Cavernous Malformations of the Brain and Spinal Cord

Cavernous Malformations of the Brain and Spinal Cord

21  Cavernous Malformations of the Brain and Spinal Cord OMAR CHOUDHRI, ROC PENG CHEN, KETAN BULSARA CLINICAL PEARLS • Cerebral cavernous malformati...

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21 

Cavernous Malformations of the Brain and Spinal Cord OMAR CHOUDHRI, ROC PENG CHEN, KETAN BULSARA

CLINICAL PEARLS • Cerebral cavernous malformations (CCMs) are vascular lesions that contain a compact bundle of pathologic capillary vessels without intervening brain parenchyma. CCMs are relatively common, affecting approximately 1 in every 200 individuals and accounting for 8% to 15% of all vascular malformations of the central nervous system (CNS). The majority of lesions occur in the brain, with most being located in the supratentorial compartment and the minority infratentorially, to include the brainstem. Approximately 3% to 5% are discovered as intramedullary spinal CCM. • Despite the high prevalence of CCM, most lesions are asymptomatic, being discovered incidentally, if ever. Only 20% to 30% of CCM patients are symptomatic during their lifetimes, presenting to medical attention most commonly during their third to fifth decades of life with symptoms such as headaches, seizures, and focal neurologic deficits due to lesion expansion following events such as thromboses and hemorrhages. • Cavernous malformations can be either familial or sporadic. The familial form of the disease often manifests as multiple lesions in the setting of a family history of neurologic disease. In the sporadic form, patients rarely have more than two lesions, and family history is typically absent. Mutations in three genes, CCM1, CCM2, and CCM3, have been discovered as being responsible for the familial disease, accounting for 96% of all mutations. De novo occurrence of lesions can occur and may impact long-term outcome. • Complete surgical resection of CCM is the only management strategy that is curative. Medical management is limited to seizure control and symptomatic relief of headaches. The

indication for radiosurgery treatment is controversial. In contrast, successful lesion resection immediately eliminates a patient’s hemorrhage risk, but up to 80% of patients achieve seizure control postoperatively. The main goal in managing CCM is to balance the risks of surgery with those of the natural history of the disease. Because both of these factors vary significantly, each CCM patient must be considered on an individual basis. • The most serious complication of CCM natural history is intracerebral hemorrhage. Patients with posterior fossa cavernomas are reported to be 6.75 times more likely to present with a bleed, and the rehemorrhage rate is higher than that for lesions in other locations. Not only were these repeat hemorrhages common, but brainstem cavernomas can result in debilitating deficits due to the high density of critical tracts and nuclei in this region. • As a result of devastating outcomes with untreated cavernomas in high-risk regions, surgical treatment must always be considered for these select patients. Four major criteria assist in determining which patients with infratentorial lesions are appropriate surgical candidates: those with (1) lesions that rise to the pial surface based on T1-weighted MRI, (2) lesions with repeated hemorrhages causing progressive neurologic deficits, (3) lesions with acute hemorrhage extending outside the lesion capsule, and (4) significant mass effect produced with a large intralesional hemorrhage. Surgery is considered only when total resection can be achieved, because lesion remnants can grow and hemorrhage as well.

Description

eye. Histologically, the lesions are composed of a single layer of endothelial cells and lack structural elements found in mature vessels, including smooth muscle and elastin (Fig. 21.1). Other elements usually found in the blood-brain barrier, including astrocytic foot processes and pericytes, are also diminished or completely absent.1–3 Macroscopically, the lesions appear reddish purple. They are often multilobulated and can be encapsulated by a variable layer of fibrous

Cerebral cavernous malformations (CCMs), or cavernomas, are low-flow vascular lesions consisting of clusters of dilated, thin-walled vascular channels lacking intervening neural parenchyma. They typically range in size from 1 mm to several centimeters and can be found anywhere in the central nervous system (CNS) as well as in other organs such as the skin and

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50 µm • Figure 21.1  Histologic picture of a human cavernous malformation shows a single layer of endothelial cells (arrowheads) surrounding sinusoidal spaces with thrombosed red blood cells within them. Note the lack of normal brain parenchyma within the lesions. Hematoxylin and eosin (H&E) stain. Scale bar represents 5 µm. (Courtesy of Dr. Angeliki Louvi, Yale University School of Medicine.)

adventitia, giving them their characteristic mulberry-like appearance. Given a lack of tight junctions in cavernomas walls, they tend to be leaky, resulting in hemorrhages with blood products of various ages. Cavernous malformations can be either familial or sporadic. The familial form of the disease usually manifests as multiple lesions in the setting of a family history of neurologic disease (Fig. 21.2). In the sporadic form, patients rarely have more than two lesions, and family history is typically absent. Mutations in three genes, CCM1, CCM2, and CCM3, have been discovered as being responsible for the familial disease, accounting for 96% of all mutations. Radiographically CCMs are best detected on magnetic resonance imaging (MRI), where they appear as a mixture of high and low T1 and T2 signal intensity surrounded by hemoglobin degradation products. These different components give lesions a characteristic popcorn appearance, with a surrounding hemosiderin ring due to chronic bleeds, that appears hypointense both on T1- and T2-weighted imaging. Axial T2 gradient echo or susceptibility weighted images are most sensitive in identifying cavernous lesions but possess a significant blooming artifact due to blood products (Figs. 21.2 and 21.3). Because computed tomography (CT) findings for cavernomas are nonspecific, this imaging modality is less useful for detection. Angiography is similarly of little diagnostic help because lesions are usually angiographically occult. After a hemorrhage, however, developmental venous anomalies (DVAs) can be detected on angiography and should alert the clinician to a concomitant cavernoma, which frequently coexists with DVAs. CCMs are relatively common, affecting approximately 1 in every 200 individuals and accounting for 8% to 15% of all vascular malformations of the CNS.4,5 The majority of lesions occurs in the brain, with 63% to 90% of these being located in the supratentorial compartment and 7.8% to 35.8%

• Figure 21.2  Axial T2 gradient echo MRI image demonstrating multiple hypointense areas consistent with multiple cerebral cavernous malformations in a patient with familial multiple cavernoma syndrome.

infratentorially.4,6 Between 9% and 35% of infratentorial lesions are located in the brainstem.6 Despite the high prevalence of CCM, most lesions are asymptomatic, being discovered incidentally, if ever. Only 20% to 30% of CCM patients are symptomatic during their lifetimes, presenting to medical attention most commonly during their third to fifth decades of life with symptoms such as headaches, seizures, and focal neurologic deficits due to lesion expansion following such events as thromboses and hemorrhages.7 Asymptomatic patients also occasionally present to health care providers after having one or multiple CCMs detected incidentally on imaging studies obtained for other purposes. Given this highly variable presentation and disease progression in patients with CCM, choosing the appropriate management strategy can be challenging. This chapter explores the different treatment options available for CCM and provides suggestions as to the appropriate management in different circumstances. Before doing so, however, the natural history of these lesions will be discussed, as sound understanding of the natural history of the disease is paramount in any decision-making process with regard to treatment.

Natural History The natural history of CCM can vary widely among patients. Although once believed to be congenital, it is now recognized that CCM can also occur de novo.8 Once present, these lesions are dynamic, expanding as lesions thrombose and hemorrhage, and regressing as they recanalize and as blood products from hemorrhages are resorbed.8,9 The most common symptom

CHAPTER 21  Cavernous Malformations of the Brain and Spinal Cord

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• Figure 21.3  A 45-year-old female presented with right hemibody paresthesias and numbness. (A) Axial FLAIR MRI demonstrating a left parietal lesion with hypointense margin consistent with a cavernoma (white arrow). The lesion is again demonstrated on a coronal T1 and sagittal T1 postcontrast MRI image (white arrow). (D) Operative view with cavernoma surrounded by two cortical veins. Characteristic mulberry like appearance of cavernoma with dilated vascular channels and blood at different stages noted. (E) Hemosiderin stained pseudocapsule around the lesion with small capillary feeders seen. (F) Resection bed lined with surgical hemostatic fabric. Hemosiderin not removed given proximity to sensorimotor cortex.

reported in CCM patients is seizures, which are especially common with frontal or temporal lobe lesions.10 Cavernoma lesions are typically surrounded by reactive gliosis, which, at least in certain cases, is thought to serve as an epileptogenic focus. The estimated annual seizure risk is approximately 1% to 2%, and in patients with supratentorial lesions several seizure types including simple, complex partial, and generalized have been reported.10,11 Gross apoplectic hemorrhages are the most severe presentation of CCM. Because cavernomas are low-flow, low-pressure lesions, most bleeds are relatively small and result from blood extravasation from the leaky vascular channels of the lesion. Larger bleeds can and do occur, though, with an annual hemorrhage risk ranging between 0.25% and 6% depending on a variety of factors.11 Larger and deeper lesions have been reported to have an increased bleeding risk, as do lesions in older patients, pregnant patients, and patients who have suffered a previous bleed.7,12 Rehemorrhage could be as high as 30% especially with infratentorial and brainstem lesions.12 Asymptomatic patients or those presenting with seizures

typically have the lowest risk, which usually ranges from 0.4% to 2% annually.13 Symptoms from a hemorrhage are typically maximal at the time of the bleed and gradually improve as the hemorrhage undergoes organization and resorption. With repeat hemorrhages, however, neurologic deficits often worsen, and the risk that such deficits will become permanent increases.14 Progressive neurologic deficits are usually the most common presenting symptom of infratentorial CCM. Because this region has a higher density of eloquent neural structures compared to supratentorial regions, lesions here usually become symptomatic at smaller sizes.15

Management Options Current medical literature recognizes four options for managing CCM: expectant management, medical management, surgical resection, and stereotactic radiosurgery. Understanding which technique or combination of techniques is appropriate for a particular patient depends on a variety of factors and will be discussed in a later section. This section focuses on

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describing the four available options as well as highlighting some of their pros and cons.

Expectant Management Expectant management consists of regular radiographic followup of lesions, usually every 1 to 2 years. Because MRI is the best modality for visualizing CCM, it is the imaging technique of choice when following lesions expectantly. Each new MRI is compared to prior ones in order to detect evidence of lesion changes over time. Of particular interest are signs of lesion expansion or hemorrhage. If present, there may be a need for intervention, especially for lesions located in neurologically high-risk areas. For patients who are not operative candidates owing to their age or because of significant medical comorbid conditions, expectant management may be the only option. Asymptomatic patients, especially those with lesions in eloquent brain regions, are also best managed nonoperatively.

Medical Management Options for medically managing cavernomas are unfortunately limited. There is no medical cure for cavernomas, so current medical therapy is limited to providing symptomatic relief through analgesics for headaches and antiepileptic medications for seizure control. Antiepileptics can control not all patients’ seizures, though, and therefore surgical intervention should be considered for patients with seizures refractory to pharmacologic agents. Similar to patients being managed expectantly, these patients should also be followed with regular MRIs, and particular attention should be given to scans if patients have had changes in their symptoms despite taking their medication regularly as prescribed. In vitro and in vivo studies on animal models have shown that activation of Rho GTPases in CCM lesions and RhoA activation in endothelial cells is now considered to be the final common pathway for CCM development. Statin therapy, which is known to inhibit signaling through these molecules, might have a role in medical treatment.16 The investigational drug fasudil, which disrupts RhoA activity, is another exciting candidate for medical therapy.17 However, clinical trials are needed to test the validity of these agents in CCM patients.

patients, however, surgical interventions usually have good outcomes. The surgical approach to cavernous malformations is determined by the location of the cavernous malformation. A detailed understanding of MRI images is necessary before recommending and planning surgery. Localization of hemorrhage, cavernous malformation, and the developmental venous anomaly is necessary. The best operative approach is one that allows removal of the lesion while minimizing contact with normal brain tissue and preserving the associated DVA. For superficial supratentorial lesions, a craniotomy centered over the lesion is used, followed by a gyral or sulcal route for resection. Eloquent lesions in the thalamus, basal ganglia, or brainstem require a number of different approaches depending on where the malformation comes closest to surface as well as anatomic safe entry zones (Table 21.1). Stereotactic navigation as well as intraoperative ultrasound can be employed to allow an accurate surgical trajectory. Intraoperative brainstem auditory evoked potentials, somatosensory evoked potentials, and cranial nerve mapping are important operative adjuncts. A small pial opening is made to enter the malformation or hemorrhage cavity where it comes closest to the surface. Bipolar electrocautery is minimized, especially in eloquent locations, and microinstruments are used to dissect out the cavernoma. The cavernoma is dissected from the surrounding neural tissue, a process that is often made easier by the presence of a gliotic pseudocapsule around the lesion that can provide a circumferential surgical plane, before its removal. While resecting brainstem cavernomas, en bloc resection is avoided to prevent injury

TABLE Basic Operative Approaches to Thalamic, Basal 21.1  Ganglia, and Brainstem Cavernous

Malformations

Site

Sub Location Approach

Basal ganglia

Posterosuperior Transsylvian transinsular Anteroinferior Supracarotid infrafrontal

Thalamus

Medial Pulvinar

Midbrain

Ventrolateral

Surgical Resection (Figs. 21.3, 21.4, and 21.5) Microsurgical resection is the only definitive and curative treatment for cavernous malformations. The goal of surgery is to resect the malformation with minimal risk to surrounding tissue. Not only does a successful lesionectomy immediately eliminate a patient’s hemorrhage risk, but 75% to 80% of patients achieve seizure control postoperatively.18,19 As the most invasive treatment option, however, surgical resection is also the riskiest, with potential complications including permanent neurologic deficits and even death. The recommendation for surgery is based on balancing the risk of cavernoma hemorrhage with the operative risk. When offered to appropriate

Ventral

Dorsal

Pons

Ventrolateral Dorsal

Medulla

Ventrolateral Dorsal

Transcallosal transventricular Lateral supracerebellar infratentorial Pterional, orbitozygomatic/ transsylvian Subtemporal transtentorial +/− anterior petrosectomy/transsylvian Supracerebellar infratentorial (midline/paramedian/ lateral) Retrosigmoid/subtemporal transtentorial Suboccipital telovelar/ transvermian Far lateral Median suboccipital transventricular

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• Figure 21.4  A 59-year-old female with giant cavernous malformation involving the superior cerebellar surface and vermis resected by a supracerebellar infratentorial approach. (A) A coronal T2 MRI demonstrating a cavernoma with the characteristic popcorn appearance (arrow) and surrounding hemosiderin stain. (B) Sagittal T1 MRI again demonstrating the cavernoma (arrow) displacing the cerebellum and abutting fourth ventricle as well as tectum. (C) Operative view demonstrating mulberry-like cavernoma (arrow) with thrombosed dilated vessels and blood at various stages. (D) Deepest portion of the cavernoma involving ependymal surface of the floor of fourth ventricle. No attempt was made to resect this portion given the involvement with the facial nerve nucleus.

to surrounding tracts and nuclei. Instead the cavernoma can be removed piecemeal with microforceps and microdissectors.20 Choudhri and colleagues described a no touch technique for resecting cavernomas using carbon dioxide laser, which is a useful adjunct for deep-seated lesions.21 Following excision of the cavernoma, a decision must be made regarding the pseudocapsule. In supratentorial lesions, this area is generally removed provided it is not in or near a critical structure. In general, because the gliotic tissue of the pseudocapsule is thought to serve as an epileptogenic focus, the benefits of removing this tissue in symptomatic patients could outweigh the risks associated with leaving these regions intact. For infratentorial lesions and eloquent supratentorial lesions, however, the pseudocapsule is generally left intact. Finally, before closing, the area should be examined for evidence of satellite lesions and cavernoma remnants, all of which should be resected to prevent lesion recurrence. Care

should be taken, however, to preserve any associated branches of nearby DVAs, as their destruction may lead to venous infarcts with potentially significant neurologic deficits.

Stereotactic Radiosurgery The use of stereotactic radiosurgery in the treatment of CCM remains controversial.15 As the only intervention available for cavernoma treatment aside from open surgery, radiosurgery seems like an attractive alternative for patients who are either not surgical candidates or who have lesions in surgically inaccessible areas. Current imagining techniques are unable to detect complete lesion occlusion, though, making it impossible to determine whether or not this treatment modality is curative.22 Efficacy therefore must be based on clinical data such as postprocedural hemorrhage rates or on histologic results such as specimens that show complete occlusion following

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• Figure 21.5  A 39-year-old male with seizures and memory problems with recurrent hemorrhage from a cavernoma in the rostrum of corpus callosum and extending to the floor of left lateral ventricle. The lesion was resected with an interhemispheric transventricular transcallosal approach with preservation of fornix. (A) Axial T2 gradient echo MRI demonstrating a left rostral cavernoma (arrow). (B) Coronal T2 MRI demonstrating the cavernoma in the floor of left lateral ventricle (arrow). (C) Operative microscope view demonstrating the cavernoma (arrow) adjoining the internal cerebral vein.

radiosurgical intervention. Several studies have looked at these parameters following radiosurgical intervention, but none of them has found evidence supporting the cure of CCM with this procedure. Although some studies report decreased hemorrhage rates following radiosurgery,23,24 others, including some of the same studies, report an increased complication rate following this intervention, such as permanent neurologic deficits.25–27 Furthermore, patients in one study had to undergo open surgical resection of their lesions after radiosurgery failed to eliminate their cavernoma.26 In terms of histologic studies, evaluation of resected cavernoma specimens from patients who had undergone radiosurgery anywhere from 1 to 10 years prior failed to show complete obliteration of their lesions. Instead, the main finding in these specimens was changes consistent with fibrinoid necrosis.28 Based on the preceding summarized data, radiosurgery does not appear to be an effective treatment strategy for CCM and should be used only in highly selected, if any, cases.

Management Decisions The main goal in managing CCM is to balance the risks of therapy with those of the natural history of the disease. Because both of these factors can vary greatly among patients, each case must be considered on an individual basis. This section further explores the different factors that contribute to these risks and provides suggestions on appropriate management techniques. One of the most serious complications of CCM is intracerebral hemorrhage. Patients with posterior fossa cavernomas are reported to be 6.75 times more likely to present with a bleed than those with lesions in other locations.29 In addition to this increased initial bleeding risk, several studies have found an increased rehemorrhage rate among these patients. Not only were these repeat hemorrhages common, but 21% to 50% of rehemorrhages from brainstem cavernomas resulted

in debilitating deficits30,31 owing to the high density of critical tracts and nuclei in this region (Table 21.1). Given this potential for devastating outcomes with untreated cavernomas in these high-risk regions, surgical treatment must always be considered for these patients. However, the locations of these lesions also make the surgery higher risk, and this risk needs to be weighed heavily against the natural course of the disease when deciding whether to operate. In the acute setting, if a patient’s neurologic status is rapidly deteriorating from mass effect related to a hemorrhage, immediate surgery might be warranted. In all other settings, four major criteria have been developed to assist in determining which patients with infratentorial lesions are appropriate surgical candidates: (1) lesions that abut the pial surface based on T1-weighted MRI, (2) lesions producing repeated hemorrhages causing progressive neurologic deficits, (3) lesions with acute hemorrhage extending outside the lesion capsule, and (4) significant mass effect produced with a large intralesional hemorrhage. In addition, surgery is considered only when total resection can be achieved because lesion remnants can grow and hemorrhage as well. Another key determinant for brainstem cavernous malformations is the number of clinically significant hemorrhages, and many surgeons consider two prior hemorrhagic events before offering brainstem surgery.32 A study by Porter and associates looked at the results of 86 patients with brainstem cavernomas who satisfied these surgical criteria and underwent resection of their lesions. Thirty-five percent of these patients suffered temporary or permanent morbidity or death, with permanent or severe deficits occurring in 12%. The overall mortality rate was 8%, with 3.5% of deaths being surgically related. Nonetheless, patients undergoing surgery seemed to do better than those receiving conservative management. At late follow-up, 87% of surgically treated patients reported doing the same or better than before surgery, compared to 58% of patients in the nonsurgical group having this outcome. In

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addition, only 10% of surgical patients were worse at this late follow-up, as opposed to 42% of those not receiving surgery. Although risky, surgery is therefore justified in these cases.6 Gross and colleagues performed a systematic review of 78 studies that looked at CCM of the brainstem. Of the 745 cases examined, 683 (92%) of the cavernomas were completely resected. Although early postoperative morbidity rates ranged from 29% to 67%, it was often temporary. Of the 683 patients who received surgery, 85% had clinical improvement, 14% had deterioration of their symptoms, and 1.9% died as a result of complications related to surgery.32 These results suggest that, although risky, surgery benefits a majority of patients and might therefore be justified in carefully selected symptomatic patients. Chen and coworkers, in their experience with 57 brainstem cavernomas undergoing surgery, demonstrated good patient selection and surgical planning as central to obtaining excellent outcomes with these difficult lesions. They were able to obtain complete recovery of preoperative motor deficits in up to 70% of cases and cranial nerve recovery rates in 20% to 80% of cases.33 Supratentorial lesions are reported to have a lower hemorrhage rate34 (see Table 21.1). Although infrequent, however, overt hemorrhages might occur. In these situations, patients are usually taken to surgery based on their rate of neurologic decline as well as the foreseeable consequences of mass effect from the bleed. Blood may interfere with the ability to visualize the cavernoma on imaging, in which case surgery may be deferred if the patient does not require immediate surgical decompression. In all other cases, two options can be considered. In the first, the patient can undergo elective exploratory surgery soon after the event, especially when the clot is subacute and thus soft. Otherwise, the patient can be managed expectantly until the diagnosis is confirmed. More commonly, though, lesions in this location are associated with seizures. Antiepileptic drugs have traditionally been the initial management strategy for such patients, with surgery being considered for patients with seizures that are refractory to medication or that intensify during pharmacologic treatment. Using this treatment approach, 65% of the 168 patients with supratentorial lesions in one study were free from their disabling seizures 3 years after surgery, with half of them remaining seizure free for this entire period.35 A few other studies suggest that this outcome can be improved with earlier surgical intervention. In one study, 100% of patients who had developed epilepsy within 2 months of surgery were completely free of seizures postoperatively. Patients who waited between 2 and 12 months and greater than 12 months after the onset of epilepsy to undergo surgery had seizure control rates of 76% and 52%, respectively.36 Regardless of when surgery is done, outcomes are usually good. For patients with solitary, superficial supratentorial CCM, the risks of surgical resection of cavernomas outside highly eloquent areas are only slightly higher than those of general anesthesia in trained hands. Furthermore, in the study of 168 patients discussed previously, which is one of the largest studies of supratentorial cavernomas, no deaths occurred, and mild postoperative neurologic deficits were seen in only 12 patients.35 Englot and

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associates, in their systematic review, found gross total resection and surgery within a year of seizure onset as the key predictors of seizure freedom after cavernoma surgery.19 Another factor to consider when operating on patients with seizures is whether or not to resect any gliotic or hemosiderinstained tissue surrounding the lesion. Although some studies report complete resolution of seizure activity with pure lesionectomies, others report a higher rate of seizure control with removal of additional elements surrounding the lesion. In a study of 31 patients, 64% of the 14 who underwent excision of the hemosiderin ring in addition to a lesionectomy were categorized as Engel class I (free of disabling seizures) 1 year later. Only 53% of patients who had undergone either a lesionectomy or a lesionectomy plus partial removal of the hemosiderin ring fell into this category. Fifty-nine percent and 46%, respectively, were still in this group 3 years postoperatively37 (Fig. 15.2). Another study had similar results, with 77.8% of patients being classified as Engel type Ia (free of all seizures) after a complete lesionectomy plus hemosiderin ring resection compared to 65.7% of those in the lesionectomy-only group, but the additional benefit of the hemosiderin ring resection was only seen in a subset of patients who received surgery within 2 years of their seizure onset38 (Table 21.2). Although most CCMs are located in the brain, intramedullary spinal cavernomas account for 3% to 5% of lesions.39–41 These cavernomas can occur alone or in combination with cerebral lesions. Lesions are typically located in the thoracic cord, with cervical cavernomas being the second most common, and lumbar or conus rare. Spinal CCMs usually present with a slowly progressive myelopathy causing deficits in sensation, motor skills, or both.42 Acute presentations of focal neurologic deficits can also occur as a result of hematomyelia, intralesional hemorrhage, and cord compression.43 Although symptoms resulting from acute presentations often resolve spontaneously, those resulting from chronic myelopathy frequently do not improve even after surgery. Surgery will stop the progression of myelopathy, though, and therefore is warranted in symptomatic patients. In a chart review of 26 patients receiving

TABLE Annual Hemorrhage Rates and Events Due to 21.2  Cerebral Cavernous Malformations by Locationa

Hemorrhage Rate (%/yr)

Event Rate (%/yr)

Infratentorial

3.8

10.6

Supratentorial

0.4

0.4

Deep

4.1

10.6

Superficial

0

Location

0

a An event refers to neurologic deterioration, defined as subjective worsening (new or increased neurologic symptoms) accompanied by objective worsening of neurologic findings, with or without a radiologically proved hemorrhage. Modified from Porter PJ, Willinsky RA, Harper W, Wallace MC. Cerebral cavernous malformations: natural history and prognosis after clinical deterioration with or without hemorrhage. J Neurosurg. 1997;87:190–197.

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TABLE Complete Seizure Control (Engel Class 1a—Free From All Seizures) in Relation to Cerebral Cavernous 21.3  Malformation (CCM) Location and Hemosiderin Ring Resectiona Engel Class 1A

Hemosiderin Resection

CCM Location

After 1 Year

After 2 Years

After 3 Years

Complete resection

Temporal Parietal Frontal Occipital

7/12 (58%) 0 2/2 (100%) 0

5/12 (42%) 0 1/1 (100%) 0

5/12 (42%) 0 1/1 (100%) 0

Partial or no resection

Temporal Parietal Frontal Occipital

5/8 3/7 0/1 1/1

(63%) (43%) (0) (100%)

4/8 1/6 0/1 1/1

(50%) (17%) (0) (100%)

1/7 1/5 0/1 0/1

(14%) (20%) (0) (0)

a

Rates of complete seizure control at 1, 2, and 3 years after resection, grouped by resection of hemosiderin ring and location of CCM31.

surgery for spinal CCM, 12 (46%) were improved at longterm follow-up, 12 (46%) were unchanged, and only 2 (8%) had worsened neurologic conditions.42 Surgery therefore might be the best option to prevent disease progression in select cases in order to potentially improve the patient’s condition. One meta-analysis found improved outcomes with spinal CCM undergoing resection within 3 months of presentation, with gross total resection and the use of a hemilaminectomy approach.44 Although less common than symptomatic patients, asymptomatic patients are often referred for management after a lesion is found incidentally on imaging studies. Because it is unknown whether these patients will ever become symptomatic, choosing a management strategy can prove to be difficult. Provided that there is no evidence of bleeding, expectant management is usually the initial recommended management for these patients.

Special Considerations Although the preceding guidelines apply to the majority of patients with CCM, several patient groups require special consideration. These patients are discussed in this section. Older patients and those with significant comorbid conditions represent one group requiring special consideration. These patients usually have a high surgical risk and therefore may not be suitable candidates for surgery. Expectant or medical management may therefore be a better option for these patients unless the risks of intervention are justified, such as repetitive bleeds with progressive decline in neurologic function or life-threatening hemorrhages. Another group requiring special consideration is patients with multiple lesions. Almost all cases of familial CCM and a small percentage of patients with sporadic cavernomas might have more than one lesion. Treatment of these patients should be handled expectantly, with intervention being reserved for symptoms that can be attributed to a specific lesion that is clinically active. For patients experiencing progressive neurologic deficits, imaging can be helpful in determining which lesions may be active based on size changes over time. Seizure

types and auras, as well as monitoring devices, can be helpful in identifying particular lesions that are symptomatic in patients presenting with seizures. If the clinically active seizures can be determined using these tools, surgical intervention may be warranted (Table 21.3). In a study of 63 patients with medically refractory CCM, 11 patients had multiple lesions, with a mean of 3.7 lesions per patient. All of these patients had only one epileptogenic zone, and removal of the cavernoma at this site resulted in 9 patients being classified as Engel class Ia and 2 as Engel Ib (free of disabling seizures) or IVc (seizure worsening postoperatively) 2 years later.45 Unfortunately, de novo occurrence of lesions is common in these patients and can have a negative impact on the patient’s long-term outcome. Genetic screening of patients with a family history of CCM is not recommended.46 The three genes currently recognized as being responsible for cavernous malformation account for 96% of familial mutations, making it possible that a fourth gene has yet to be discovered and consequently would not be detected during genetic screens.47 A study of 20 families affected by cavernomas failed to detect mutations in any of the three cavernous malformation genes in 12 of the families.48 Furthermore, the origin of sporadic CCM is unknown and could be related to environmental factors either alone or in combination with genetic factors. Patients with a positive cavernoma family history should obtain an MRI if they experience any symptoms commonly associated with cavernomas, including headaches, seizures, and focal neurologic deficits, or if they are diagnosed with a cerebral hemorrhage. In addition, genetic counseling should be offered to these patients.

Conclusion The natural history of CCM can differ greatly among patients depending on various factors, including the location, biologic state, and genetic background of the patient. Choosing an appropriate management strategy can therefore be difficult because different patients can be subject to vastly different clinical courses. In general the best treatment strategy is one that minimizes the risks associated with the disease’s natural history while also having a low procedural risk. Therefore

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infratentorial lesions with high rates of devastating hemorrhage are often treated surgically, and supratentorial lesions commonly causing seizures can be treated either medically or surgically depending on the patient’s surgical risks and seizure control. In experienced hands, outcomes from these procedures generally have low morbidity and mortality rates, and these statistics will only further improve as research provides new insight to the disease’s natural history and the long-term outcomes of different treatment options.

Selected Key References Baumann CR, Acciarri N, Bertalanffy H, et al. Seizure outcome after resection of supratentorial cavernous malformations: a study of 168 patients. Epilepsia. 2007;48:559-563.

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Brown RD Jr, Flemming KD, Meyer FB, et al. Natural history, evaluation, and management of intracranial vascular malformations. Mayo Clin Proc. 2005;80:269-281. Gross BA, Batjer HH, Awad IA, et al. Brainstem cavernous malformations. Neurosurgery. 2009;64:E805-E818, discussion E818. Kondziolka D, Lunsford LD, Flickinger JC, et al. Reduction of hemorrhage risk after stereotactic radiosurgery for cavernous malformations. J Neurosurg. 1995;83:825-831. Porter RW, Detwiler PW, Spetzler RF, et al. Cavernous malformations of the brainstem: experience with 100 patients. J Neurosurg. 1999; 90:50-58. Tu J, Stoodley MA, Morgan MK, et al. Ultrastructural characteristics of hemorrhagic, nonhemorrhagic, and recurrent cavernous malformations. J Neurosurg. 2005;103:903-909. Please go to ExpertConsult.com to view the complete list of references.

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333.e2

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Vascular Neurosurgery

42. Jallo GI, Freed D, Zareck M, et al. Clinical presentation and optimal management for intramedullary cavernous malformations. Neurosurg Focus. 2006;21(1):e10. 43. Labauge P, Bouly S, Parker F, et al. Outcome in 53 patients with spinal cord cavernomas. Surg Neurol. 2008;70(2):176-181, discussion 81. 44. Badhiwala JH, Farrokhyar F, Alhazzani W, et al. Surgical outcomes and natural history of intramedullary spinal cord cavernous malformations: a single-center series and meta-analysis of individual patient data: Clinic article. J Neurosurg Spine. 2014;21(4): 662-676.

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