**3. Grading and classification**

#### **3.1 The SM grading system**

In 1986, Spetzler and Martin published a relatively simple AVM classification system called "SM Grading" [36]. SM is considered as the gold standard to date. The system requires three parameters, evaluated using angiography, CT, and MRI (**Table 1**): size, venous drainage pattern ("superficial" if all drainage is via cortical veins and "deep" if some or all drainage is via deep veins), and neurological eloquence of adjacent brain regions ("eloquent" regions are those well-defined by a neurological function, while the regions of less defined function or disabling effects when disrupted such as temporal lobes and cerebellar cortex are considered "non-eloquent"). SM eventually sorts AVMs into five grades. Inoperable AVMs are considered grade six. Spetzler and Martin correlated their grading with the surgical outcomes of 100 patients and found it to be well-correlated with both minor and major post-operative neurological deficits. Further validations were later performed by both the authors and peers [56].

## **3.2 Modifications of SM**

Several modifications of the SM grading system have been suggested over the years. Following are some key examples. De Olivera et al. suggested including


#### **Table 1.** *Determination of AVM grade [36].*

*Advocating Intraluminal Radiation Therapy in Cerebral Arteriovenous Malformation Treatment DOI: http://dx.doi.org/10.5772/intechopen.89662*

two Grade 3 subgroups with different patient management [57]: 3a (large size, pre-operative endovascular embolization followed by microsurgical resection) and 3b (venous drainage and/or eloquence, generally treated with radiosurgery). They found their modified classification a useful guide for the best treatment but indicated that it has many exceptions. Lawton et al. suggested further subcategorizing Grade 3 AVMs into four classes for better correlating the SM grading with associated surgical risks (− less risk, + more risk) [58]: Grade 3−AVMs (small nidus size, deep venous drainage, and eloquent adjacent brain tissue) have a surgical risk similar to that of low grade AVMs and can be safely treated with microsurgical resection, Grade 3+ AVMs (medium size, superficial drainage, and eloquent) have a surgical risk similar to that of high-grade AVMs and are best managed conservatively. Grade 3 AVMs (medium, deep, and non-eloquent) have intermediate surgical risks and require judicious selection for surgery. Grade 3\* AVMs (large, superficial, and non-eloquent) are either exceedingly rare, with a surgical risk that is unclear, or theoretical lesions with no clinical relevance. Finally, fairly recently in 2016, Neidert et al. suggested a grading system for patients with ruptured AVMrelated IntraCerebral Hemorrhage (AVICH) to predict clinical outcome [59]. Their system extended SM with parameters such as age, diffuse nidus (from the Lawton-Young grading system, that added patient age, hemorrhagic presentation, nidal diffuseness, and deep perforating artery supply in 2010 to improve neurological outcome prediction and refine patient selection [60]), intracerebral hemorrhage volume (30 CC threshold), and intraventricular hemorrhage (derived from the intracerebral hemorrhage score). They demonstrated that their score predicts the outcome of patients with ruptured AVM and associated ICH better than previous grading systems (SM included). They cautioned that an external validation is needed before this score is tested in a prospective multicenter cohort. To date, no modified grading system has become as well-established as the SM grading.

#### **3.3 SRS grading scales**

Schwartz et al. tried to predict the AVM obliteration success of single-dose photon SRS for individual patients [61]. They defined the obliteration prediction index (OPI ≡ marginal dose of radiation given at the edge of the target lesion in gray/lesion diameter in centimeters). They concluded that the exponential function *P* = 1 − A *e*−B⋅OPI (where *P* is the obliteration probability and A,B are constants) is well-correlated with successive chance, partly describes the biological effect of radiation, and is independent of the device (marginal dose) used. They suggested that radiosurgery centers use this model to facilitate successful treatment prediction.

Pollock-Flickinger developed a grading system to predict excellent patient outcome (complete AVM obliteration without any new neurological deficit) following single session AVM radiosurgery [62]:

$$\begin{array}{l} \text{AVM}\_{\text{score}} = \text{0.1 AVM}\_{\text{volume}}[\text{cm}^3] + \text{0.02 patient age [years]}\\ \text{+ 0.3 AVM}^\*\_{\text{location}} \end{array} \tag{1}$$

where \* indicates: frontal or temporal = 0; parietal, occipital, intraventricular, corpus callosum, or cerebellar = 1; basal ganglia, thalamic, or brainstem = 2.

They concluded that their proposed AVM grading system strongly correlates (*R*<sup>2</sup> = 0.88) with patient outcomes but cautioned that further testing by independent centers using prospective methodology is still required.

In 2016, Pollock et al. compared five AVM grading scales—SM, radiosurgerybased AVM score (RBAS), Heidelberg score, Virginia Radiosurgery AVM Scale (VRAS), and proton radiosurgery AVM scale (PRAS)—at predicting SRS outcomes


*Vascular Malformations of the Central Nervous System*

*‡Heidelberg score: 1 = (<3 cm and* ≤ *50 years), 2 = (either <3 cm or* ≤*50 years), and 3 = (*≥*3 cm and>50 years).*

**Table 2.** *AVM grading scales [63].*

*Advocating Intraluminal Radiation Therapy in Cerebral Arteriovenous Malformation Treatment DOI: http://dx.doi.org/10.5772/intechopen.89662*


#### **Table 3.**

*Classification scheme for risk assessment during embolization procedures for brain AVMs [64].*

(**Table 2**) [63]. Their criterion was AVM obliteration without a decline in modified Rankin Scale (mRS) score (excellent outcome). They concluded that continuous scores AVM grading scales (RBAS and PRAS) outperformed integer-based grading systems in the prediction of AVM obliteration outcomes since they directly correlate with patients' existing physical attributes.

#### **3.4 Grading systems for embolization**

Even though endovascular embolization widely differs from surgical or SRS approaches, dedicated grading was not considered as a broad/general tool until fairly recently. In 2010, Feliciano et al. conducted an extensive literature survey and correlated endovascular treatment with AVM characteristics. Points were given according to feeding vessels, eloquence, and fistulae presence (**Table 3**) [64]. They concluded that a grading scale similar to SM for use in risk assessment and outcome determination in brain AVM patients treated by endovascular techniques seems adequate and clinically feasible.

#### **3.5 Summary**

Though posited in 1986, the SM AVM grading system remains the gold standard in predicting surgical treatment success. The development and assimilation of SRS led to uniquely dedicated grading. The future probably lies with "continuous" grading, where scores are directly correlated with AVM and patients' actual features and properties. Endovascular dedicated grading has just recently emerged, mostly based on large literature surveys and meta-analyses, but apparently shows real promise (though it still necessitates firmer actual validation).

#### **4. Embolization**

Embolization is intended to physically block blood flow to the AVM. It is a minimally invasive endovascular procedure carried out by an interventional radiologist. AVM embolization is considered among the most challenging in the field due to the vasculature target tortuous hemodynamic formation but, more so, due to its high-pressure arteries directly connecting with low-pressure veins (AV shunts). If arteries are proximally occluded, anastomoses develop from nearby vessels creating new shunts. Thus, proximal arterial occlusion has no curative effect and is restricted to pre-surgical situations [23]. In contrast, direct AVM treatment requires distal (transarterial) embolization. First, navigation is performed all the way to the venous section. Then, an embolic agent is super-selectively introduced into the draining veins via microcatheters that are retracted backwards as the vasculature fills up (all the way to the arterial feeders). Vessel selection tract is traditionally based on DSA.

In 1995, Frizzel et al. reviewed the cure, morbidity, and mortality associated with the embolization of 1246 brain AVMs during the previous 35 years [65]. Cure rates were 4–5%. Temporary and permanent morbidities were 10 and 8–9%, respectively. Mortality was 1–2%. These statistics improved over the years. However, to date, embolization is generally considered a pre-operative (pre-SRS) adjunctive procedure because: (I) as a sole modality, it is assumed effective only in a minority of cases [66]; (II) proximal occlusion of feeding arteries appears to be associated with recurrence [66]; and (III) it appears to increase hemorrhagic risk compared with conservative management, especially in unruptured AVMs [67].

Currently, the two most common embolization agents in cerebral AVM treatment are *N*-butyl cyanoacrylate (NBCA) and ethyl-vinyl alcohol copolymer (EVOH)-DMSO solvent (Onyx) [68, 69]. These materials are delivered in liquid form and are, hence, injectable through very narrow diameter microcatheters.

#### **4.1 Cyanoacrylates**

Cyanoacrylates solidify by polymerization initiated once they contact an anionic environment such as blood [69]. The process is very rapid but can be delayed by dilution using Lipiodol (Ethiodol in the USA) vehicle retardant. The more Lipiodol the mixture contains, the longer the delay. Optimizing dilution is a very empirical process that greatly depends on operator experience level. Cyanoacrylates' main advantages are that they: facilitate nearly instant occlusion; induce an inflammatory response within the embolized vessel walls that are believed to play an important role in the occlusion durability; are compatible in case of vascular rupture; are injectable via many microcatheter types (even the thinnest and most flexible ones currently available); have a non-glued microcatheter withdrawal that gives rise to minimal vascular network traction, so they are highly compatible with narrow diameter arterial vessels (very sensitive to traction-induced mechanical trauma); and facilitate surgical resection by helping to identify embolized vessels (compressible and easily cut with micro-scissors). Cyanoacrylates' main drawbacks are: catheter can become entrapped in the occluded vessel; difficulty in controlling the occlusion position; highly local occlusion; they can only be used by operators with extensive training; must be opacified to monitor flow during injection; and catheter position must be abandoned.

#### **4.2 EVOH copolymer-DMSO solvent (Onyx)**

Here, small polymer particles are suspended in solution using a DMSO solvent [69, 70]. Following mixture injection, DMSO diffuses to surrounding tissue, resulting in particle aggregation occluding the lumen. Flow is omnidirectional and typically includes artery reflux along the microcatheter tip. Following injections progressively colonize adjacent arteries, only then traveling towards the draining veins. Consequently, microcatheter tip trapping is a typical feature. This led manufacturers to develop catheters with detachable tips. Onyx's main advantages are: relatively high complete obliteration rate with the evidence of stability over time [70]; slow solidification facilitates prolonged/controlled injection with deeper nidus penetration; and mid-procedure angiography and reduced catheter adherence even during reflux. Onyx's main drawbacks are: DMSO is toxic—rapid injection can

*Advocating Intraluminal Radiation Therapy in Cerebral Arteriovenous Malformation Treatment DOI: http://dx.doi.org/10.5772/intechopen.89662*

cause vasospasm, necrosis, and acute respiratory distress syndrome (ARDS) [71]; DMSO-compatible catheters and syringes must be used; high radiopacity causes poor visualization during reflux in very small vessels and masking by previously embolized regions potentially leading to subsequent healthy vasculature embolization; over-reflux can potentially harm adjacent functional healthy arteries; and mixture must be shaken for at least 20 min prior to usage in order to homogenize the tantalum powder used for opacity.

## **4.3 Precipitating hydrophobic injectable liquid**

PHIL is a recent liquid agent composed of a non-adhesive copolymer (polylactide-co-glycolide and polyhydroxyethylmethacrylate) dissolved in DMSO. Triiodophenol is used as an iodine component, being covalently bound to the copolymer for radiopacity [72]. Initial studies show embolization characteristics, embolization extent, and biocompatibility to be comparable with those of Onyx [72–74]. However, further studies are required to fully evaluate its safety and efficacy [74]. PHIL main advantages are: shorter pause times that result in significantly higher embolization success compared with Onyx; lower volumes required for the same extent of embolization compared with Onyx; it comes ready for use (does not require preliminary preparation); and improved visibility compared with Onyx. PHIL's main drawbacks are: still necessitates DMSO; embolization performance (efficacy) is only comparable with that of Onyx but does not improve on it; and could result in the exertion of traction on the vascular network upon catheter extraction.

#### **4.4 AVM embolization complications**

Post-embolization hemorrhage is the most severe, dramatic, and morbiditymortality-related complication [75]. Up to 14% of patients exhibit neurological deficits [75, 76]. The combined death and permanent disabling neurological deficit rate is below 3.9% per patient [77, 78]. Risk predictors for endovascular treatment differ from those for AVM surgery [76]. Some studies report no morphological AVM characteristics test predict treatment complications [76]. Others suggest AVM location in an eloquent brain part, and fistula presence and a venous glue deposition are associated with complications [77]. Yet, others consider that basal ganglia location is weakly associated with new post-embolization neurologic deficits [78]. This topic is controversial. It appears that extensive devascularization and the absence of post-procedure hypotension increase hemorrhage risk [75]. Thus, partial (25–30%) devascularization per session and post-procedure hypotension induction were recommended [75]. Overall, there is a consensus that brain AVMs' embolization is associated with low overall mortality and disabling morbidity rates [77, 78]. The hemorrhage mechanisms are typically: artery perforation by a microguide/ microcatheter during navigation; excessive pulling on a stuck microcatheter; and hemodynamics-related rupture due to changes in flow patterns and commination (size reduction) in venous drainage. These are typically the most severe and occur within 48 h following embolization. Finally, thrombus formation and its migration from the carrier catheter leading to ischemic complications is a feasible though non-frequent scenario.

Embolization complications dictate clear design recommendations for future endovascular devices: gradual blood vessel closure in which no abrupt flow changes take place inside the nidus; the ability to treat small and big blood vessels, easier to operate when treating patients—requiring reasonable training and experience (and skills); and avoiding exerting significant mechanical stresses on the delicate vasculature.
