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Stereotactic Gamma Knife Surgery In Management Of Intracranial AVM Raef F.A.hafez;MD Neurosurgery International Medical Center (IMC)-Gamma Knife Center-Cairo-Egypt

IMC

Intracarnial AVM Angioarchitecture Vascular abnormality constituted Of a complex tangled web of afferent arteries and draining veins linked by an abnormal dysplastic intervening immature capillary bed Composed of: a) Arterial feeder b) Nidus c) Draining vein d) Intervening gliotic neural parenchyma AVM associated aneurysms in about 2.%

Nidus (epicenter) The AVM nidus is a compact tangle of dysplastic, thin -walled vessels of varied length with Intervening gliotic neural parenchyma connecting feeding arteries to draining veins. Within the nidus, arterial blood is shunted directly into draining veins without passing through a normal, high-resistance arteriolar capillary network. An AVM nidus can either be globular or conical in shape and may be compact or diffuse.

The Overall Detection Rate For AVM 1.1 per 100,000 person-years No sexual preference . Mean age of presentation 20 - 30 years . At least 15% remain asymptomatic, based on autopsy series. Account for 3% of stroke and 30% of primary intracranial bleeding in young adults. Cheng-Chia Lee et al ,J Neurosurg;2015

Etiology Initially thought to be congenital as failure of the embryonic vascular plexus to fully differentiate and develop a mature capillary bed in the affected area. Developmental theory has been challenged. It is likely that a combination of congenital predisposition and extrinsic factors lead to their generation.

Natural History AVMs are dynamic i.e., they undergo continuous subtle anatomic and hemodynamic changes. A cerebral AVM becomes clinically evident when the host’s capacity to effectively compensate has reached its threshold. Enlargement of brain AVMs is observed in young patients (under 30 years of age), and especially in Childhood. Spontaneous obliteration of cerebral AVMs is rare.

Distribution Based on autopsy findings: • Cerebral hemisphere – 60 to 70%. • Cerebellum - 11 to 18%. • Brain stem - 12 to 15%. • Deep seated - 8 to 10%.

Presentation Hemorrhage 78% Seizures 14% Headache 3% Neurological deficits 2% Asymptomatic 2% Pediatrics hydrocephalus, heart failure1%

Annual Rate Of Hemorrhage From Untreated AVM Annual risk for 1st hemorrhage 3 - 4% per year Annual risk for Recurrent hemorrhage 6 -10% in 1 st year, declines to pre hemorrhage rates over 5 years Peak age: 15-25 years 10 % mortality; 30-50% morbidity ICH(80%) / IVH/ SAH B.Karlsson, Ch.Lindquist and L.Steiner.Neurossurgery;1997 Karolinska Hospitall: n= 930 patients 1970-1990 B.Karlsson:Neurosurgery;1997 Cheng-Chia Lee et al ,J Neurosurg;2015

Factors Associated With Increasing Risk Of AVM Hemorrhage Nidus 72% small AVMs (less than 3 cm) 19% medium-sized AVMs (3–6 cm) 9% large AVM ( greater than 6 cm) Large AVMs can often present in other ways than hemorrhage, and may lead to an overestimate. Location Some authors suggest that AVMs in deep locations such as in the basal ganglia or in the periventricular or intraventricular space, have an increased risk of bleeding ?. Other factors Deep Venous Drainage Venous Stenosis Single draining vein Feeding Artery Pressures Lunsford.et al; GKS : A Twenty year perspective on AVM pats: Cinical Neurosurgery ; 2008

Spetzler- Martin Grading Established to grade AVMs according to their degree of surgical difficulty and the risk of surgical morbidity and mortality;1986 Size of nidus Small (<3 cm) 1 Medium (3–6 cm) 2 Large (>6 cm) 3 Cortical Eloquence non-eloquent 0 eloquent 1 Deep venous drainage superficial only 0 deep 1 AVM grade = sum (size + eloquence + deep component) There are 5 grades : Low grade AVM: Grade I,II,III High grade AVM: Grade IV, Grade V Inoperable lesions: Grade VI

Management Of Intracranial AVM AVMs may be suitable for one or more of four management strategies alone or in combination: Conservative Microsurgery Embolization Radiosurgery

Conservative Management The AVM may be very extensive, located deeply with supply from deep perforating vessels which are not amenable for surgery or endovascular treatment. Very old age would be consideration for conservative treatment. Obviously poor medical condition, such as advanced heart diseases, respiratory insufficiency or cancer with metastasis would be contraindication to a definitive AVM treatment.

Microsurgery Microsurgical AVM excision is the most effective treatment for small and some medium sized intracranial AVM especially not deeply seated location with or without embolization with high success rate and low morbidities and mortality in proper circumstances Factors associated with increased surgical risk are large size, deep venous drainage, deep location, diffuse nidus, feeders from deep perforating system.

Embolization First described in 1960 by Luessenhope and Spence A rapidly evolving technique. Initially used as an adjunct to microsurgery or radiosurgery. In some cases can be a sole treatment modality. Aim of Embolization Curative embolization Partial (staged embolization) Pre-op embolization Pre-radiosurgery embolization

Radiosurgery Radiosurgery is an effective alternative treatment for selected AVM patients rather than microsurgery , especially in those with surgically inaccessible lesions with comorbidities which hinder surgical intervention or if microsurgery is not feasible. Currently GKS (Cobalt-60) is the mainly used world wide form of Radiosurgery In terms of radiobiology, AVM are late responding target within late reaction of normal tissue. Following bleeding , part of nidus may be hidden or compressed by clots hence it is rational to wait till resolution of hematoma (average 2- 3 months).

Leksell Gamma Knife Treatment Statistics Report 1968-2016

Leksell Gamma Knife society ® Over 1 040 000 cumulative patients treated worldwide through 2016 The percentage of centers submitting their numbers each year has varied between 68-100% from 1968 to 2016 , 1991 reflects cumulative numbers since 1968

Leksell Gamma Knife Society ® Vascular disorders, cumulative patients treated worldwide The percentage of centers submitting their numbers each year has varied between 68-100% from 1968 to 2016. 1991 reflects cumulative numbers since 1968

Leksell Gamma Knife Society ® Treatments by indication 1968 – 2016, worldwide

Arteriovenous malformations, cumulative patients treated worldwide Leksell Gamma Knife Society ® Arteriovenous malformations, cumulative patients treated worldwide

Leksell Gamma Knife Society ® Vascular disorders, cumulative patients treated worldwide The percentage of centers submitting their numbers each year has varied between 68-100% from 1968 to 2016

Effects Of Radiation On Cerebral Vasculature The goal is to induce an inflammatory response in the vessel wall which will result in: Endothelial cell degeneration and necrosis Fibrosis of adventitia Intimal proliferation with massive endothelial thickening Thrombosis and luminal occlusion Obliteration of AVM

Histopathological Changes Of Cerebral AVM After GKS Irradiation Intermediate stage: Narrowing of the vascular lumen by intimal hyperplasia with proliferation intimal cells. Later stage: Complete occlusion of the vessel with intraluminal thrombosis, hyalinization of the vessel Wall. Schneider BF. et al .Histopathology of AVM after GKS J Neurosurg. 1997.

Our Criteria For Symptomatic AVM Treatment With GKS At The IMC Micro AVN (<=1 cm) Small AVM (<=2 cm) Moderate AVM (2 – 5 cm): -In none eloquent area,& or after bleeding with encephlomalcia we start with GKS -In eloquent area or without surrounding encephlomalcia first embolization then GKS for suitable residual. Large AVM (>5 cm) –Embolization first , then GKS for a suitable size residual , or conservative from start. Suitable for GKS

Gamma Knife Technique The leksell stereotactic coordinate frame is fixed to the patient's head after mild sedation and application of a local anesthesia ,placing the frame with AVM nidus toward the frame center as much as possible. General anesthesia may be required for frame application and subsequent imaging and treatment in patients younger than 8 years of age. AVM nidus target localization and delineation are achieved using: High resolution stereotactic MRI with contrast obtaining, T2 fast spin echo and TOF contrast-enhanced three-dimensional MRI both with thin 1-2 mm slice thickness on zero angle with no gap. Stereotactic digital subtraction angiography with appropriate images selection (usually the early arterial phase). .

All imaging studies then sent to the Gamma plan work station ,Where pictures are merging to delineate exactly location and volume of the AVM nidus assisted with the radiologist to Obtain 3-D volume target . When MRI is contraindicated in patients with pacemakers or other implants. In these cases we use contrast-enhanced stereotactic computed tomography imaging along with angiography. The Elekta - Leksell Gamma knife with automatic positing system and gamma plan 10,1 software version are used for treatment planning protocol on LGP that then transferred to LGK to fulfill the planned treatment. The 4 and 8mm collimator are the commonly used helmets .

Stereotactic Gamma Knife Leksell GKS-4C-APS IMC  

Stereotactic Angiography For AVM Localization And Definition

Target Volume And Localization After Merging Stereotactic Angiogram And MRI

Target Volume And Localization After Merging Stereotactic Angiogram And MRI

AVM Dose Planning Precision and sharp fall-off of the radiation dose outside of the target volume are the main advantages of GKS , (maximal selectivity). The final dose selection depends on location, volume, estimated adverse radiation risks, pre-existing neurological conditions, and bleeding history. GKS doses at the margin of the AVM typically range from 16 to 25 Gy in a single session.

AVM Obliteration After GKS Lindquist and Steiner in 1988, defined AVM obliteration as satisfactory result only when the arteriogram shown a complete absence of pathological vessels in the former nidus, and the disappearance or normalization of draining veins from the area. The most important factor associated with obliteration after AVM radiosurgery is the AVM nidus marginal dose that controlled mainly by AVM volume and location. Radiosurgery does not reduce the risk of hemorrhage immediately; the risk does not fall until the AVM is obliterated (often around 2–3 years post GKS).

GKS Outcome In Nataf et al, 2001: series of 705 AVM patients treated by SRS alone or in combination with embolization or surgery, the overall complete obliteration rate (OR) was correlated to the size and the marginal dose. OR nidus max diamt 77% <15 mm 62% 15 mm - 25 mm 44% >25-60 mm Mortality was 1.6%, due to recurrent bleeding. Rate of recurrent bleeding during latency period was 3 % /year/ patient. Neurological deficits related to radiosurgery and not related to hemorrhage were observed in 5% of the cases and were permanent in 1.5% Nataf et al. Results of series of 705 AVM treated by SRS.Neurochirurgie;:2001

The Obliteration Rate Increases With Increased Dose To Nidus Periphery The Curve Illustrating This Relation Increases Logarithmically To A Value Of 87 % B.Karlsson, Ch.Lindquist, L.Steiner: Neurossurgery:1997; Karolinska Hospitall: n= 930 patients

Clinical Algorithm A number of factors are considered while making a recommendation for AVM treatment . These factors include: Volume of AVM Location of AVM Previous bleed Prior procedures Patient’s age Patient’s medical condition Presenting symptoms Recommendation is usually influenced by the recommending neurosurgeon , neurologist and interventional radiologist along with patient preference. Lunsford.et al, GKS: A Twenty year perspective on AVM pats. Cinical neurosurgery :2008

IRSA (International Radiosurgery Association) March 2009. Clinical Algorithm For Choosing Management Option For Patients With Intracranial AVM IRSA (International Radiosurgery Association) March 2009.

Radiological Assessment For Intracranial AVMs Post GKS MRI: MRI done after 6 months post GKS then annually till 3rd year. T1-weighted imaging (T1WI) with contrast, helps to interpret the possibility of the presence of subacute microhematoma, thrombus and gliotic brain tissue. T2-weighted imaging to evaluate the severity of perinidal brain edema and draining vein status. (TOF) 3D time-of-flight images, displays the flow and existence of the nidus. Angiography: The gold standard for evaluating the post–stereotactic GKS AVM obliteration .Cerebral angiography is done at the end of 3rd year post GKS .

Transient Radiation Reaction Gamma Knife Treatment Of AVM Before treatment After 12 months After 24 months After 36 months

Gamma Knife Treatment Of AVM 3ys after GKS MRI + angiography before GKS Obliteration with Persisting Contrast Enhancement in MRI

Angiographic Follow-up And Retreatment Policy GKS Angiography after 36 months Obliteration Nidus smaller or unchanged Repeated angiography after 48 months Obliteration Nidus unchanged or residual GKS Retreatment

Gamma Knife And Embolization Male pat. 16 y Occipital AVM Residual post embolization. AVM obliteration 3 ys post GKS

Gamma Knife And Embolization Male pat 34 y Pre GKS treatment Stereotactic Angio. residual post emb.AVM 4 ys post GKS Obliteration

AVM Post GKS Non-obliteration Why And What To Do Reasons for Treatment Failures; Insufficient Definition of Nidus Re-expansion after hematoma reabsorption Recanalization after embolization Suboptimal radiation dose in large volume and or in eloquent area Radio resistant nidus (?)

GKS Retreatment For Residual AVM Nidus Female 24ys.post.parietal post emb.AVM V=4.3cc.Max D=30.4mm GKS for Residual large post emb. AVM 3 ys post GKS still residual nidus 4 ys still small AVM residual Retreated With GKS

Illustrative Cases

Case 1 Male 40 ys ,post.emb.- Rt. Parietal ,V=0.67CC Max D=11.7mm

Stereotactic angio-post emb Obliteration Of the AVM Stereotactic angio-post emb 3 ys post GKS

Case 2 Female 27 ys, Rt. Parietal AVM ,V=0.47cc Max D= 9.7mm

Stereotactic angiogram Obliteration Of the AVM Stereotactic angiogram 3 ys post GKS

Case 3 Female 26 ys Post.emb AVM pineal area ,V=2.8cc Max D=17.5mm

Stereotactic angio-post emb Obliteration Of the AVM Stereotactic angio-post emb 4 ys post GKS

Case 4 Male 25 ys Lt parietal AVM post emb. V=3.2cc Max D=26.2mm

Stereotactic angio-post emb. Obliteration Of the AVM Stereotactic angio-post emb. 4 ys post GKS

Drawbacks Of Radiosurgery Risk of bleed during latency Unknown long term perspective Unknown individual radio sensitivity Neurologic deficits related to Radiosurgery AVM radiation dose, AVM volume, and AVM location are the most important factors influencing the risk for delayed GKS radiation-related complications .

Radiation complications and prediction The risks of developing permanent symptomatic sequelae from AVM radiosurgery and not rebleeding seem to be well predicted through AVM location ,volume and the normal tissue volume received >=12Gy . Complications: The overall rate of neurological complications (transient or permanent deficits) was 6%: Radiation injury to brain parenchyma 4% Cranial nerve deficit 1% New or worsened seizure 1% Permanent neurological deficit was 2% Flickinger et al. Data of AVM complications in 1187 pats treated by SRS Multicenter Study : Int J Radiation Biol Phys:2000

Radiosurgery Of Large AVMs The risks of permanent symptomatic sequelae from AVMs treated with GKS vary dramatically with marginal radiation dose , AVM volume and location. GKS of a large extensive volume AVM results in either unacceptable radiation-related risks due to exposure of large volumes of normal brain tissue, or low obliteration efficacy, therefore the chances of achieving a high obliteration rate with a low complication rate for large AVM with GKS are slim. Lunsford et al; Clinical Neurosurgery 2008

Remarks GKS is not an emergency procedure for treatment intracranial AVM and should be done as selective option in proper circumstances , in term of radiobiology AVM are late responding target for radiation within late reaction of normal tissue. It is reasonable to perform GKS post surgery or post hemorrhage once the patient has achieved a stable neurological recovery and blood clots resolution (generally within 2 - 3 mos.). Post embolization for GKS generally we wait for a period of several weeks to stabilize the patients clinical condition ,resolution of blood clots if there is bleeding and to reduce the likelihood of vascular ischemic changes or cerebral edema sometimes associated with embolization .

Remarks The annual risk of hemorrhage in the latency period post GKS is about 3% ,till AVM obliteration is achieved Post GKS clinical examinations and MRI studies are requested at 6 months after treatment, then annually till the 3rd year. Angiography is done at the end of the 3rd year to assess AVM obliteration. If angiography after 3 years demonstrates that the AVM nidus is not obliterated, angiography is repeated after another year, if still not obliterated or residual ,repeated GKS is recommended. Although AVM embolization prior to radiosurgery has been used for patients with large AVMs, recanalization was observed in 6-8% of patients.

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