Clinical Research Of Gamma Knife For Cerebral Cavernous Malformations

BackgroundCerebral cavernous malformation is a congenital, occult cerebrovascular malformation. Digital Subtraction Angiography is generally hard to find it. It is composed of numerous thin-walled blood vessels cavernous abnormal vascular group. These vascular malformation group close relatively, vascular with no or minimal brain parenchyma. Under the naked eye, CCM is a mass accumulation of thin-walled vessel lumen with mulberry-like, boundary visible hemosiderosis. Under microscope, it is constituted by a number of irregular, abnormal widening antral vascular space and hyaline collagen matrix, no smooth muscle and elastic fibers, endovascular surface with a single layer of flat endothelial cells, and only a small amount of connective tissue without basement membrane, lesions with vascular repeated bleeding, the vessel lumen machine thrombosis, calcification and vascular recanalization, surrounding hemosiderin deposition and glial hyperplasia. The CCM crowd incidence is from0.4%to0.8%, accounting for10%to15%of brain vascular malformations. Its annual bleeding rate is from0.31%to3.5%. The natural course of rebleeding rate is from3.8%to22.8%. The incidence of epilepsy has the range of 25%to79%, more common in women (male to female ratio of1:5), and40to50-year-old adult.64%-84%patients of CCM locate in supratentorial, common in temporal lobe and frontal. Patients are common in pons and cerebellum when the lesion in infratentorial. A few patients are multiple.CCM variation of the three genes play an important role in the pathogenesis, such as respectively cerebral cavernous malformation gene1(CCM1), CCM2, CCM3. The head computed tomography imaging performance is clear round boundary or oval high density, uniform density, sharp edges or slightly irregular. High density lesion connects with increased hemosiderin after hemorrhage and calcification. A small number lesion with cystic and then become mixed density or low density, with no or mild edema, the enhanced scan with mild enhancement or no enhancement. DSA inspection is often negative. T2-weighted imaging(T2WI) of magnetic resonance imaging(MRI) shows characteristic lesions with central the lower hybrid signal intensity, surrounded by a the black low signal ring. According to the different manifestations of MRI performance, CCM are divided into4types. Type I: T1-weighted imaging(T1WI) shows high signal lesion core (including methemoglobin). T2WI starts with high signal, followed by a gradual narrowing lesions which appears around the low signal ring. Type Ⅱ:T1WI shows lesion core with reticular mixed signal. T2WI shows lesion core with mixed signal, low signal ring around the core, type Ⅲ:T1WI shows equal signal or low signal. T2WI shows low signal, type Ⅳ:T1WI and T2WI show punctate or focal low signal intensity. CCM gradient echo sequence shows multiple needle size low signal. Susceptibility weighted imaging (SWI) is mainly circular, a class round fully low signal or low signal with punctiform, strip or mulberry-like high signal around the wide low signal ring obvious target loop. It is higher sensitivity than the traditional check, and more easily to find different ingredients within lesions. SWI mainly body through the iron-based magnetic susceptibility imaging of different organizations.The main defect of SWI is difficult to distinguish small veins, hemorrhage, thrombosis and calcification.The CCM chief clinical manifestations are headache, seizure, focal neurological dysfunction, and so on. These symptoms are due to haemorrhage. Bleeding mainly shows lesion recurrent bleeding or chronic bleeding around, few into the subarachnoid space. Supratentorial lesions are more common in epilepsy. The glial hyperplasia lesions around, deposition of hemosiderin and calcification stimulating the cortex, induced epilepsy. Infratentorial lesions are more common in cerebral hemorrhage and focal neurological dysfunction.Currently, the primary treatments of CCM are craniotomy and Gamma Knife radiosurgery. CCM patients with asymptomatic or mild headache could choose conservative treatment and regular follow-up. When patients have lack of significant neurological symptoms, refractory epilepsy, the lesion progressively increases or associated with intracranial hypertension, they should prefer to choose surgical treatment. When the lesions were located in the functional region, the patients do not receive surgery or non-surgical conditions, we could consider GKRS treatment. The principle of GKRS treatment CCM is to project201cobalt60high dose ion ray, or gamma ray geometry to focus on the lesion by large doses of gamma ray irradiation, resulting in deformity vascular endothelial cell edema, degeneration, proliferation of the vascular wall thickening, luminal narrowing, thrombosis eventually lead to deformity vascular occlusion. Gamma Knife treating CCM can reduce rebleeding rate and incidence of epilepsy, and make part of the lesion shrink. Rebleeding is more common in middle-aged women and a history of bleeding. Low marginal dose of gamma knife treatment has good effect and few complications.Domestic and international studies have shown that the lesion rebleeding rate is from1.6%to9.8%; The epilepsy control rate is from45.0%to90.5%, The lesions shrink is from24.0%to48.0%; The incidence of cerebral edema is from7.6%to27.0%after Gamma Knife treatment. However, The factors which impact the epilepsy control rate, the the lesions shrink rate and complications, are lack of systematic research.In this study, a retrospective analysis of the Gamma Knife Center treatment in our hospital from January2002to December2008,107cases of CCM and micro-surgical treatment of brainstem cavernous malformations (BCM)15cases are brought into. As to GKRS treatment CCM, we analyse epilepsy changes the changes in lesion size and complications, summarize efficacy, analyse the factors that affect the efficacy.As to BCM petients, we analyse Gamma Knife and microsurgical treatment of BCM patients with Glasgow Outcome Score (GOS), the Karnofsky Performance scale (KPS), The National Institutes of Health Stroke Scale(NIHSS), evaluate whether the differences between the two treatment on BCM patients with clinical symptoms improvement. We explore the optimal therapeutic dose of Gamma Knife, provide clinical data for the choice of CCM treatment.Objective1.Analysis the impact of dose、lesion size、lesion site to epilepsy changes, lesions shrink rate and perifocal cerebral edema;2.Statistics the GOS, KPS and NIHSS score before and after Gamma Knife or microsurgical treatment for BCM patients, analysis different efficacy of Gamma Knife and microsurgery.3.Preliminary explore indications of gamma knife treatment for CCM, and the effective dose.ImplicationThis study explores the efficacy and its influencing factors of gamma knife treating CCM, provides reference for dose planning and programs designed, and also provides clinical evidence in treating CCM for future.Methods1.Clinical dataWe retrospective analysed107patients of CCM which had complete medical information such as follow-up data, clinical data and the image data, who were treated from January2002to December2008in the Gamma Knife Center of the General Hospital of Guangzhou Military Command. The data consisted by52males and55females, who aged from4to73years, with an average of34.5years. The primary clinical manifestations were headache, dizziness66cases, nausea、vomiting28cases, limb movement disorder17cases,24cases of sensory disturbances, five cases with eye movement disorders or drooping eyelids or blurred vision or diplopia, eight cases with facial numbness or hearing loss, three cases with dysarthria or dysphagia, two cases the mouth askew, two cases ataxia,25cases had seizure. Before gamma knife treatment, all patients underwent cranial MRI check and diagnose for CCM. Lesion location:single lesion in95cases, temporal lobe19cases,16cases of frontal, seven cases of parietal, one case of occipital, deep hemisphere with13cases, five cases of basal ganglia, four of thalamus, eight cases of the cerebellum, medulla oblongata six cases, pons in12cases, four cases in the midbrain;12cases of multiple lesions. Lesion volume was based on magnetic resonance T2WI. It was between0.15-27.52cm3, with an average of4.12cm3.Retrospective analysed15BCM patients with microsurgery, which consisted of7males and8females, aged from11to49years, with an average of32.5years. Of the15patients’lesion location, two cases of lesions located in the medulla oblongata,10cases in the pons, three cases in the midbrain. It’s mainly clinical manifestations: eight cases with headache or dizziness, three cases of nausea or vomiting,11cases with cranial nerve injury, ataxia with three cases, nine cases of numbness or sensory impairments, meaning obstacles one cases.2.TreatmentInstalling Leksell-C type headstock under local anesthesia lesion centered, MRI slim quick scan positioning, image incoming gamma knife dose planning system for the design of treatment programs. Marginal dose was ranged from8Gy to18Gy, average13.4Gy. Optic nerve or optic chiasm irradiation dose was less than lOGy. The isocenter was ranged from1to11, with an average of2.4. Patients accepted single treatment on MRI positioning when had single lesion. However when patients had multiple lesions, they should accept batch treatment. The first treatment could choose the lesion causes symptoms suspicious responsibility and2to3lesions surrounding, which single stereotactic head frame could cover, after3to6months then deal with other lesions. Children and those not go with the Gamma Knife treatment were under intravenous anesthesia, who were choosed the same installation head frame and target selection as adults.Surgical approach of BCM micrographic surgery patients:lesions in ventral pons through temporal approach with four cases, ventrolateral lesions of the pons through suboccipital sigmoid sinus with five cases, lesions bridge at the junction of the pons dorsal and medulla oblongata (that is, close to the fourth ventricle bottom) through by the suboccipital midline approach with six cases, intraoperative brainstem auditory evoked potential and somatosensory evoked potential monitoring.3.Follow-up methods:The follow-up methods were outpatient review, telephone, letters and other follow-up. Every follow-up could review one head MRI six months after treatment, then annually review once thereafter, and a detailed examination of the nervous system every follow-up.4.Grouping factors:We divided into two groups as less than5cm3and more than or equal to5cm3, which accorded to the rate change in lesion size of the lesions shrink. Peripheral dose was divided into two groups as less than and more than or equal than14Gy, which accorded to peripheral dose between8and18Gy in our hospital CCM data, and the number of cases. The lesion site divided into single lesion and multiple lesions,and single lesions grouped according to the different parts again. BCM patients were divided into Gamma Knife and micro-surgery group. We analysed the differences of GOS, KPS, NIHSS score after treatment, which reflect the degree of clinical improvement.5.Assessment standards:The evaluation time was basis as the patients before treatment and the last follow-up time. Epilepsy assessment standards adopted Tan Qifu efficacy criteria. We considered epilepsy reduced more than50%vas effective, rest epilepsy change as invalid. Lesion size is determined based on MRI scans T2WI. We considered volume reduced by25%for standards determining tumor shrinkage accoding to Lunsford.1. Lesions shrink (lesions reduced by25%or more compared with the preoperative volume); lesion increases (lesions rebleeding increased more than25%);3no significant change in lesion size (lesion volume change of less than25%). Considered lesions shrink or disappear as effective, no significant change in lesion and increases as invalid. Cerebral edema assessment standards:conventional MRI cross-sectional scanning brain edema was surrounded by a lesion in the class finger, small pieces, banded abnormal signal, T1WI low signal, T2WI high signal, negative for before and after surgery had no edema, or edema preoperative in conventional MRI cross-sectional scanning T2WI, but no postoperative increase or no change, or reduced. Positive for preoperative no edema, postoperative edema; preoperative edema, postoperative edema more serious than before.6.Statistical methods:According to the follow-up data, we analysed whether peripheral dose, pre-treatment lesion size and lesion site could impact seizure control, lesions shrink rate and perifocal brain edema, applied χ2test statistical method. We analysed GOS, KPS, NIHSS score difference before and after treatment from BCM patients with Gamma Knife group and micro-surgery group, applied nonparametric test. The data was applied SPSS13.0statistical software analysis, a=0.05, P<0.05indicated a statistically significant difference.ResultsAfter gamma knife treatment, the clinical symptoms reduced or disappeared in78patients (72.9%),20patients (18.7%) stable and nine cases (8.4%) aggravated. Nine cases had seizure completely disappeared, six cases decreased more than75%, decreased among50%to75%in four cases,25%to50%of the four cases, less than25%reduction or aggravate in two cases. According to different peripheral dose, pre-treatment lesion size grouping, epilepsy reduction>50%considered valid, other epilepsy change invalid. After χ2test, there was no significant difference (P>0.05) between peripheral dose, statistically significant (P<0.05) between lesion size pre-treatment. The epilepsy control was more efficiency in lesions’volume less than5cm3significantly higher in lesions’ volume more than or qaual to5cm3group. There was no significant difference (P>0.05) between different lesion size, but the epilepsy disappearance rate had higher in frontal lobe group than the other groups.This data was collected a total of123lesions in107patients.35cases (32.7%) or35lesions (28.5%) shrinked or disappeared after gamma knife radiosurgery.68cases (63.6%) or84lesions (68.3%) had no significant changes, four cases (3.7%) or four lesions (3.2%) had lesion increased. There was no significant difference (P>0.05) in lesions shrink rate between peripheral dose and different lesions site, statistically significant (P<0.05) between the different size, χ2testing. but the shrink rate in basal ganglia thalamus, cerebellum was higher compared to the other parts.9cases (8.4%) had cerebral edema after gamma knife radiosurgery and no radiation-induced brain necrosis, among which only5cases had edema around the lesion, which occurred in4to11months after treatment, the median time of7months, among which one case in temporal lobe, one in deep hemisphere,1in mesencephalon, one in the pons, and one with multiple lesions. The cerebral edema got better after dehydration and hormone therapy.4patients (3.7%) rebleeding in lesions were located in one case of frontal, pons, medulla oblongata and multiple lesions, which occurred within2years after GKRS treatment, a median time of14months, among which three cases had surgical treatment and one received GKRS treatment again, and the condition was relieved after treatment again. Throngh χ2test, there was statistically significant difference (P<0.05) between peripheral dose and lesion size in the incidence of brain edema, no significant difference (P>0.05) between the different site.Two cases of the22cases for BCM patients had rebled after Gamma Knife treatment,and induced to lesion increased. The BCM rebleeding rate was9.1%. Six cases (27.3%) had lesion shrink.14lesions were no significant changes.2patients had transient cerebral edema and improved after dehydration, hormone therapy. Nerve dysfunction improved in9cases (40.9%). The GOS and KPS score increased average by0.05and1.82, NIHSS decreased by0.82after gamma knife.15cases of the BCM patients had microscopic surgery treatment, among which1case (6.7%) in pontine had postoperative residual, no further bleeding, no deaths. Two cases (13.3%) with perifocal brain edema and transient aggravated neurological dysfunction had improved after active treatment. Two cases (13.3%) had irreversible neurological dysfunction. Symptoms improved after surgery in11patients (73.3%). The GOS, KPS score increased by0.20and6.62, NIHSS decreased by1.20. By nonparametric test analysis the GOS, KPS, and the NIHSS score difference, according to the surgical group and Gamma Knife group before and after treatment, there was not statistically significant (P>0.05), which indicate no significant difference between the two treatments, but the surgery group in GOS, KPS and NIHSS score difference was higher than the Gamma Knife group.ConclusionGKRS is safe, effective to treat CCM patients, and can reduce the incidence of epilepsy, reduce the rate of rebleeding and improve clinical symptoms. When the site is in the basal ganglia, thalamus, the lesions’ volume is less than5cm3, patients have non-surgical conditions, we could consider gamma knife treatment, choose peripheral dose less than14Gy. The BCM patients in the choice of treatment should be based on the circumstances. When the patients have indications for surgery, willing to accept the surgery,we could choose to consider surgery. While patients with mild clinical symptoms and no obvious neurological dysfunction, and they do not accept surgery, you can consider gamma knife treatment, the surrounding dose generally less than14Gy.