Cerebral cavernous malformations

Cavernous angioma (CA) is a hamartomatous hemorrhagic lesion which has received a great deal of attention in recent years due to improvement of neuroimaging with magnetic resonance and heightened clinical awareness. Long considered to be rare, its actual prevalence is now recognized to be of 0.9%. Cavernous angiomas may be multiple, particularly in patients with familial form. It may be associated with a variety of clinical syndromes attributed to focal microhemorrhages or less frequently to gross bleeding. CA are usually diagnosed between the age of 20 and 50 with a highest clinical incidence in the fourth decade. A female predominance is observed in regard to bleeding. The male patients are more at risk for seizures. The recent series of MR imaging confirm that CA even when multiple can be asymptomatic in a significant number of cases. Surgery is the treatment of choice in order to eliminate the risk of hemorrhage and improve the control of seizures. Minimally invasive approaches are now adopted with reduced postoperative morbidity. We report our experience in surgical management of cerebral CA and suggest a classification of the lesions according to surgical accessibility and residual morbidity. [Neurol Res 1998; 20: 597-606]

Keywords: Cavernous angioma; cavernous malformation; hemorrhage; epilepsy; surgery

INTRODUCTION

Definition and pathophysiology

Reported for the first time by Luschka in 1853(1), cavernous angioma (CA) was described by Virchow in 1863(2). Long considered to be a rare vascular malformation, its actual prevalence is now demonstrated in recent MRI series and autopsy studies to be of 0.9%3-9. More frequently sporadic, CA present a familial clustering in 10% to 30% of cases 10-27. A gene responsible for the familial form linked to chromosome 7q is now identified28-30. On pathological examination, CA consists of a well-circumscribed red-to-purple lesion composed of dilated capillaries with a simple endothelial lining and thin fibrous adventitia without intervening neural tissue. Smooth muscle and elastic tissue are entirely lacking31-36. The arterial supply is rarely visualized. The blood remains essentially stagnant and the vascular channels can be thrombosed 35,37. Repeated small hemorrhages and slow lysis of sequestrated red cells allow pigments to diffuse into the adjacent brain tissue and induce gliosis which may significantly encapsulate the lesion38-41. They are present in every lesion regardless of clinical history. Gross hemorrhage occurs in 8% to 37% of cases in the literature. The consequences of hemorrhage would generally be limited to changes in size of the lesion without overt exsanguination into the parenchyma. This mechanism explains the high prevalence of good outcome in most patients. Hemosiderin and gliosis may also account for the formation of a seizure focus42-45.

Distribution of the lesions and clinical presentation

Most common frontal or temporal, supratentorial lesions amount to 75% of the total1,7,8,37,46-49. They tend to be located cortically and subcortically, paraventricular or in the basal ganglia48. The infratentorial lesions are equally distributed between the cerebellum and the brain stem, where they are most commonly pontine8. It is now well recognized that about 14% to 19% of CA are discovered in asymptomatic patients who underwent brain MRI for unrelated symptoms7-9,21. Supratentorial CA are more likely to present with seizures and infratentorial CA with focal neurological deficits8,47,50-52. Multiple CA are found in 33% of patients with the sporadic form but up to 73% in the familial form10-20,22-24. When multiple, the lesions do not seem to influence one another and may be considered independent entities21. There is no clear relationship between lesion size and clinical presentation. Seizures is the most frequent clinical presentation in the literature, followed by focal neurological signs and headache8,34,45,53-57. An equal distribution is observed in both sexes with a female predominance in patients aged between 30 and 60(6,36,46-48,58). Patients are usually aged between 20 and 50 on onset of symptoms and the highest incidence is observed in the fourth decade6,8,36,46,47,58,59. Patients under the age of 40 present mainly with seizures while patients over the age of 40 complain initially of focal neurological deficits51. Males are more likely to present with seizures and females to present with focal neurological deficit and/or headache51,60 The pediatric cases account for one fourth of the total.

Diagnostic work-up

CT scan is frequently the first imaging study in patients with acute symptoms57,60-62. The high sensitivity of MRI makes it the examination of choice in evaluating CA8,39,41,62-65. It improves preoperative localization and demonstrates multiple lesions not recognized on CT. The MRI appearance is specific although not pathognomonic. The value of angiography in the evaluation of CA is primarily in exclusion of arteriovenous malformations or recognition of coexistent vascular malformations such as venous angioma, which must be preserved at the time of surgery, as CA is angiographically occult5,48,66.

Hemorrhage and related risk factors

Hemorrhage on onset is present in 6% to 30% of cases5,8,36,41,45,54,56,57,68-70. The risk of first overt hemorrhage ranges from 0.25% to 0.7% per lesion per year7,8. Factors that significantly impact on hemorrhagic risk are previous hemorrhage, age and sex8,59. A greater tendency toward hemorrhage is well observed in young female patients8,60,69. The risk of hemorrhage after a known diagnosis of CA is maximal in young adults8,60. Nearly 25% of unoperated cases presenting with gross hemorrhage have rebled within 1 year58,60,71. Subarachnoid or intraparenchymal hemorrhage is very uncommon. Increased intracranial pressure from mass effect is likewise exceptional.

Risk factors in nonhemorrhagic CA

Predictive factors of bad outcome in CA not associated with hemorrhage are infratentorial location, evolutive focal neurological deficits and intractable seizures8,51. Nine percent of nonoperated CA present an increase of size on MRI follow-up8,51.

MATERIALS AND METHODS

From 1982 to April 1996, 74 patients with cavernous angioma were admitted to the Department of Neurosurgery of the Erasmus Hospital. Sixty-seven patients presented with cavernous angiomas of the CNS, including two cases with intramedullary cavernous angioma. Six patients had a cavernous hemangioma of the orbit. One patient had a lumbar epidural cavernoma. The diagnosis was based on histological examination or MR imaging.

We reviewed a series of 65 cases with cerebral CA (Figure 1). The mean age of the patients was 37 years, ranging from 3 to 83, with a sex ratio of 1: female to male. The mean age in female patients was lower than in male patients (34.2 years and 39.6 years respectively). Sixty-nine percent of females but only 45% of males were aged under 40 at the onset of symptoms (Figure 2). All but one female patients were aged under 50 at the onset of symptoms. Three patients were less than 16 years (5%). The great majority of patients presented with solitary lesion. Multiple lesions were found in five patients (6%), ranging from two to five in number. Seventy-six percent of the lesions were supratentorial, more frequently lobar (temporal 28%, rolandic 22%, frontal 22%, parieto-occipital 19%, insular 9%). One patient was operated for a giant hemispheric lesion. Ventricular and paraventricular CA were observed in 5 cases (13%). Thalamic and basal ganglia locations were observed in three cases (5%). A single case of CA of the genu of the corpus callosum was reported. Infratentorial CA were more frequently located in the brainstem and particularly affected the pons. No patient with familial history was recorded. Focal neurological deficit was the most frequent clinical presentation, observed in 31 cases (48%). It consisted mainly of diplopia, ataxia, motor or sensitive deficits. Seizures were observed in 22 cases (34%) and headache in 20 cases (30%). Cognitive disorders, loss of consciousness, vomiting and vertigo were met less frequently. Thirty-six patients presented with hemorrhage (55%), either with fresh clots around or inside the cavernous angioma at the time of surgery or with evidence of intra- or perilesional bleeding on imaging studies on admission. Sixty-two percent of them were females. Clinical presentation in this group consisted mainly of focal neurological deficit and headaches (Figure 3). Some of them had associated seizures. Patients without associated hemorrhage on onset were predominantly males, presenting with seizures and/or focal neurological deficits. Only three patients had no symptoms on diagnosis (5%). CA was discovered incidentally on CT or MRI in patients with mental anorexia, cervical myelopathy or acoustic neurinoma. This low percentage may result from the fact that, as reference hospital, we received a majority of symptomatic patients, asymptomatic patients with CA being probably treated conservatively in those referring centers.

Indications for treatment

Surgery was considered in order to control the risk of hemorrhage and remove the hematoma when present, and/or improve the control of seizures. The procedure allowed also the performance of pathological examination. The decision for surgical resection was conditioned by the general condition of the patient and by the accessibility of CA. This depended on the localization of the lesion and on the residual morbidity related with the surgical approach.

The lesions were classified in three types according to their surgical accessibility (Table 1):

- type I consisted of easily accessible CA in noncritical areas of the brain and the cerebellum. Total removal was possible in all cases without additional morbidity.

- type II consisted of superficial CA located in critical brain areas (e.g., pial CA of the rolandic or insular area (Figure 4), C A of the ependymal surface of the thalamus, CA of the pial or ependymal surface of the brainstem). Total removal with low risk of permanent morbidity was possible in those cases, using stereotactic techniques when necessary to improve the localization of the lesion and to reduce the dissected area necessary to approach the lesion.

- type III consisted of deep CA in critical brain areas (e.g., deep rolandic area, basal ganglia, thalamic or brainstem CA without access to the surface (Figure 5). Some patients were managed surgically on admission when imaging studies suggested partially superficial CA. The surgical exploration demonstrated however that some CA were not accessible for removal. An expectancy follow-up with serial MRI studies was adopted in all cases. Total removal was however possible in some patients when recurrent bleedings made the CA accessible to surgery (Figure 6).

Surgical considerations

Forty-six patients out of 65 underwent surgery (71%). Surgery was chosen as first treatment in forty-five cases. It consisted of total removal of the lesion in 41 cases, but was limited to surgical exploration in four cases. There were 19 patients with type I CA, 22 patients with type II CA and 4 patients with peroperative type III CA (Table 2) despite MRI studies on admission suggestive of accessible type II CA. Four patients had multiple lesions (8%). Two of them underwent multiple surgical procedures. Solitary CA were supratentorial in 35 cases (83%), more commonly lobar (temporal, frontorolandic and occipital in decreasing frequency respectively). Seven solitary lesions were infratentorial (17%). In two cases, the lesion was discovered on post-operative MRI after an emergency drainage of a spontaneous intracerebral hematoma. The removal of the residual lesion was achieved at a second operative time in both cases. Surgery consisted only of exploration sometimes associated with biopsies in two patients with deep rolandic CA, in two patients with solitary peduncular CA and in one case with CA in the roof of the fourth ventricle. A total removal was however achieved at a second operative time in one of the patients with peduncular CA after recurrent hemorrhage made the lesion accessible to surgery. One patient presenting with type III deep brainstem CA on admission, was operated on after six years of expectant management when recurrent hemorrhage made the lesion accessible to surgery. Total removal was consequently performed in a total of 42 patients. Resection was stereotactic-guided in five of them.

Surgical technique was based on 'en bloc' resection after gentle and smooth coagulation of the CA surface with bipolar forceps. This induced shrinkage of the lesion and helped to coagulate and divide all the small vessels which were feeding it. Separation of the CA from the surrounding brain was then easy.

Nonoperative treatment

A nonsurgical management was considered in 19 cases (29%). Surgery was initially refuted in 20 cases with type III CA. Only one patient, presenting with deep brainstem CA, was operated on after six years of conservative management. In 14 cases, the operative risk remained unacceptably high because of the localization of the CA despite recurrent hemorrhage in three cases. CA affected the deep brain stem in eight patients and the deep parieto-occipital area or the thalamus in six cases. Two patients with poor general condition were managed conservatively. Three patients with surgically accessible CA of the brain convexity refused surgery. Radiosurgery was considered in one patient with CA of the medial occipital lobe but without visual impairment. The treatment was performed in the department of Prof. Lindquist (Sweden) in 1986.

RESULTS

Surgical outcome

No recurrence of hemorrhage was observed in totally removed lesions. Three operated patients developed new episodes of hemorrhage. In two cases with multiple CA, the bleeding occurred in a new location. One patient who underwent first surgical exploration experienced recurrence of bleeding at the same lesion. This episode fortunately then made the lesion accessible to surgery. Ten patients with preoperative normal examination remained unchanged (Figure 7). One patient with normal preoperative examination developed a slight residual post-operative facial hemiparesis. Three patients presenting with slight preoperative deficit, seven with moderate and two with severe neurological disorders made a total post-operative recovery. Five patients with moderate preoperative deficits had a fair outcome. Six patients with moderate and three patients with severe preoperative deficits were partially improved. Three patients with slight preoperative deficits and three with severe deficits remained post-operatively unchanged.

Twenty-two out of 46 operated patients had a normal post-operative examination (48%). Twenty-six patients with preoperative deficits were improved, twelve totally, five moderately and nine slightly. Six patients were postoperative stabilized. Eleven out of 19 patients with preoperative epilepsy were seizures-free (58%). Two patients died (4%). In the first case, the death was related to a post-operative sepsis (Staphylococcal pneumonia and Enterococcal meningitis). In the second case with multiple CA, a massive intracerebral hemorrhage occurred in another location on the 1 5th post-operative day.

Conservative outcome

Two asymptomatic patients remained symptom-free. Four patients with slight, one with moderate and one with severe deficit made a spontaneous total recovery. Three patients with slight deficit remained unchanged. One patient with moderate and one with severe deficit had slight residual disorders. Moderate residual deficit were present in one patient with moderate and one patient with severe disorders on onset. Two patients with severe deficit remained unchanged. Four patients were lost to follow-up. The patient treated by Gamma-knife experienced no recurrence of hemorrhage. After ten years follow-up, the imaging appearance of that CA remains unchanged on serial MRI studies.

DISCUSSION

In our series, the patients presented in decreasing frequency with focal neurological deficits (diplopia, ataxia, sensory disturbances and hemiparesis), seizures and headache respectively. In contrast, seizure is the most frequent symptom reported in the literature, accounting for 40% to 70% of cases although focal neurological deficits are present in 35% to 50% of cases and headache in 25% to 30%8,34,45,53-57. Onset of symptoms was acute in the great majority of patients (85%). Twenty-two female patients had an associated hemorrhage (65%). Eight patients, with an equal proportion of females and males, experienced multiple episodes of bleeding (12%). Fourteen patients of the series had brainstem CA. One patient presented with severe, ten with moderate and three with slight neurological deficits. Seven were operated on (type II) and seven treated conservatively because of deep located lesion (type III). Two operated patients were post-operative markedly improved, one patient recovering a normal neurological examination. Five patients were slightly improved or remained unchanged. Two patients treated expectantly recovered spontaneously a normal neurological examination, three had slight residual deficits and one remained unchanged. One patient was lost to follow-up. The favorable outcome of those patients led us to consider surgery only in type II (pial or ependymal surface) brainstem CA and to propose an expectant management with close followup in those with type III CA. Ten patients with type II rolandic or insular CA were operated on. All but one underwent a total removal of the lesion. Six were postoperatively improved, three remained unchanged and one patient with normal preoperative examination developed a slight facial hemiparesis.

Nineteen patients presenting with epilepsy out of 22 were operated on. In two cases total removal was completed by temporal lobectomy for intractable epilepsy. Eleven patients were post-operative seizure-- free (58%).

Conservative management

An expectant management should be considered with multiple asymptomatic lesions or with solitary type III (deep-seated) CA of the brainstem and the thalamus36,65,71-75. The patients must however be followed-- up clinically and with sequential MRI studies. Surgery will be considered only if gross hemorrhage or increase in size changes a type III to type II lesion.

Surgical management

In our experience, all accessible symptomatic type I and II CA should be resected in order to control the risk of hemorrhage and remove the associated hematoma, to improve the focal neurological deficits and give easier treatment of epilepsy46,56-58,67,68,76-80. Total removal can be performed in cortical, subcortical or paraventricular supratentorial CA and pial or ependymal surface brainstem CA with low post-operative morbidity and mortality rate54,66,81,82. However, considering the significantly high cumulative risk of bleeding, surgery should also be considered in young asymptomatic patients with types I and II solitary CA, particularly in childbearing-age female patients before pregnancys8,75,79. With a very-small-risk procedure, it is possible to eliminate risk of hemorrhage from those lesions. Only symptomatic lesions are concerned by surgery in patients with multiple lesions. Surgery improves the control of seizures with 50% to 91% post-operative seizure-free patients8,42,43,59,79,83-93. Well-recognized predictive factors of poor post-operative outcome in patients with associated epilepsy are the duration of symptoms, particularly when superior to 12 months93, the number, of episodes, particularly if superior to five, the age at onset of epilepsy, the lower the age the higher the risk60,94,95, and the sex, female patients presenting more risks for post-operative residual seizures (64% versus 40% in male patients)86,94. In those patients, additional excision of epileptogenic surrounding brain should be considered in order to control intractable epilepsy42,59,83,93,94,96.

Radiosurgical management

We have no personal experience in radiosurgical management of CA. However, controversial results have been obtained in series reported in the literature17,73,84,97. A latency interval of minimum two to three years is commonly accepted to appreciate the results of radiosurgery in vascular malformations. In CA however no imaging test exists to confirm obliteration of the lesion. Close clinical follow-up and absence of new episodes of bleeding is an indication but not a confirmation of the absence of residual hemorrhagic risk98. No change in neuro-imaging studies was observed in some series with however radiation-associated morbidity and recurrence of hemorrhage74. Risks of radiosurgery may be higher in CA because of the critical location of the lesion in comparison with arteriovenous malformations. Dose reduction had diminished the intensity but not the incidence of associated morbidity98.

CONCLUSION

After having brought the actual prevalence of cavernous angioma of the CNS to the light, magnetic resonance imaging now sets the question of preventive surgical resection in asymptomatic patients. The spontaneous evolution demonstrates a significant risk of hemorrhage. This consideration has lead us to consider surgery in asymptomatic young patients with accessible solitary lesions, particularly in childbearing-age females before pregnancy. Total removal can now be achieved with a very low risk in type I and type II supra- and infratentorial CA. Type III CA must however remain under close clinical and imaging follow-up because spontaneous evolution can make the CA resectable with time.

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C. Chaskis and J. Brotchi

Department of Neurosurgery, Erasmus Hospital, U.L.B., Brussels, Belgium

Correspondence and reprint requests to: Professor J. Brotchi, Department of Neurosurgery, Erasmus Hospital - U.L.B., Route de Lennik 808, 1070 Brussels, Belgium. Accepted for publication May 1998.

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