Intracranial Arteriovenous Malformation, Cavernous Angioma, Venous Angioma, and Capillary Telangiectasia

Abnormalities of the vascular structures of the head and brain have long been recognized. McCormick published an influential classification system in "The Pathology of Vascular ('Arteriovenous') Malformations." ^[1] He described the arteriovenous malformation (AVM), cavernous angiomas, venous angiomas, telangiectasia, and varix. Intracranial varices are not of significant current clinical concern. AVMs are congenital lesions that are composed of a complex tangle of arteries and veins connected by one or more fistulas and most commonly occur in young adults, with morbidity being 30-50% and death occurring 10-15% of patients.

The overall risk of hemorrhage for cerebral AVMs is 2-4% per year. Characteristics may include small size, deep venous drainage, deep or posterior fossa location, and venous ectasia. ^{[2, 3, 4]}

Cavernous angiomas can be found in any part of the brain at any location along the vascular bed. Intracranial, extracerebral cavernous angiomas also occur but are less common. Cavernous angiomas can also occur in the spinal cord, where they frequently coexist with multiple brain lesions. They can  range in size from under a millimeter to several centimeters, with up to 20% being located in the brainstem. Radiological studies play a pivotal role in diagnosing cerebral cavernous angiomas with MRI as the modality of choice. MRI  demonstrates smoothly circumscribed lesions  of variable signal intensities, which are consistent with hemorrhage in various stages of evolution. Computed tomogram (CT) scanning plays only a limited role largely because of its relative lack of specificity. ^{[5, 6, 7]}

Venous angiomas are enlarged collections of veins and are the most common type of intracranial vascular malformation. The architecture is essentially normal, except for the size. No interruption of physiologic drainage occurs. The characteristics of pure venous malformations may include patulous, dysplastic, non-cylindrical morphology (globoid, fusiform, or falcine); clear connection to the superficial or deep venous system of the brain or the dural sinuses; delayed venous emptying; ipsilateral location when associated with extracranial anomalies; and the absence radiographic evidence of venous hypertension. ^[8]

Brain capillary telangiectasias are slow-flow vascular malformations composed of dilated capillary-like vessels, are classically located in the pons, and are typically benign and discovered incidentally. These lesions are more likely to be apparent on susceptibility-weighted imaging and gradient echo sequences. Most capillary telangiectasias are clinically silent and are found on autopsy. Generally, no treatment is indicated. ^{[9, 10, 11]}

(See the image below.)

Luschka and Virchow originally described arteriovenous malformations (AVMs) in the mid 1800s. Olivecrona performed the first surgical excision in 1932. Lesions of the cerebral vasculature develop such that blood flows directly from the arterial system to the venous system without passing through a capillary system. The arteriovenous (AV) shunt is the definitive characteristic of these lesions. The estimated incidence of AVM in the US general population is 0.14% (140 cases per 100,000 persons or 1 case per 700 persons). This is approximately one fifth to one seventh the incidence of intracranial aneurysms.

Etiology

One or more persisting direct connections from the arterial to the venous systems are present. AVMs are considered congenital lesions and are characterized by a failure of the embryonic vascular plexus to fully differentiate and develop a mature capillary bed in the affected area. The formation of AVMs probably relates to sequential formation and resorption of cerebral surface veins. Their structures may change and grow postnatally but only in relation to a prenatally extant lesion. Molecular biologic factors are thought to be important to AVM development. These may include vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Tissues adjacent to the AVM may be persistently mildly hypoxic because the malformation may steal blood from adjacent healthy tissue, further promoting angiogenesis.

Pathophysiology

The direct connection between the arterial and venous systems supplies a low-resistance shunt for arterial blood and exposes the venous system to abnormally high pressures. This results in a system of enlarged feeding vessels, the tangled nidus of the AVM itself, and enlarged draining venous structures.

Clinical presentation

Clinical presentation of AVM includes the following:

• Hemorrhage (53% of cases): acute onset of severe headache; may be described as the worst headache of the patient's life; depending on the location of hemorrhage, may be associated with new fixed neurologic deficit
• Seizure (46%)
• Headache (34%)
• Progressive neurologic deficit (21%): may be caused by mass effect or ischemia resulting from local vascular steal phenomenon, presence and nature of deficit depend on location of lesion
• Pediatric patients: heart failure, macrocephaly, prominent scalp veins

Hemorrhage is more likely to be caused by small lesions, while seizures are more likely to be caused by large lesions. An increasing number of lesions now are found incidentally upon brain imaging.

The annual risk of intracranial hemorrhages associated with AVMs is 2-3% but could be as high as 33% depending on the specific features of the AVM. The following factors increase the risk for intracranial hemorrhage ^[12] :

• History of cerebrial hemorrhage
• AVM location deep in the brain or brain stem
• Deep venous drainage

The annual risk of hemorrhage correlates with the number of factors present: 

• No factors (< 1%)
• 1 factor (3-5%)
• 2 factors (8-15%)
• 3 factors (>30%)

The mortality rate associated with the initial bleed is 10%. The mortality rate associated with the second bleed is 13%, and the rate increases to 20% for each subsequent bleed. The incidence of new neurologic deficit occurring with each bleed is 50%. These numbers are generalized for all AVMs. The location and size of each patient's lesion greatly affects their risk of morbidity and mortality.

Patients with an AVM have an increased risk of developing a cerebral aneurysm. Approximately 7.6% of patients with an AVM develop an aneurysm. Alternatively, 1.1% of patients with an aneurysm are found to have an AVM. Most commonly, aneurysms are found on arteries feeding the AVM.

Rare case reports describe multiple intracranial AVMs and/or concomitant intracranial and intraspinal AVMs, but these are too rare to be well characterized. AVMs may present as part of a neurocutaneous syndrome, including Sturge-Weber syndrome or Rendu-Osler-Weber syndrome.

Workup

Workup for AVM includes the following:

• Lab studies (these are for routine preoperative evaluation and not for diagnosis, per se): CBC count, prothrombin time (PT)/activated partial thromboplastin time (aPTT), typing, screening

• CT scan is the first imaging choice in an emergent setting in which a patient is thought to have an intracranial bleed. It is fast and widely available.

• CT angiography provides better vascular detail than MRI or magnetic resonance angiography (MRA), and can be performed in most emergency rooms. It can be a useful noninvasive alternative to cerebral angiography.

• MRI is the first imaging choice in a nonemergency setting (eg, workup of seizure, headache, or neurologic deficit). It provides significantly greater resolution and flexibility in diagnosis. MRAs can reveal the anatomy of the AVM noninvasively but have lower resolution than conventional angiography and do not provide functional information. MRI is useful compared to computed tomoangiography (CTA) or cerebral angiography in that it provides better visualization of the surrounding cerebral structures. Functional MRI can assist in treatment planning by defining the functionality of adjacent brain. ^[13]

• Cerebral angiography provides definitive diagnosis. It documents a functional AV shunt; however, because it is an invasive test, it is not performed as the first imaging study. Cerebral angiography also allows grading of the AVM via the following Spetzler and Martin criteria.

• The Spetzler-Martin grading system (described in Table 1, below) helps predict the likelihood of satisfactory outcome if an attempt at surgical resection is made. The Spetzler-Martin grade is determined by adding the 3 individual scores from the table. High-grade AVMs are more difficult to resect, and therefore, neurologic deficits from the surgery itself are more likely. Other grading systems have been proposed for radiosurgery planning.

• A supplemental Spetzler-Martin grading system has been created that includes factors such as patient age, hemorrhagic presentation, nidal diffuseness, and deep perforating artery supply. It has been shown in some studies to have high predictive value of neurologic outcome after AVM surgery. ^{[14, 15, 16]}

• The Spetzler Martin grading system leaves a great deal of variety, particularly in the grade 3 type AVMs. Lawton proposed a supplemental grading scale to the classic Spetzler-Martin system to aid in treatment of middle-grade AVMs. ^[17]

Table 1 . Spetzler-Martin Grading System for AVMs (Open Table in a new window)

The Lawton supplemental Spetzler-Martin grading scale is as follows:

• Age younger than 20 years - 1 point
• Age 20-40 years - 2 points
• Age older than 40 years - 3 points
• Unruptured - 0 points
• Ruptured - 1 point
• Not diffuse - 0 points
• Diffuse - 1 point

Vessel-selective 4-dimensional magnetic resonance angiography (VS-4D-MRA) has been shown to be a useful technique for evaluating of intracranial AVMs, especially for detecting feed arteries and estimating details of the nidus structure. One study showed detectability of feeding arteries by VS-4D-MRA was significantly higher than those of time-of-flight MRA and non-vessel-selective 4D-MRA. ^[13]

Treatment

Complete obliteration is the goal of treatment as partial obliteration does not affect the rate of hemorrhage. Final obliteration rate has been noted to be as high as 85- 90% with current treatments. ^{[2, 3]}

Surgery (craniotomy)

Advantages: Cure is immediate and permanent after complete resection by craniotomy. Surgery is generally recommended for grade 1, 2, and 3 lesions, sometimes for grade 4 lesions, and not for grade 5 lesions.

Disadvantages: The potential for significant intraoperative bleeding, damage to adjacent neural tissue, and ischemic stroke are disadvantages. The "arteries of passage" supply intact neural tissue and must not be destroyed while attempting to interrupt the arterial supply to the AVM. A risk also exists for perfusion-breakthrough bleeding (ie, hemorrhage into the healthy part of the brain caused by sudden hemodynamic shifts), which results from the removal of a large AV shunt and the subsequent increased flow to previously underperfused vessels. Reports of rates of permanent neurologic deficit range from 0-15%, while mortality rates are close to zero in Spetzler-Martin grades 1-3 AVMs. Much higher morbidity and mortality rates are reported with grades 4-5 AVMs.

Endovascular neurosurgery (obliterating vessels with glues or particles delivered via arterial catheter in the angiography suite)

Advantages: Significant reduction of pathologic blood flow through the lesion can be achieved. Its main use is as adjuvant therapy prior to craniotomy to decrease intraoperative bleeding and technical difficulty. It has also been used to decrease the size of an AVM to make it sufficiently compact for effective targeting by stereotactic radiosurgery. Embolization may be curative in lesions less than 1 cm in diameter that are fed by a single artery. Improved obliteration rates of approximately 20% have been reported when using the embolic agent Onyx.

Disadvantages: This is an invasive procedure, and its major risks are similar to those for open surgery (ie, ischemia and hemorrhage). The main risk is causing ischemic stroke by occluding a feeding vessel that also supplies normal brain. Postembolization hemodynamic alterations can cause rupture of the AVM, resulting in new neurologic deficit from subarachnoid and/or intraparenchymal hemorrhage, analogous to the perfusion-breakthrough bleeding described above. This technique is not normally used by itself, as it rarely achieves complete eradication of the lesion and the pathologic vessels usually recanalize over time.

Stereotactic radiosurgery

Advantages: Stereotactic radiosurgery is noninvasive and can access all anatomic locations of the brain. New techniques available include staged radiosurgery for larger lesions (grade IV and V), which has promising results.

Disadvantages: It is used to treat smaller lesions (< 3 cm in diameter) and requires 2 or more years for a full destructive effect. ^[18] The risk for hemorrhage is not reduced during this lag time. The risks of radiation necrosis of adjacent healthy tissue or cyst formation also exist. The cure rates for lesions smaller than 3 cm range from 81-90%. Therefore, a small subset of these lesions still hemorrhage after treatment.

The current gold standard for assessing  AVM obliteration after stereotactic radiosurgery is digital subtraction angiography (DSA). In one study, MRI/MRA predicted AVM obliteration after SRS in most patients, but DSA should still be performed to confirm AVM nidus obliteration after SRS. ^[19]

Integration of 3-dimensional rotational angiography into stereotactic radiosurgery treatment planning has been reported. Conti et al reported that this volumetric angiographic study can be integrated into computer-based treatment planning and offers a superior 3-dimensional view as a result of high spatial resolution. This technique allows a better 3-dimensional understanding of the target volume and distribution of the radiation doses within the volume. Further developments in the temporal resolution and the development of software tools to improve the performance of 3-dimensional contouring are necessary. ^[20]

Combination therapy

Total eradication of the lesion may require more than one modality. Partial treatment may increase the risk of hemorrhage. Endovascular neurosurgery can be performed before surgical excision to reduce the difficulty of surgery or before radiosurgery to bring the size of the lesion to within the limits of the machine.

Radiosurgery may be used to eradicate small residual disease left after craniotomy (due to technical difficulty or involvement of eloquent structures).

Treating aneurysms associated with AVM

Aneurysms on an artery that does not feed the AVM can be managed as any unruptured intracranial aneurysm. Aneurysms less than 5 mm in size have been reported to regress after treatment of AVM; in other cases, they have ruptured after treatment. Given concern about aneurysms greater than 5 mm, treatment via microsurgical clipping or endovascular coiling is generally done prior to the treatment of the AVM.

Outcome and prognosis

Prognosis for untreated AVMs has been reported to include either a 2-3% or a 4% (depending on study cited) risk of bleeding per year, with an approximate 10% mortality rate associated with the bleed. Some studies suggest a 1% yearly mortality risk. The yearly combined major morbidity and mortality risk has been reported to be 2.7%. This figure includes only new clearly fixed neurologic deficits. It does not include other problems, such as seizures, personality changes, or memory disturbances, which also may have a significant disabling impact on the patient's life and functioning.

Risks of conservative management and surgical intervention vary dramatically depending on the location and specific characteristics of individual lesions, which must be considered when applying this data to each patient.

Typically, attempts should be made to completely eradicate the lesion. Regardless of which method or combination of methods is used for treatment, eradication is considered definitive and recurrence is not a concern (except in occasional reports in the pediatric population).

Outcomes for patients with a subarachnoid hemorrhage caused by an AVM are better than outcomes for patients with a subarachnoid hemorrhage caused by an aneurysm. Outcome studies suggest that most patients return to full preoperative psychosocial function.

Guidelines

The Society of NeuroInterventional Surgery (SNIS) has produced the following guidelines for management of brain AVMs ^[21] :

• Digital subtraction catheter cerebral angiography (DSA), including 2D, 3D, and reformatted cross-sectional views when appropriate, is recommended in the pretreatment assessment of cerebral AVMs.
• It is recommended that endovascular embolization of cerebral AVMs be performed in the context of a complete multidisciplinary treatment plan aiming for obliteration of the AVM and cure.
• Embolization of brain AVMs before surgical resection can be useful to reduce intraoperative blood loss, morbidity, and surgical complexity.
• The role of primary curative embolization of cerebral AVMs is uncertain, particularly as compared with microsurgery and radiosurgery with or without adjunctive embolization. Further research is needed, particularly with regard to risk for AVM recurrence.
• Targeted embolization of high-risk features of ruptured brain AVMs may be considered to reduce the risk for recurrent hemorrhage.
• Palliative embolization may be useful to treat symptomatic AVMs in which curative therapy is otherwise not possible.
• The role of AVM embolization as an adjunct to radiosurgery is not well-established. Further research is needed.
• Imaging follow-up after apparent cure of brain AVMs is recommended to assess for recurrence. Although noninvasive imaging may be used for longitudinal follow-up, DSA remains the gold standard for residual or recurrent AVM detection in patients with concerning imaging and/or clinical findings.

Future and controversies

Multidisciplinary teams likely will become increasingly important for optimal management of each individual patient. Such teams may include neurosurgeons, interventional neuroradiologists, and stereotactic radiation specialists. Continuing advances in microsurgical, neurointerventional, and radiosurgical techniques will affect approaches to treatment. Algorithms guiding whether to treat or follow particular lesions will evolve. Advances in the efficacy and safety of the available interventions may emerge. Patients' individual psychological factors will remain critical. For every patient, the immediate risks of intervention versus the likelihood of cure must be balanced. ^[22]

Results of a randomized trial were published after early termination of the study. ^[23] The results indicated a significantly higher risk of stroke with disability and seizures in the intervention/surgical treatment group. The results of this study should be interpreted cautiously because of its poor enrollment; also, a small number of patients actually had surgical resection (n=5) or combined embolization with surgical resection (n=12), compared to endovascular embolization alone (n=30) or radiosurgery (n=15). Clearly, these treatment modalities are not comparable, and surgical resection is usually curative compared to embolization or radiosurgery.

It is important to evaluate each patient with an arteriovenous malformation on a case-by-case basis, weighing the risks of various treatment modalities versus the risks of the patient having a symptomatic hemorrhage and deciding what is best for each individual patient.

Cavernous angiomas are also known as cavernous malformations, cavernous hemangiomas, or cavernomas and can occur anywhere in the central nervous system. Occurrence is usually sporadic, but a significant proportion of cavernous angiomas are familial. These lesions were thought to be rare until the advent of MRI. They have since been identified in 0.5-1.0% of the population.

Three autosomal dominant genes are associated with the familial form. The precise function of these gene products are not known. They are as follows:

• ccm1 on 7q chromosome and expresses KRIT1
• ccm2 on 7p chromosome and expresses MGC4607
• ccm3 on 3q chromosome and expresses PCD10

Pathology

Cavernous angiomas consist of enlarged capillaries with characteristics as follows:

• Sinusoidal
• Single layer of endothelium
• Thin collagenous wall
• Lack of smooth muscle fibers and elastic fibers

Capillaries are immediately adjacent to each other, with no intervening neural tissue. They typically are not associated with enlarged feeding arteries or draining veins, and blood flow is low or even stagnated. Grossly, they may range from soft to hard. Thrombosis, calcification, or ossification results in a harder lesion.

Hallmark pathologic appearance is as follows::

• Blood leakage (This results in hemosiderin staining; iron salts may incite an epileptogenic focus.)
• Gliotic reaction in the adjacent brain

One review of the literature reported the following incidences among those lesions that become symptomatic:

• Seizure (39%)
• Hemorrhage (32%)
• Mass effect (29%)

A significant percentage of lesions are asymptomatic, although accurately determining the frequency of asymptomatic lesions is difficult. Studies indicate that 10-25% of lesions are symptomatic. New research is suggesting that certain immune responses may be associated with proliferation and hemorrhage of cavernous malformations.

Occurrence generally is sporadic. One study revealed increased prevalence in Mexican American families, who also are more likely to have multiple lesions.

Workup

Lesions may be demonstrated on brain imaging studies. Radiological studies play a pivotal role in diagnosing cerebral cavernous angiomas with MRI as the modality of choice. ^[4] MRI  demonstrates smoothly circumscribed lesions  of variable signal intensities, which are consistent with hemorrhage in various stages of evolution. MRI scans reveal well-defined lesions on T1 and T2 sequences with sensitivity and specificity nearing 100%. The hemosiderin ring is visualized on a T2 sequence. Blood products of various ages can be observed in the center, and local edema may be present. ^[24]

The diagnosis largely depends on identifying the characteristic “popcorn” appearance on MRI, with a rim of signal loss due to peripheral hemosiderin deposition. ^[25]

CT scanning plays only a limited role largely because of its relative lack of specificity. ^[4]  CT scans may show focal hyperdensity, reflecting calcification or recent hemorrhage or mass effect, and intravenous contrast may show faint enhancement. Cerebral angiograms demonstrate no vascular abnormalities, although 8% of developmental venous anomalies have an associated cavernoma, which can be seen on angiography.

Treatment

Surgical removal eliminates mass effect and hemorrhage risk. It also removes the seizure focus. When the lesion is in a surgically accessible location, surgical removal can often be accomplished with relative ease and minimal risk. Functional MRI scans preoperatively may make resection safer. Brainstem cavernomas can be resected if the lesion reaches a pial surface. Currently, the role of radiosurgery is still debatable due to lack of follow-up studies and a reliable method to detect active lesion on radiographic examinations. ^{[26, 27]}

Because of the greater life expectancy and the known higher functional recovery in children, surgical treatment has been suggested to be undertaken early in young patients who present with surgically accessible brainstem lesions that have an aggressive clinical course. ^[28]

In a study, by Bubenikova et al, of cohorts with 8994 patients treated for cerebral cavernous malformations, efficacy for prevention of  hemorrhage was 97% for surgical treatment, 86% for radiosurgical treatment, and 77% for conservative treatment. Brainstem and deep-seated lesions were associated with higher rates of bleeding. ^[29]

Prognosis

One study showed a 0.7% annual hemorrhage rate in cases of lesions followed prospectively. This rate increases dramatically if lesion enlargement within 1 year is documented. The estimated lifetime risk for hemorrhage, epilepsy, and other neurologic sequelae is 50-70%. Intractable seizures, increase in lesion size on MRI, and an incident of gross hemorrhage are indications for removal of surgically accessible lesions.

Symptomatic lesions are likely to remain symptomatic or progress, but patients treated surgically experience remission or a reduction of symptoms. Approximately 50% of patients experience elimination of seizures, and the remainder have a decreased frequency of seizures. Elimination of seizures is more likely if the patient has not had seizures for many years. Successfully excised lesions are considered cured, and recurrence is not a concern.

Introduction and pathology

The venous angioma, also known as a developmental venous anomaly, is the most common type of intracranial vascular malformation, as determined by incidental findings at autopsy. One autopsy study estimated a prevalence of 2.6%.

Pathologically, a venous angioma is an enlarged collection of veins. The architecture is essentially normal, except for the size. The veins receive drainage from adjacent healthy tissues. The veins appear as a radial arrangement, all converging on an enlarged central venous trunk. This trunk drains into healthy superficial or deep venous systems. No interruption of physiologic drainage occurs; therefore, the lesions are considered anomalies rather than pathologic structures. Venous angiomas are postcapillary structures and are not associated with abnormal arteries.

Presentation, treatment, and prognosis

Venous angiomas frequently are incidental radiographic findings, although some patients may present with intracranial hemorrhage. Patients also may present with a seizure or focal neurologic deficit. Posterior fossa lesions are more likely to result in a deficit.

Angiograms usually have a "hydra" or caput medusae appearance, resulting from the image of smaller radial veins converging on a central draining venous trunk. CT scan or MRI reveals a curvilinear structure that is described as resembling the spokes of a wheel. CT scans also may reveal a rounded enhancing area. MRI images may have sufficient resolution to reveal the caput medusae form.

Venous angioma has either no risk or very low risk of hemorrhage. Generally, patients are completely asymptomatic, and their cases should be followed conservatively.

Excision or ablation of venous angiomas is avoided. The angioma may be part of normal venous drainage for adjacent healthy neural tissue. Therefore, excision can lead to venous infarction of this tissue and significant morbidity and mortality.

Because many lesions are clinically silent and likely to escape diagnosis, comparing the natural history and associated prognosis of treated lesions versus untreated lesions is difficult.

Importantly, venous angiomas have been postulated to be pathophysiologically related to cavernous angiomas. In the case of a hemorrhage associated with a venous angioma, investigate for an adjacent cavernous angioma. If a cavernous angioma is found, resect the clot and the cavernous angioma, but do not resect the venous angioma.

Introduction and pathology

The presence of capillary vessels with saccular or fusiform dilations characterizes capillary telangiectasias. These vessels lack muscular and elastic components in their walls. They are intercalated among healthy brain parenchyma. They are not associated with gliosis. Typically, no evidence of associated hemorrhage is present. Upon gross inspection, they are tiny lesions having the appearance of punctate hemorrhages.

Capillary telangiectasias almost always are clinically silent and not detectable radiographically. They are found incidentally on autopsy. Clinically significant intracranial hemorrhage has been reported very rarely.

These lesions may be related pathologically to cavernous angiomas. Some recommend considering the 2 lesions as a single entity, referred to as capillary malformation.

Presentation, treatment, and prognosis

Most capillary telangiectasias are clinically silent and are found incidentally on autopsy. Rare anecdotal reports of substantial hemorrhage exist. Previously, these lesions were undetectable radiographically. However, they may be visualized as a tiny area of hypointensity on T2-weighted MRI scans. These hypodensities may represent previous subclinical hemorrhage.

No treatment is indicated.

Importantly, capillary telangiectasias have been postulated to be pathophysiologically related to cavernous angiomas. Transitional forms with vessel histology sharing features of each entity have been described.

In a review, by Larson et al, of  99 patients with brain capillary telangiectasias, 33 were hemorrhagic, and 66 were non-hemorrhagic. Mean age at presentation of patients with hemorrhagic lesions was 25.5 years, and the most common location was the supratentorial CNS (54.5%), with motor disturbance being the most common symptom (26.1%).  Mean age at presentation in patients with non-hemorrhagic lesions was 39.8 years, with the pons being the most common location (78.5%), and headache was the most common symptom (22.2%). ^[9]