Abstract
Objective
A small number of patients has been reported to develop a completely new or de novo arteriovenous malformation (AVM) after brain surgery, haemorrhage, head trauma or ischaemic stroke. The natural history of these lesions is unknown. In this review, both ruptured and unruptured de novo AVMs and their treatments were reviewed.
Methods
Published literature in the PubMed database citing ‘de novo cerebral arteriovenous malformation’ was reviewed. Additional studies were identified through reference searches in each reviewed article. A review was performed using all published cases, the treatment approaches and outcomes.
Results
A total of 38 patients, including 37 de novo AVMs reported from 1988 to 17 November 2017 and our one patient, was collected. The age at AVM diagnosis was 5–73 years (mean ± SD, 27.6 ± 20.5 years). The duration time, from negative examination to AVM diagnosis, was 2 months to 25 years (mean ± SD, 6.6 ± 4.9 years). The presentation of de novo AVM was headaches in three (7.9%) patients, bleedings in 12 (31.6%), incidental in 14 (36.8%) and seizure in nine (23.7%). The estimated risk of haemorrhage was 4.8% per year. Seventeen (44.7%) patients were treated with surgical resection, 10 (26.3%) were conservatively observed, nine (23.7%) were treated with radiosurgery and two (5.3%) were endovascularly embolised. The morbidity and mortality were reported as 5.3% and 7.9%, respectively.
Conclusion
Post-natal de novo AVMs have been reported. Their annual haemorrhage risk is 4.8%. Most of them are treated by surgical resection and are associated with morbidity and mortality.
Keywords: Arteriovenous malformation, de novo AVM, treatment, outcome
A small number of patients has been reported to develop a second, new arteriovenous malformation (AVM), anatomically unrelated to their initial lesion.1–4 These AVMs are termed ‘de novo’. By definition, a de novo AVM is a lesion that develops from a region that had been normal on previous imaging studies. There are no published studies that have estimated the risk of forming a de novo AVM. Previous studies have involved genetic susceptibility and environmental triggering factors for de novo aneurysm formation.2,5 Although there are reports on the formation of de novo AVMs, there are very few published data studying the clinical behaviour of these lesions. A fundamental question is whether these AVMs have a similar natural history to an unruptured incidentally discovered AVM. Our goal is to evaluate the risk, treatment and outcome of these lesions in this review.
Methods
A review search was performed for all available published studies on PubMed up to 17 November 2017. A PubMed literature search was performed using ‘de novo cerebral arteriovenous malformation’. No publication date or publication status restrictions were imposed. Additional studies were identified through reference searches in each reviewed article. A review was performed using all published cases, the treatment approaches and outcomes (Figure 1).
Figure 1.
Flow chart showing the selection of studies.
The data elements extracted from patients published included: (a) the number of patients; (b) age; (c) gender; (d) publishing year; (e) duration of investigation; (f ) presentation of AVM; (g) AVM location; (h) Spetzler–Martin (SM) grade; (i) AVM treatment and ( j) outcome.
Statistical analysis
Patient age and length of time between initial examination and de novo AVM diagnosis were analysed by t-test. Initial previous haemorrhage and SM grade were analysed by χ2 test. The analysis was conducted using SPSS 16.0 (IBM SPSS Statistics, Chicago, IL, USA). All statistical tests were two-sided, and statistical significance was defined as P < 0.05.
Results
Thirty-seven patients were identified with de novo AVMs on routine surveillance imaging in the literature research (Table 1).1–3,6–33 Our own patient presented with headaches and seizure from de novo AVM (Figures 2 to 4). The demographics and characteristics of these 38 patients are shown in Table 2. Seventeen (44.7%) of the 38 patients were women. For the 13 (34.2%) patients with a history of bleeding, magnetic resonance imaging (MRI) and angiograms were used to search for a possible AVM in the acute phase. The mean age at diagnosis of the de novo AVMs was 27.6 ± 20.5 years (range 5–73 years). Four patients (48.6%) presented with initial AVM.
Table 1.
De novo AVM cases reported in the literatures and our case.
| Ref. (first author) | Cases | Initial onset | Baseline imaging | AVM presentation | Location | SM grade |
|---|---|---|---|---|---|---|
| Shimoda31 | 1 | HHT | MRI | Headache | Parietal | III |
| Isayama11 | 1 | Haemorrhage | DSA | Haemorrhage | Temporal | NA |
| Morioka21 | 1 | Haemorrhage | DSA | Seizure | Frontal | III |
| Fuse9 | 1 | Haemorrhage | DSA | Incidental | Frontal | II |
| Rodríguez-Arias27 | 1 | Right parietal AVM | DSA | Incidental | Parietal | III |
| Harris4 | 1 | Anaplastic astrocytoma | DSA | Incidental | Thalamus | III |
| Jeffree12 | 3 | Haemorrhage | DSA | Haemorrhage | Basal ganglia | III |
| Haemorrhage | DSA | Incidental | Temporoparietal | II | ||
| Haematoma | DSA | Haemorrhage | Parietal | I | ||
| Mathon16 | 1 | Medulloblastoma | MRI | Incidental | Sylvian fissure | I |
| Miyasaka19 | 1 | Haematoma | DSA | Haemorrhage | Multiple cerebral AVMs | NA |
| Friedman7 | 1 | Dural arteriovenous fistula | MRI, DSA | Incidental | NA | NA |
| Nakamura22 | 1 | Haemorrhage | MRI, DSA | Haemorrhage | Frontal | II |
| Shidoh30 | 1 | Aneurysm | MRI, DSA | Incidental | Postcentral gyrus | II |
| Pabaney26 | 1 | Ischaemic stroke | MRI, DSA | Haemorrhage | Frontal | II |
| Shi29 | 2 | Severe headache | MRI | Incidental | Temporooccipital | II |
| Left frontal AVM | MRI, DSA | Haemorrhage | Temporooccipital | II | ||
| Koch14 | 1 | Seizure | MRI | Seizure | Choroidal fissure | III |
| Yeo33 | 2 | Seizure | MRI | Seizure | Cerebellar | III |
| Seizure | MRI | Headache | Temporal | II | ||
| Neil23 | 1 | Seizure | MRI | New-onset seizures | Parietal | II |
| Morales-Valero20 | 2 | Hepatic encephalopathy | MRI | Haemorrhage | Parietooccipital | II |
| TIA | DSA | TIA | Frontal | I | ||
| Miller18 | 1 | TBI, surgery | MRI | New-onset seizures | Parietal | I |
| Kilbourn13 | 1 | Congenital hydrocephalus | CT, MRI | Haemorrhage | Brainstem | IV |
| Fujimura8 | 1 | Moyamoya disease | MRI | Incidental | Occipital | II |
| Bai3 | 1 | Cerebral arteriovenous fistula | MRI, DSA | New-onset seizures | Frontal | I |
| Alvarez2 | 1 | Giant cavernoma | MRI | Incidental | Third ventricle | III |
| Mahajan15 | 1 | Bell’s palsy | MRI | New-onset seizures | Frontoparietal | III |
| Ozsarac25 | 1 | Seizure | DSA | New-onset seizures | Temporal | III |
| McKinney17 | 1 | Thalamic haemorrhage | MRI | Neurological deficits | Frontoparietal | III |
| Stevens32 | 1 | Band heterotopia | MRI | Seizure and neurological deficits | Parietooccipital | III |
| O’Shaughnessy24 | 1 | Ischaemic events | MRI | Incidental | Sylvian fissure | I |
| Gonzalez10 | 1 | Mild head injury | MRI | Seizure | Temporal | III |
| Akimoto1 | 1 | Resection of two other AVMs | DSA | Haemorrhage | Corpus callosum | III |
| Bulsara6 | 1 | Inflammatory or demyelinating | DSA | Haemorrhage | Temporal | I |
| Schmit28 | 1 | Moyamoya disease | DSA | Incidental | Parietal | II |
| Our case | 1 | Haemorrhage | DSA | Seizure | Parietal | III |
AVM: arteriovenous malformation; SM: Spetzler–Martin; DSA: digital subtraction angiography; CT: computed tomography: MRI: magnetic resonance imaging; HHT: hereditary haemorrhagic telangiectasia; TIA: transient ischaemic attack.
Figure 2.
(a) An axial computed tomography scan at 9 years of age showing a haemotoma in the right parietal lobe. (b) A digital subtraction angiography of the right internal carotid artery showing no obvious vascular anomaly.
Figure 3.
Axial T2-weighted magnetic resonance image at 18 years of age demonstrating a vascular malformation around the old blood products in the right parietal lobe.
Figure 4.
(a) Axial T2-weighted magnetic resonance image at 22 years of age demonstrating an arteriovenous malformation (AVM) consisting of a cluster of fine vessels seen in the right parietal lobe and a prominent vein draining into the sagittal sinus. (b) A digital subtraction angiography outlining a diffusion AVM nidus.
Table 2.
Characteristics of 38 patients who developed de novo AVMs.
| Characteristic | Value |
|---|---|
| Women | 17 |
| Men | 21 |
| AVM at initial presentation | 4 |
| Age at diagnosis of de novo AVM (years) | 27.6 ± 20.5 |
| SM I–II | 23 |
| SM III–IV | 15 |
| History of haemorrhage | 13 |
AVM: arteriovenous malformation; SM: Spetzler–Martin.
The duration time, from negative examination to AVM diagnosis, was 2 months to 25 years (mean ± SD, 6.6 ± 4.9 years). The presentation of de novo AVMs was headache in three (7.9%) patients, bleedings in 12 (31.6%), incidental in 14 (36.8%) and seizure in nine (23.7%). A 57-year-old man, who presented with an anaplastic astrocytoma, was negative on initial angiograms. The patient developed the de novo AVM on 2-month follow-up angiograms. He died of a tumour at 4 months after gamma knife treatment of the AVM.
Risk factors for haemorrhage of de novo AVMs
We identified 38 de novo AVMs in the 38 patients. We analysed these AVMs individually for location, size and haemorrhage. Twelve (31.6%) of the 38 AVMs bled. There was a total of 250.2 years of imaging follow-up. This led to an estimated risk of haemorrhage of 4.8% per year. The 12 AVMs that bled were compared with the 26 that did not bleed. The comparison between these two groups is shown in Table 3. There was a significant between-group difference in the history of initial previous haemorrhage (66.7% in the group that haemorrhaged compared with 19.2% that did not, P = 0.004). There was no statistically significant difference in the patients’ age, length of time between the initial examination and the discovery of the de novo AVM and SM grades.
Table 3.
Statistical tabulation of 38 de novo AVMs (in 38 patients) stratified by the presence of haemorrhage: comparison of patient and AVM characteristics in the two groups.
| Ruptured 12 | Unruptured 26 | P value | |
|---|---|---|---|
| Mean age ± SD | 36.4 ± 19.3 | 23.5 ± 20.0 | 0.069 |
| Duration time | 7.3 ± 4.3 | 6.2 ± 5.2 | 0.529 |
| Initial haemorrhage | 8 (66.7%) | 5 (19.2%) | 0.004 |
| SM III–IV | 4 (33.3%) | 11 (42.3%) | 0.599 |
AVM: arteriovenous malformation; SM: Spetzler–Martin.
Treatment and outcome
Seventeen (44.7%) patients were treated with surgical resection, 10 (26.3%) were conservatively observed, nine (23.7%) were treated with radiosurgery and two (5.3%) were endovascularly embolised. The morbidity and mortality were reported as 5.3% and 7.9%, respectively.
Discussion
The first description of a ‘de novo’ AVM was published by Morioka and Nishio in 1988.27 Case reports have been documented since.1–3,6–33 The findings support the concept that the process of AVM formation is multifactorial and is related to congenital, environmental and haemodynamic factors.2,5 De novo AVM risk factors noted included a history of haemorrhage, ischaemic stroke, radiation exposure, familial AVMs and aneurysm, dural arteriovenous fistula, Moyamoya disease or cavernoma on initial diagnosis.1–3,6–33
There are no papers addressing the subsequent clinical behaviour of these lesions. An unanswered clinical question is whether the behaviour of a de novo AVM is similar to that of an initially discovered AVM. An incidentally discovered AVM has a very low risk of haemorrhage. The annual risk of haemorrhage from unruptured AVMs was 2.4–4.6%.34–36 There are no published data studying the natural history and risk of haemorrhage of de novo AVMs. Previous studies involve case reports and literature review. In this paper, we did not attempt to calculate the risk of formation of these AVMs. Our goal in this paper was to evaluate the risk of haemorrhage and the treatment once a de novo AVM is discovered. In our study, the risk of haemorrhage from de novo AVMs was 4.8% per year.
The exact mechanism of AVM formation has yet to be elucidated, but most likely involves the possible role of angiogenesis,28 genetic susceptibility and environmental triggering factors.2,5 Recent studies have suggested a role for genetic factors in the pathogenesis of sporadic AVM;37,38 Alk1 in endothelial cells in adult mice lead to an increased local endothelial cell proliferation during brain angiogenesis.38 Fatty acid binding protein 4 (FABP4) is an intracellular lipid chaperone, which is expressed in a subset of endothelial cells. FABP4 enhances the angiogenic responses of endothelial cells and is not expressed in normal cerebral vasculature. Heterogenous FABP4 expression was detected in 100% of AVM samples.37 Findings in an experimental study suggest that pregnancy can also increase the angiogenic activity of AVM tissues.39
Study limitations
Thus far, a limited number of de novo AVMs has been reported. Biases and low sample size may have distorted the results, thus limiting the generalisability of our conclusions. The relatively small numbers preclude definitive conclusions. The biggest weakness in our data is the lack of consistent follow-up. With the advent of non-invasive imaging studies, we believe more data will be available in the future.
Conclusion
De novo AVMs may form after brain surgery, trauma, haemorrhage and ischaemic stroke. We agree with other authors who suggest the mechanism of AVM formation is genetic susceptibility and environmental triggering factors. The annual risk of haemorrhage of a de novo AVM was 4.8%. A history of initial previous haemorrhage is a risk factor for de novo AVM haemorrhage. Our data suggest the possibility that a de novo AVM has a similar risk of haemorrhage to an incidentally discovered initial AVM. Most de novo AVMs were treated with surgical resection.
Conflict of interest
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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