An arteriovenous malformation (AVM) can develop in any tissue in the body. Normally blood carries oxygen from the lungs to the cells that require it to live and function. The oxygen laden blood is pumped through muscular blood vessels called arteries. These enter a network of tiny vessels within the tissues called a capillary bed. It is here that the oxygen is delivered before being returned to the lungs via non-muscular vessels called veins. It is characteristic of an AVM that the capillary bed is absent or deformed and the oxygenated blood under its original high pressure is diverted directly to the veins placing unusual stress upon them.
Angioarchitecture
Central to understanding the nature of different vascular pathologies is the concept of the arteriovenous shunt. With an AV shunt pressurised blood, laden with oxygen travels directly from the muscular arteries to the thinner walled veins without passing through an intervening capillary bed. Consequently the veins are distended and may weaken as a result. Should they become so distended that the flow of blood becomes turbulent the a clot may form blocking the egress of blood from the malformation and therefore increasing the pressure within it risking tears developing in contributing blood vessels.
Arteriovenous Malformation
An arteriovenous malformation is characterised by an AV shunt that passes via a nidus. This is a tangle of malformed and immature in place of a capillary network. The term itself derives from the latin word for "nest".
The nidus cannot deliver oxygen to the tissues and as a result the tissue nearby is often malformed itself on a microscopic level and does not function normally. Layers of cells damaged by pulsation and low oxygen levels may discharge electrochemical signals abnormally kindling the electrical storms within the brain we know as seizures. Less commonly the relative reduction in blood flow can affect neurological function in adjacent brain but as AVMs usually develop in-utero or early childhood, the brain develops around it rather than vice-versa and function is often displaced from the brain immediately adjacent to the nidus.
Associated Aneurysms and Stenoses
Aneurysms are balloon-like dilations that may develop on any of the contributing vessels to an AVM. They may be considered as a sign of "wear and tear" on the vessels coping with more blood flow than designed for. They are seen on arteries, veins and within the nidus. As such they might be a source of bleeding from an AVM. However the evidence that their presence should direct treatment is not conclusive. Preventative treatment of arterial aneurysms has the strongest evidence base to avoid bleeding in the future.
Stenoses are narrowing that develop in veins leaving the AVM. These may develop because of stresses on the vein or represent the recanalisation of a clot obstructing a vein. If restricting the blood flow out from the malformation they might contribute to increased pressure within the nidus, still further vascular stress and possibly bleeding as a result.
Arteriovenous Fistula
An arteriovenous shunt is described as a fistula when there is not an intervening nidus between artery and vein. AV fistulae involving vessels in the leathery coverings of the brain are termed dural arteriovenous fistulae and have a quite distinct behaviour from AVM. Should these find a communication to the veins draining from the surface of the brain though they can pose a greater risk of bleeding than a malformation. These are are more often acquired later in life although there are rare genetic drivers for their development in children.
If the fistula develops on the surface of the brain its behaviour may be more in keeping with AVM and the treatment options are similar. Fistulas may be identified in assosciation with an AVM even if the blood passing through them does not pass through the nidus.
Mixed or Complex Malformations
There is another element to the body's circulatory system called the lymphatic system. The lymphatics are vital in delivering elements of the immune system (white cells, antibodies for e.g.) to where they are required. They also play a role in the regulation of fluid in the tissues and have an intimate relationship with the venous system. They too can form part of a vascular malformation.
While not recognised within the brain they form in the soft tissue of the head and neck typically as part of mixed malformation with veins. The arterial element is not typically high flow and arteriovenous shunting is usually not present to a large degree. When different combinations of tissues are involved such malformations may be referred to as complex. They present with symptoms related to mass in their native tissues or presenting cosmetic concerns. There is a rare form of complex malformation that can include the nervous system as well as its surrounding tissues and there is more information about those here.
A summary classification with known genetic assosciations for all types of vascular malformation may be viewed here.
Why Do AVM Develop?
It was believed that AVMs formed in the developing foetus or in the period immediately after birth. However, there are now well-documented cases where the AVM clearly developed later in childhood. This tells us that the development of an AVM can be a dynamic process affected by the body's "software"- genes- with possibly environmental factors influencing them.
Somatic Gene Mutations
In 2018 Nikolayev and colleagues reported that they had identified somatic mutations of the KRAS gene in sporadic brain AVMs. A somatic mutation is one which occurs only in the tissue affected by the disease and therefore is not passed to the next generation necessarily.
KRAS mutations were already well recognised in several cancers e.g. lung, pancreas and colorectal carcoinoma a molecular signalling pathway called the RAS/MAPK pathway affected. These changes to that pathway seem to affect how the cells in the inner wall of the blood vessel (endothelial cells) develop and move but not how they proliferate. Therefore the growth of AVMs seems to arrest early in life.There is a great deal yet to be learned about why AVMs develop in tissues and through understanding these processes it is hoped new treatments may emerge.
Constitutional (Germline) Gene Mutations
Most AVMs encountered in clinical practice are isolated lesions but there are uncommon conditions where an aberrent gene programs AVMs and other vascular malformations to develop throughout life.
Hereditary Haemorrhagic Telangetasia
This is a collection of conditions characterised by the development of multiple AVMs in various locations including the brain, skin, eyes, mucus membranes and lungs. Telangectasia are small bright red vascular malformations in the skin. It is thought to affect between 0.1-0.2% of the population. An understanding of the HHT gene mutation provided the prototype for a deeper understanding of how all vascular malformations develop. In particular it shed light on the importance of a protein called Endoglin and its vital role in new blood vessel development.
There are several subtypes of HHT recognised:
HHT-1 is caused by a mutation of the ENG gene. Patients develop AVMs in the lung and in the brain.
HHT-2 is caused by a mutation of the ACVRLI gene. AVMs of the brain and lung develop but patients are affected later in life than in HHT-1.
HHT-3 is assosciated with more frequent involvment of the liver than types 1 and 2. The exact gene abnormality is not known but thought to be on chromosome 5. 30-79% of those with HHT3 also harbour one or more cavernoma.
HHT/Juvenile Polyposis Syndrome is the result of a mutation of the SMAD4 gene and results in a propensity to develop polyps in the gastrointestinal tract as well as AVMs. Such polyps are not found in HHT types 1-3.
Craniofacial Metameric Syndrome
This is again a collective term for a group of related conditions, some of which have been recognised in isolation for a long time.The human body develops in discrete sections called metameres. Vascular malformations of the head, neck and brain occur in this condition within the discrete metameres that make up the head and neck. A rare variety of spinal coloumn AVM ("juvenile" or "metameric" AVM) likely results from the same process ("SAMS"). This group of conditions may encompass the Sturge-Weber and Wyburn-Mason Syndromes. :
CAMS-1 sees AVMs develop in the region of the nose, the frontal part of the brain and the hypothalamus.
CAMS-2 is characterised by AVMs of the mid-face, retina, visual pathways within the brain, the thalamus and the occipital lobes.
CAMS-3 affects the hindmost parts of the brain (pons, cerebellum) and the jaw.
Capillary Malformation- Arteriovenous Malformation Syndrome
(CM-AVM types 1 and 2)
CM-AVM is a condition first described in 2003. It results from a mutation of he RASA1 gene. RASA1 provides instructions for making a protein called p120-RasGAP. This protein helps regulate a signalling pathway from a cells nucleus to the elements of the cell outside the nucleus. This is the RAS/MAPK signaling pathway and it is involved with several important cell functions.In the CM-AVM syndromes, AVMs develop on the face, arms and legs but may also be found in muscle, bone, brain and spinal cord. Sometimes only malformations of the capillaries develop. . In others both capillary malformations and arteriovenous malformations co-exist.Usually an individual affected by CM-AVM will have inherited the condition from one affected parent (autosomal dominant inheritence).t is possible, however, for the condition to arise with no previous family history of the disease as a result of a new gene mutation. The condition affects approximately 1:100000 persons of northern european descent.
Epidemiology
A new brain AVM is diagnosed in about 0.89 to 1.34 per 100000 people each year and the incidence is increasing likely as a result of the increased use of sensitive cranial imaging. It is not known with certainty how common they might actually be. A well-designed population study in Scotland identified 18 per 100000 people (0.02% of the population). A study of German Airforce recruits found an AVM rather more often at 0.51% (95% CI 0.29 to 0.9%, n=2536).
How AVM Are Discovered
About 50% of brain AVMs coming to medical attention do so because the individual suffered a brain haemorrhage. After that it is most frequent that they are encountered in people undergoing investigation for neurological symptoms. While tempting it can be difficult to be certain that neurological symptoms are always caused by the often alarming-looking malformation. Conditions such as migraine are encountered more frequently in people harbouring vascular malformations but that may not mean the migraine would resolve with treatment of the AVM.
Evaluating Brain AVMs
Brain arteriovenous malformations (AVMs) represent a diverse array of conditions. While certain architectural patterns are identifiable, they exhibit significant variability in size and location. Blood flow may be facilitated by a single artery and exit through a single vein, or alternatively, multiple arteries may supply the AVM with only a few veins for drainage, or vice versa. The volume of blood flow can also differ markedly between malformations. This diversity implies that each AVM is unique to the individual, necessitating caution when extrapolating risk from limited documented cases of brain AVMs.
It may be helpful to classify common features amongst AVMs and attempt to model risk from the disease itself or from its treatment. You may notice that the "grade" of your AVM is referred to in correspondence and notes. Below are described the most frequently used grading systems used in our practice. While this approach does harmonise decision making to a degree there are AVMs that fail to fit the model or an element of subjectivity creeps into the application of a grading systems. Therefore decisions based on such gradings require expertise and context.
Spetzler-Martin Grading
The best established clinical grading system used to assist clinical decision making is based on the retrospective analysis of surgical outcomes collected by Professor Robert Spetzler and colleagues and published in 1986. They identified three characteristics of AVMs that are consistently associated with the outcome of surgical removal.
The simplicity of the Spetzler Martin grading system is one of its strengths and it has become the criterion standard in describing an AVM of the brain. It does not apply to other types of arteriovenous shunt or spinal cord AVM.
Spetzler-Ponce Classification
The authors refined the Spetzler-Martin system still further by recognising three groups within the spectrum of Spetzler-Martin grades and published this as the Spetzler-Ponce system. Group A comprises SM grade 1 and 2 AVMs that consistently display favourable outcomes from microsurgical resection. SM grade 4 and 5 AVMs are associated with unfavourable outcomes and are most often preferred for a conservative approach- Spetzler-Ponce class C. Spetzler-Martin grade 3 AVMs make up the Spetzler-Ponce class B and comprise a group with less consistent outcomes. Some SPc-B AVMs do well with surgery but others are more difficult to treat. Consequently there have been many attempts to provide more granularity about outcomes for this particular group.
Lawton-Young Supplemental Grading
Lawton and colleagues retrospectively analysed multiple factors believed linked to poor surgical outcomes in a large concutve series of surgically treated brain AVMs at the Barrow institute and UCSF, subsequently validating their findings in large international cohorts. They produced a practical, pragmatic tool to that affords greater resolution particularly for SPc-B/SM3 lesions but is still simple to apply. The factors used to weight risk are age, a history of bleeding from the AVM and whether the nidus is described as "compact" or "diffuse". The resulting points are added to the Spetzler-Martin grade to provide a score out of a possible 10. The morbidity of surgery is generally accepted to become excessive for lesions with a supplemented grade above 6.
This supplemented scoring system has been validated in large international cohorts and in our own series of surgically treated brain AVMs. While the Spetzler-Martin system performs well supplementation improves the accuracy of our risk estimates particularly for larger AVMs.
