Surgical management of intracranial cavernous malformations: the Louisiana State University Health Sciences Center, Shreveport experience.

Abstract: Intracranial cavernous malformations are vascular anomalies consisting of endothelium-lined caverns filled with blood at various stages of thrombosis and organized and separated by a collagenous stroma devoid of mature vessel wall elements. They represent a clinical challenge both in diagnosis and management due to the variety of presenting symptoms and neuroradiological features. This study analyzes the clinical manifestations and surgical outcomes in 16 patients with cavernous malformations who were treated surgically at the Louisiana State University Health Sciences Center in Shreveport. The most common presenting features were headache, seizure, and focal neurologic deficits. Three patients had deep lesions (two in the brainstem and one in the basal ganglion), and 13 patients had superficial lesions. All patients underwent surgery and had complete excision of the lesion. The overall outcome was satisfactory for all patients with significant symptom relief over a mean follow-up period of 60 months. The optimal management of cavernous malformations should be determined on a case-by-case basis and, when indicated, surgery provides good outcome.

Key Words: intracranial cavernous malformations, cavernoma, hemorrhage

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Intracranial (IC) vascular malformations have been recognized for quite some time, but distinct clinicopathological profiles of these lesions have only recently been identified, following the development of histopathological diagnostic criteria and more sophisticated neuroimaging. (1,2) Traditionally, vascular malformations of the central nervous system were considered to be congenital hamartomas, distinct from true vascular neoplasms and each with characteristic gross and microscopic morphology. (1) IC vascular malformations currently are classified into four basic categories: arteriovenous malformations, cavernous malformations (CMs), capillary telangiectasias, and venous malformations. (1,2) Because no abnormal vascularity is seen on angiography, CMs have been included in the description of cryptic or occult vascular malformations, a term that has been used to describe any vascular malformation that cannot be seen on angiography. (2) CMs have also been called cavernous hemangioma or cavernoma, but more recently the term cavernous malformation has become more widely accepted, explicitly distinguishing these lesions from true vascular neoplasms as suggested by the term angioma.

The diagnosis of CM was rarely made before operation or autopsy when CT was not in routine clinical use. After MRI became widely available, imaging characteristics of CMs were defined, which allowed a rapid and precise diagnosis to be established in many cases. (3) CMs are usually iso- to moderately hyperdense on nonenhanced CT. Enhancement following contrast administration varies from none (or minimal) to striking. On MRI, CMs show a typical popcorn-like lesion with a well-delineated complex reticulated core of mixed signal intensities representing hemorrhage in different stages of evolution. A low signal rim that completely surrounds the lesion, due to hemosiderin, is typical for CM. This low signal becomes even more prominent on T2-weighted images. Gradient echo studies should always be included to reveal multiple lesions, as all lesions are not always visible on standard spin echo images. In the majority of cases, cavernous angiomas are angiographically occult. In cases with hemorrhage, an avascular area with moderate mass effect can sometimes be identified. Occasionally, a faint blush on the late capillary or early venous phase can be seen. (2) The advances in imaging have also resulted in increasing reports of incidental asymptomatic CMs. This further emphasized the need to explore and study the natural history of this particular lesion (4,5) and develop a clinical management rationale based on individual risk factors, institutional results, and expertise.

Materials and Methods

Sixteen patients with the diagnosis of CM underwent surgery at the Louisiana State University Health Sciences Center in Shreveport between 1991 and 2003. Twelve patients (75%) were female and four (25%) were male. The youngest patient was 17 years old, and the oldest was 60 years old (mean = 39.4). The shortest follow-up period was 34 months and the longest was 150 months with a mean follow up of 60 months.

The initial presenting symptoms included (but in most cases were not limited to) headaches in 11 (68.75%) patients, seizures in 10 patients (62.5%), and focal neurologic deficits in five patients (31.25%). Thirteen (81.25%) patients had superficial lesions in the cerebral hemisphere; whereas, three patients (18.75%) had lesions with deep localization (two in the brainstem and one in the basal ganglia). All patients except one had solitary lesions. Familial association was present in one patient whose three daughters were also found to have asymptomatic CMs. Indications for surgery were drug-resistant seizures in 10 patients, focal neurologic deficits in five patients, and intracerebral hemorrhage in one patient. Image-guided neuronavigation was used to localize the lesion and facilitate adequate resection in nine patients. Intraoperative ultrasonography was used to localize the lesion in two patients. In one case, a combination of neuronavigation and intraoperative electrocorticography was used to tailor the extent of the epileptogenic focus along with the cavernous malformation (Table 1). For all cases, a total resection of the lesion was achieved and the diagnosis of CM was histopathologically confirmed.

Results

Clinical outcome was categorized into five groups: excellent, good, fair, poor, or death (Table 2). (5) Two of the five patients presenting with focal neurologic deficits experienced worsening of their existing neurologic deficit immediately following surgery. One of these patients developed postsurgery pneumocephalus that resolved within 48 hours. At the last follow-up, both of them were back to their preoperative neurologic functioning level with the remaining three of five neurologically impaired patients being intact (symptom reduction; 3/5: 60%). Eleven patients (68.75%) presented with headaches that were interfering with their daily activities, of whom seven (symptom reduction; 7/11: 63.6%) became completely asymptomatic after the surgery. We achieved a similar result regarding the seizures where seven patients out of 10 (symptom reduction; 7/10: 70%) became completely seizurefree following the surgery (Table 3).

Overall, seven of the 16 patients (43.75%) were asymptomatic with no neurologic or functional dysfunction. Of the 10 patients presenting with seizures, 7 (70%) were cured without antiepileptic drug therapy. The remaining three patients continued to experience seizures but fewer than before surgery. These three patients are currently on regular anticonvulsants. Two of the patients who initially presented with focal neurologic deficits had mild residual hemiparesis. Their neurologic condition improved following surgery and they were able to function independently (Table 2). As our surgery improved their neurological condition, they were classified within the good outcome group. None of the patients had a poor or dismal outcome in our experience (Table 2).

[FIGURE 1 OMITTED]

Discussion

A cavernous malformation is a grossly discreet, well-circumscribed lesion with a reddish purple, multilobulated appearance. In contrast to arteriovenous malformations, CMs lack the features of high flow or the enlarged arterial feeders and draining veins that are associated with arteriovenous shunting. (1) Microscopically a CM contains sinusoidal spaces lined by a single layer of endothelium and separated by a collagenous stroma devoid of elastin, smooth muscle, or other mature vascular wall elements. The lack of intervening brain parenchyma is one of the characteristic pathologic markers of CMs. The surrounding parenchyma consistently exhibits evidence of prior microhemorrhage, hemosiderin discoloration, and hemosiderin-filled macrophages. Hyalinization thrombosis with varying degrees of organization, calcification, cysts, and cholesterol crystals are common within the lesion. (1,6) A gliomatous reaction of the surrounding parenchyma is characteristic and may form a capsule around the lesion. Mixed or transitional lesions containing features associated with more than one class of vascular malformation have been described. (7) A CM may be associated with capillary telangiectasias adjacent to or remote from the lesion. All surgical specimens from our patients were histopathologically examined and the diagnosis of CM was confirmed for each and every case (Fig. 3).

The prevalence of CMs has often been projected from the relative ratio among other vascular malformations. (6) Although early clinical reports often considered these lesions to be rare, several large MRI-based retrospective studies suggest that CMs are more common than was previously thought. (3,8) Since the introduction of MRI in the routine diagnostic evaluation of CMs, the number of reported patients with CMs has risen dramatically. Still subject to inherent selection biases, MRI-based studies take advantage of the increased sensitivity and specificity to detect CMs, including incidental ones. Depending on how stringent the selection criteria is for MRI testing, the prevalence in MRI-based series goes up to 0.9%, (9) and this data correlates well with the reported prevalence in autopsy studies. (9,10) In general CMs are now thought to account for 5% to 13% of all IC vascular malformations. (5) MRI has also permitted the identification of asymptomatic patients and provided a powerful screening tool for familial CMs. The existence of a familial form characterized by multiple lesions and an autosomal dominant inheritance pattern has been linked to chromosome 7q, and it is suggested that Hispanic patients may have a higher predilection for familial CMs. (5,6,11,12) In our series of 16, only one patient demonstrated familial association, with three daughters who were also diagnosed with asymptomatic CM following a screening MRI.

With the exception of a few reports showing preponderance for either sex, the majority of studies and all recent large MRI-based analyses demonstrate an equal prevalence of male and female patients with CMs. (4,5,7,13) However, there is a marked sex difference in clinical presentation and neurologic disability in patients with CM. Female patients are more likely to manifest gross hemorrhage and neurologic deficits; whereas male patients are more likely to present with epilepsy. (14) In our series, the incidence of seizures at presentation was 75% for male and 50% for female patients. The literature suggests female patients with CMs display a significantly greater degree of neurologic disability compared with male patients. Also, female patients have a preponderance of mixed vascular malformations, (7) as well as a greater propensity to form multiple lesions. (5) The lesion size may increase during pregnancy and regress after delivery. (5) The female preponderance (F/M:3/1), as noted in our series, may suggest some role of hormonal factors in influencing the biologic behavior of these malformations. (4,5) It is also of note that the Louisiana State University Health Sciences Center in Shreveport is a regional referral center, and most of our patients present with symptomatic rather than being incidental lesions. This also supports the literature data that female patients with CMs are more prone to become symptomatic and seek surgical attention.

[FIGURE 2 OMITTED]

Although CMs are less commonly reported in children, age seems to play a significant role in the natural history of CMs. (5) Most lesions are diagnosed in the 3rd or 4th decade of life. The average age at presentation was 39.4 years in our series. The majority of patients presenting at < 30 years of age are male; whereas female patients predominantly manifest symptoms in the 30- to 60-year-old age range. (5) Those patients < 40 years old are more likely to present with seizures; whereas older patients usually manifest focal neurologic deficits. (5) In our series, the average age at presentation was 32.7 years for male patients and 41.6 years for female patients, and the average age for patients presenting with seizures was 37.6 versus 42.3 for patients presenting without seizures (Table 1).

The natural history of CMs remains largely unexplored due to lack of diagnosis and follow up before symptomatic clinical presentation. Relatively benign and slow growth is attributed to recurrent small hemorrhages that lead to vascular proliferation and gliosis. The most common clinical manifestations are headaches, seizures, progressive neurologic deficits, and minor hemorrhages. (4,5) We observed the exact same trend in our own patients (Table 3). Cavernous malformations located in the cerebral and cerebellar hemispheres are categorized as superficial. Those in the brainstem and diencephalon are categorized as deep. (13) Deep lesions are usually less frequently encountered, as was the case in our own series (18.75%).

[FIGURE 3 OMITTED]

The role of surgery in the treatment of CM is being re-evaluated. Even though fatal hemorrhages secondary to CMs can occur, the annual clinically significant hemorrhagic risk has been estimated at 0.7% to 1.1% per lesion per year; (5) thus, preventing a hemorrhage is not always an absolute indication for surgical resection. Similarly, focal neurologic deficits due to CMs may recover spontaneously in many patients, but some patients will still be candidates for surgery to prevent or stop neurologic deterioration. The risk of developing a seizure or having ongoing seizures that cannot be controlled with anticonvulsants appears to be relatively high in those with CMs. Resection of the CMs, including the surrounding glial scar and hemosiderin-laden tissue, may reduce the frequency and severity of seizures. Surgical resection of the CM can often resolve the seizure disorder, and a medically intractable seizure due to an accessible CM should always be considered as a clear indication for surgical resection. Therefore, the spectrum and severity of the neurologic findings, as well as their relationship to the CM and the surgical accessibility of the lesion, must all be considered before deciding to proceed with surgical resection. We were able to achieve an overall 70% reduction in seizures.

The role of stereotactic radiosurgery in the management of CM has yet to be defined. As these lesions are mostly well-circumscribed, they make potentially good targets for radiosurgery, when they occur in surgically inaccessible areas. Most centers adhere to an inclusion criterion of at least two previous hemorrhages for cavernous angioma radiosurgery, but if the location of the lesion suggests serious morbidity or mortality, gamma knife radiosurgery could be performed after the first hemorrhage as was demonstrated in one of our cases. Although it has been suggested that gamma knife radiosurgery could reduce the annual rate of hemorrhage and seizure incidence, the efficacy of this treatment in the management and prevention of complications has not been adequately demonstrated. (4,15) Our current practice is to reserve radiosurgery as a treatment option for patients who are not amenable to surgical treatment.

Conclusion

Cavernous malformations are more readily diagnosed with the widespread use of MRI imaging. With proper microneurosurgical techniques, these relatively benign malformations can be excised completely without any significant deficit. The potential risks and benefits of surgery must be carefully and individually determined for every patient. We advise that these patients be referred to neurosurgical care soon after diagnosis for appropriate management.

Table 1. Clinical characteristics in 16 patients with CMs

                                                                Follow
                         Focal                        Surgical  up
Case  Age  Sex  Ha  Sz   deficit      Location        aids      (months)

 1    37   F    +   +    -            Temporal        USG       150
 2    21   F    -   +    Hemiparesis  Frontal         -         102
 3    50   F    +   -    Dysphasia    Frontal         IG         76
 4    23   M    +   -    -            Occipital       -          72
 5    58   F    -   -    -            Parietal        -          66
 6    17   F    +   -    Numbness     Basal-ganglion  IG         56
 7    33   M    -   +    -            Temporal        -          54
 8    27   F    +   +    -            Frontal         USG        48
 9    40   F    +   +    -            Temporal        IG         47
10    41   F    +   +    Hemiparesis  Temporal        IG         44
11    46   M    +   +    -            Parietal        IG         42
12    52   F    +   +    -            Multiple        IG         42
                                      brainstem (3)
13    29   M    -   +    -            Occipital       IG         42
14    50   F    +   +    -            Parietal        IG/EcoG    42
15    46   F    -   -    Hemiparesis  Brainstem       IG         38
16    60   F    +   -    -            Occipital       -          34

Ha, Headache; Sz, Seizure; EcoG, Electrocorticography; USG,
Ultrasonography; IG, Image guidance.

Table 2. Patient outcome

Outcome    n (%)

Excellent  7 (43.75)
Good       6 (37.5)
Fair       3 (18.75)
Poor       0 (0)
Death      0 (0)

Table 3. Disease specific outcome parameters for cavernous angiomas (a)

        Preoperative          Postoperative (% symptom reduction)
   Headache  Seizure  FND          Headache   Seizure  FND

n  11        10        5            4 (63.6)   3 (70)   2 (60)
%  68.75%    62.5%    31.25%       25%        18.75%   12.5%

(a) FND, Focal neurological deficit.

References

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RELATED ARTICLE: Key Points

* Intracranial cavernous malformations represent a clinical challenge.

* Cavernous malformations are more readily diagnosed with the widespread use of MRI imaging.

* With proper microneurosurgical technique, these relatively benign malformations can be excised completely without any significant deficit.

* The potential risks and benefits of surgery must be carefully and individually determined for every patient.

Caglar Berk, MD, Mark Shaya, MD, Rajesh Acharya, MB, MCH, and Anil Nanda, MD, FACS 

From the Department of Neurosurgery Louisiana State University Health Sciences Center in Shreveport, Shreveport, LA.

Reprint requests to Anil Nanda, MD, FACS, Professor and Chairman, Department of Neurosurgery, LSU Health Sciences Center in Shreveport, 1501 Kings Highway, PO Box 33932 Shreveport, LA 71130. Email: [e-mail]