Management of Brainstem Cavernous Malformations

Current Treatment Options in Cardiovascular Medicine DOI 10.1007/s11936-012-0181-x

Cerebrovascular Disease and Stroke (M Alberts and C Helgason, Section Editors)

Management of Brainstem Cavernous Malformations Tarek Y. El Ahmadieh, MD Salah G. Aoun, MD Bernard R. Bendok, MD, FACS, FAANS H. Hunt Batjer, MD, FACS, FAANS* Address *Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, 676 North St. Clair Street—Suite 2210, Chicago, IL 60611, USA Email: [email protected]

* Springer Science+Business Media, LLC 2012

Keywords Brainstem I Cavernous malformations I Brainstem cavernous malformations I BSCM I Natural history I Surgery I Diffusion tensor imaging I Surgical approach I Hemorrhage rate I Re-hemorrhage rate I Risk factors I Outcomes I Indications I Radiosurgery

Opinion statement The risk of hemorrhage from brainstem cavernous malformations (BSCMs) ranges between 2.33 % and 4.1 % per patient-year across natural history studies and between 2.68 % and 6.8 % per patient-year across surgical series. The recurrent hemorrhage rate from BSCMs ranges between 5 % and 60 % per patient-year. Asymptomatic BSCMs tend to have a benign course, whereas symptomatic lesions often have a more aggressive course and carry an increasing risk of hemorrhage with subsequent bleeds. Hemorrhagic presentation, female gender, family history, and associating venous anomalies have been correlated with an increased risk of hemorrhage from BSCMs. MRI is the diagnostic imaging method of choice for the detection of CMs. Preoperative T1-weighted MRI can help assess the proximity of the lesion to the pial or ependymal surface of the brainstem and is thus essential to operative planning. Fluid attenuated inversion recovery (FLAIR) sequences can detect inflammatory activity and perilesional gliosis and may therefore correlate with an increased biological activity in the CM. This might help predict the aggressiveness of these lesions and their clinical activity. Due to the potential risks of surgery, conservative management with close follow-up should be the primary treatment option for patients with BSCMs. At least two clinically significant hemorrhagic episodes and an anatomical pial representation of the lesion are required before considering surgical intervention as an option because of the potential irreversible neurological damage to the patient. Life-threatening bleeds and rapidly progressive neurological deterioration are also potential indications for surgery. Complete removal of BSCMs when feasible is crucial to the prevention of future hemorrhage from BSCMs. An intraoperative ultrasound and a post-operative MRI can be used to rule out any unnoticed residual lesion. Minimizing the risk of surgery can be achieved by undergoing a case-based selection of the optimal surgical approach that allows for easy access to the lesion with minimal manipulation of normal neural tissues. Preserving

Cerebrovascular Disease and Stroke (M Alberts and C Helgason, Section Editors) any associated venous anomaly during surgery is crucial in order to avoid any undesirable hemorrhagic infarction. Advanced imaging techniques, such as diffusion tensor imaging integrated with intra-operative neuronavigation MRI, can be used to determine the anatomical relation between BSCM and the surrounding eloquent structures. Radiosurgery is not considered an effective treatment option for BSCMs. It is reserved only for extremely biologically aggressive lesions that cannot be accessed surgically.

Introduction Cavernous malformations (CMs) are well-circumscribed, benign vascular hamartomas consisting of irregular thick and thin walled sinusoidal channels that can be located in the brain or spinal cord [1]. They represent 5 % to 15 % of all vascular malformations in the central nervous system (CNS) and are a wellknown cause of hemorrhagic stroke [2, 3]. CMs are low-flow, low-pressure systems that lack large feeding arteries and draining veins [4]. They can rarely become a cause of life-threatening intraventricular or subarachnoid hemorrhage [1, 5]. More commonly, successive intralesional or perilesional microbleeds may lead to the compression, displacement, and damage of adjacent neural structures [6, 7]. This can be of particular significance in narrow and densely eloquent areas such as the brainstem [8]. Brainstem cavernous malformations (BSCMs) tend to present with neurologic deficits early in the course of the disease [9, 10] and are often associated with higher morbidity and mortality rates compared to lesions in other locations [7, 11]. Despite favorable patient outcomes reported by several surgical series in the literature, especially with the innovation of novel and more efficient surgical approaches [7, 9, 11–27], the management of BSCMs remains a controversial issue in neurosurgery. There are currently no clear-cut guidelines or consensual algorithms for the management of these lesions. Decision making is often based upon balancing the odds of hemorrhage against the potential risks of surgery on a case by case basis. This requires a critical awareness of the predictors of hemorrhage in patients with BSCM, as well as an experienced and careful interpretation of reported bleeding and rebleeding rates [7, 9, 10, 28–39]. An extensive knowledge of the surgical and functional anatomy of the brainstem is also crucial for minimizing the risks of surgery. Modern imag-

ing techniques, such as preoperative tractography and integrated intraoperative magnetic resonance navigation, in addition to cranial nerve monitoring, appear to play an important role in the surgical approach to these lesions and may correlate with improved surgical and clinical outcomes [40, 41].

Epidemiology and natural history The incidence of intracranial CMs has been on the rise over the past two decades. This has been mainly attributed to an increase in detection rates caused by the advances and increased use of magnetic resonance imaging (MRI) technology [7, 23, 28]. The prevalence of CMs is currently estimated to range between 0.4 % and 0.8 % in the general population [29, 32]. They account for 62 % to 96 % of all angiographically occult vascular malformations (AOVMs) [7]. CMs can occur sporadically or in an autosomal-dominant pattern of inheritance, with multiple simultaneous lesions often seen in the latter form [31, 42]. They can present at any age, most commonly in middleaged individuals, and have no predilection for sex. They are often associated with venous angiomas [10, 43–46]. BSCMs account for 4 % to 35 % of all intracranial CMs [7]. The majority of these lesions occur in the pons (43–66 %) [13, 22, 27]. Pathogenesis

Although there is currently no clearly defined mechanism behind the formation and clinical progression of CMs, genetic and environmental factors have been shown to play a central role in their pathogenesis [6, 47]. Autosomal dominant inheritance of one of the CCM genes (CCM1, CCM2, or CCM3) increases the susceptibility for CM development. However, an additional somatic

Management of Brainstem Cavernous Malformations mutation also known as “second hit” of the second normal copy of the same gene, or of another gene belonging to the same functional pathway, is necessary for the initiation of the disease process [47, 48]. Systemic factors such as angiogenic and growth factors, as well as inflammatory cytokines, can act as second hits leading to the formation of CMs, and can even alter the biological activity of preexisting lesions, leading to the progression of the disease with an increase in the rate of rupture. The overexpression of angiogenic factors, namely vascular endothelial growth factor (VEGF), can lead to the development of capillary dysplasia, with endothelial cell proliferation and an increased permeability of the blood–brain barrier (BBB) [6, 47, 49–51]. Inflammatory cells, specifically B lymphocytes and plasma cells and the cytokines that they release, such as tumor necrosis factor α, have also been detected in CMs and are thought to induce angiogenesis and the breakdown of the BBB [52–54]. These observations can partially account for the aggressive nature of some lesions that may present with devastating, recurrent bleeding episodes. Moreover, the de novo formation of CMs has been reported in association with venous angiomas, which are also thought to play a causative role in their genesis [7, 45, 55]. The hemodynamic stress and venous hypertension caused by venous angiomas can cause repeated microhemorrhages, with hemosiderin deposition, which can stimulate angiogenesis and CM formation [45, 56]. This phenomenon is known as “hemorrhagic angiogenic proliferation.” Radiation can be another cause of de novo formation of CMs. It can also increase CM rupture rates by inducing the proliferation and dilatation of the vascular endothelium [7, 57]. Initial hemorrhage rate

Reliable information on the natural history of intracranial CM hemorrhage started to materialize in the early 1990s as more asymptomatic lesions were being incidentally discovered by conventional MRI scanners [32]. Estimates of CM hemorrhagic rates varied greatly among different studies. In one of the first retrospective reports on the natural history of CMs, Del Curling et al. [28] reported a symptomatic hemorrhage rate of 0.25 % per patient-year. However, the possibility of de novo formation of additional CMs suggested that the computation of the lifetime hemorrhagic risk at any given time may be an underestimate as there is always a chance that new lesions would appear [29, 58–60].

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Nevertheless, the average hemorrhagic rate of intracranial CMs across several prospective studies was estimated to be 2.4 % per patient-year [7, 29, 30, 38, 61]. In their review of the literature on the natural history of BSCMs, Gross et al. [7] reported a hemorrhagic rate ranging between 2.33 % and 4.1 % per patient-year. The studies of Cantu et al. [34], Kondziolka et al. [30], Kupersmith et al. [10], Moriarity et al. [38], and Porter et al. [61] reported hemorrhagic rates of 2.33 %, 2.4 %, 2.46 %, 3.1 %, and 4.1 % per patient-year, respectively. However, a higher hemorrhagic rate ranging between 2.68 % and 6.8 % per patient-year was reported across surgical series [7]. More recently, Abla et al. [13] retrospectively reviewed 260 patients with BSCMs and consistently reported an annual hemorrhage rate of 4.6 % per patient-year. Similarly, Chen et al. [16] reported a hemorrhagic rate of 4.7 % per patient-year in their retrospective review of 55 patients with BSCMs. The higher rates of hemorrhage reported in surgical series can be explained by the fact that more aggressive, symptomatic lesions are usually referred to surgical centers. These rates however may not reflect the actual hemorrhagic rate of asymptomatic patients in the general population. In a retrospective review of 34 conservatively treated patients presenting with deep CMs, Mathiesen et al. [62] reported a hemorrhagic rate of 7 % per patient-year in 23 patients presenting with symptomatic lesions, whereas a 2 % per patient-year hemorrhagic rate was reported in 11 patients presenting with asymptomatic lesions. This further supports the observation that asymptomatic lesions usually have a more benign course compared to symptomatic lesions. However, given the high clinical impact of even minor bleeding episodes occurring in the brainstem, it is crucial to consider all risk factors that may account for BSCM hemorrhage. An illustrative series by Porter et al. [61] reported a higher clinical event rate of 10.6 % per patient-year for deep CMs (including brainstem lesions) compared to 0 % per patientyear for superficial lesions. Complete resolution was seen in approximately one-third of cases (37 %) over a follow-up period of 46 months, confirming the high morbidity of BSCM hemorrhage. Rate of recurrent hemorrhage

The risk of recurrent hemorrhage from CMs appears to increase transiently after the first bleed [9, 27, 30, 33,

Cerebrovascular Disease and Stroke (M Alberts and C Helgason, Section Editors) 39, 63, 64]. According to Barker et al. [65], the re-hemorrhage risk increases shortly after the initial bleeding event, then decreases from 2.1 % per month to 0.8 % per month (2.4-fold) after a period of 2 to 3 years. This phenomenon is described as “temporal clustering” [65, 66]. Across several studies in the literature, the rate of recurrent hemorrhage from BSCMs ranges between 5 % and 60 % per patient-year [16, 27, 30, 33, 63, 64]. In their retrospective review of a prospective database of 122 patients with CMs, Kondziolka et al. [30] identified 43 patients with BSCMs and reported a re-hemorrhage rate of 5.0 % per patient-year after a mean follow-up period of 34 months. Similar rates were reported by Kupersmith et al. [10] in their review of 37 patients with BSCMs at the neuroophthalmology services of two different institutions. A mean follow-up period of 4.9 years resulted in an annual re-hemorrhage rate of 5.1 %. On the other hand, Porter et al. [63] described a significantly higher re-hemorrhage rate in their retrospective surgical series of 100 patients with BSCMs, and reported a re-hemorrhage rate of 30 % per patient-year. Further, in their surgical series of 137 patients with BSCMs, Wang et al. [27] reported a very high re-hemorrhage rate of 60 % per patient-year. More recently, the rate of symptomatic re-hemorrhage (clinical event rate) was calculated by Hauck et al. [9] in their retrospective review of 44 patients with symptomatic BSCMs. The clinical event rate after the first symptomatic hemorrhage was 42 % per patient-year, but increased to 8 % per month after the second symptomatic hemorrhage [9]. Risk factors for CM hemorrhage

Due to the rarity of CMs, it remains difficult to conduct large, prospective studies that can prospectively and reliably determine the risk factors accounting for CM hemorrhage. However, potential predictors of hemorrhage have been extensively described across surgical case series and natural history studies throughout the literature. A “non-lobar or deep location” of CMs has been reported as a significant risk factor for hemorrhage [10, 34, 35, 61, 63, 64]. It is argued that despite biological similarities, deep CMs (including BSCMs) tend to have a more aggressive clinical course compared to superficial CMs [7, 29]. This can be explained by the presence of highly eloquent neural tissues present in deeper locations, leading to the development of neurologic signs and symptoms after only minor bleeding [29]. On the other hand, some

studies especially those using a less strict definition for hemorrhage do not report a significant difference between the bleeding rate of deep and superficial CMs [30, 33, 38]. A “hemorrhagic presentation” has also been reported as a major risk factor for future hemorrhagic episodes [9, 30, 31, 33, 62]. This observation agrees with the tendency of CMs to bleed in clusters [65, 67, 68]. In a recently published study, Flemming et al. [66] retrospectively reviewed the records of 292 patients who presented with intracranial CMs. A prospective follow-up of the records and radiographic findings was performed, with a median follow-up duration of 7.3 years. A hemorrhagic presentation was found to be the primary predictor of future CM re-hemorrhage (hazard ratio = 5.14; 95 % CI, 2.54–10.4; PG0.001). Other significant predictors included male gender and the presence of multiple lesions. Infratentorial location of CMs could prove statistical significance in the univariate analysis of risk factors; however, it did not maintain significance after multivariate adjustment. The median time period for a second bleed to occur in patients presenting with hemorrhage was estimated to be 8 months. A decrease in the hemorrhagic risk was noted after 2 years of followup [66], consistent with previous reports of temporal clustering [65]. The size of CMs has not been shown to influence the risk of hemorrhage; however, in one study by Aiba et al. [33], brainstem lesions 91.5 cm have been correlated with worse outcome. Patient “age” has been reported as a risk factor for CM hemorrhage [65, 69]. Acciarri et al. [69] reported a higher hemorrhagic rate in children (defined as individuals aged between 0 and 18 years) compared to adults. Female gender and pregnancy have also been reported as risk factors for CM hemorrhage [10, 33, 38, 63, 70–73]. This can be explained by the potential influence of estrogen hormones on CM growth and behavior [7, 73]. In their series of 100 patients with BSCMs, Porter et al. [63] reported hemorrhagic presentation in seven pregnant women (11 %) of 62 women described in the series. On the other hand, in an isolated study, Flemming et al. [66] reported male sex as a risk factor of CM hemorrhage. Other factors contributing to CM hemorrhage include a familial history and the presence of associating venous angiomas [36, 39, 74]. The multiplicity and the de novo formation of new lesions, reported by familial studies,

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are thought to alter the natural history of CMs by increasing the overall risk of hemorrhage [31, 37, 39]. In an analysis of 163 consecutive CM families, Denier et al. [75] found that patients harboring the CCM3 mutation are more likely to present with hemorrhage at a younger age as compared to patients with CCM1 and CCM2 mutations. Associated venous malformations have been reported as risk factors for CM hemorrhage in several studies as they have been shown to increase the aggressiveness and de novo formation of CMs [7, 55, 67, 74].

lesions, whereas midbrain lesions often resulted in diplopia, increased intracranial pressure, rubral tremor, paroxysmal coma, involuntary laughing, and vertical gaze paralysis. All patients with medullary BSCMs presented with dysphagia [27]. BSCMs presenting as multiple focal neurologic deficits may simulate brainstem infarction syndromes such as Wallenberg, Parinaud, Benedikt, Millard-Gubler, and Weber syndromes [5, 7, 27, 46, 77–79].

Clinical presentation

Diagnostic imaging MRI is the diagnostic imaging method of choice for the detection of CMs [7, 28, 70, 76]. Its high sensitivity and specificity allow for the detection of lesions of variable sizes and provide high resolution images that may help in the preoperative planning for safe surgical approaches [70, 80]. Several studies in the literature have described the pathognomonic appearance of CMs on MRI as “mulberry-like” or “popcorn-like” reticulated core of mixed signal intensity surrounded by a rim of decreased signal intensity [80–82]. Zabramski et al. [39] classified the MRI appearance of CMs into four types. Type I lesions showing a hyperintense core on T1-weighted MRI and a hypo- or hyperintense core with a surrounding hypointense rim on T2-weighted MRI. Type II lesions showing a reticulated mixed signal core on T1- and T2-weighted MRIs. Type III and Type IV lesions showing a hypointense core, with the latter representing small, punctate lesions that are best detected by gradient-echo and susceptibility-weighted MRIs [7, 39, 83]. Fluid attenuated inversion recovery (FLAIR) sequences can detect inflammatory processes and perilesional gliosis and may therefore correlate with an increased biological activity. Although this could mean that MRI sequences showing an increase in perilesional FLAIR signal could evoke an increase in the biological activity of a CM and perhaps an imminent rupture, it should be noted that an increase in perilesional FLAIR signal could be the result of a recent subclinical bleeding episode. This area of imaging should undergo further study before it can be efficiently used in clinical practice as a means to predict CM behavior. Associated

BSCMs may be responsible for various clinical signs and symptoms depending on their location within the brainstem and on the number of previous hemorrhagic episodes. They often present with suddenonset neurologic deficits [13, 27, 70], and may have a fluctuating relapsing and remitting or a progressive clinical course [7, 76]. Patients with multiple hemorrhagic episodes are more likely to suffer severe and irreversible neurologic impairment [27]. The differential diagnosis may include demyelinating diseases (eg, multiple sclerosis), brainstem tumors (eg, gliomas), and brainstem infarction syndromes (eg, Wallenberg and Parinaud’s syndromes) [7, 27, 76]. In a surgical series of 260 patients, Abla et al. [13] described the most common presenting signs and symptoms of patients with BSCMs. They were, in decreasing incidence, cranial neuropathy (63 %), sensory deficits ( 53 %), hea daches (39 %), motor deficits (37 %), diplopia (33 %), ataxia (29 %), vertigo (25 %), nausea/vomiting (17 %), dysarthria (12 %), and dysmetria (8 %). In this series, only cranial nerve (CN) palsies were statistically correlated with the affected brainstem level. CN III palsy was reported in lesions involving the midbrain, whereas CN V, VI, VII, and VIII palsies were associated with pontine lesions. Hiccup and vocal cord paralysis were mostly seen in medullary lesions [13]. In another surgical series, Wang et al. [27] described in detail the distribution of clinical signs and symptoms according to different CM locations in the brainstem. They reported hemiparesis and ataxia as the most common clinical manifestations of BSCMs. Sensory deficits were commonly associated with pontine and medullary

Cerebrovascular Disease and Stroke (M Alberts and C Helgason, Section Editors) venous angiomas can be detected on contrast-enhanced MRI showing a pathognomonic caput medusa appearance [84]. Preoperative T1-weighted MRI can help assess the proximity of BSCM to the pial or ependymal surface of the brainstem and thus can assist in planning the best

surgical approach [85]. Furthermore, three-dimensional constructive interference in steady state MRI and diffusion tensor imaging can play an important role in identifying the relation of BSCMs to safe entry zones and vital white fiber tracts [40, 86, 87].

Management Surgical principles &

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The primary goals of surgical intervention in patients with BSCMs are to achieve complete resection of the lesion, to minimize damage to nearby neural structures, and to preserve any associating venous anomaly [63]. Complete removal of BSCMs is crucial to the prevention of future hemorrhage [15, 76]. An intraoperative ultrasound and an immediate post-operative MRI can be done to rule out any unnoticed residual lesion [7, 15]. Abla et al. [13] reported postoperative re-hemorrhage in 18 of 29 patients with incompletely resected BSCMs (62 %). Minimizing the risk of surgery can be achieved by a case-based selection of the optimal surgical approach that allows for relatively easy access to the lesion with minimal manipulation of normal neural tissues (Table 1) [76]. The two-point method has been typically used to determine the best access point to the BSCM [13, 76]. This can be achieved by drawing a line between the center of the lesion and the point where it comes closest to the brainstem surface. This method, however, may not be optimal for lesions associated with venous angiomas. A change in the surgical approach has been recommended if an angioma is found in the trajectory between the two points [5]. Preserving these associated anomalies is crucial in order to avoid any undesirable hemorrhagic infarction [7, 63, 76]. In the event where intra-operative pial representation of a BSCM is not as optimal as expected via pre-operative imaging studies, the use of intraoperative MR navigation or ultrasound may be worthwhile to determine the exact depth of the lesion. If available, diffusion tensor imaging technique (tractography) integrated to the intraoperative MR navigation may also be helpful in determining the proximity of the lesion to eloquent white fiber tracts such as the pyramidal tract This could prevent dissecting through these white fibers and causing permanent disability. The surgeon may wish to abandon the surgery altogether if the potential risks are higher than the initially anticipated benefit. Three-dimensional constructive interference in steady-state MRI can help better identify anatomical boundaries of the lesion and its spatial relation to safe entry zones [86]. Also, advanced imaging techniques, such as diffusion tensor imaging integrated with intraoperative neuronavigation MRI, are recently being used to determine


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Table 1. Commonly described approaches to brainstem cavernous malformations Location of interest

Surgical approach

Advantages

Dorsal and dorsolateral midbrain

Supracerebellar infratentorial approach Paramedian supracerebellar infratentorial approach Extreme lateral supracerebellar infratentorial approach (modified retrosigmoid) Occipital transtentorial approach Far posterior subtemporal approach Pterional/orbitozygomatic transsylvian approach Subtemporal approach

NA Lateral exposure Patients with a steep slope to the tentorium

NA Good for interpeduncular lesions Good for lateral lesions Good for pontomesencephalic lesions Dorsal pons Suboccipital approach NA Ventral and ventrolateral pons Retrosigmoid approach NA Extended retrosigmoid approach More exposure Anterior transpetrosal Low risk of damage to the vein of Labbe Hearing preservation Lesions approximating the Vermis splitting NA fourth ventricle Trabscerebellomedullary fissure (intertonsilar) approach Low risk of truncal ataxia Dorsal medulla Suboccipital approach NA Ventral and ventrolateral Retrosigmoid NA medulla Far lateral partial transcondylar approach Good exposure to the ventral brainstem Ventral and ventrolateral midbrain

NA not applicable

the anatomical relation between BSCM and the surrounding eloquent structures [16, 40, 87, 88]. These techniques have been correlated to increased safety and better surgical outcomes [16, 87]. Electrophysiologic monitoring of cranial nerve nuclei, as well as motor and somatosensory-evoked potential monitoring, are also valuable intra-operative tools [7, 76, 89].

Surgical approaches &

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Several safe entry zones described in the literature provide relatively easy access to brainstem lesions with minimal damage to eloquent neural structures and perforating arteries [7, 8, 24, 76, 90–102]. These approaches are of particular importance when surgically accessing deeply situated BSCMs that do not reach the pial or ependymal surface of the brainstem [25]. These lesions are very challenging and are often associated with high rates of surgical morbidity. Surgery should be performed by well-trained neurosurgeons that have the expertise to tackle such lesions and are familiar with all the appropriate surgical approaches. Lesions of the dorsal midbrain are commonly accessed via the supracerebellar infratentorial or occipital transtentorial approach [7, 24, 85, 102, 103]. In their retrospective review of 45 patients with BSCMs, De Oliveira et al. [102] described the median, paramedian,


&

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and extreme lateral variants of this approach that allow access to most dorsal and dorsolateral lesions of the midbrain, including superior cerebellar peduncle and tectal plate lesions. The far posterior subtemporal approach has also been used to access dorsal midbrain lesions [90]. Lesions of the ventral and ventrolateral midbrain are commonly accessed using the standard or modified pterional/orbitozygomatic transsylvian approach [103–105]. This allows access to interpeduncular lesions of the midbrain. On the other hand, more lateral lesions are best accessed via a subtemporal approach [7, 78]. Dorsal pontine lesions can be resected via a suboccipital craniotomy [103], whereas ventral and ventrolateral pontine lesions are best accessed via a retrosigmoid or extended retrosigmoid approach [7, 76, 93]. The anterior transpetrosal (Kawase) approach is a modified subtemporal approach that has also been used to access ventrolateral lesions [98]. Lesions approaching the floor of the fourth ventricle are best accessed via the trans-cerebellomedullary fissure (intertonsilar) approach [7, 76]. Lesions of the ventral and ventrolateral medulla can be accessed via a retrosigmoid or a far lateral partial transcondylar approach [7, 78], whereas dorsal medullary lesions are best accessed using a suboccipital craniotomy [103].

Surgical outcomes &

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Multiple surgical series and novel surgical approaches described in the literature have reported favorable long-term outcomes for patients with BSCMs [7, 9, 11–27]. In an extensive review of the literature, Gross et al. [7] identified 683 patients across 45 surgical series with long-term follow-up data reporting improvement or no change in clinical signs and symptoms in 85 % of cases. Complete obliteration was achieved in 684 of 745 BSCMs (92 %). Early postoperative morbidity ranged between 29 % and 67 % due to intraoperative manipulation of neural tissues and transient post-operative brainstem edema. Long-term follow-up led to a morbidity and mortality of 14 % and 1.9 %, respectively [7]. Morbidity was defined as the deterioration in neurologic status caused by the surgical intervention. More recently, Abla et al. [13] reported complete obliteration of BSCMs in 231 of 260 patients (89 %). Early postoperative morbidity was seen in 137 of 260 patients (53 %). Longterm follow-up for a mean of 51 months showed clinical improvement in 68 % of patients. The mortality rate was low (1.2 %). Another study by Ramina et al. [11] retrospectively reviewed 43 patients with BSCMs and reported an obliteration rate of 98 %; however, only 33 % of patients in this series showed clinical improvement. Early post-operative morbidity was reported in 14 % of cases. Tarnaris et al. [26] also provided a review of the literature including surgical and conservative series for patients with BSCMs. Long-term follow-up showed improvement or no change in clinical signs and


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symptoms in 87.8 % of surgically treated patients, whereas only 67.4 % of conservatively treated patients showed similar outcomes. The difference was statistically significant in favor of surgery (P≤ 0.001). However, in their own series of 21 patients with BSCMs, Tarnaris et al. [26] described favored outcomes for conservative management. Similar results were reported by Kupersmith et al. [10], suggesting a more benign course for BSCMs. Predictors of surgical outcomes were described by Hauck et al. [9] in a retrospective review of 44 patients who underwent surgery for BSCMs. The mean post-operative follow-up duration was 11 months. Univariate analysis of variable risk factors showed that the preoperative modified Rankin scale (mRS) score and the number of bleeding events as well as midbrain location (P=0.02) and preoperative hemiparesis (P=0.02) were associated with worse surgical outcomes. However, only the pre-operative neurological status (mRS92) was found to be a significant predictor of worse surgical outcome upon multivariate analysis [9].

Patient selection and indications for surgery &

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Decision making regarding management of BSCMs is frequently based upon balancing the risk of hemorrhage against the potential risks of surgery on a case by case basis. Although it is currently difficult to obtain a precise and reliable estimate of the BSCM hemorrhage risk, variable risk factors described in the literature can give clues about their proper management [7, 9, 10, 28–39]. In general, most asymptomatic BSCMs tend to have a benign course, whereas symptomatic lesions tend to be more aggressive and may carry an increasing risk of hemorrhage with subsequent bleeds [7, 68, 76]. However, due to the potential risks of surgery, conservative management with close follow-up should be the primary treatment option for patients with BSCMs. Our practice is to require at least two clinically significant hemorrhagic episodes and anatomic pial representation of the lesion before considering a surgical intervention. The importance of having an accessible point of entry to the lesion at the area where it reaches the pial surface of the brainstem or the ependymal surface of the fourth ventricle cannot be overemphasized [7, 76]. Preoperative thin-cut T1-weighted MRI is a good method to assess the proximity of the lesion to the pial or ependymal surface of the brainstem and can provide the surgeon with considerable assistance in planning an appropriate surgical approach [85]. This sequence can potentially avoid artifacts due to the “blooming effect” of hemosiderin on T2weighted imaging. The indications for surgery in more deeply located symptomatic BSCMs have varied among different case series. These lesions are not readily accessible through conventional surgical approaches and their


resection requires the manipulation of normal neural structures and thus carries a high risk of disability. Although most authors agree that life-threatening bleeds and rapidly progressive neurologic deterioration are clear indications for surgery, many argue on whether to intervene following the first clinically significant bleed or wait for a second episode [3, 7, 9, 16, 76]. Chen et al. [16] recommended conservative management after a first bleed, particularly for patients with deep BSCMs or those presenting with mild symptoms. They reported two cases in which recurrent hemorrhages pushed the BSCM to the pial surface of the brainstem, thereby promoting surgical resection. Conversely, in their retrospective review of 44 surgically treated patients, Hauck et al. [9] described less favorable outcomes in patients who suffered multiple hemorrhagic episodes. They recommended surgical intervention after the first bleed, even for deep lesions [9]. However, the surgical risk in these patients may outweigh the morbidity and mortality of a second bleed, as dissecting through or manipulating normal brainstem tissue would be mandatory for an appropriate lesional resection. This is especially true if the CMs are associated with venous angiomas. Surgical resection of the venous angioma has been reported to result in hemorrhagic infarction of the brainstem. The presence of a venous angioma by itself might be problematic and can actually increase the risk of surgical resection significantly, especially in a tight exposure such as inside the brainstem.

Timing of surgery &

The timing of surgical intervention after hemorrhagic presentation has also been a subject of controversy and debate. Some authors recommend early surgical intervention to avoid the formation of surrounding gliosis [22, 76], whereas many others report the subacute stage (days to weeks) as the preferred timing of surgery [7, 11, 27, 76]. This allows enough time for the reduction of post-hemorrhagic edema and the formation of a well-defined gliotic plane between the lesion and the surrounding tissue [76].

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Although several radiosurgical series found in the literature have reported favorable long-term outcomes for BSCMs therapy [106– 108], it is now argued that these outcomes may actually reflect the natural history of CMs [65, 66]. According to Barker et al. [65], the risk of re-hemorrhage increases shortly after the initial bleeding event, then decreases from 2.1 % per month to 0.8 % per month after a period of 2 to 3 years. In a review of the literature by Gross et al. [7], permanent morbidity rates following radiosurgery ranged between 7 % and 27 % across several studies [109–112], with mor-

Radiosurgery


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tality rates reported between 0 % and 13 %. Recently, Lunsford et al. [113] retrospectively reviewed 103 patients presenting with solitary symptomatic CMs. Deep CMs (including BSCMs) were reported in 93 patients. The rate of hemorrhage decreased from 10.8 % per patient-year within 2 years post-radiosurgery to 1.06 % per patientyear after 2 years. Morbidity (new neurologic deficits) was reported in 13.5 % of cases. The study suggested that radiosurgery can be a safe treatment option for deep CMs carrying a high surgical risk. Overall, radiosurgery is not considered an effective treatment option for BSCMs. It is reserved only for extremely biologically aggressive lesions that cannot be accessed surgically. It is not certain whether the positive outcomes after radiosurgery reported in the literature are in fact related to the treatment, or if they only reflect the natural history of the disease. The effectiveness of radiosurgery in treating this disease remains highly controversial.

Disclosure No conflicts of interest relevant to this article were reported.

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