Evaluation of Nidus Occlusion After Gamma Knife Radiosurgery of Cerebral Arteriovenous Malformations Using Magnetic Resonance Imaging
Evaluation of Nidus Occlusion After Gamma Knife Radiosurgery of Cerebral Arteriovenous Malformations Using Magnetic Resonance Imaging
Cerebral arteriovenous malformations (AVMs) are abnormal vessels, connecting cerebral
 arteries and veins. They form a bundle which is called nidus. Rupture of an AVM leads to
 intracranial hemorrhage often causing neurological impairment or even death. As treatment can
 be associated with high rates of morbidity and mortality, AVMs still remain a considerable
 challenge for neurosurgeons. For smaller AVMs, a well-established treatment option is
 non-invasive Gamma Knife radiosurgery (GKRS). GKRS uses radiation to obliterate the AVM nidus
 hence, eliminating the risk of hemorrhage. However, after Gamma Knife radiosurgery, occlusion
 of the AVM nidus takes about two years. To evaluate treatment success after GKRS, invasive
 digital subtraction angiography (DSA) is still the gold standard. For this procedure,
 patients have to undergo puncture of the femoral artery for application of a contrast media
 to receive adequate imaging of the cerebral arteries. In recent literature it has been
 discussed whether sufficient evaluation of treatment is possible with non-invasive magnetic
 resonance imaging (MRI). At present, it is unclear whether this method could replace the
 current invasive gold standard for treatment evaluation. To investigate on this issue, a few
 studies have compared the two methods however, only retrospective data exist. Thus, the
 investigators are conducting this prospective study including 50 patients with cerebral AVMs
 treated with GRKS to evaluate the sensitivity for nidus obliteration of MRI using DSA as a
 reference.
Background

 Cerebral arteriovenous malformations consist of tangled blood vessels forming a so-called
 nidus which connects arteries to veins without the interposition of a capillary bed. Due to
 subsequent structural changes of draining veins within the nidus, patients are at risk of
 cerebral hemorrhage. Bleedings of AVMs are associated with high morbidity and mortality.
 Therefore, once a cerebral AVM is diagnosed, preventive treatment usually is aimed for. If
 hemorrhage already occurred treatment is necessary because of a high chance of re-bleeding.
 Cerebral AVMs are likely to cause neurological symptoms such as seizures and focal deficits
 without bleeding. These symptoms are usually due to the AVM's mass effect however, they have
 also been discussed to be caused by a vascular steal syndrome.

 Etiology

 The etiology of cerebral AVMs is not known. Aside from the possibility of a multifactorial
 cause it seems that genetic mutation and angiogenetic stimulation could play a role in their
 development. It is also discussed whether AVMs develop in utero or through an angiopathic
 reaction following ischemia or hemorrhage.

 Epidemiology

 The prevalence and incidence of cerebral AVMs are about 10 per 100,000 and 1 per 100,000;
 respectively without sex predilection. The annual risk of intracranial hemorrhage ranges from
 1.2% in unruptured AVMs to 4.8% when hemorrhage already occurred before. The mortality rate
 among AVM patients after intracranial hemorrhage is 10-15%. The morbidity varies from 30-50%.
 Of all AVM patients without hemorrhage about 15-40% suffer from seizures. Progressive
 neurological deficit occurs at 6-12%.

 Diagnosis

 Cerebral AVMs are usually diagnosed by an MRI examination. They can easily be identified on
 enhanced images but may also be visible without contrast due to edema or mass effect. The
 current gold standard of diagnosis and evaluation of treatment success of cerebral AVMs is
 digital subtraction angiography (DSA). This method uses injection of a contrast agent into
 the patient's arteries and X-rays to visualize cerebral vessels. Imaging of the blood flow
 over time and therefore accurate distinction of feeding and draining vessels within the nidus
 is the major advantage of DSA. Subtraction of bones and soft tissue enables an optimal view
 of the vascular system.

 DSA has to be carried out as an inpatient procedure because of its invasiveness. Occurrence
 of hematoma or pseudoaneurysm at the site of puncture and endovascular injury with
 consecutive embolism are rare but possible complications. Further disadvantages of DSA are a
 substantial exposure to radiation and the necessity of 24 hours of bed rest after the
 procedure which may lead to an increased risk of thrombosis.

 Classification - The Spetzler-Martin grading-system

 Evaluation of the Spetzler-Martin grade (SM grade) requires three characteristics of the AVM.
 first it is the size of the malformation regrouped into three categories. Next, the drainage
 is of importance: one can differentiate between superficial only and deep veins partaking in
 drainage. Finally, the eloquence of the brain tissue surrounding the lesion is considered.
 Areas responsible for higher functions such as movement and sensibility, vision and language
 are called eloquent. The thalamus, hypothalamus, brainstem and cerebellar peduncles are
 eloquent regions. On the cerebral cortex sensorimotor areas and those responsible for
 language and primary vision are eloquent.

 The Spetzler-Martin system was developed to estimate the prognosis before surgical
 intervention, but is also used for other treatment methods. The SM grade correlates well with
 the difficulty of surgery and its outcome.

 Treatment

 There are different treatment options for cerebral AVMs: Microsurgical resection,
 endovascular embolization and Gamma Knife radiosurgery, or combinations thereof. Independent
 of AVM specifications and treatment option, any therapy bears the risk of cerebral hemorrhage
 and ischemia and therefore permanent neurological deficit and death. Hence, the decision if
 and how an AVM should be treated has to be made carefully with the intention to offer a
 result better than the natural course of the disease. In order to answer the question if a
 wait-and-see strategy is a valid option, a prospective, non-blinded, randomized, multicenter
 study was conducted in 2014. The study compared the risk of death and stroke as well as
 functional outcome between treated and untreated AVM patients.

 The so-called ARUBA trial was interrupted six years after the beginning of randomization due
 to an apparent superiority of the untreated group. The authors concluded that unruptured
 cerebral AVMs should be managed conservatively.The study was harshly criticized by many
 experts due to its setting and the interpretation of the data. One major limitation is that
 different treatment options were not evaluated separately but as one interventional group.
 Other limitations of ARUBA are a low number of cases - only 116 patients were randomized for
 intervention and of those only five underwent microsurgical resection - and a short follow-up
 of 33 months. At least, ARUBA shows the controversy existing among experts concerning
 cerebral AVM treatment. The established treatment options will be explained below.

 Microsurgical Resection

 As microsurgical resection eliminates the risk of bleeding immediately, it still represents
 the therapy of choice for most of the cerebral AVMs reaching a Spetzler-Martin score of one
 to three. In order to expose a cerebral AVM, a bone flap of the patient's skull is raised and
 the dura opened. Feeders are identified, coagulated and cut so the AVM can be resected in
 total. Outcome of patients with an unruptured AVM undergoing microsurgery depends on their
 Spetzler-Martin (SM) grade. According to a prospective cohort study from 2014 a permanent
 neurological deficit is postoperatively seen in 1.6% of patients with SM scores 1 and 2. In
 patient with SM grade 3 the risk of permanent neurological deficit after surgery rises to
 14.0% and to 38.6% in patients with SM grades 4 and 5.

 Endovascular Embolization

 Endovascular embolization of an AVM is performed via the arterial route after puncture of a
 peripheral artery. The AVM nidus is occluded by injection of an embolic material which clogs
 its feeding arteries. According to a systematic review including more than 1,000 AVM patients
 who had undergone endovascular embolization, this therapy lead to nidus occlusion in an
 average of 13%, with a wide range from 0 to 94%. Permanent neurological deficit after
 embolization was averagely seen in 6.6%, ranging from 0 to 28%. The endovascular approach is
 often used to close small AVMs or to make larger AVMs amenable for radiosurgery or
 microsurgery.

 Gamma Knife Radiosurgery

 Gamma Knife Radiosurgery can be performed either as a single therapy or in combination with
 other treatment methods, most commonly combined with endovascular embolization. At the
 Department of Neurosurgery, MUV radiosurgery of cerebral AVMs is performed with Gamma Knife
 Perfexion® which uses 192 cobalt 60 sources to apply high dose radiation into an exactly
 defined volume within the cranium. Gamma Knife radiosurgery is generally performed in local
 anesthesia thus enabling the fixation of the stereotactic frame to the skull. In children
 below 14 years of age Gamma Knife radiosurgery is performed under general anesthesia. Whereas
 endovascular and surgical treatment immediately eliminate the risk of bleeding if carried out
 successfully, nidus occlusion after Gamma Knife radiosurgery usually takes about two years.
 During this time the bleeding risk is reported to be the same as in untreated patients. The
 major advantage of radiosurgery is its non-invasiveness. Rates of complete nidus occlusion
 after Gamma Knife radiosurgery of cerebral AVMs are reported to be about 85% for AVMs with a
 SM grade 1 to 3. A much lower rate of 54% for AVMs with a SM grade 4 and a rate of 0% for
 AVMs with SM grade 5 show the dependence of the Spetzler-Martin grade. However, even if nidus
 occlusion is not achieved in many AVMs with higher SM grade, a reduction of their size may
 enable further treatment. Permanent neurological deficit after radiosurgery was seen in 5.1%
 with a range from 0 to 21%.23 Complications of radiosurgery are adverse radiation effects
 (ARE) which occur many years after intervention and include perilesional edema and cyst
 formation. Those have to be differentiated from radiation induced changes (RIC) arising in
 the first 1-2 years after treatment and including focal necrosis, white matter injury,
 microangiopathy, sinus inflammation and atrophy.

 Treatment Evaluation

 The gold standard for the evaluation after AVM therapy is the catheter angiography; digital
 subtraction angiography (DSA). As already mentioned in chapter Diagnosis, DSA has several
 disadvantages like invasiveness, necessity of inpatient treatment and peri-interventional
 risks. So far, MRI/MRA is a regularly performed evaluation method after Gamma Knife treatment
 of AVMs but it still remains unclear if its accuracy is sufficient compared to that of DSA.
 Numerous MRI protocols for imaging of cerebral vascular pathologies exist. According to a
 small prospective study a specific MRI protocol focusing on blood flow characteristics called
 arterial spin labeling (ASL) was superior to conventional contrast enhanced MRI in the
 evaluation of AVM nidus occlusion after stereotactic radiosurgery. Using DSA as a reference,
 seven out of seven patients with complete nidus occlusion where assessed correctly by ASL
 imaging, so were three patients with a persisting AVM nidus.

 However, in those three cases, according to the contrast enhanced MRI the nidus was falsely
 rated as occluded. A retrospective study comparing conventional MRI/MRA to DSA found 80%
 sensitivity and 90% specificity of standard MRI/MRA for detection of AVM nidus occlusion
 after stereotactic radiosurgery in a series of 136 patients.

 Objectives and hypotheses

 Objective:

 To evaluate sensitivity and specificity of a standardized MRI/MRA protocol compared to that
 of DSA for detection of nidus occlusion after Gamma Knife radiosurgery of cerebral AVMs

 Hypotheses:

 H0: There is significant difference in sensitivity and specificity between MRI/MRA and DSA
 for detection of nidus occlusion after Gamma Knife radiosurgery of cerebral AVMs.

 H1: There is no significant difference in sensitivity and specificity between MRI/MRA and DSA
 for detection of nidus occlusion after Gamma Knife radiosurgery of cerebral AVMs.

 Methods

 In this preliminary study the investigators plan to include about 50 radiosurgically treated
 patients with cerebral AVMs. Patients participating in the study will not be exposed to any
 additional risk compared to patients not participating in the study. Participants will
 undergo a standardized MRI protocol at the Department of Radiology, MUV two years after Gamma
 Knife treatment. The standardized MRI protocol replaces the follow-up-MRI two years after
 treatment that is usually performed in private practice and often does not include all
 required sequences. The standardized MRI protocol includes specific sequences allowing
 analyzation of vascular pathologies. Those are a contrast enhanced three-dimensional MRA (T1
 GE 3D +/- KM), a time-of-flight magnetic resonance angiography (TOF-MRA), arterial spin
 labeling (ASL) and time resolved MRA with interleaved stochastic trajectories (TWIST-MRA).
 Three dimensional MRA and TOF-MRA produce conventional images of vascular structures. ASL
 enables more detailed imaging of the cerebral blood flow. TWIST-MRA produces time resolved
 images. Hence, the major advantage of DSA should be reproduced with this method.

 For evaluation of the parenchyma adjacent to the AVM, DWI and SWI sequences will allow
 detection of ischemic areas and hemorrhage. Standard sequences (T2 sagittal, axial and
 coronal) will also be produced. Participants of this study will be enrolled at the Gamma
 Knife outpatient clinic of the Department of Neurosurgery, MUV. Nidus occlusion will be
 evaluated by a neuroradiologist and compared to the gold standard of DSA performed at the
 Department of Neurosurgery, MUV. Since the angiography (DSA) is the current gold standard in
 AVM evaluation it will be performed in any case and is thus rated as outside of this study
 protocol. Thus, sensitivity and specificity of MRI/MRA for detection of AVM nidus occlusion
 will be assessed in comparison to the gold standard. Due to the fact that every case of
 cerebral AVM treated by stereotactic radiosurgery at the Department of Neurosurgery, Medical
 University of Vienna is assessed by MRI and DSA examinations after treatment, the
 post-radiosurgical procedures of diagnosis do not pose any additional effort or risk for
 patients participating in the study. In fact, patients may benefit from participation as they
 do not need to care for scheduling of their MRI examination in private practice.

 Statistical analysis

 Due to an uneven distribution of data, statistical analysis will be performed with
 nonparametric tests. Descriptive analysis of characteristics of patients and AVMs as well as
 Gamma Knife parameters includes the median value and range as well as frequencies, numbers
 and percentages. Statistical calculations for comparison between eventual treatment groups
 include the Kruskal-Wallis, Mann-Whitney-U and Chi-square test for independent samples. To
 support the hypothesis, the result of the MRI examination must be in accordance with the
 result of the DSA examination in a vast majority of cases. The investigators set a 95%
 threshold for the sensitivity of MRI examinations to be sufficient for confirming the
 hypothesis in this preliminary setting. Relevant findings have to be confirmed in a larger
 (multicenter) prospective study.

 Sample size

 The approximate sample size of 50 patients is due to the planned study duration of 3 years.
 The study serves as a preliminary study and results may be confirmed by a larger
 (multicenter) study.

 Recruiting of patients

 Patients will be recruited in the Gamma Knife outpatient clinic of the Department of
 Neurosurgery, MUV. Patients must undergo or have undergone Gamma Knife radiosurgery due to
 cerebral AVM. For inclusion patients must have their two-year follow-up MRI exam within the
 duration of study. All patients have to sign a form for participation in the study after
 purpose and process of the study has been explained to them. The investigators plan to enroll
 about 50 patients for this study.

 Quality and protection of data

 Entry and handling of patient data will only be executed by trained medical staff involved in
 the planning and conduction of the study. Patient data will be entered anonymized in a SPSS
 file using IBM SPSS Statistics for Windows (Version 25.0 Armonk, NY: IBM Corp.).

 Variables used in the registry

 Patient sex: male/female Source: EDP system

 Patient age: years Source: EDP system

 AVM diameter: cm Source: pre-radiosurgical MRI

 AVM localization: frontal, parietal, occipital, temporal, insular, limbic, cerebellar, brain
 stem, basal ganglia, thalamus, intraventricular, corpus callosum Source: pre-radiosurgical
 MRI

 Number of AVM feeders: Number Source: pre-radiosurgical DSA

 AVM-haemorrhage: Yes/No Source: Anamnesis in EDP system

 RBAS (Modified Radiosurgery Based AVM score): <1 to >2 Source: Pre-radiosurgical MRI

 VRAS (Virginia Radiosurgery AVM Scale): 0 to 4 points

 Treatment: Radiosurgery only, Radiosurgery+Endovascular embolization, other combinations
 including Radiosurgery Source: EDP system

 Date of treatment: Date Source: EDP system

 Gamma Knife parameters: Isodose (%), Marginal dose (Gy), Maximum dose (Gy), Radiation volume
 (ccm) Source: EDP system

 Substance for embolization in case of additional endovascular treatment to radiosurgery:
 Histoacryl, Onyx, ethanol, coils, cyanoacrylate, Glubran
Inclusion Criteria:

 -  Patients must undergo or have undergone Gamma Knife radiosurgery due to cerebral AVM

 -  For inclusion patients must have their two-year follow-up MRI exam within the duration
 of study

 -  All patients have to sign a form for participation in the study after purpose and
 process of the study has been explained to them.

 -  For patients younger than 18 years, a parent or legal guardian has to sign a form for
 participation after being informed about purpose and process of the study have been
 explained to them.

 Exclusion Criteria:

 -  Patients who do not give informed consent to participate

 -  Patients younger than 16 years