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Seizures and AVMs
Pearls
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Presentation of iAVMs with seizures is more common in adult than in pediatric populations.
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AVMs in the frontal, temporal, and parietal lobes more commonly are associated with seizures.
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Size (> 3–4 cm), cortical location, long arterial feeders of middle cerebral artery origin, and superficial venous drainage with varicosities and tortuosity are risk factors for seizures.
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Surgical removal of iAVMs, with or without adjunctive embolization, is associated with a 30% reduction in seizures.
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Stereotactic radiosurgery provides similar seizure control to resection only when the iAVM is completely obliterated.
Introduction
Focal or generalized seizure is a common initial presenting symptom for patients with an intracranial arteriovenous malformation (iAVM), accounting for roughly 25% of all symptoms precipitating new diagnoses of iAVM in recent literature. There are three recently published case series involving more than 1000 patients with iAVMs that report the rate of seizure prompting presentation. In the largest of these studies, a single-center series of 3299 cases collected over 35 years in Beijing, China, the rate of seizure at presentation was 20.9%. In the other two, an international multicenter series of 1289 cases and a single-center US series of 1007 cases, the rates were 30% and 22.7%, respectively. Overall, recently published series have reported seizure presentation in between 20% and 44% of iAVM patients ; however, in all series involving more than 100 patients, the range is narrower—approximately 20%–30%. Only the smallest included series, one that involved 45 patients treated at a single center, reported the rate of seizure presentation to be as high as 44%.
The largest published series of iAVM cases reports an average patient age of 31 years at the time of diagnosis. Most case series that analyzed the association of age and epilepsy in iAVM patients have shown a statistically significant trend toward higher rates of seizure presentation with decreasing age relative to the iAVM patient population as a whole. However, there are exceptions to this trend, and it is inconsistent across all series in the recent literature. Male sex is reported to be significantly associated with seizure presentation. This association with male sex is also seen with regard to an increased risk for persistence of a seizure disorder after iAVM treatment. While some association between race and risk of iAVM hemorrhage has been reported, no associations between racial, ethnic, or national origin and risk of seizure in patients with iAVMs have been reported.
Multiple genetic syndromes are associated with iAVMs, probably most famously hereditary hemorrhagic telangiectasia (HHT), also called Osler-Weber-Rendu syndrome. This syndrome and other genetic disorders associated with iAVMs are rare, and there is not a robust body of literature studying epilepsy in these patients. However, in one series of 10 patients with HHT and iAVMs, 2 patients (20%) presented with seizure, a rate that is very similar to the rates of seizure presentation summarized earlier for the general iAVM patient population.
In addition to patient demographic characteristics, multiple anatomic characteristics of iAVMs affect the risk of seizure and subsequent epilepsy, summarized in Table 9.1 . Increasing size of AVM nidus has consistently been reported to be associated with seizures. A threshold nidus diameter where this increased seizure risk is realized has been reported at between 3 and 4 cm. Risk of seizure has consistently been reported to be lower in patients with AVMs centered in the occipital lobe and higher when the lesions are in the frontal, temporal, or parietal lobes. While there is consistency across these studies in occipital lobe location as protective against epilepsy, there is some variability regarding which lobe appears to carry the highest risk of seizures. However, in all cases where a statistically significant difference between the frontal, temporal, and parietal lobe locations was found, either a frontal or temporal location carried a greater risk than a parietal location. With regard to nidus location, supratentorial and superficial cortical AVMs are consistently associated with epilepsy, as compared to deep location and infratentorial location, which instead carry a higher risk of hemorrhagic presentation.
Table 9.1
Factors Affecting the Risk of Epilepsy in Patients With iAVMs
| Category | Higher Risk | Lower Risk |
|---|---|---|
| Demographics | Younger | Older |
| Male | Female | |
| Location | Supratentorial | Infratentorial |
| Cortical | Deep | |
| Temporal (++) | Occipital | |
| Frontal (++) | ||
| Parietal (+) | ||
| Arterial supply | Cortical supply | Deep supply (e.g., lenticulostriate) |
| Middle cerebral | ||
| Posterior cerebral | ||
| Dilated feeder | ||
| Venous drainage | Superficial | Deep |
| Venous varix | ||
| Outflow stenosis |
+ More likely; ++ most likely.
Certain aspects of the angioarchitecture of a given iAVM have been associated with an increased risk of epilepsy as well. Multiple studies have reported that AVMs supplied by branches of the middle and posterior cerebral arteries carry a higher risk of seizure. Dilation of an arterial feeder measured relative to a nearby normal vessel of the same order and in the same distribution (e.g., an M 3 branch supplying an AVM compared to an adjacent M 3 branch that does not, as in Fig. 9.1 ) is also associated with increased seizure risk. Superficial cortical arterial supply in any distribution carries a higher risk of seizure in comparison to arterial supply deep to the AVM nidus (e.g., lenticulostriate or other perforator artery). Superficial venous drainage is consistently associated with epilepsy, as is venous ectasia or a varix. Venous outflow stenosis and associated parenchymal congestion are also associated with seizures.
Mechanisms of AVM-Related Epilepsy
Pathophysiology of AVM-related epilepsy
With improved imaging technologies and better understanding of the hemodynamics of AVMs, a more nuanced understanding of the epileptogenicity of these lesions is emerging, although there is still much to be learned. Initial efforts to characterize epileptogenic AVMs focused on clinical and anatomic characteristics, while more recent explanations have centered around their hemodynamic behavior. The three main causes of AVM-related epilepsy are (1) history of hemorrhage or subclinical hemorrhage resulting in hemosiderin deposits and gliosis, (2) arterial steal resulting in local perinidal hypoxia, and (3) venous congestion.
Seizure risk in patients with a history of avm rupture
Multiple studies have found that prior rupture is associated with an increased prevalence of seizures; however, this is not universally agreed upon. Notably, two large cohort studies found no significant difference or even a higher rate of seizures in iAVM patients without a history of AVM rupture.
Microscopic and histologic examination of resected AVM specimens has demonstrated hemosiderin deposits. In a study of 27 patients with a history of AVM-related epilepsy and no known history of hemorrhage, hemosiderin deposits were found in 10 cases and focal hemorrhage in four. Similarly, another case series found focal hemosiderin deposits in the walls of abnormal blood vessels and surrounding brain parenchyma. This histologic finding is thought to represent subclinical hemorrhage or red blood cell extravasation through abnormally leaky capillary walls.
In a microscopic analysis of resected AVM specimens, Tu et al. found that perinidal capillaries traversing from the nidus to normal capillaries were dilated and lacked the normal blood-brain barrier ultrastructural features of basement membranes and astrocytic foot processes. In specimens from patients with a known clinical history of AVM rupture, there was hemosiderin staining of the normal cerebral cortex surrounding the perinidal capillaries. None of the specimens from patients without a clinical history of hemorrhage had this feature. The authors also described separated endothelium, a paucity of pericytes, and extravasation of red blood cells from perinidal capillaries.
Much of the literature relating hemosiderosis to seizures comes from cavernous malformation–induced epilepsy and the impact of resection of the hemosiderin deposits surrounding the cavernoma with respect to seizure freedom. Multiple studies have shown improved seizure rates with resection of the hemosiderin-rich tissue immediately adjacent to cavernous malformations. The mechanism behind this is thought to be related to peroxidative injury, as studies have shown that seizure activity, measured by intraoperative electrocorticography (ECOG), increases with increasing peroxidase activity in the cortex injected with iron.
Hemodynamic characteristics
There are two main hemodynamic phenomena that may be responsible for seizures in the setting of iAVMs. The first is chronic hypoxemia secondary to arterial steal. Several morphologic characteristics of AVMs related to high-flow systems are seen more frequently in patients presenting with seizures. These include pial recruitment, perinidal angiogenesis, and intranidal aneurysms. The low-resistance system of an AVM functions as a sump, redirecting arterial blood flow from normal brain tissue to the AVM. In some cases, this does not exhaust the cerebrovascular reserve and is thought to represent “functional” steal, while in others there is chronic local hypoxia akin to ischemic stroke. Focal neurologic deficits are associated with ischemic arterial steal, while seizures are frequently seen with the functional steal phenomenon.
Chronic hypoxia is associated with gliosis, which is an additional risk factor for the development of seizures. The pathogenetic mechanism likely involves modulation of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), since a reduction of stimulus-evoked inhibitory postsynaptic potentials (IPSPs) and paired-pulse inhibition is seen with ongoing hypoxia. Hypoxia and gliosis cause a depolarizing shift in potentials, interfering with neuronal ion transport mechanisms. The affected cortex becomes hyperexcitable, as GABAergic inhibitory mechanisms are inhibited to a greater degree than excitatory postsynaptic potentials (EPSPs), with neurons firing uninhibited. IPSPs recover from the effects of hypoxia at a slower rate as well.
In addition to arterial variation, AVMs differ in their venous anatomy, and certain venous drainage patterns predispose patients to venous congestion, which is associated with increased seizure risk. Venous congestion occurs when the venous input overwhelms the venous output. This can occur with excess inflow or restricted outflow. The sump effect, as discussed earlier, or fistulas can result in increased venous inflow through AVMs. Outflow is limited functionally by the shared drainage system of the surrounding normal brain and by stenosis or thrombosis of the draining veins. The arterialized draining vein does not adequately drain surrounding normal tissue, so the longer and more winding the course, the greater amount of parenchyma is affected, and the more congestion there is. Outflow restriction also occurs secondary to progressive thrombosis or stenosis of the draining vein. Chronic venous congestion causes development of tortuous pial veins (called a pseudophlebitic pattern), an angiographic characteristic found to correlate with increased seizure risk. This results in perinidal edema, which is also epileptogenic.
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