Endovascular treatment of intracranial vascular malformations in children

Aetiologies and pathogenesis

Although the exact pathogenesis of aneurysms is not yet understood, several hypotheses have highlighted the contribution of maladaptive vascular remodelling triggered by haemodynamic stress and inflammatory responses.¹³ Intracranial aneurysm is a common condition; the genetic findings that emerged from studies of various approaches and large cohorts of familial and sporadic cases point to multiple underlying factors. These genetic factors can act at different levels from predisposition to intracranial aneurysms and their possible rupture.¹³ In the future, with the new genetic progress (whole-exome sequencing), functional variants directly implicated in development of aneurysms should be identified.¹⁴ Familial intracranial aneurysms (a hereditary subtype of saccular aneurysms) is suspected when two or more affected first- to third-degree relatives are present in a family.¹⁴ Patients with familial intracranial aneurysms have an increased risk for aneurysm formation and rupture compared with the general population, and screening of all first-degree relatives by magnetic resonance or computed tomography angiography is recommended. However, studies of families with aneurysms suggest incomplete genetic penetrance with a late disease onset. Although several loci and candidate genes have been identified, a conclusive gene–disease association has not yet been made for non-syndromic families. The incidence of intracranial aneurysms in paediatric patients with significant comorbidity was reported to be around 28%.^9-12 Indeed, the risk of aneurysms is higher in some connective-tissue-related genetic disorders. Autosomal dominant polycystic kidney disease is associated with saccular aneurysms. This disease is secondary to mutation of PKD1 or PKD2 genes and is associated with defects in vascular endothelium. Other genetic disorders associated with aneurysms include neurofibromatosis type 1, Elhers–Danlos syndrome, Loys–Dietz syndrome, Marfan syndrome, hereditary haemorrhagic telangiectasia (HHT), endocrine neoplasia type 1, Kawasaki disease, Majewski osteodysplasic dwarfism type II, PHACE syndrome, Parry–Romberg dysplasia, and MYH11 mutation. These are more frequent in various forms of moyamoya disease, some forms of immunodeficiency or cardiovascular anomaly, radiation injury, and traumas.^13-15

Three specific pathomechanisms may be identified for some paediatric intracranial aneurysms: trauma, infection, and dissection.¹⁶ Traumatic intracranial aneurysms are very rare in adults whereas they account for 14% to 39% of paediatric intracranial aneurysms. They have a 12:1 male:female incidence ratio and cause haemorrhagic symptoms usually a few weeks after the injury (closed head injury, more rarely penetrating injury). These injuries result in a pseudo-aneurysm or can be dissecting in nature and require adapted treatment.^{17, 18} Infectious arterial aneurysms account for 15% of all paediatric intracranial aneurysms. These are most often of bacterial origin, more rarely of mycotic origin. In intracranial aneurysms of distal small arteries, the infectious agent circulates during a septicaemia (septic emboli). In large arteries, a progressive infection from adjacent structures to the vessels wall (sphenoid sinus infection, etc.) is noticed. Infectious aneurysms can occasionally be treated medically if the patient is severely ill, but both endovascular and conventional surgical treatments should be considered. Dissecting aneurysms are four times more common than in adults and account for up 50% of paediatric intracranial aneurysms. In dissecting aneurysms, symptoms can be related to mass effect, ischaemia, or subarachnoid haemorrhage. Two types of dissecting aneurysm exist: (1) acute segmental arterial dissection or tear with subarachnoid haemorrhage which, without treatment, has a high risk of recurrence; (2) focal dissection with partial thrombosis with rare subarachnoid haemorrhage and less recurrence, the symptoms of which can be related to ischaemia caused by distal embolism or mass effect.

Clinical aspects

The most common location of intracranial aneurysms in paediatric patients is the internal carotid artery bifurcation.^{2, 9, 10} Multiple intracranial aneurysms may be detected but they are less frequent than in adults. The incidence of rupture, causing a subarachnoid haemorrhage, in paediatric intracranial aneurysms varies from 22% to 100%, which is higher than for adults. For patients between 0 and 5 years old, seizure is the most common symptom whereas for older children it is a sudden onset of severe headache.^9-12 For children, non-haemorrhagic presentation such as headache, neurological deficit, or epilepsy is more common than for adults.²

Computed tomography angiography of the brain is recommended to detect subarachnoid haemorrhage and evaluate intracranial vessels. Thanks to progress in imaging techniques, incidental intracranial aneurysms are also frequent and have been reported in almost 20% of cases.^{12, 17-19}

Treatments

Over the past 20 years, EVT has been established as the first-line treatment of intracranial aneurysms. The choice between surgery and EVT must be made by a multidisciplinary team to offer the best therapeutic option. Although a recent meta-analysis has shown a more favourable outcome after EVT, there is no statistically significant difference on a long-term course between both treatments.¹⁸ The rate of favourable outcome was 88.3% after EVT and 82.7% after surgery. In daily practice, physicians usually adopt treatment guidelines for adults and generalize them to the treatment of paediatric patients.¹⁷

Prognosis and follow-up

Some authors showed that, despite a death rate of about 20%, two-thirds of children younger than 15 years who suffered from ruptured or symptomatic cerebral aneurysms had long-term favourable outcomes.²⁰ Cerebral ischaemia occurring initially or delayed within the first few months was a factor of poor clinical outcome, and an aneurysm larger than 5mm was the only factor associated with recurrence.²⁰

The longer anticipated lifespan and greater recurrence risk of paediatric intracranial aneurysms explain why these patients need an aggressive therapeutic approach with cure as the goal and a lifelong imaging follow-up to detect aneurysm recurrence and de novo aneurysm formation.^{19, 20} As in the adult population, for patients with unruptured aneurysms there were no clear clinical data to propose a conservative attitude or any other treatment.²¹ Given the limitations imposed by these non-random studies and the relatively short duration of clinical follow-up, we believe that strong consideration should still be given to intervention for children with unruptured aneurysms.¹⁸

Case 1

An 18-month-old child presented with macrocrania and hydrocephalus. Brain magnetic resonance imaging (MRI) was performed, which showed a giant and partly thrombosed intracranial aneurysm of the posterior circulation (Fig. S1a, online supporting information). Conventional digital subtraction angiography (DSA) showed a fusiform aneurysm involving both vertebro-basilar junctions and the proximal basilar artery (Fig. S1b). Staged EVT was performed. First, the right vertebro-basilar junction was occluded by coiling. Forty-eight hours later, an angiographic test occlusion of the basilar artery was performed which showed a good collateralization via the posterior communicating arteries. Therefore, an endovascular occlusion of the left vertebro-basilar junction and the aneurysmal sac was done by coiling (Fig. S1c,d). The patient woke up with a normal neurological examination and was discharged 2 days later. At 12 months, DSA and MRI showed a stable complete intracranial aneurysm occlusion with a significant decrease in size (Fig. S1e).

Genetic findings associated with arteriovenous shunts

Osler–Rendu syndrome or HHT is an autosomal dominant disorder caused by mutation in the ENG gene encoding endoglin or by mutation in the ACVRL1 gene encoding activin receptor-like kinase. These mutations lead to dysregulation of angiogenesis with the development of mucocutaneous telangiectasia and visceral arteriovenous shunt (cerebrospinal, pulmonary, and hepatic). An overlap syndrome was also described secondary to SMAD4 mutation (juvenile polyposis and HHT).^{23, 24} In this syndrome, one can observe AVM (mostly located superficially), AVF, and micro-AVM or capillary vascular malformations. In some series, 40% of the patients had multiple brain vascular malformations (1% in the non-HHT population). The diagnosis of HHT is based on some clinical characteristics: mucocutaneous telangiectasia, nosebleeds, AVM, and an affected first-degree relative (Curacao criteria).

Capillary malformation-AVM syndrome type 1 is a dominant autosomal disease caused by RASA1 gene mutations. These patients have multifocal capillary malformations associated with AVM or AVF. In the case of this mutation, micro-AVM or capillary vascular malformations can be observed.²⁵ Capillary malformation-AVM syndrome type 2 is a dominant autosomal disorder caused by EPHB4 mutation. These patients present intra- and extracranial AVM, multifocal capillary malformations, and telangiectasia. Several individuals have Parkes Weber syndrome (capillary malformation, micro-AVF, and excessive soft-tissue and skeletal growth of an affected limb).²⁶ Importantly for follow-up and therapeutic options, the risk of recurrence of brain haemorrhage of an AVM should be higher in the patients with HHT than in those with RASA1 mutation or in the sporadic population.²³

PAVF are often associated with two types of hereditary vascular disease: HHT or Osler–Rendu syndrome in up to 25% of cases and capillary malformation-AVM syndrome.

For DAVF, some genetic and environmental risk factors have been reported: HHT, neurofibromatosis type 1, hypercoagulable states, and trauma.^{24, 27} Finally, in one of the largest series reported, several patients presented with congenital vascular anomalies such as venous or lymphatic malformations, and peripheral haemangiomas.⁸

Currently, VGAM is considered a sporadic congenital disorder. Rare cases of VGAM have been associated with Mendelian disorders including instances of autosomal dominant capillary malformation-AVM syndrome type 1 caused by RASA1 mutations and of autosomal dominant capillary malformation-AVM syndrome type 2 caused by EPHB4 mutation.^{26, 28} Loss-of-function mutations in EPHB4 should be responsible for VGAM, associated or not with capillary malformations, in more than 10% of patients.^{28, 29}

An overlap exists, in terms of genetic aetiology, with the various paediatric presentations of cerebral arteriovenous shunts. It is important to propose a genetic evaluation, especially for children presenting with AVM and cutaneous capillary malformation. A genetic diagnosis allows guidance of possible treatments, the follow-up and research of other visceral manifestations, and to give familial-genetic counselling.

Neonatal and antenatal clinical presentation

VGAM are occasionally detected on antenatal ultrasound scans (from about 25 weeks’ gestation). Antenatal MRI will confirm the diagnosis and allow assessment of any pre-existing damage to the brain. It will also allow treatment planning with delivery at a centre having the appropriate facilities and expertise: neonatology, paediatric cardiology/neurology, intensive care, and interventional neuroradiology.

More commonly, VGAM are diagnosed after birth. Often delivery and the first 24 hours are unremarkable. However, larger shunts may then show rapid deterioration with progressive CHF leading to multiorgan failure.

In a recent article, Taffin et al.²⁹ insist on the importance of the results of the analysis of the fetal and neonatal brain MRI to guide the therapeutic management.

For newborn infants, the existence on brain MRI of encephalomalacia (defined as locoregional brain parenchyma atrophy and/or hyperintensity on T1-weighted sequences on cerebral MRI) is a poor prognosis; a therapeutic abstention with palliative care is, therefore, proposed. If at birth the patient does not present a drug-controllable heart failure but has middle cerebral artery pseudo-feeders on MRI, Taffin et al.²⁹ proposed embolization in emergency. Similarly, on antenatal fetal MRI, in the absence of encephalomalacia but with middle cerebral artery pseudo-feeders, if the weight of the fetus is more than 2kg, they propose early delivery with emergency embolization. These proposals need confirmation by additional multicentre data.^{30, 31}

Infancy clinical presentation

Occasionally, children present later in childhood with macrocrania or prominent facial veins secondary to venous outflow obstruction. Macrocrania with hydrocephalus constitutes the primary revealing factor when the diagnosis has not been made previously. Hydrocephalus and prominent facial veins are secondary to cerebral venous hypertension. Intellectual disability and seizures are the main symptoms seen if the correction of the VGAM is not performed in due time, and often occur in children referred late or after ventricular shunting. Focal haemorrhage or acute hydrocephalus is rarely noticed.

Treatment

Many neonatal centres use the Bicêtre Neonantal Evaluation Score, which guides patient therapy and gives information about the significant non-neurological outbreak and the neurological status.³ A score less than 8 out of 21 implies a decision of no treatment; a score between 8 and 12 out of 21 requires an emergency endovascular intervention; and a score of more than 12 out of 21 implies the decision to manage with medical treatment until the child is at least 5 months old.

Embolization by the transarterial route is the first-line treatment^{3, 4} for neonates. EVT is a high-risk procedure and, when possible, the child is medically treated for CHF until the age of 6 months with regular clinical assessment. Embolization is usually performed in several sessions with glue (liquid embolic agent) such as Histoacryl (Braun, Melsungen, Germany) opacified with tantalum powder.

The authors of the largest published study³ showed that, in many cases, complete disappearance of the shunt is not achieved at the end of embolization. The remaining shunt represents less of a risk compared with technical difficulties in complete obliteration. In these circumstances, rupture of the VGAM is not identified.

Some teams complete the treatment of embolization by gamma knife radiosurgery to achieve complete obliteration of the VGAM.³² However, stereotactic radiosurgery has significant limitations: (1) it is not possible, because of the frame placement, in young patients with open cranial sutures; and (2) it has a limited effect on large and/or high-flow fistulas.³³

Prognosis and neurodevelopmental outcome

Where there is evidence of pre-existing brain damage (progressive atrophy or ‘melting brain syndrome’, parenchymal calcification) or severe multiorgan failure, a poor outcome, death, or survival with severe brain damage is inevitable.

When treatment is performed before significant brain damage has occurred, a good outcome is anticipated. In a recent meta-analysis,⁴ outcome was favourable in 68% of patients and unfavourable in 31% with a mortality rate of 16%. The worst prognosis was seen, as expected, in infants with the largest shunts, presenting as neonates with severe CHF.

In their study of outcome of postneonatal presentations of VGAM, Gopalan et al.³⁴ showed that the outcome was categorized as good in 20 out of 28 patients. The observed deficits were speech delay, cognitive disabilities, and behavioural difficulties. A following publication³⁵ of this group described longer-term follow-up and noted that only half of the surviving patients had a good outcome. These results were confirmed by a recent French study,²⁹ in which the long-term evaluation described was much poorer. Furthermore, in the group with a good outcome, 25% of patients reported fatigue or poor memory, and nearly half of the patients had poor concentration. In children who have a good outcome, it will be important to propose a long-term follow-up and assessments to detect neuropsychological disabilities such as attention-deficit disorder, memory difficulties, and executive function abnormalities, and to propose appropriate rehabilitation or medical management.

Case 2

This patient was diagnosed antenatally with a VGAM with ultrasound imaging followed by fetal MRI. CHF developed at the end of the pregnancy so that EVT had to be performed early after delivery. Conventional DSA showed a choroidal type VGAM (Fig. S2a,b, online supporting information). The first embolization (Fig. S2c) was performed at 24 hours and a second at 8 days to restore a normal heart function. Three other embolizations were performed at 3, 24, and 30 months, achieving a 90% occlusion of the VGAM (Fig. S2d,e). All embolizations were performed via a transarterial access and consisted of glue injection within the numerous arteriovenous shunts to occlude them (Fig. S2c). No procedural and clinical complication occurred. Complementary gamma knife radiosurgery was planned for the residual malformation.

Case 3

A 12-month-old child presented with macrocrania and a normal neurological examination. MRI revealed a left PAVF within the sylvian fissure (Fig. S3a, online supporting information). Conventional DSA showed a direct left middle cerebral artery AVF (Fig. S3b). Staged EVT was performed. Four embolizations were performed via a transarterial approach. Embolic coils and glue were used to occlude the arteriovenous shunts (Fig. S3c). No procedural or clinical complication occurred. At the end of four sessions, the PAVF was completely occluded (Fig. S3d).

DSMs

These are focally dilated and bulging dural sinus ectasia.³⁸ The pathogenesis of DSM is associated with uncontrolled development of sinuses, and venous thrombosis with secondary remodelling of the venous drainage. Therefore, the possibility of the venous drainage being rerouted is a favourable prognostic factor. The presence of the so-called cavernous capture, which is the opening of the cavernous sinuses to drain the deep and superficial veins, provides an alternative outlet for the brain and the DSM to drain. Early symptoms can be CHF in neonates, coagulation disorders (consumption syndromes), and moderately increased intracranial pressure (irritability, macrocrania, neurocognitive delay, and seizures) in infants. DSMs away from the torcular with a cavernous capture have a more favourable outcome. Those localized on the torcular have a worse prognosis.

Infantile DAVF

These are dural high-flow, low-pressure shunts, often multifocal, draining into normal sinuses. According to the DAVF location, symptoms may include cranial nerve deficits and facial vein enlargement. Over time, with venous hypertension and the relative venous ischaemia, macrocrania, and neurocognitive delay may be seen.

Adult-type DAVF

As with DAVF in adults, these paediatric fistulas are thought to be a focal angiogenic response to focal venous/sinuses thrombosis. According to the DAVF location, symptoms may include oculomotor nerve palsies, proptosis, and intracranial bruit. Prognosis is often favourable as spontaneous occlusion frequently occurs.³⁸

Treatment

EVT is the first-intention therapeutic option for DAVF; surgery and radiosurgery are indicated if EVT fails or is not possible owing to difficult endovascular access. In most cases, several embolizations are needed with embolic agents such as coils and/or glue. In the particular subgroup of DSM, anticoagulation is indicated to avoid a spontaneous thrombosis.

Compared with the other paediatric arteriovenous shunts, DAVF have lower rates of complete occlusion and poorer clinical outcomes.⁸ As with adults, the presence of cerebral venous reflux is the most predictive feature for future neurological manifestations. In the series by Hetts et al.,⁸ 55% of patients with venous reflux had poor outcomes whereas all patients without venous reflux had good outcomes.

Long-term follow-up is mandatory because these patients have a higher risk of developing de novo DAVF later in life.³⁶

Case 4

This patient was diagnosed antenatally with a DAVF with ultrasound imaging followed by fetal MRI. CHF developed at the end of the pregnancy so that EVT had to be performed early after delivery. Fetal MRI (Fig. S4a,b, online supporting information) and conventional DSA (Fig. S4c) showed a DSM of the left lateral sinus with a giant ectasia of the sinus (arrows in Fig. S4a–c). Embolization (Fig. S4d) was performed at day 1 via a transarterial access and consisted of coil occlusion of the main arterial feeders close to the shunt zone. No procedural and clinical complication occurred. Angiographic controls at the end of EVT showed a significant flow reduction within the DSM (Fig. S4e,f). Low molecular mass heparin was administered and kept for a few months. A first MRI control was performed at day 8 which showed a significant decrease of the giant ectasia of the sinus (arrows in Fig. S4g,h). The patient could be discharged with a normal neurological examination and no more CHF. MRI control was scheduled.

Treatment

Because brain AVM carry a higher risk in children than in adults, most patients are treated with the aim of achieving a complete AVM occlusion. Therapeutic options include embolizations, radiosurgery, and surgery, and are often combined. In the literature, outcome is favourable in 76.4% to 83% of patients and poor in 17% to 19% including death in 4.7% to 6.5%.^{22, 40, 42}

Endovascular embolization is made step by step with large intervals between sessions. This can stabilize a critical situation. The aim of partial treatment is to eliminate progressively dangerous portions of AVM and their effects on adjacent brain parenchyma, or to reduce seizures, progressive neurological deficits, or headaches. Even if EVT is the primary choice, complete exclusion is not always obtained and complementary treatment is usually planned.^{42, 43} With radiosurgery treatment, the obliteration rate ranges from 100% in very small lesions to 50% in large lesions. Combinations of embolization or microsurgery and stereotactic radiosurgery are routine in some centres, allowing complex lesions to be cured. Radiosurgery also offers an excellent treatment option in inaccessible, deep, or eloquently placed paediatric AVM presented with haemorrhage, epilepsy, or headaches. Even though the existing data confirm radiosurgery as a safe and efficacious modality for selected children with AVM, long-term follow-up is needed because long-term effects of ionizing radiation on the developing nervous system have not yet been fully evaluated. Complications such as intracranial malignancy or neuropsychological deficits have been reported but are still not well studied.^43-46 Moreover, symptomatic radionecrosis has been reported in about 3% to 4% of cases and is highly dependent on the dose:volume ratio of the treated target; it appears on neuroimaging as focal oedema. Neurological sequelae are seen in 5% to 15%.

Although the outcomes for patients treated for an AVM depend on the initial presentation, and the size and the location of the AVM, several studies have shown favourable functional and educational outcomes for these patients.⁴⁴ Last but not least, rare regrowth of an AVM can be seen, even several years after complete occlusion.⁴⁷ Therefore, long-term follow-up imaging and neurodevelopmental evaluations are needed, including the period from adolescence into young adulthood.

Case 5

A 10-year-old male presented with a sudden onset of headaches. Computed tomography of the brain revealed a left occipital haematoma (Fig. S5a, online supporting information). Conventional DSA was performed and showed an AVM with two flow-related intracranial aneurysms on the feeding arteries (Fig. S5b). Urgent EVT was performed with glue injection, which achieved a complete occlusion of the lesion (Fig. S5c). The patient was discharged 2 weeks later; at 12 months he had a normal neurological examination, and a DSA control confirmed the stable and complete occlusion of the AVM (Fig. S5d).