Epidemiology

Cavernous malformations (CMs) constitute 5 to 13% of all vascular lesions in the brain and spinal cord. ¹ With advanced imaging techniques, the detection rate, and therefore the incidence, of these lesions appears to have increased over the past three decades. The incidence of CMs is estimated to be 0.4 to 0.5% among the general population, and the prevalence is estimated to be 0.4 to 0.8%. ^{2,​ 3,​ 4}

CMs are vascular malformations consisting of endothelium-lined, grossly dilated, vascular channels that lack the typical tight junctions of normal blood vessels. The absence of tight junctions allows for blood to extravasate from the malformed vessels. ⁵ CMs can occur in any location in the central nervous system (CNS). They are mostly supratentorial; however, infratentorial CMs are well described. They occur less frequently in the brainstem. An estimated 15 to 18% of all CNS CMs arise in the brainstem. ⁶ The majority of brainstem CMs occur in the pons, followed by the midbrain and finally the medulla. This distribution has been attributed to the sheer volume of tissue in the pons compared to that in the other segments of the brainstem. ^{7,​ 8}

29.2 Clinical Presentation

The clinical presentation of patients with brainstem CMs depends on the size and location of the lesion. Patients with these lesions can be completely asymptomatic or can die as a result of the CM. The most common reported presentation is cranial neuropathy. Other manifestations include sensory loss, motor deficits, ataxia, headache, nausea, vertigo, and dysarthria. Recognition of these distinct clinical features can aid the neurosurgeon in localizing the malformation within the brainstem. ⁷

29.3 Imaging Characteristics

Magnetic resonance imaging (MRI) is the most sensitive and specific imaging modality available for diagnosis of CMs. These lesions are hypointense or isointense on T1-weighted MRI, whereas they have a heterogeneous “popcorn” appearance with mixed hyperintense and hypointense signals on T2-weighted MRI. Their hypointense appearance on gradient echo T2* images (due to hemosiderin deposition in and around the CM) is virtually pathognomonic. CMs generally do not enhance upon administration of intravenous gadolinium. The role of computed tomography is limited for the diagnosis of brainstem CMs. Typically, such lesions have a hyperdense appearance with or without calcification. CMs are angiographically occult because of low or absent blood flow and the high incidence of thrombosis. ^{9,​ 10,​ 11} Nonetheless, a catheter angiogram may be helpful in excluding a small arteriovenous malformation in patients with acute hemorrhage when other diagnostic modalities have not been definitive.

29.4 Natural History

The pathogenesis of CMs remains largely unknown. They are thought to arise during early embryogenesis and then to grow according to changes in blood and mechanisms of malformation. ¹² However, many CMs arise de novo, with some occurring after radiotherapy. ¹³ Most lesions are solitary and sporadic, whereas some are multiple and inherited in an autosomal dominant fashion. ¹⁴

The natural history of CMs, particularly those present since birth, stems from their risk of bleeding and rebleeding. This topic has been an area of debate for the past few decades. Retrospective reports indicate an annual risk of hemorrhage of 0.5 to 2.7% and of rehemorrhage of 21 to 60% per year; prospective studies report a hemorrhage rate of 0.2 to 0.7% and a rehemorrhage rate of 5 to 7% per year. ^{3,​ 7,​ 15,​ 16,​ 17,​ 18,​ 19} The hemorrhage and rehemorrhage rates for brainstem CMs (especially during the first 2 years) have been estimated to be higher than the rates for CMs in other locations. ^{16,​ 20,​ 21} Moreover, although numerous CM hemorrhages go unnoticed, the majority of brainstem CM hemorrhages produce symptomatic clinical features because of the eloquence of this region. Studies have demonstrated a significant increase in the risk of rehemorrhage among patients with a previous CM hemorrhage. ^{15,​ 19,​ 22}

Garcia and colleagues developed a grading system to categorize brainstem CMs that is similar to the widely used Spetzler–Martin grading system for brain arteriovenous malformations. ^{7,​ 23} In their grading system, five elements (age, lesion size, extension across the midline, the presence of an associated developmental venous anomaly, and the presence of hemorrhage) are graded for a total score of up to seven points. The total score is used to assign a grade (from 0 to 7) to the patient, which predicts the surgical morbidity and outcome (higher total score associated with a worse outcome).

29.5 Management Options

The optimal management of brainstem CMs is widely debated. Three management paradigms constitute the most commonly used modalities to address these lesions.

29.5.1 Observation

Conservative management of brainstem CMs in the form of clinical observation and neuroimaging surveillance is acceptable both for patients with incidentally discovered asymptomatic CMs and for patients with complete clinical recovery after an initial hemorrhage. The risk of hemorrhage among incidentally discovered brainstem CMs has been reported to be less than 1% per year. ^{7,​ 15,​ 16,​ 17,​ 18,​ 19} The higher rates of morbidity (9.6–45%) and mortality (0.96–1.5%) associated with surgical intervention make conservative management of such patients preferable. ^{6,​ 7,​ 24,​ 25}

29.5.2 Radiotherapy

The role of radiotherapy, including in its various modes of delivery (stereotactic radiotherapy or gamma knife [Elekta AB] radiotherapy), has produced contradictory results for the management of brainstem CMs. Radiosurgery has been recommended specifically for CMs arising in locations not amenable to surgical intervention. However, this modality is also associated with high rates of morbidity (15–59%) and mortality (0–8%). ^{26,​ 27,​ 28,​ 29}

Although some reports document the superiority of radiotherapy compared to conservative management, others have argued that the observed improvement among patients with brainstem CMs is merely due to the natural history of the disease rather than the result of the radiotherapy. ^{27,​ 30,​ 31} Radiotherapy has even been implicated as a culprit in the pathogenesis of these lesions. ¹³ Notably, the decrease in the hemorrhage rate observed in patients with lesions treated with radiotherapy occurs mainly after a latent period of 2 years. ³² Similarly, CMs that are managed conservatively have a substantially decreased risk of spontaneous hemorrhage after 2 years. Thus, the question remains regarding whether the observed hemorrhage reduction is due to radiotherapy or the natural history of CMs. ³¹ Moreover, as Almefty and Spetzler pointed out, radiologic studies obtained after CMs were treated with radiotherapy have failed to demonstrate resolution of the CMs, further questioning the clinical efficacy of this modality. ³¹ Thus, there is inadequate evidence-based medicine to document the superiority of radiotherapy over conservative management or vice versa.

29.5.3 Surgery

For decades, surgery has been contraindicated in the brainstem, which has been considered to be a “no man’s land.” The presence of multiple cranial nerve nuclei and tracts in this small area make any manipulation a great risk for morbidity and mortality.

Surgical intervention generally depends both on the location of the lesion within the brainstem and on the clinical presentation of the patient. Indications for surgery of brainstem CMs include, but are not limited to, a lesion abutting the pial surface of the brainstem, bleeding with progressive neurologic deterioration, acute hemorrhage outside the capsule of the lesion, and clinically significant mass effect caused by intralesional bleeding.

Hemorrhages of brainstem CMs are generally classified as acute, subacute, or chronic. ^{7,​ 24,​ 33} During the acute stage, surgical intervention should be avoided because of the firm nature of the hematoma and the presence of extensive edema, which limits the degree of manipulation and exploration of the lesion. During the subacute stage of hemorrhage (6–8 weeks after the initial hemorrhage), the edema resolves and the blood liquifies. This process creates a surgical plane that separates the lesion from the surrounding parenchyma, which aids the neurosurgeon in establishing complete resection of the lesion. Finally, during the third stage of chronic hemorrhage, extensive fibrosis, gliosis, and hematoma reorganization ensue. This process causes the CM to adhere firmly to the surrounding eloquent parenchyma, which limits the exposure and the ability to manipulate microsurgical instruments. ^{7,​ 24,​ 33} In a retrospective study on the impact of the timing of surgical intervention for 397 patients with brainstem CMs, Zaidi et al, found that surgery within 6 to 8 weeks of hemorrhage was associated with a statistically significant likelihood of superior recovery compared to that of patients who undergo later surgery (odds ratio 1.73, 95% confidence interval 1.06–2.83, p = 0.03). ²⁴ Therefore, most authors advocate surgical intervention during the subacute stage.

The presence of multiple CMs is considered a contraindication for surgical intervention unless the clinical manifestations can be attributed to a single lesion that might be addressed surgically. The outcomes of surgical intervention are delineated in the section on clinical outcomes.

29.6 Operative Considerations

The goal of surgery for brainstem CMs is to achieve complete surgical resection to prevent the risk of hemorrhage while minimizing the need to tranverse eloquent parenchyma. Subtotal resection has been shown to result in repeat hemorrhage rates of up to 62%. ⁶

Some authors recommend opening the pial surface of the brainstem with microforceps instead of a blade so as to spread the neural fibers at the desired safe entry zone rather than cutting through them ( ▶ Table 29.1). ³⁴ Moreover, it is not uncommon to see an associated venous anomaly in conjunction with a CM, and these must be preserved to avoid the risk of venous infarction.

The surgical approach depends on the location and size of the lesion, as well as on the expertise of the neurosurgeon. For the sake of simplification, a two-point method has been developed to determine the best surgical approach to reach the CM. ³⁵ Two points are drawn on an MRI, one at the center of the lesion, and the other at the periphery closest to the pial surface. When the two points are connected, the resultant straight line determines the best surgical approach. Although this simplified method can be used in the majority of cases, some cases require a different approach than the one inferred by the two-point method because of the potential traversing of critical eloquent neural structures and pathways. Thus, knowledge of the brainstem anatomy and surgical approaches is essential in the surgical planning for treatment of these lesions ( ▶ Table 29.1, ▶ Table 29.2). We advocate the use of diffusion tensor imaging MRI when the direction of displacement of important white matter tracts is questionable.

The development of lighted microsurgical instruments has greatly aided surgical resection of brainstem CMs. These instruments function in a dual fashion, performing their intended task (e.g., suction) while also providing illumination to aid in the visualization of the lesion and the adjacent anatomy. ³⁴ Proper patient positioning also allows the neurosurgeon to operate without having to use fixed retraction of eloquent brain tissue. ³⁶

The use of an intraoperative image-guided system integrated into the operative microscope is useful for the resection of brainstem CMs. It allows for optimal planning of, and navigation through, the surgical corridor. ³⁷ Of equal importance is the use of intraoperative neurophysiological monitoring. Monitoring somatosensory evoked potentials, motor evoked potentials, electroencephalography, brainstem auditory evoked potentials, and cranial nerve function should be conducted during the surgical resection of brainstem CMs. As imaging techniques have advanced, intraoperative MRI has increasingly been proposed as a valuable adjunct in the management of brainstem CMs to ensure the complete removal of these lesions. ³⁴

29.7 Operative Procedure

Various surgical approaches are used for the management of brainstem CMs, depending on their location within the brainstem ( ▶ Table 29.2). As an example, a 56-year-old man presented with diplopia on right gaze. His examination revealed left upper limb weakness (4/5) and bilateral dysmetria. His imaging showed a midbrain CM ( ▶ Fig. 29.1). There was a history of three prior hemorrhages. A left lateral supracerebellar infratentorial approach was used to approach the lesion in the prone position ( ▶ Fig. 29.2, Video 29.1). Somatosensory evoked potentials and motor evoked potentials were monitored. Complete resection was achieved ( ▶ Fig. 29.3).

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