Endovascular Treatment of Pulmonary and Cerebral Arteriovenous

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1 Endovascular Treatment of Pulmonary and Cerebral Arteriovenous Current Pharmaceutical Design, 2005, 11, /05 $ Â 2005 Bentham Science Publishers Ltd. Teleangiectasia E. De Cillis1, N. Burdi2,*, A.S. Bortone1, D. Dâ Agostino1, T. Fiore4, G.C.Ettorre3 and M. Resta2 1Institute of Cardiac Surgery - University of Bari, Bari, Italy; 2Department of Radiology - â œss. Annunziataâ Hospital â AUSL TA/1, Taranto, Italy; 3Department of Radiology - University of Foggia, Foggia, Italy and 4Department of Anaesthesiology â University of Bari, Bari, Italy Abstract: Hereditary Haemorrhagic Teleangiectasia (HHT) is a vascular disorder of angiogenesis transmitted in an autosomal dominant pattern, characterised by heterogeneity in clinical manifestations. One of the most important organ involved is lung, including pulmonary arteriovenous malformations (PAVM). PAVM occur in 20 to 30% of the HHT population and recently are considered a marker of disease. PAVM are direct artery-to-vein connections with low pressure and without an interveining capillary bed. PAVM are classified as simple (supplied by one feeding artery) or complex (receiving blood supply from two or more feeding artery). According to the international reports, treatment itâ s recommendable for all PAVM with feeding vessels 3mm or larger, in order to reduce the risk of cerebral ischaemia and neurologic manifestations frequently attributed to paradoxical embolisation. Transcatheter embolotherapy of PAVM is a form of treatment based on occlusion of the feeding artery to a PAVM by using platinum coils or detachable balloons. The technique of coil embolisation involves the exact localisation of PAVM by pulmonary angiography followed by superselective percutaneous caheterisation of feeding artery obtained by using a dedicated 7F guiding catheter, which coaxially allocates a 5F hydrophilic catheter advanced in order to perform both superselective angiography of feeding artery and embolisation itself. Inside the 5F catheter the platinum coils are advanced using a.035â guide-wire and released until an optimal occlusion of feeding artery is achieved. At the end of the procedure angiographic control is performed in order to verify the occlusion of feeding artery. The use of platinum coils is preferable over detachable balloons when feeding artery are greater than 7mm in diameter and have irregular anatomical configuration. On the other hand, the principal advantage of using detachable balloons is that the balloon itself can be deflated and repositioned if necessary. Transcatheter embolotherapy is technically safe and clinically effective and may represent the primary choice of treatment in HHT patients. On the other hand the most common complications of this treatment (pleurisy and air embolism) can be prevented by using some tips during the embolisation procedure like â œanchor technique,â â œscaffold techniqueâ and â œballoon assisted technique.â Cerebral arteriovenous malformations (CAVM) are present in 10-20% of patients with HHT and multiple in 50% of cases. Cortical surface is the most frequent localisation. Angiography is needed to diagnose all CAVM and to clarify the angioarchitecture of the lesion. In HHT CAVM are usually either micro-avm, with a nidus not bigger than 1 cm, or small AVM, with a nidus between 1 and 3 cm. Quite frequently there are lesions characterised by arteriovenous fistulas. In the three patterns of CAVM usually found in HHT, small AVM are the most risky for bleeding although the risk is lower than that associated with sporadic ones. It is estimated from 0.38 to 0.69% per year in spite of the general incidence of bleeding in sporadic CAVM that ranges from 2 to 4% per year. In HHT patients, at present, the precise indications and timing of treatment are not established. Trend is to treat small AVM and AVF and to follow-up micro-avm with MRI and angiography. As for sporadic CAVM, treatment of small AVM is usually referred to stereotactic radiosurgery. Endovascular embolisation is proposable if the lesion is easily reachable by microcatheterism and the position of the microcatheter is safe. Glue is used for embolisation and the technique is briefly discussed. Key Words: Hereditary Haemorrhagic Teleangiectasia (HHT), Pulmonary arteriovenous malformations (PAVM), Cerebral arteriovenous malformations (CAVM), Percutaneous transcatheter embolotherapy INTRODUCTION The expectancy of life in the patients affected by Hereditary Haemorrhagic Teleangiectasia (HHT) has increased *Address correspondence to this author at the Radiology Unit, Ospedale â œss. Annunziataâ, Via Bruno, 1, 74100, Taranto, Italy; Tel: + 39 (080) ; Fax: + 39 (080) ; niburdi@tin.it; e.decillis@cardiochir.uniba.it significantly in the last few years thanks to the better understanding of the disease and to the possibility of performing mini-invasive treatments of the mucocutaneous and visceral arteriovenous malformations (AVM). Endovascular treatment is used for the visceral localisations of the disease. Transcatheter embolisation is now the method of choice for the therapy of pulmonary 2 Current Pharmaceutical Design, 2005, Vol. 11, No. 00 Cillis et al. arteriovenous malformations (PAVM) and it is considered in

2 the treatment of cerebral vascular malformations, too. PULMONARY ARTERIOVENOUS MALFORMATIONS PAVM represent a relatively late expression of HHT also known as Rendu-Osler-Weber disease. This hereditary condition, which is transmitted in an autosomal dominant pattern and characterised by extremely various clinical manifestations, is associated with PAVM especially in type 1 (caused by mutation of endoglin). Several studies show [1] that the incidence of PAVM is higher in families with endoglin mutation. PAVM occur in 20 to 30% of the HHT population and more recently are considered a marker of the disease. PAVM can be defined as high flow, low pressure shunts consisting typically in a single feeding artery (that normally grows from the pulmonary artery) abnormally connected via an aneurismal sac to an efferent vein (draining generally in left atrium) without an intervening capillary plexus. The aforementioned is defined as simple type and represents the 80-90% of total detected lesions [2-4]. The remaining belongs to complex variety with 2 or 3 feeding arteries and two or more draining veins. A small group of patients has a diffuse and often bilateral disease defined as arteriovenous malformations involving every subsegmental artery or at least one pulmonary lobe [5]. A not slight part of patients has been reported to have multiple localisations, often bilateral. The presence of a single fistula of less than 2cm in diameter is generally not associated with symptoms, but the incidence proportionally grows according to the increase of PAVM in number and diameter. So that PAVM wider than 2cm in diameter, with feeding artery bigger than 3mm, are symptomatic and are called for treatment due to the high incidence of neurological complications in the untreated patients. Indeed recent reports have documented that PAVM less than 2cm in diameter, with feeding artery more than 3mm, are able to cause neurological complications as cerebral ischaemia, stroke, and brain abscess due to paradoxical embolisation [6]. This strong, well-established association between PAVM and neurological complications, focuses on the benefit of therapeutic PAVM embolisation in preventing neurological events. The natural history of untreated PAVM goes towards a progressive enlargement so that White and coll. [7] have recommended treatment of all PAVM with the feeding artery larger than 3mm. Despite great advances in the non-invasive techniques for the diagnosis of PAVM in the HHT disease (as contrast echocardiography, contrast-enhanced ultra fast CT, MRI), pulmonary angiography remains the gold standard in the detection of pulmonary localisations especially when they are amenable to transcatheter embolotherapy. This technique represents actually the definitive modality of treatment in HHT patients with PAVM, having surgical intervention demonstrated to be associated to high mortality and post-operative complications, due to thoracotomy and long hospital stay. Embolisation therapy is a percutaneous treatment based on the occlusion of the feeding arteries, using platinum coils or detachable balloons. The technique of coil embolisation involves the exact localisation of PAVM by pulmonary angiography followed by superselective catheterisation of feeding artery. Selective pulmonary angiograms are obtained with a 7F angiographic catheter inserted via right femoral vein with a 7F introducer sheath. The percutaneous procedure is carried out in the angiography suite under local anesthesia. One hundred IU/kg of heparin are administered intravenously in order to get activated clotting time (ACT) values of s. The patient is monitored with electrocardiography

3 and arterial oxygen saturation is measured noninvasively with digital pulse oximetry. The first step is to identify the affected portion of lung parenchyma by selective injection of contrast medium into each pulmonary artery. Angiograms are performed in right anterior oblique 30 (RAO) and left anterior oblique 45 (LAO) views; sometimes the latero-lateral view is used. Each portion of pulmonary fields is checked in order to look for all possible lesions even those ones involving pleura, and to detect any possible intra and extrathoracic vascular communication. The diagnostic catheter is replaced with a 7F guiding Lumax-White catheter which coaxially allocates a 5F hydrophilic catheter advanced in order to perform both superselective angiograms of feeding arteries and embolisation itself. The tip of the catheter is advanced as close as possible to the neck of PAVM in order to allow an optimal cross-sectional occlusion and at the same time to preserve the proximal vessels supplying the normal surrounding lung parenchyma. Inside the 5F catheter, the fibered Nester coils (Cook Inc., Bloomington, IN), platinum coils added with synthetic fibres (available in different sizes:.018â,.035â,.038â ), are advanced using a.035â guide-wire and released until an optimal occlusion of feeding artery is achieved. The envelopment of the coils into the aneurismal sac with the potential systemic migration must be avoided. The fibered Nester coils are softer than similar ones and are projected to assess perfectly into the vessels while the synthetic fibres enhance the clot formation. Finally angiographic control is performed in order to verify that feeding artery has been tightly filled and blood flow to the PAVM has ceased. Then, the system was withdrawn. The use of fibered coils seems preferable over detachable balloons when feeding artery are greater than 7mm in diameter and have particularly irregular anatomical configuration. On the other hand, the use of detachable balloons is recommended when the vessel profile is very regular. The balloon catheter is, in this case, exchanged over the wire and positioned at the neck of PAVM. The balloon is then inflated with radio-opaque contrast dye and after verifying angiographically the complete occlusion of feeding artery the balloon is detached. The principal advantage of this technique is that the balloon can be deflated and repositioned if necessary. Actually the detachable balloons have no more label approval for use in treatment of PAVM because the coaxial catheter is considered unsafe. When PAVM are solitary (simple or complex) the diagnostic assessment and the embolisation procedure can be performed in the same session compatibly with tolerance to contrast dye and side effects such pleural effusion and pain. Also multiple PAVM may be treated by single but it seems preferable to subdivide the treatment in different sessions to reduce side effects. A hiatus of 2-3 weeks can be adequate to complete the procedure and to achieve the occlusion of all lesions detected minimising the development of pleurisy. The latter is the most common Endovascular Treatment of Pulmonary and Cerebral Current Pharmaceutical Design, 2005, Vol. 11, No complication of procedure especially when it involves large PAVM with feeding artery greater than 8mm and it is probably due to thrombosis of aneurismal sac near to visceral pleura. It occurs in the first 24-48h following the embolisation procedure and generally it responds to non steroidal anti-inflammatory drugs. Another collateral effect due to a uncorrected procedure is the air embolism related to the wrong withdrawn and advancement of embolisation materials and it can involve the onset of angina, bradycardia and perioral paresthesias [3-8]. As regard to the groups of

4 patients having a severe and diffuse often bilateral PAVM, according to recent papers, [5] almost 70% of these patients had a history of neurological complications. In this group, after a superselective angiography, it is possible to perform a thrombotic segmentectomy by embolising all subsegmental branches. As a matter of fact, until the 70% of PAVM are detected in the lower lobes [3-9] and the segmentectomy of segmental arteries, promoting the pulmonary flow redistribution, increases the recruitment towards the middle-upper pulmonary fields in order to reduce systemic oxygen desaturation and to improve exercise tolerance. (Fig. 1) Moreover, these patients have, besides a high risk of neurological events, also an additional one of systemic infections due to lost of filter capacity of the pulmonary capillary plexus. Different technical tips and tricks can be used during the embolisation procedure. The most well-known is the â œanchor techniqueâ (Fig. 1), introduced by White and coll., that allows a safe placement of the coils in the feeding artery avoiding the slippage forwards into aneurismal sac and systemic migration. In practise, since the coil it is normally 2mm larger than the diameter of feeding artery, the first 2cm of a long fibered coil is anchored in side branches while the remaining is packed tightly with additional coils into a nest until the artery is occluded. For large PAVM it is possible to perform a technique called â œscaffold techniqueâ : a sort of endoskeleton is constituted by using high radial force coils, then the occlusion of the artery is definitely achieved with fibered coils added and packed (Fig. 2). Finally, the latest technique is the so called â œballoon assistedâ obtained by temporary occlusion of the feeding artery in order to reduce the pulsatile flow which allows a safely realising of coils in larger feeding arteries and high flow lesions. By using correctly the aforementioned techniques usually the increase of oxygen saturation associated with no reperfusion of the treated lesions as well as the complete thrombosis and retraction of aneurismal sac were reported [4]. CEREBRAL ARTERIOVENOUS MALFORMATIONS Cerebral arteriovenous malformations (CAVM) are present in 10-20% of patients with HHT but only 2% of CAVM are associated with HHT [10]. In HHT, CAVM are multiple in 50% of cases while, in the whole population of patients with sporadic CAVM, they are multifocal in 1% to 3% of cases [11]. Cortical surface is the most frequent localisation for CAVM in HHT [11]. Magnetic resonance imaging (MRI) is used for screening of patients with suspected HHT although Fulbright et al. reported that MRI could underestimate the prevalence of CAVM in HHT patients [12]. Angiography is needed to diagnose all CAVM and to clarify the angioarchitecture of the lesion. a b Fig. (1). Selective angiography of right lower lobe showing a diffuse involvement before (a) and after (b) thromboembolic segmentectomy by using the â œanchor techniqueâ. Usually CAVM in HHT are micro-avm with a nidus not bigger than 1 cm (Fig. 3). They are found in approximately 43% of cases [13], while only 10-12% of individuals with HHT have small AVM with a nidus between 1 cm and 3 cm (Fig. 4). Quite frequently there are lesions characterised by arteriovenous fistulas (AVF), found by Matsubara et al. in 28, 6 % of their patients [11]. 4 Current Pharmaceutical Design, 2005, Vol. 11, No. 00 Cillis et al. a

5 b Fig. (2). Selective angiography of the left upper lobe showing a large and high flow solitary PAVM before (a) and after (b) successful occlusion by using the â œscaffold techniqueâ. Micro-AVM has very often a simple architecture characterised by a single feeding artery and a single vein usually draining in the superficial venous system. On the other hand angioarchitecture of small AVM may be more complex having usually multiple feeders and single veins draining often in the deep venous system with frequent pouches. AVF, at last, have generally single feeding artery and single draining vein with pouches [11]. Bleeding from a CAVM is related to the presence of one or more of the following three factors: a flow-related aneurysm, a stenosis in the draining vein, a pure deep venous drainage [14]. The risk of morbidity and mortality linked to a CAVM is graded by a scale proposed by Spetzler and Martin [15]. It assigns points based on the size of the AVM, the eloquence of the area and the pattern of the venous drainage (Table 1). Grading goes from 1, the mildest risk, to 5, the most severe one. In the three patterns of CAVM usually found in HHT, small AVM are the most risky for bleeding although the risk is lower than that associated with sporadic ones. Willemse et al. calculated the bleeding risk in their group of 24 HHT patients with at least one CAVM [16]. It ranged from 0.38 to 0.69% per year compared to the general incidence of bleeding in sporadic CAVM that ranged from 2 to 4% per year [14]. Table 1. Grading of Arteriovenous Malformations According to Spetzler and Martin [15] Graded Feature Points assigned Points assigned Size of AVM Small (< 3 cm) Medium (>3 <6 cm) Large (> 6 cm) Eloquence of surrounding brain Noneloquent Eloquent 0 1 Venous drainage Superficial only Deep 0 1 Nevertheless, according to the Spetzler and Martin grading system, cerebral bleeding can be disastrous [17] and therapy must be considered in every kind of CAVM. Goal of the therapy is to remove or obliterate the nidus of a lesion. This goal can be reached by endovascular embolisation, stereotactic radiosurgery or neurosurgical removal. Current opinion refers to radiosurgery sporadic CAVM having nidus not bigger than 3 cm, particularly when they Fig. (3). Selective angiography of the left vertebral artery â lateral view. Multiple cerebellar microavm (white arrows) in a HHT patient. Endovascular Treatment of Pulmonary and Cerebral Current Pharmaceutical Design, 2005, Vol. 11, No are located in deep areas of the brain. Embolisation is preferred in larger CAVM with the aim of reducing permanently the volume of the nidus before radiosurgical obliteration. Neurosurgical removal is considered in cases of superficial AVM in not eloquent areas of the brain.

6 a b Fig. (4). Selective angiography of the left internal carotid artery â lateral views: a typical small AVM (white arrow in a) in HHT patient. The malformation is fed by a single artery (black arrow in a) and drained by a single vein toward the superficial sagittal sinus (black short arrow in b). In HHT patients, at present, the precise indications and timing of treatment are not established. Trend is to treat small AVM and AVF and to follow-up micro-avm with MRI and angiography [18]. As for sporadic CAVM, treatment of small AVM, with nidus up to 3 cm, is usually referred to stereotactic radiosurgery. But complete obliteration of a nidus verifies in 1 to 4 years after radiosurgery. In this latency interval before complete obliteration patients continue to be at risk for AVM hemorrhage and the annual bleed rate for the first 3 years after radiosurgery has been reported as 3, 7% to 16% [19]. Furthermore, the wait for treatment in radiosurgical centres often requires a lot of months with consequent increase of the risk. That is why, in our opinion, if the lesion is easily reachable by microcatheterism and the position of the microcatheter is safe, embolisation by glue is proposable (Fig. 5). Fig. (5). Small AVM in HHT patient. The tip of the microcatheter is wedged in the nidus (white arrow) in safe position for glue embolisation. The embolisation is performed on the patient under general anesthesia. A 6F guiding catheter is placed in the internal carotid artery as close as feasible to the skull base and a flow-directed 1.2F microcatheter is coaxially introduced. During the procedure both the catheters are continuously flushed with saline. Systemic heparinisation is not used routinely, but just when feeding arteries are small and tortuous. The microcatheter is easily advanced by flow control through the cerebral vasculature and its visualisation is enhanced by flushing with water-soluble iodine contrast material. Once the tip of the microcatheter is wedged in the nidus of the AVM or at the entrance of the AVF, superselective angiograms are obtained in the two orthogonal projections in order to evaluate the flow characteristics, the angioarchitecture and the venous drainage of the lesion. Glue is composed by N-butyl-2-cyanoacrylate (NBCA), a substance that polymerizes in contact with blood. In order to make it radiopaque and to increase the polymerisation time, NBCA is mixed with iodised oil (Lipiodol) and the appropriate mixture is determined by the previous evaluation of the mentioned patterns. Under subtracted roadmapping, radiopaque glue is slowly injected until the nidus has filled or there is back reflux of glue extending along the microcatheter. At this point, the microcatheter is quickly, but gently, withdrawn and a control angiogram is performed by the guiding catheter. Depending on the size of the AVM and the number of the feeders, multiple microcatheterisms with glue injections may be necessary. The small CAVM frequently found in HHT generally need one or two glue injections to be totally obliterated. However, the AVM pat6 Current Pharmaceutical Design, 2005, Vol. 11, No. 00 Cillis et al. tern may be sometimes complex and multiple embolisation sessions, with several glue injections, may be needed. If a very high-flow AVF is encountered, it may be necessary to slow down the flow in the feeding artery by the release of a detachable platinum coil immediately before the embolisation with pure glue. This technique can be useful in order to prevent the undesired occlusion of the draining vein whose consequences may be devastating.

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