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Cerebrovascular disease
Research paper
Brain arteriovenous malformations and seizures: an Italian study
  1. F Galletti1,2,3,
  2. C Costa1,
  3. L M Cupini4,
  4. P Eusebi3,5,
  5. M Hamam6,
  6. N Caputo7,
  7. S Siliquini1,
  8. C Conti8,
  9. E Moschini2,
  10. P Lunardi9,
  11. S Carletti2,8,
  12. P Calabresi1,3
  1. 1Clinica Neurologica, Università degli Studi di Perugia, Perugia, Italy
  2. 2Neurologia, Ospedale S Maria di Terni, Terni, Italy
  3. 3Fondazione S Lucia IRCCS di Roma, Roma, Italy
  4. 4Neurologia, Ospedale S Eugenio di Roma, Roma, Italy
  5. 5Assessorato alla Sanità, Regione Umbria, Italy
  6. 6Neuroradiologia, Ospedale S Maria della Misericordia di Perugia, Perugia, Italy
  7. 7Neuroradiologia, Ospedale S Maria di Terni, Terni, Italy
  8. 8Neurochirurgia, Ospedale S Maria di Terni, Terni, Italy
  9. 9Clinica Neurochirurgia, Università degli Studi di Perugia, Perugia, Italy
  1. Correspondence to Professor Paolo Calabresi, Clinica Neurologica, Università di Perugia, Ospedale S Maria della Misericordia, 06156—S Andrea delle Fratte, Perugia, Italy; calabre{at}unipg.it

Abstract

Objective To evaluate seizures as first clinical manifestation of brain arteriovenous malformations (AVMs), in relation to angioarchitectural features of these vascular anomalies.

Methods We performed a prospective observational study, collecting records of patients with AVMs consecutively admitted to the Neurological and Neurosurgery Units of Perugia University and to the Neurosurgery Unit of Terni Hospital, during a 10-year period (1 January 2002 to 1 June 2012). Two groups of patients, with or without seizures as AVM first presentation, were analysed to identify differences in demographic and angiographic features. A multivariate logistic regression model was also developed.

Results We examined 101 patients with AVMs, 55 male and 46 female. Seizures were the initial clinical manifestation in 31 (30.7%) patients. We found a significant difference (p<0.05) between two groups of patients, with or without seizures as AVM first presentation concerning location, side, topography and venous drainage. A multivariate logistic regression model showed that clinical presentation with seizures was correlated with a location in the temporal and frontal lobes, and with a superficial topography. The strongest association (OR 3.48; 95% CI 1.77 to 6.85) was observed between seizures and AVM location in the temporal lobe.

Conclusions Vascular remodelling and haemodynamic changes of AVMs might create conditions for epileptogenesis. However, here we show that malformations with specific angiographic characteristics are more likely to be associated with seizures as first clinical presentation. Location is the most important feature related to epilepsy and in particular the temporal lobe might play a crucial role in the occurrence of seizure.

https://doi.org/10.1136/jnnp-2013-305123

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    Introduction

    Unruptured brain arteriovenous malformations (AVMs) commonly present with epileptic seizures.1

    The percentage of patients with AVMs showing seizure varies between 17% and 30%.1–4 Studies investigating risk factors for seizure recurrence show that, after a first unprovoked seizure, patients with AVM experience additional seizures suggesting the development of symptomatic epilepsy.5 It has been reported that clinical course, therapeutic approaches and also pathogenetic mechanisms of epilepsy associated with AVMs are peculiar.1 Seizures could represent an initial manifestation in unruptured AVMs but also a consequence of a complication, such as an intracerebral haemorrhage.6 Patients with AVMs present a 1% per year chance of developing epilepsy and this percentage increases after surgical treatment or bleeding.7

    To explain the pathophysiology of epilepsy in patients with AVMs several hypotheses have been postulated including haemodynamic modifications, haemosiderin deposits and vascular remodelling.6 ,8 However, only a few studies have addressed the analysis of the angioarchitectural features of AVMs and their relationship with epileptic seizures.6 ,7 ,9 A recent French study investigating seizures as initial presentation of AVM found as predisposing factors male sex, superficial venous drainage, frontal lobe and arterial border-zone location.10 Thus, the aim of this prospective study was to evaluate seizure presentation in a group of Italian patients with AVMs and the relationship of seizures with angioarchitectural AVM features in order to establish possible links with pathogenetic factors.

    Methods

    This observational prospective multicentre study was approved by an internal review board. We collected records of a cohort of patients with AVMs, consecutively admitted to the Neurological and Neurosurgery Unit of Perugia University and to Neurosurgery Unit of Terni Hospital in a 10-year period (1 January 2002 to 1 June 2012). These centres represent an excellence network within the Umbria region for the diagnosis and treatment of brain AVMs in Italy. A multidisciplinary team of neurologists, neurosurgeons and interventional neuroradiologists took care of included patients.

    Patients’ clinical assessments were examined by a neurologist or a neurosurgeon.

    We evaluated sex, mean age at the time of diagnosis and initial clinical manifestation. Seizures’ clinical pattern was characterised according to International League Against Epilepsy Classification criteria.11

    All patients, after a written consent, underwent diagnostic cerebral angiography. The angiograms were analysed by two interventional neuroradiologists.

    For each AVM the following angioarchitectural characteristics were examined: size, location, side, topography, type of nidus, the presence or absence of feeders from external carotid artery, characteristics of venous drainage and the presence or absence of pseudoaneurysms.12 AVMs were distinguished according to size as small (diameter less than 3 cm), medium (diameter from 3 cm to 5 cm) and large (diameter more than 5 cm). The location was classified as: frontal, temporal, parietal, occipital, multilobar and cerebellar. Malformations of corpus callosum, basal ganglia and brain stem were also included. With regards to side AVMs were differentiated as malformations in the right or in the left hemisphere, or located along the midline. Corpus callosum, cerebellum and brain stem were considered midline structures. Topography was classified as: superficial (with a cortical arterial feeder), deep (with a perforating arterial feeder) or mixed. Type of nidus was distinguished as plexiform, fistulous or mixed. Concerning venous drainage, we evaluated depth (superficial, deep or mixed) and number of draining veins (single or multiple).

    Except for mean age at diagnosis, all the variables were categorical and reported as count and percentage. χ2 test was performed to analyse differences between the two groups of patients, with or without epilepsy as AVM first clinical presentation. The statistical analysis included demographic (age and sex) and angiographic (size, location, side, topography, type of nidus, presence of feeders from external carotid artery, kind of venous drainage, number of draining veins, presence of pseudoaneurysms) features. The statistical level of significance was p=0.05. Moreover, a multivariate logistic regression model was developed to further investigate the correlation between seizures and demographic as well as angiographic variables.

    Results

    We examined 101 patients with AVMs, 55 (54.5%) male and 46 (45.5%) female. The age at the time of diagnosis ranged from 9 years to 81 years (mean 39.1±15.1 years) (table 1).

    View this table:
    Table 1

    Demographic and clinical features of patient population

    Initial clinical manifestations were haemorrhage in 36 (35.6%) patients, seizures in 31 (30.7%), and headache in 17 (16.8%). Eleven (10.9%) subjects were asymptomatic at the time of diagnosis, while in six (5.9%) cases there appeared a focal neurological deficit (table 1).

    Angiographic characteristics

    AVMs were small in 38 (37.6%), medium in 50 (49.5%) and large in 13 (12.9%) patients. Concerning location, 23 (22.8%) AVMs were frontal, 20 (19.8%) temporal, 10 (9.9%) parietal and 12 (11.9%) occipital. A multilobar AVM was observed in 10 (9.9%) patients. Finally, 3 (3.0%) subjects had an AVM located in the corpus callosum, 11 (10.9%) in the cerebellum, 3 (3.0%) in the brain stem and 9 (8.9%) in the basal ganglia. AVMs were in the left side in 54 (53.5%) patients, while 33 (32.7%) subjects had a malformation in the right hemisphere. A midline location was observed in 14 (13.9%) patients. Concerning topography, 30 (29.7%) subjects had a superficial AVM, 51 (50.5%) patients showed a deep malformation and 20 (19.8%) individuals had a mixed variant. Nidus was plexiform in 15 (14.9%) cases, fistulous in 12 (11.9%) and mixed in 74 (73.2%) patients. AVMs had feeders from external carotid artery in 27 (26.7%) patients. Venous drainage was superficial in 28 (27.7%) AVMs, deep in 33 (32.7%) and mixed in 40 (39.6%) subjects. In 87 (86.1%) patients AVMs had multiple draining veins. Pseudoaneurysms were observed in 27 (26.7%) subjects. According to the Spetzler-Martin grading scale, 7 (6.9%) AVMs had 1 as score, and 16 (15.9%) had 2 points. A score of 3 was found in 51 (50.5%) AVMs, while in 17 (16.8%) AVMs, a score of 4 was seen. Finally, 10 (9.9%) AVMs had 5 points (table 2).

    View this table:
    Table 2

    AVMs angiographic characteristics (n=101)

    Seizures as AVMs initial manifestation

    In 31 (30.7%) patients seizures were the first clinical presentation of the AVMs. Among these patients, 6 (19.3%) had a single seizure at the time of diagnosis, while 25 (80.7%) had epilepsy which led to the discovery of the AVMs. Nineteen (61.3%) patients were male and 12 (38.7%) female. Mean age at the time of diagnosis was 38.8±9.9 years (table 3). Concerning the type of seizures, 14 (45.2%) patients had simple partial seizures, 4 (12.9%) complex partial, 5 (16.1%) partial evolving to secondary generalised seizures and 1 (3.2%) patient had generalised seizures. Finally, in seven (22.6%) cases seizures’ clinical pattern could not be established. All patients were treated with antiepileptic drugs. EEG showed epileptiform anomalies in four patients (12.9%), and focal theta activity in five (16.1%). It was normal in 8 (25.8%) cases, while in 14 (45.2%) subjects it was not available (table 3).

    View this table:
    Table 3

    Clinical and electroencephalographic patterns of patients with seizures

    As for angiographic features of AVMs of this group of patients, 8 (25.8%) AVMs had a small size, 18 (58.1%) had a medium size and 5 (16.1%) were large. Location was frontal in 12 (38.7%) patients, temporal in 13 (41.9%) and parietal in three subjects (9.7%). No malformation was located in the occipital lobe. Finally, two (6.5%) AVMs were multilobar, and one (3.2%) callosal. Concerning the side, 23 (74.2%) patients had a malformation located in the left hemisphere, 7 (22.6%) subjects had an AVM in the right side, while in 1 (3.2%) case malformation was along the midline. Regarding topography, 19 (61.4%) patients had a superficial AVM, in 6 (19.3%) cases malformations were deep, while 6 (19.3%) AVMs were mixed. Type of nidus was plexiform in 5 (16.1%) patients, fistulous in 5 (16.1%) malformations, and mixed in 21 (67.8%) subjects. Twelve (38.7%) AVMs had feeders from the external carotid artery. Venous drainage was superficial in 16 (51.6%) patients, deep in 3 (9.7%) malformations and mixed in 12 (38.7%) subjects. Veins were multiple in 26 (83.9%) AVMs. Ten (32.3%) patients had a malformation with pseudoaneurysms (table 4).

    View this table:
    Table 4

    Demographic and angiographic features in patients with and without seizures

    Statistical analysis showed no difference regarding demographic characteristics, such as sex and age, between patients with or without seizures. Conversely, we found a significant difference concerning angiographic features, such as location (p<0.001), side (p=0.013), topography (p<0.001) and venous drainage (p<0.001). Particularly, in patients with seizures there were predominant AVMs in the temporal lobe on the left side, with a topography and venous drainage of superficial type (table 4).

    Moreover, the logistic regression model showed that clinical presentation with seizures was correlated with a location in the temporal (OR 3.48; 95% CI 1.77 to 6.85, p<0.001) and frontal (OR 2.81; 95% CI 1.48 to 5.37, p=0.002) lobes, and with a superficial topography (OR 2.68; 95% CI 1.51 to 4.76, p=0.002) (table 5).

    View this table:
    Table 5

    Multivariate logistic regression model

    Discussion

    In this study, we found that seizures were the second most frequent initial clinical manifestation of AVMs, after intracranial bleeding. Seizures occurrence led to malformation diagnosis in 30.7% of Italian patients, according to the results of studies in other populations.1–4 Mean ages of seizures’ appearance and clinical pattern (mainly simple partial seizures) were similar to data previously reported.7 However, in contrast with a recent French study reporting male sex as a predisposing factor for seizures in patients with AVM,10 we found no difference in relation with demographic characteristics.

    It has been reported that epilepsy associated with AVMs is peculiar for clinical course, therapeutic implications and also pathogenetic mechanisms.1 Vascular remodelling and haemodynamic changes of AVMs could create conditions for epileptogenesis.13 Venous portion of the nidus might be susceptible to haemodynamic modifications and hypoxia.8 Moreover, the brain tissue around the AVM is more susceptible to hypoperfusion, due to a ‘steal phenomenon’ or due to the loss of autoregulation of cerebral circulation.8 Recently, an impaired perinidal cerebrovascular reserve associated with venous congestion in patients with AVMs and seizures was observed.14 Additionally, recurrent hypoxia could stimulate release of vascular growth factors, and neoangiogenesis. This consequent vascular and structural rearrangement could potentiate neuronal excitatory pathways, favouring an epileptogenic mechanism.15 Conversely, microhaemorrhage due to dilatation of the perinidal capillary network determines haemosiderin deposits, with iron-hydroxide complex.7 Iron could trigger free radicals production and lipid peroxidation reactions. These events might, in turn, modify cell membrane fluidity and cause functional changes of ionic channels, receptors and transporters of excitatory neurotransmitters leading to epileptogenesis.13 Additionally, astrocytes are also involved in mechanisms of vascular remodelling.16 Astrocytes reaction determines release of inflammatory mediators and promotes structural rearrangements, in favour of an increase of excitatory signals, as just described in epilepsy pathogenesis.17

    Although AVM cellular pathophysiology might represent a critical mechanism in epileptogenesis, in the present study we found that only malformations with specific angiographic characteristics are associated with seizures as first clinical presentation. We observed, in fact, that in patients with epilepsy there were predominant AVMs in the temporal lobe, on the left side, with a superficial topography and venous drainage. The logistic regression model showed that clinical presentation with seizure was correlated to a location in the temporal and frontal lobes, and with a superficial topography.

    Interestingly, our results are in line with previous studies showing that a superficial AVM location is related to seizures.6 ,10 ,18 Moreover, a recent French study, in accordance with our findings, found that all AVMs presenting with seizures have a superficial venous drainage.10 The superficial AVM topography as well as its superficial venous drainage, mainly found in patients with seizures could explain the high susceptibility to epileptogenesis in cortical AVM. It might be postulated, in fact, that cortical neurons around AVMs show an altered physiology with a predisposition to hyperexcitability as it has been demonstrated in areas adjacent to cavernous malformations and tumours.19 Nevertheless, this result should be interpreted with caution. This association may, in fact, reflect a greater haemorrhage risk of AVMs with a deep venous drainage, as shown in other studies.20

    Although in our study a significant association between frontal AVM location and seizure was found in agreement with the French study,10 the strongest association was observed with the temporal lobe location. This latter finding is in line with a previous population based study9 while it is in contrast with the French study that did not report a significant association with the temporal lobe location.10 Several factors might account for these discrepancies including possible bias in the selection of patients as well as methodological issues. However, the anatomical location represents a key factor in the generation of seizures in these patients. Interestingly, in fact, epileptogenic mechanisms might mainly operate in the cortex of frontal and temporal lobes representing the major substrates of focal epilepsies.21 In particular, the mesial part of the temporal lobe is susceptible to synchronisation processes and to persistent epileptic discharge.22 Thus, AVMs in the temporal lobe might produce a sort of ‘kindling-like’ phenomenon involving the entorhinal-hippocampal circuitry.23

    As for the association between epilepsy and AVMs located on the left side, there are few studies showing that the left hemisphere is more susceptible than the right to epileptogenesis.24 Nevertheless, more structural anomalies were described in patients with left temporal lobe epilepsy than in subjects with a focus on the right side.25 Then, it could be hypothesised that our data have been partially influenced by AVMs location in the temporal lobe. Moreover, manifestation of seizures from the right temporal lobe may be underestimated, because their clinical pattern did not include speech disturbances.

    Nevertheless, our results support the view that location is the most important AVM angioarchitectural feature influencing clinical presentation. This interpretation is also confirmed by a previous study of our group showing that an occipital location of the malformation could determine a clinical manifestation with a ‘migraine-like’ headache.26

    Results obtained in this study should be interpreted with caution, because of some potential biases. In fact, this is not a population-based study, but we have selected only patients admitted to the major hospitals in our region, considered as high specialisation centres for treatment of vascular malformations. In this research, we did not consider patients with seizures after bleeding. We are aware that it is possible that this approach would underestimate the occurrence of epilepsy in patients with AVM. However, the goal of our study was to evaluate the risk of epilepsy as a first clinical event in these patients.

    Further studies are required to clarify the circuitry and the mechanisms underlying the link between AVM location and seizures. Additional information about this topic could be taken from studies addressing outcome of seizures after AVM treatment. We are aware that a large multicentre international trial about unruptured AVMs is under way to evaluate the benefit of AVM eradication for stroke prevention, and for reducing seizures’ frequency. Results from this trial might provide more data on this interesting issue.27

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    Footnotes

    • Contributors FG and PC: study concept and design, acquisition, analysis or interpretation of data, drafting/revising the manuscript; PE: statistical analysis; PL, SC and LMC: study concept and revising the manuscript; CC, CC, SS, EM: acquisition of clinical data; MH and NC: acquisition and analysis of neuroimaging data.

    • Competing interests PC serves as an editorial board member of Lancet Neurology, Movement Disorders, the Journal of Neuroscience, and Synapse; receives research support from Bayer Schering, Biogen, Boehringer Ingelheim, Eisai, Novartis, Lundbeck, Sanofi-Aventis, Sigma-Tau and UCB Pharma; and from Ricerca Corrente IRCCS, Ricerca Finalizzata IRCCS (European Community Grants SYNSCAFF and REPLACES), the Italian Minister of Health and AIFA (Agenzia Italiana del Farmaco). No disclosure is reported for the other authors.

    • Ethics approval The study was approved by an internal review board because it was an observational study.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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