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Treatment of epilepsy caused by cerebral arteriovenous malformations
Treatment of epilepsy caused by cerebral arteriovenous malformations. Cerebral arteriovenous malformations (AVMs) is a complex vascular disease characterized by the direct flow of arterial blood into the draining vein without passing through the capillary bed. Usually due to the lack of resistance generated by small arteries and capillaries, and the resulting arterial pressure is directly transmitted to the venous structure, resulting in a significant increase in blood flow, which will eventually lead to vasodilation and tortuous growth. In addition to changes in the anatomical structure of cerebral blood vessels, significant changes in cerebral hemodynamics also occur, such as reversal of venous blood flow, venous hypertension, and insufficient blood perfusion in the area around AVM.
The most serious and common clinical symptom of AVM is hemorrhagic stroke caused by rupture, which is about 2% to 3% per year. Epilepsy is the second largest clinical manifestation of the disease, accounting for 20% to 45% of the diagnosis and treatment of AVMs. Epilepsy will bring a series of problems to patients, such as occupational restrictions, more accidents than normal people, and higher Mortality and social censure, plus the need for medication and side effects caused by medication. Therefore, these are important factors to be considered in the management of AVMs-related epilepsy cases.
1. Epidemiology of arteriovenous malformations with epilepsy
In population-based studies, the reported incidence of newly diagnosed AVMs ranged from 0.89 to 1.34 cases per 100,000 person-years. In recent studies, with the increase in non-invasive brain imaging (CT or MRI) examinations, the incidence tends to rise, and the proportion of unruptured or even asymptomatic AVMs in patients has increased year by year. A German study conducted head MRI examinations on more than 2500 healthy young people (applicants serving in the Luftwaffe) and found that the prevalence of accidental AVMs was 0.2%.
For the total prevalence of AVMs, including all asymptomatic lesions, due to the rarity of this disease, it is still difficult to reliably estimate. Although AVMs may be asymptomatic for life in many carriers, they are by no means despised disease. In different study populations, the overall annual mortality rate ranged from 0.7% to 2.9%. In a large number of case studies, seizures are present in 20% to 40% of AVM patients.
In 2011, Josephson et al. reported that the risk of epilepsy in accidentally discovered AVMs without a history of epilepsy was relatively low, 8% within 5 years, or 1.1% per year. If the patient initially shows bleeding, the risk of the first attack within the next 5 years increases to 23%. AVM patients with one seizure have a 58% risk of epilepsy within 5 years.
Crawford et al. In a study of 153 non-surgical patients followed up for 20 years, 18% of the patients developed epilepsy. In a 20-year follow-up study, when AVM was diagnosed, young patients aged 10 to 19 years were found to have a 44% risk of disease, while patients over 30 years old were only at a 6% risk. As for positioning, Brelie found that temporal lobe and frontal lobe positioning were the most common in the analysis of 103 patients, 37.9% and 33%, respectively.
AVMs are composed of atypical and malformed blood vessels and do not contain neurons. Epilepsy is usually caused by abnormal discharge of neurons, so seizures are not caused by AVM itself, but by the influence of AVM on the adjacent cortex. The exact mechanism of epilepsy caused by AVM is still unclear, but in experimental and clinical studies, the following factors are predisposing factors for epilepsy: glial hyperplasia, blood-brain barrier destruction, ischemia, hemosiderin deposition and microhemorrhage After the scar.
Recently Kovacs et al. found that astrocytes play an important role in the formation of epilepsy. Although astrocytes do not produce paroxysmal discharges, they play a role in K+ ion buffering and transforming glutamate receptor signaling. The destruction of the blood-brain barrier has been found to play a role in the process of epilepsy, especially the leakage of serum protein, which leads to inflammatory reactions and an imbalance in the homeostasis of the extracellular space, leading to increased excitability of neurons, resulting in a balance of excitatory and inhibitory components Change.
Can et al. believe that epilepsy related to lesions such as AVM has different effects in different areas of the brain, and is more common in the temporal and frontal lobes. Among the several factors related to epilepsy caused by AVM, AVM bleeding, the size of AVM, the area supplied by the middle cerebral artery, the presence or absence of aneurysm, male sex, the larger surface of AVM and superficial venous drainage are the most studied and most studied Scholars agree.
Raabe et al. believed that the storage of albumin in astrocytes around vascular lesions is related to AVM-related epilepsy. Since epileptic seizures are caused by AVM acting on the surrounding cortex through ischemia, microhemorrhage, gliosis, inflammatory processes and albumin extravasation, it is not surprising that epilepsy may stop after AVM resection.
On the other hand, despite the removal of AVM, there are still some patients with persistent seizures, which is probably because these changes induce permanent epileptic areas in the adjacent cortex. The longer the seizure process caused and maintained by AVM lasts, the more likely it is that AVM-related epilepsy will persist after the vascular malformation is removed. Most of these secondary epileptic foci are located in the vicinity of AVM, and may also occur in cortical areas far from the direct border of AVM.
3. Factors affecting epileptic seizures caused by AVMs
Epilepsy is a common symptom of AVMs, and its importance is often overlooked because patients and physicians pay attention to intracranial hemorrhage. However, AVM-related epilepsy can have a very negative impact on patients’ physical and mental health and quality of life. Seizures are the most common manifestation of unruptured AVMs and the second most common manifestation of AVM patients after bleeding. Seizures caused by AVMs are related to the following factors.
The possibility of AVM complicated by epilepsy is greater in adolescents than patients older than 30 years old, but those with onset after 30 years of age have better surgical results, and about 83% of AVM patients have postoperative seizures.
3.2 The location, size, distribution and drainage of vascular malformations
Veins are obviously related to the occurrence of epilepsy. Vessel malformations in the temporal lobe have a higher rate of epilepsy than other parts, followed by parietal lobe, frontal lobe, and occipital lobe. Those with a diameter greater than 3 cm are prone to epilepsy, while those with a diameter less than 3 cm. It is prone to bleeding; the incidence of epileptic seizures is much higher in patients with lesions located in the cortex and venous tumors in the cortex than in those in the deep part, and epilepsy is also likely to occur in those with the input artery in the cortex.
Ding assessed the data of 1,007 AVM radiosurgery patients, of which 229 had epilepsy (22.7%). The incidence of epileptic seizures in the cortex of AVMs was higher than that in the non-cortex (33.1%:6.6%). Among the cortical locations, the occipital lobe AVMs had the lowest seizure rate (21.5%, P=0.0012), while the frontal lobe (37.3%), temporal (37.7%) and parietal lobe (34.0%) had similar seizure rates.
There is an increased chance of epilepsy after bleeding from cerebrovascular malformations.
4. Clinical manifestations and examination of epilepsy caused by AVMs
4.1 Clinical manifestations
The most common type of seizures in patients with AVM is generalized tonic-clonic seizures. In partial seizures, half of the epilepsy will have secondary generalization. AVMs located in the temporal lobe tend to have complex partial seizures, however, many of them later spread into generalized seizures. In the case of AVM with refractory epilepsy, the initial focal seizures are more frequent. From the perspective of an epilepsy surgeon, epilepsy related to AVMs can be divided into three situations, and this classification is helpful for subsequent treatment.
① Occasional seizures: patients with only 1 or 2 seizures. ②Chronic epilepsy: All patients had more than 2 seizures, but they did not meet the criteria for drug-resistant epilepsy (DRE). ③DRE: If you tolerate two kinds of appropriately used antiepileptic drugs, the epilepsy cannot be controlled even if it lasts for more than 2 years. This kind of epilepsy is called DRE in epilepsy terminology. DRE can include multiple or several episodes, such as 4 times a year, 4 times a month, or more. The mechanism by which epilepsy turns into DRE is unclear.
4.2 Imaging examination
Whether AVM has epilepsy or not, the routine neuroradiology examination is the same. Digital subtraction angiography (DSA) must include both internal carotid arteries and vertebral arteries to understand the comprehensive blood supply and venous drainage of the malformed vascular mass.
Conventional magnetic resonance imaging (MRI) examination and susceptibility imaging can not only indicate microhemorrhage in the glial area, edema area, and AVM boundary, but can also indicate edema in the dilated or narrow drainage vein area outside the AVM area. These abnormal changes include It may be a potential epileptic cortex.
PET or SPECT plays an extremely important role in the location of the epileptic zone in primary epilepsy. During the interictal phase, the epileptogenic zone shows low metabolic changes, but for epilepsy caused by cerebrovascular disease, the cerebrovascular disease itself It is manifested as low metabolic changes. This type of examination has certain difficulties in distinguishing the ischemic area caused by the epileptic focus and the malformed vascular disease. Therefore, PET and SPECT are not suitable for the sporadic AVM epileptic area location inspection.
But for DRE, in order to find the suspected epileptic foci in the distant part of the lesion, as a preoperative examination of epilepsy, PET examination of brain metabolism is still necessary.
4.3 EEG performance
Cerebrovascular malformations located in the deep, generally have no specific changes on the electroencephalogram, but focal epileptic discharges often occur in cerebral vascular malformations near the cortex. If there is a secondary injury, there can be different types of epileptic discharges in different parts. During the interictal period, focal slow waves can be seen, and sometimes sharp waves or sharp slow waves can be seen. Such as bleeding caused by large softened foci can show the resting area of EEG. Only sporadic AVMs do not require special electrophysiological examinations.
For chronic epilepsy, if the frequency of seizures is high and the type or frequency of seizures has a significant impact on the patient’s life and work, a long-term video EEG examination must be performed. For DRE cases, because the removal of AVM is carried out in accordance with the standard method of epilepsy, video EEG examination is required to record at least 2 seizures.
For the lesion itself, there are currently three main treatment methods, namely radiosurgery (gamma knife), interventional therapy and surgical resection, and some are a combination of the three methods.
For sporadic seizures, such as one seizure at intervals of several years and mildly abnormal long-term EEG, taking into account the side effects of long-term drug use, anti-epileptic drugs may not be used. For patients with AVM diagnosed with a seizure for the first time but without bleeding, the first treatment is medication, unless there is an indication for surgical removal of the AVM. In any epilepsy patient, the chance of obtaining seizure-free seizures after the application of anti-epileptic drugs is about 70%, but it is only 60% in a large-scale study of AVM population.
If the risk of AVM bleeding is not considered, surgical treatment (including interventional or radiotherapy) is not superior to anti-epileptic drug treatment in terms of controlling epilepsy alone. Although DRE occurs in approximately 30% of epilepsy patients, the proportion of DRE in epilepsy associated with AVM is much lower.
Among 103 AVM patients counted by BrelieV, 24 had DRE. In Englot’s case series, 18% of epilepsy cases had DRE. In general, the higher the frequency of seizures, the larger the lesions, the more cortex affected, and the longer the epilepsy lasts. The greater the possibility of epileptic cortex near AVM, and the greater the chance of patients developing DRE. More.
5.2 Interventional therapy
There are not many studies related to the outcome of epileptic seizures. In some studies, the results of different patterns of seizures vary greatly. If the AVM is completely blocked by intravascular intervention, the effects of epileptic factors on the local cortex and the whole body can be eliminated as soon as possible.
Lv et al. reported that of 30 AVM patients who received endovascular treatment, 70% had no seizures or occasional aura during short-term follow-up. Hoh et al. found that 50% of the patients had no seizures after embolization. Interventional therapy is still difficult to completely eliminate or completely seal most AVMs. Only 30% or 40% of the smaller AVMs can be completely sealed, which leaves most of the factors that interfere with the cortex.
Baranoski et al. pointed out in a meta-analysis that endovascular treatment achieved an average seizure-free rate of 49.3% in 5 studies.
The potential mechanism of stereotaxic radiosurgery (SRS) in the treatment of epilepsy is largely hypothetical. In animal studies, ionizing radiation acts on the brain parenchyma to inhibit protein synthesis and neuromodulation, thereby inhibiting epilepsy.
Clinical data has observed a link between the occurrence of vasogenic edema and the reduction of epilepsy, supporting that ionizing radiation may cause local vascular damage and neuron reduction in the target area to improve epilepsy.
A fact that everyone basically agrees is that compared with patients with residual lesions, patients with AVMs occlusion are more likely to have seizure-free. Therefore, the mechanism of action is considered to be that after the main purpose of SRS is achieved (that is, to eliminate the risk of AVM bleeding) Elimination of lesions) and the additional benefit of improving the outcome of epilepsy. Radiosurgery treatment provides a satisfactory rate of improvement in epilepsy for AVM patients with epileptic seizures.
Ironside conducted a meta-analysis of 27 studies from January 1987 to January 2018, including 4826 patients. Among them, 34.7% (26.0% to 43.9%) of patients with one or more epilepsy occurred. After gamma knife treatment, 73.1% (66.9%-78.9%) achieved epilepsy control (no seizures or improvement in epilepsy). However, 55.7% (44.5%～66.6%) had no seizures at all.
Ding analyzed 1,400 cases of AVM treated with Gamma Knife from 1989 to 2013. The improvement rate of seizures after Gamma Knife treatment was 57.6% (132/229), of which 20.1% were seizure-free (46/229) and seizure frequency decreased 37.6% (86/229).
There is no obvious change, the same is 37.6% (n=86), and the worse is 4.8%. No previous seizures but new epilepsy after treatment accounted for 1.7%. Compared with microsurgery, the risk of new epilepsy in cases without seizures is very low.
For AVM patients who do not exhibit epilepsy, because the risk of recurrence after radiosurgery is very low, preventive anti-epileptic drug treatment is not required.
Patients with complete disappearance of AVM after radiosurgery have a higher seizure-free rate. Chen et al. found that in the partially occluded AVM, only 41% of the complete epilepsy remission rate, while the completely occluded AVM was 82%.
For patients with epilepsy before treatment, the seizure improvement rate was 29% at 3 years, 36% at 5 years, 50% at 10 years, and 60% at 15 years, and the overall Engel I result was 53%. These figures indicate that complete AVM clearance is an important factor in achieving a higher seizure remission rate. As for the predictors of no seizures after treatment, reports are inconsistent.
Ding believes that the original bleeding in AVM, longer follow-up time, and no bleeding after radiotherapy are predictors of seizure improvement in multivariate analysis. Ironside believes that the disappearance of AVM, short duration of seizures, type of generalized seizures, and previous AVM bleeding are related to seizure-free seizures after treatment. The two opinions are the same only in that the previous AVM has bleeding.
On the one hand, ionizing radiation has a direct inhibitory effect on epileptic seizures in the cerebral cortex. On the other hand, when applying radiosurgery to treat temporal lobe epilepsy, the frequency of seizure auras increases significantly during the first 6 to 9 months, so there is no doubt that radiosurgery may induce seizures in a short period of time.
Yang et al. believe that although radiosurgery has been used to treat medial temporal lobe epilepsy, radiosurgery may cause delayed epilepsy through radiochemical damage (necrosis, edema).
5.4 Surgical treatment of arteriovenous malformations with epilepsy
Considering surgery, prevention of bleeding is a typical indication of AVM, not a treatment for epilepsy. Therefore, if unruptured AVM is found due to one or several seizures, seizures do not constitute an indication for surgery. Surgical treatment is mainly to completely remove AVM using the same microsurgical technique as in cases without epilepsy.
In patients with few seizures, the probability of obtaining seizure-free seizures by simple AVM resection is very high. Therefore, in addition to the small-scale gliosis and hemosiderin deposited cortex close to the border of AVM, It seems unnecessary to adopt a specific resection strategy to ensure that the functional area cortex is not affected.
For AVMs patients with chronic refractory epilepsy, some epilepsy surgery concepts are worth noting. Ideally, the cerebrovascular surgeon should pay attention to the two factors of the lesion and the epileptogenic lesion when planning the resection of AVMs, and strive to expand the epileptogenic method or remove the epileptogenic lesion at the remote site while removing the lesion.
5.4.1 Concept of epilepsy surgery applicable to AVM resection
For epilepsy caused by AVM, as with other focal brain epilepsy, there are several options:
- Simple resection of brain lesions (such as resection of AVM lesions only);
- Lesion resection plus peripheral edge cortex resection and enlarged lesion resection, such as lesion resection plus edge cortex resection;
- DRE with secondary epileptic foci or “dual pathology” lesions, according to the concept of epilepsy surgery for both excision.
Expanded cortical resection can consider the cortex defined by the edge of the lesion. In temporal lobe epilepsy, it may include the amygdala and hippocampus, or, in rare cases, even temporal lobe resection. There are few data on the surgical treatment of DRE in AVM cases.
Yeh, in a group of DRE-based cases, 10 out of 17 temporal lobe AVMs were associated with distal epileptic foci, and 25 out of 54 patients underwent additional cortical resection, such as enlarged foci resection. Twelve are located at remote sites, that is, secondary epileptic foci. Brelie received epilepsy evaluation in 13 of 24 cases of DRE, and 11 of them underwent epilepsy surgery.
Although it can be seen that the concept of epilepsy surgery in chronic epilepsy or AVM resection of DRE has obvious advantages, it has not been proven so far, but the success in non-AVM cases supports the application of this concept.
5.4.2 Results of epileptic seizures after microsurgery
The judgment of epilepsy results varies greatly among authors. In general, about 45% to 80% of AVM-related epilepsy do not have seizures after microsurgery. The seizure-free rate reported by Brelie et al. was 76.7%. Among them, 85.7% of sporadic seizures had no seizures, and 80.5% of chronic seizures had no seizures, while the seizure-free rate of DRE seizures was only 58.3%. Obviously, the duration of preoperative seizures has a considerable impact on the outcome of epilepsy surgery.
Interestingly, with the extension of follow-up time, the effect gradually improved. The seizure-free rate from 1 year (77%) to 79% at 5 years and 84% at 10 years. This is similar to the long-term results of the gamma knife. Baranoski et al. conducted a meta-analysis of several treatment modalities and found that in all groups, compared to the radiosurgery group an average of 63% seizure-free rate and an average of 49% in the endovascular embolization group.
The microsurgery group had the most consistent seizure-free probability (78%). In the same study, they found that patients with surgically treated epilepsy and ruptured AVMs had a higher seizure-free rate than patients treated with radiation. Among patients with unruptured AVMs, there was no difference in epileptic seizure outcomes between the microsurgery group and the radiosurgery group or the embolization group.
However, in a subset analysis, they found that if epilepsy were completely eliminated by radiosurgery, the proportion of patients who did not develop epilepsy was 85%, higher than those who were treated by microsurgery.
5.4.3 Early postoperative seizures and new-onset epilepsy
Unfortunately, those who have never experienced seizures before AVM removal may develop new seizures after surgery. One or two seizures in the early postoperative period do not constitute epilepsy. Occasional single epilepsy in the early postoperative period is not uncommon and is not the same as persistent epilepsy. In a large case series reported by Piepgras, 6% of patients developed new-onset epilepsy; the incidence of new-onset epilepsy reported by Rohn was as high as 17.6%.
Piepgras found that the frequency of new-born seizures seems to be affected by the size of AVM: new-onset epilepsy in AVMs <3cm is 3%, 3-6cm is 6%, and >6cm is 16%. Persistent and repetitive seizures, if more than 2 times are called epilepsy, should not be confused with 1 or 2 seizures within 7 to 10 days after surgery. They are likely to be derived from surgical trauma to the cerebral cortex, similar to the occasional seizures after other types of brain surgery.
In a meta-analysis, Baranoski found that 9.1% of 547 microsurgery patients had new epilepsy, 5.4% of 568 stereotactic radiosurgery patients, and 39.4% of patients in the endovascular intervention group had new epilepsy. Seizures.
For AVM without epileptic seizures or occasional seizures: use appropriate treatment methods without the need for preventive anti-epileptic drugs. In the case of microsurgery, microhemorrhage and gliosis adjacent to the cortex must be removed. For AVM with more than 2 seizures, multiple seizures, or chronic epilepsy, if microsurgery is selected, a small part of the border adjacent to the normal cortex should be included when removing the AVM.
For long-term chronic epilepsy or obvious debilitating seizures, it is recommended that long-term video EEG examinations are used to capture and record at least 2 seizures to detect the epileptic cortex that may expand.
In temporal AVM, secondary epilepsy of the medial temporal lobe structure should be excluded before surgery. For DRE AVM, trying to get rid of epilepsy is as important as complete occlusion or removal of AVM. Like other DRE cases, a typical preoperative evaluation is necessary to detect the cortical area of the epileptic foci that may expand.
(source:internet, reference only)