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Modern Management of Brain Aneurysms and Vascular Malformations by Gregory J. Zipfel, MD It has become

Modern Management of Brain Aneurysms and Vascular Malformations

by Gregory J. Zipfel, MD

It has become apparent that a multidisciplinary approach is mandated for best management of cerebrovascular patients.

Modern Management of Brain Aneurysms and Vascular Malformations by Gregory J. Zipfel, MD It has become

Gregory J. Zipfel, MD, 1-year MSMA member, is Assistant Professor of Neurological Surgery in the Departments of Neurological Surgery and Neurology at Washington University in St. Louis.

Contact: zipfelg@nsurg.wustl.edu

Abstract

The

management of

brain aneurysms and vascular malformations has evolved rapidly in recent years. More of these lesions are being diagnosed due to higher fidelity imaging, treatment has become more refined and often less invasive, and patients have become more integrated in their own care due to advances in information technology. This article reviews the clinical characteristics and therapeutic options for patients harboring these lesions, with a particular focus on recent advances in the field.

Introduction

Over the past decade, substantial

improvements in natural history, diagnosis, and intervention have occurred for numerous cerebrovascular diseases including brain aneurysms and vascular malformations. Specific examples include more robust natural history data, enhanced sensitivity and

specificity of noninvasive imaging

modalities, improvement and increased utilization of less invasive therapeutic modalities including endovascular therapy and Gamma Knife radiosurgery, and refinements in surgical technique. This article highlights recent advances

and provides a detailed review of best practice for the care of patients harboring aneurysms, cavernous malformations, and arteriovenous malformations (AVMs) of the brain.

Aneurysms

Epidemiology

The prevalence of brain aneurysms in the general population is 1-3%; however, certain individuals are at increased risk 1 . Female gender and family history of aneurysm or subarachnoid hemorrhage (SAH) are known risk factors. Autosomal dominant polycystic kidney disease (ADPKD) is also associated with increased aneurysm prevalence. Active cigarette smoking not only increases the risk for aneurysm formation, but also increases the probability that a known aneurysm will rupture. Finally, presence of an AVM markedly increases the risk of aneurysm formation, owing to the hemodynamic stress associated with these high flow lesions.

Diagnosis

Unruptured aneurysms most commonly present incidentally, while a distinct minority present with aneurysm specific symptoms. Examples of the latter include aneurysms arising near the optic nerve presenting with visual

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deficits, aneurysms in close proximity to the oculomotor nerve presenting with diplopia or ptosis, and aneurysms having intraluminal thrombus presenting with ischemic stroke. Ruptured aneurysms, on the other hand, most commonly present with symptoms referable to SAH. Classically, these include a “thunderclap” headache, nausea, vomiting, neck stiffness, decreased mental status, and/or focal neurological deficits. The radiographic study of choice for evaluation of a patient with suspected SAH is head computed tomography (CT) (Figure 1A). The sensitivity of head CT is very high within the first 24 hours; however, sensitivity drops quickly when patients present in delayed fashion. Lumbar puncture is often used when head CT is negative or equivocal. Results consistent with SAH include increased red blood cell count in serial tubes as well as xanthochromia (i.e. yellowish discoloration due to red blood cell breakdown). Catheter cerebral angiography has for decades been considered the gold standard for aneurysm detection and characterization (Figures 1B and C). However, noninvasive imaging techniques such as computed tomographic angiography (CTA) and magnetic resonance angiography (MRA) have vastly improved in recent years and have begun to approach the sensitivity and specificity of catheter- based angiography, especially for lesions >3mm in size.

Natural History

Unruptured Aneurysms

The landmark International Study of Unruptured Intracranial Aneurysms (ISUIA) 2 was a large scale multicenter observational study aimed at assessing hemorrhage risk of unruptured aneurysms. Several important observations were noted. First, critical

Figures 1

Subarachnoid hemorrhage and cerebral aneurysm.

Figure 1A

Non-contrast head CT demonstrating acute subarachnoid blood (hyperdensity) within the basal cisterns and sylvian fissures.

deficits, aneurysms in close proximity to the oculomotor nerve presenting with diplopia or ptosis, and aneurysms

Figure 1B

Two-dimensional catheter angiogram revealing a large anterior communicating artery aneurysm.

Figure 1C

Three-dimensional catheter angiogram demonstrating the detail architecture of a large anterior communicating artery aneurysm including two views of the aneurysm neck and arterial branches.

deficits, aneurysms in close proximity to the oculomotor nerve presenting with diplopia or ptosis, and aneurysms

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Figures 2

Treatment options for cerebral aneurysms.

Figures 2 Treatment options for cerebral aneurysms. Figure 2A Surgical clipping. Intra-operative photograph of complex internal

Figure 2A

Surgical clipping. Intra-operative photograph of complex internal carotid artery aneurysm obliterated by two fenestrated aneurysm clips.

Figures 2 Treatment options for cerebral aneurysms. Figure 2A Surgical clipping. Intra-operative photograph of complex internal

Figure 2B

Endovascular coiling. Intra-procedural photograph demonstrating deployment of platinum metal coils via microcatheter within large basilar artery aneurysm.

aneurysm size associated with increasing hemorrhage risk was found to be 7 mm. Second, aneurysm location significantly affected hemorrhage risk, as lesions arising from the anterior cerebral, middle cerebral and internal carotid

arteries carried lower risk compared to lesions arising from the vertebral, basilar, and posterior communicating arteries. Third, patients with history of SAH were at increased risk of aneurysm rupture. Fourth, the overall hemorrhage risk of

unruptured aneurysms appeared less than that previously reported. Though ISUIA was subject to a strong selection bias as well as other study weaknesses, it remains the most robust prospective natural history data available to date.

Ruptured Aneurysms

While

hemorrhage

risk

of

unruptured aneurysms remains incompletely defined, bleeding risk of ruptured aneurysms is well documented, with most studies reporting rebleeding rates of 40% in the first four weeks after SAH 3 . Moreover, though the morbidity and mortality associated with initial SAH is high (50% of patients die and 50% of survivors suffer long-term cognitive deficits), the consequences of re-hemorrhage are even greater (80% of patients die or remain severely disabled) 3 .

Overall Management

Much of SAH management is focused on preventing or managing one of the following complications:

1) hydrocephalus 2) aneurysm re-bleeding 3) seizures and 4) cerebral vasospasm. Regarding hydrocephalus, this is a very common complication that occurs within hours of ictus. Acute treatment is mandatory and involves insertion of a ventriculostomy for drainage of cerebrospinal fluid (CSF). As blood within the subarachnoid space dissipates over time, many patients can be weaned from the ventriculostomy while others will require permanent CSF shunting. Regarding aneurysm re-bleeding, the risk is very high as described above. In decades past aneurysm treatment was often delayed; however, modern management includes aneurysm obliteration within 24-48 hours of presentation. Early aneurysm treatment not only reduces re-bleeding

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rates, but also allows for aggressive hemodynamic therapy for cerebral vasospasm. Seizures are a fairly common event after SAH and are to be avoided; particularly prior to aneurysm treatment when seizure activity and its attendant rise in blood pressure could promote aneurysm re-rupture. Antiepileptic drugs are prescribed in all patients upon admission and continued for at least several days. Longer term antiepileptic treatment is only required in those deemed at particular risk for ongoing seizures. Cerebral vasospasm is the greatest source of secondary neurological injury following SAH. It is defined as delayed narrowing of large cerebral arteries in response to the initial SAH. Its incidence is high, with angiographic evidence of vasospasm occurring in 60- 70% of SAH patients and vasospasm- induced ischemic neurological deficits occurring in 30-40% of SAH patients 4 . Treatment for cerebral vasospasm is multifaceted 3 . First, all patients are prophylactically placed on a calcium channel blocker (Nimodipine), which is proven to reduce secondary neurologic deficits due to vasospasm. Second, patients who develop vasospasm- induced symptoms are treated with hemodynamic therapy (i.e. induced hypervolemia and/or hypertension) as well as select use of endovascular therapy, i.e. intra-arterial vasodilators and/or angioplasty. Despite these measures, vasospasm-induced brain injury remains a significant source of neurological morbidity after SAH.

Aneurysm Treatment

Direct surgical approaches for aneurysm obliteration have been the mainstay of treatment since the late

1960s and early 1970s, and involves

placement of a

titanium metal clip

across the neck of the aneurysm

(Figure 2B). More recently, the utility and efficacy of endovascular therapy has gained widespread acceptance. Endovascular treatment involves insertion of platinum metal coils via a microcatheter to achieve aneurysm obliteration (Figure 2C). Adjuvant use of balloon and stent technology to assist with coil embolization has further broadened the applicability of endovascular treatment.

Ruptured Aneurysms

Due to the very high incidence of re- bleeding after SAH and the acceptable risks associated with surgical and endovascular aneurysm repair, the vast majority of patients with SAH should undergo aneurysm treatment in the acute period. Withholding aneurysm treatment is typically reserved only for those patients with very poor prognosis (e.g. patients who are elderly, medically infirm, and/or in very poor neurological condition). Importantly, a trial period of CSF drainage via ventriculostomy should be provided in the vast majority of patients, as many experience dramatic improvement in their neurological status and subsequently warrant aneurysm treatment. In regards to choice between surgery and endovascular therapy, many factors must be considered. Size, configuration, and location of the aneurysm are critical. Several patient factors are also important, including patient age, medical co-morbidities, presenting neurological condition, and patient preference. Local availability and depth of experience of microvascular surgery and endovascular therapy can also affect treatment choice. Finally, results from the International Subarachnoid Aneurysm Trial (ISAT) should be considered. ISAT 5 was a landmark randomized controlled trial (RCT) designed to evaluate safety and efficacy of

surgical versus endovascular therapy for ruptured aneurysms. It included patients with recent SAH where the treating physicians felt that the offending aneurysm was equally amenable to surgical or endovascular therapy – a scenario termed “clinical equipoise.” Patients were randomized to surgical or endovascular therapy. Importantly, enrolled patients in this study represented only 22% of those patients having ruptured aneurysms at the participating institutions, suggesting that superiority of one treatment over the other was present in the majority of patients. Results from ISAT found an overall superior outcome at one year for patients treated with endovascular vs. surgical therapy – a benefit that occurred despite increased chance of re-treatment and increased incidence of re-bleeding in the endovascular patients. This result favoring endovascular therapy has had a major impact on practice patterns for ruptured aneurysms, with many institutions experiencing an increase in endovascular aneurysm treatment after its publication.

Unruptured Aneurysms

By the early 1990s, a general consensus in the neurologic community had been achieved regarding best practice for unruptured aneurysms – that is, these lesions were felt to be quite dangerous and should be repaired by surgical means in most patients. Since that time, two events have significantly challenged this treatment paradigm. One, new data regarding the natural history of unruptured aneurysms became available. Two, development and widespread application of endovascular therapy dramatically altered aneurysm treatment paradigms. Regarding the former, data from ISUIA 2 suggested that annual hemorrhage risk for unruptured aneurysms, particularly

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Figure 3

Cavernous malformation. T2-weighted MRI demonstrating cavernous malformation in the right parietal lobe. Note characteristic hypointense hemosiderin ring surrounding the lesion.

Cavernous Malformations

Epidemiology, Diagnosis, and Natural History

Cavernous malformations are discrete, well-described multilobulated lesions characterized by abnormally enlarged capillary cavities without intervening brain parenchyma. Their prevalence in the general population has been estimated as 0.1-0.5% 6 . They are best identified on MRI where they have a well-defined lobulated appearance and a characteristic rim of signal hypointensity on T2 weighted images (Figure 3). Cavernous malformations most commonly present with cerebral hemorrhage, seizure, or as an incidental finding. When they bleed, the extent of hemorrhage is typically smaller and the neurological deficits less severe than that associated with aneurysms or AVMs. The annual hemorrhage risk of a previously unruptured cavernous malformation is thought to be 0.5-1% per year, while the annual hemorrhage risk of a recently ruptured cavernous malformation is thought to be 4-5% per year for several years 7 .

Treatment

Therapeutic options include expectant management, antiepileptic therapy, surgical excision, and in rare cases Gamma Knife radiosurgery. Patients with incidental lesions are typically treated with expectant management, owing to the low annualized risk of debilitating hemorrhage. Patients presenting with seizures but without hemorrhage are also commonly managed without surgical intervention. These patients are treated with antiepileptic medications and if seizures are well controlled, no further therapy is required. For those wishing to avoid long-term antiepileptic therapy and

Figure 3 Cavernous malformation. T2-weighted MRI demonstrating cavernous malformation in the right parietal lobe. Note characteristic

those less than 7 mm in size, was less than previously reported. Regarding the latter, the availability and excellent safety profile of endovascular therapy led to a marked increase in its use for unruptured aneurysms. However, no RCTs comparing surgery vs. endovascular therapy for unruptured aneurysms have been reported to date. Therefore at present, no direct evidence to suggest superiority of one treatment modality over the other exists for unruptured lesions. Decisions regarding choice of treatment modality consequently remain at the discretion of the treating physician, and are based on thorough evaluation of multiple factors that might affect hemorrhage and procedural risk, including aneurysm characteristics, patient factors, and issues of local surgical and endovascular expertise.

having a surgically accessible cavernous malformation, lesion resection can be considered. When a cavernous malformation presents with hemorrhage and is in a surgically accessible region (e.g. cerebral or cerebellar cortex), lesion resection is often recommended due to the relatively high risk of recurrent bleeding and the generally low risk associated with surgery. Because the neurological deficits associated with cavernous malformation bleeding are often non-disabling, expectant management is also reasonable. When surgically accessible lesions hemorrhage on multiple occasions, however, lesion resection is usually pursued. When a cavernous malformation presents with hemorrhage but is in a surgically difficult to access or high risk region (e.g. basal ganglia or brainstem), lesion resection is often not pursued, at least initially. This is due to the significant risk associated with cavernous malformation removal from these brain regions. However, because deep seated lesions are associated with particularly high risk for recurrent hemorrhage, some advocate resection for select deep-seated lesions even in patients who have suffered a single hemorrhage. When deep-seated lesions hemorrhage on multiple occasions, even greater consideration for surgical intervention is given. Finally, Gamma Knife radiosurgery has been utilized by some practitioners as a means for treating cavernous malformations. Evidence supporting the efficacy of this approach, however, is not robust. If pursued at all, Gamma Knife radiosurgery is only indicated in select cases where patients have suffered multiple hemorrhages and harbor a cavernous malformation that does not permit surgical removal.

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Figures 4 Arteriovenous malformation. Figure 4A T2-weighted MRI demonstrating a tangle of vascular flow voids in
Figures 4
Arteriovenous malformation.
Figure 4A
T2-weighted MRI demonstrating a
tangle of vascular flow voids in the
right frontal lobe, consistent with an
arteriovenous malformation.
Figure 4B
Catheter angiogram demonstrating
a high-flow right frontal
arteriovenous malformation.
Figures 4 Arteriovenous malformation. Figure 4A T2-weighted MRI demonstrating a tangle of vascular flow voids in

Arteriovenous

Malformations

Epidemiology, diagnosis, and natural history

AVMs are congenital lesions composed of a nidus of thin walled dysplastic vessels that permit shunting of high pressure arterialized blood from dilated feeding arteries to thin-walled draining veins. Most AVMs are well demonstrated on CT and MRI (Figure 4), though small lesions are sometimes difficult to identify. All AVMs require formal catheter angiography to fully assess their architecture and to examine for associated aneurysms. Based on several autopsy studies, the prevalence of AVMs appears to be 1-4% 8 . AVMs most commonly present with cerebral hemorrhage, which is associated with 10-20% morbidity and 10-30% mortality 8 . Seizure is the second most frequent presentation. This is most common for superficial AVMs and in particular those residing within the temporal lobe. Other modes of presentation include headache, progressive neurological decline, and as an incidental finding. The natural history of AVMs, in contrast to that of aneurysms, is well defined, with several studies demonstrating a 2-4% annual hemorrhage risk for unruptured

lesions. This risk appears to be temporarily higher following AVM rupture, with most studies documenting 6% annual hemorrhage risk in the first post-hemorrhage year followed thereafter by a 2-4% annual hemorrhage risk 8 .

Treatment

Management options for AVMs include observation, craniotomy for resection, Gamma Knife radiosurgery, endovascular embolization, or multimodality treatment. The latter may include a combination of surgery, radiosurgery and/or embolization depending on the complexity and clinical scenario of a given AVM. Surgical resection for AVMs has been a mainstay of treatment since the 1960s. It has the advantage of acutely eliminating risk of rupture and may also improve seizure control for those with history of seizure. Its disadvantages are that it is invasive, that it can at times carry significant risk, and that it entails a several-day hospitalization and a several-week overall period of recovery. Radiosurgery involves a one-time delivery of stereotactically targeted high-dose radiation to the AVM with minimization of radiation to the surrounding brain. It has the advantage of being an outpatient procedure

with a very short period of recovery as well as an attractive procedural risk profile. Its disadvantages include gradual obliteration of the AVM nidus over 1-3 years during which the risk of hemorrhage remains, higher risk for incomplete AVM obliteration, and limitation to predominantly smaller lesions (i.e. diameter 3 cm). Endovascular therapy involves manipulation of a microcatheter into the AVM nidus, followed by administration of an embolic agent designed to reduce blood flow. Its advantages include a less invasive procedure, a brief period of hospitalization, and a relative short period of overall recovery. Its disadvantages are that endovascular therapy can at times carry significant risk and that it uncommonly leads to complete AVM obliteration. Due to the latter, endovascular treatment is infrequently used as a stand alone procedure, but more commonly employed as a preoperative adjunct to improve the overall safety of surgical resection. Patient factors to be considered during therapeutic decision making include: patient age, medical co- morbidities (both of which make surgical and endovascular therapy less attractive), and patient preference. Certain AVM characteristics must also

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be considered, the most important of which are size and location. For most small and moderate sized AVMs that are located apart from eloquent brain regions, surgical resection is generally considered treatment of choice. This relates to its very high chance of complete AVM obliteration, acute elimination of bleeding risk, and a generally attractive procedural risk profile. For lesions 3cm in diameter and located within eloquent brain, Gamma Knife radiosurgery is typically best. This relates to its high chance of AVM cure and superior procedural risk profile. When AVMs fall outside these treatment categories, controversy exists regarding best practice. Many believe such lesions are best left untreated, though these patients remain at substantial risk for hemorrhage. Others have reported relative success via multimodal therapeutic approaches that typically involve staged radiosurgery or staged embolization followed by radiosurgery. The majority agrees that surgical intervention for most of

the more formidable AVMs is to be avoided.

Conclusion

Over the past 10-15 years, great advancement in the management of patients with cerebrovascular disease has been achieved by refinements in natural history, introduction of new and less invasive therapeutic procedures, and advancements in surgical technique. It has also become apparent that a multidisciplinary approach is mandated for best management of cerebrovascular patients, as an ever-growing breadth of expertise is required in order to deliver optimal care. This entails a collaborative spirit between numerous specialists including cerebrovascular surgeons, endovascular specialists, vascular neurologists, neurointensivists, radiosurgical and radiation therapists, neuroradiologists, as well as many other physician and non-physician caregivers. It is anticipated that further advances in the care of cerebrovascular patients will continue to occur over time, as novel and often less invasive technologies become further refined and validated.

References

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Lasserve E. Genetics of cavernous angiomas. Lancet

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2001;32(6):1458-71.

Disclosure

None reported.

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