shed light on factors involved in parietal homeostasis, as follows: Genetics~early somatic germinal mutations cause a metameric distribution of lesions. Somatic mutations occurring later are better corrected or better compensated but occur at a crucial moment in the development of blood vessels of the skull base; an example is abnormal fusion or persisting branchial embryonic arteries. Growth factor disorders, resulting in proliferative malformations, such as fusiform or giant aneurysms. Abnormal vascular remodeling resulting from flow or pressure disorders, occur later, alter long-term programs, and potentially cause aneurysms that may rupture. Parietal aggression by unpredictable extrinsic factors, such as infectious agents, another cause of aneurysm development. Segment vulnerabilitys (Fig 1) leads to aneurysms as a result of

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Fig 1. Crossed etiological and morphological classifications of arterial aneurysms. PIERRE LASJAUNIAS

the combination of weak and resistant segments on blood vessels and certain types of aggressors or aggression. Each one of the aforementioned disorders, each time marker, may lead to clinical, morphologic, and topographic phenotypes that currently make up the core of modern classifications. For each of these lines (Fig 2), we should be able to trace the physiopathology and compare the proposed treatment with the calculated prospective risk.

Age of Aneurysms Although the acquired aspect of aneurysms has often been proposed, aneurysms likely do not develop haphazardly. The age of lesions is a more immediate challenge (Table 3). Aneurysms are the visible part of an iceberg:

A symptomatic clinical stage (eg, due to compression, vascular accident, subarachnoid hemorrhage). This clinical stage results from the collective effects of decompensating factors during the previous stage. An asymptomatic clinical stage. This is a morphologic phase during which aneurysms develop slowly without disturbing the organism's stability, until triggering factors make it symptomatic. This is the stage during which prevention of bleeding from nonruptured aneurysms is currently discussed. The identification of triggering factors appears to be a key element to stop the progression of asymptomatic aneurysms to the symptomatic stage. The clinically asymptomatic morphologic stage (of unknown duration) is due to the incapacity of the body to repair the previous biologic stage.

TABLE 3. Age of Vascular Lesions

Clinicalsymptomaticstate Clinicalasymptomatic(morphological)state Preclinicalstate (quiescentphase) Biologicalstate (somaticmutation) Pregeneticstatevulnerability Germlinemutation

A biologic stage. This is the stage during which the disorder becomes engrained in the cell and detectable by triggering factors, whereas it was dormant before. At this time, repair fails to occur. The biologic stage varies in duration. It seems to be long in the case of germinal mutations. Over this long period, an inversion of the male-to-female ratio is noted, thought to be due to hemodynamic triggering factors (eg, hypertension, high flow), general stress, and smoking. Some have suggested that a secondary mutation occurs to explain that a genetic disorder may lead to a local disease, even though arteries and veins all are carriers of the same defect. The mutation may involve the loss of the normal allele or a mutation impeding the compensation of the initial abnormality (Figs 3 and 4). A prepathologic stage. This stage applies to somatic mutations. The time at which they occur determines the risk of contracting a muhifocal disorder. The developing endothelium and pericytes 3,4,6,7 are exposed to various agents, depending on their degree of vulnerability. Mutations express a specific outside factor for a given segment of artery or the acquired or innate vulnerability of a particular segment of artery (eg, human immunodeficiency virus, familial candidiasis). The mutagenic factor probably does not re-

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ANEURYSMAND ANEURYSMALVASCULOPATHIES

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and imagining questions while modeling the answers are stepping stones in the direction of knowledge. The fourth dimension, time, has been introduced to understand physiopathologic mechanisms, with the extremes being apoptosis and cellular immortality. Anchored in the middle is biologic aging. The quest for the highest quality preventive treatment, if it could be given during the biologic stage, would resemble that of the dLxir for

Conclusion Regardless of the technical progress made, the mystery behind a disease increases as we learn to explore it. Making hypotheses

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Fig 4. Clonal mutation/clonal phenotype. Specificity of the timing (window) and a specific trigger: A mutation involves a clone of cells. Specificity of the character and recognition by the trigger: A genotype or phenotype shared by a group of cells at a certain moment creates an identity and a recognizable group. 164

PIERRELASJAUNIAS

eternal youth. That is mere utopia from another age, however, and it should not interfere with the clinical, ethical, and scientific challenges clinicians face daily in an effort to preserve patients from illness and erroneous information.

References 1. Kassel NF, Iorner JC, Haley EC Jr, et al: The international cooperative study on the timing of aneurysm surgery. Part I Overall management results. J Neurosurg 73: 18-36, 1990 2. Wiebers O: Unruptured intracranial aneurysms: risk of rupture and risks of surgical intervention. N Engl J Med 339:1725, 1998

ANEURYSM AND ANEURYSMAL VASCULOPATHIES

3. Campos C, ChurojanaA, Rodesch G, et al: Multiple intracranial arterial aneurysms: a congenital metameric disease? Interventional Neuroradiology 4:293, 1998 4. Campos C, Churojana A, Rodesch G, et al: Basilar tip aneurysm and basilar tip anatomy. Interventional Neuroradiology 4:121, 1998 5. Lasjaunias P: Segmental identity and vulnerability in cerebral arteries. I nterventional Neuroradiology 6:113-124, 2000 6. Benjamin LE, Hemo I, Keshet E: A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-# and BEGT. Development 125:1591,1998 7. Carmeliet P: Mechanisms of angiogenesis and arteriogenesis. Nat Med 6:389, 2000

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