Sunday, March 30, 2008

The Brain and Cell Phones: Back to Future and The AVM


Mobile phones"more dangerous than smoking"
Mobile phones are convenient and frequently invaluable, yet exposure to their electromagnetic radiation is invisible. Therefore, any danger this exposure poses may be easily dismissed.
* Exposure is long-term and its effects on the body, particularly its electrical organ, the brain, are compounded by numerous other simultaneous long-term exposures including continuous waves from radio and TV transmitter towers, cordless phone base stations, power lines, and wireless/WiFi computing devices.
* A malignant brain tumour represents a life-ending diagnosis in the vast majority of those diagnosed. There is a significant and increasing body of evidence, to date at least 8 comprehensive clinical studies internationally and one long-term meta-analysis, for a link between mobile phone usage and certain brain tumours.
* Taken together, the data presented below compellingly suggest that the link between mobile phones and brain tumours should no longer be regarded as a myth. Individual and class action lawsuits have been filed in the USA, and at least one has already been successfully prosecuted, regarding the cell phone-brain tumour link.
* The "incubation time" or "latency" (i.e., the time from commencement of regular mobile phone usage to the diagnosis of a malignant solid brain tumour in a susceptible individual) may be in the order of 10-20 years. In the years 2008-2012, we will have reached the appropriate length of follow-up time to begin to definitively observe the impact of this global technology on brain tumour incidence rates.
* There is currently enough evidence and technology available to warrant Industry and Governments alike in taking immediate steps to reduce exposure of consumers to mobile phone-related electromagnetic radiation and to make consumers clearly aware of potential dangers and how to use this technology sensibly and safely.
* It is anticipated that this danger has far broader public health ramifications than asbestos and smoking, and directly concerns all of us, particularly the younger generation, including very young children.
* Scientists and physicians from some academic centres worldwide came together in mid-2007 to propose safer standards regarding public exposure to electromagnetic fields (Click the link for details).

1. What is an arteriovenous malformation (AVM)?

An arteriovenous malformation (AVM) is a site of abnormal connectivity between arteries and veins. It is basically like a tangle of worms, where the greatest concentration of worms in the central portion of the AVM (this part is the "nidus") is made up of abnormal blood vessels that are hybrids between true arteries and veins. AVMs are fed by one or several arteries, and are drained by one or more major draining veins; these feeding and draining vessels may be unusually tortuous (winding like rivers), and unusually large. They can occur in the brain (brain AVMs) or along the spinal cord (spinal AVMs).

The vessels of an AVM are abnormal and so may leak or rupture (hemorrhage; that's the main problem; see 5. below). The blood flow and pressure in especially the larger vessels of an AVM are unusually high and may lead to significant shunting of blood to and from the lesion. Higher flow-pressures in addition to abnormal AVM vessel wall structure can lead to the formation of aneurysms on arteries feeding the AVM (i.e., "parent artery" or "pedicle" aneurysms) or within the AVM itself (i.e., "intranidal" aneurysms). These can also rupture. Somewhere around 6-7% of brain AVMs have aneurysms associated with them, and when AVMs rupture, some think it may be these aneurysms which have ruptured (although the abnormal nonaneurysmal components of the AVM can rupture too). About 75% of the aneurysms associated with AVMs are found on arteries feeding the AVM (pedicle aneurysms), while 25% of aneurysms associated with AVMs are found within the core (nidus) of the AVM (intranidal aneurysms). Interestingly, with good treatment of the AVM, pedicle aneurysms can fade away or disappear entirely.

Brain Arteriovenous Malformation:

Figure 1 shows the the surface of the brain with an AVM originating there. Note the large and tortuous (bendy) feeding arteries (red) and draining veins (blue), which may also be deeper in the substance of the AVM. The nidus of the AVM is deeper, and the AVM usually forms a cone-shaped mass that extends from the (pial/cortical) surface of the brain down towards one of the fluid-filled cavities of the brain (ventricle).

Note that an AVM is not the same thing as a dural arteriovenous fistula (DAVF), even though people and literature sometimes fail to make the distinction between these two very different entities. DAVFs can occur in the brain (intracranial DAVF) or in the spinal canal (spinal DAVF), or at the junction between the skull and spinal column (craniocervical junction DAVF). A DAVF is an abnormal connection between an artery (usually one, but sometimes multiple) and a vein (frequently one big arterialized draining vein, but may be multiple), with the key differences between the two types of entities ("lesions" or "anomalies") being that the DAVF: (i) is intimately associated with the leathery covering (dura) of the brain or spinal cord/spinal nerve root; (ii) has no nidus and therefore pathologically is not made up of a tangle of hybrid vessels (despite possibly having abnormal structure/architecture to some of the vessels of the DAVF); (iii) has a small web of capillaries interposed between the arterial supply and venous drainage sides; and (iv) is (in the brain) frequently associated with a blockage to a major draining venous pathway (i.e., a venous sinus occlusion/stenosis) and therefore (in the brain) is typically an abnormality that is acquired rather than the person being born with it (congenital). Spinal DAVF are thought to be congenital, and not typically associated with neighboring blocked veins. A ruptured DAVF is worth treating early to prevent further neurological impairment from a rehemorrhage.

2. How common is an arteriovenous malformation?

AVMs are relatively rare lesions, much rarer than brain aneurysms. Depending on what you read, the population prevalence of AVMs [i.e., what percentage are present (in 100% of) the population at any one timepoint] is probably somewhere around 0.2% (i.e., 1 in 500 persons), i.e., 5-25 times less than the prevalence of brain aneurysms (which is somewhere between 1-5% by most reports). DAVFs are extremely rare lesions, much rarer than AVMs.

3. Why does an arteriovenous malformation develop?

Unlike brain aneurysms, there are no well established risk factors for AVM formation, growth and rupture. They are regarded as "developmental" or "congenital" vascular anomalies, i.e. you're born with them and they typically increase in size as the brain enlarges. There are rare instances of persons with multiple AVMs (Wyburn-Mason syndrome, which involves multiple central nervous system AVMs, including in the eye's retina) said to be nonhereditary, but probably due to some yet-unknown genetic event).

4. What are the symptoms of an arteriovenous malformation?

Most brain AVMs present with a brain hemorrhage (abrupt onset of severe headache, nausea, vomiting, collapse/loss of consciousness). Note that instant death rate (instant mortality) is believed to be about 10% for first-time hemorrhages from a brain AVM, and this is about the same as the instant mortality rate for first-time brain aneurysm ruptures. Many AVMs present with seizures, and some present with neurological symptoms (some sort of motor (paralysis) or sensory disturbance) due to the mass of the blood vessel tangle causing direct compression of neighboring brain or cranial nerve tissue (mass effect). In rare instances, severe face/head pain (trigeminal neuralgia or some atypical facial pain) can be due to arteriovenous malformations near the trigeminal nerve complex. Some brain AVMs present with a stroke-like event(s) due to "stealing" blood flow from neighboring brain territory. Rarely, an unruptured AVM can present with persistent headaches, with or without nausea and vomiting (i.e., raised intracranial pressure).

Very rarely, in some very young kids, a particular type of vascular malformation known as a "Vein of Galen" malformation (VOGM) (incorrectly termed "Vein of Galen Aneurysm") is due to an arteriovenous fistula (Type I VOGM) or arteriovenous malformation (Type II VOGM) near the deep brain structures (midbrain and/or thalamus), and can present with hemorrhage, seizures, and associated neurological impairment. The Type I VOGM (this a fistula, but it's not a dural arteriovenous fistula) frquently presents in a newborn, with congestive heart failure, hydrocephalus (raised pressure in the brain due to impaired drainage of the brain's cerebrospinal fluid or CSF; "water on the brain") and an enlarged head diameter (macrocephaly due to hydrocephalus).

As mentioned above, some AVMs (about 6%) have one or more aneurysm(s) associated with them, and these aneurysms may rupture, i.e., a brain surface (subarachnoid) hemorrhage or brain tissue (intraparenchymal) hemorrhage. This can lead to the same type of presentation as described elsewhere in this Site ( take me to the Brain Aneurysm section now).

5. More about brain arteriovenous malformation hemorrhage and rehemorrhage.

The peak age for hemorrhage from an AVM is somewhere in the late teens (age 15-20 yrs). There is a 10% instant mortality associated with the first hemorrhage, and up to 30% mortality associated with each rebleed (rehemorrhage). The first hemorrhage has a 30-50% chance of causing some neurological impairment (deficit). The hemorrhage itself is usually within the substance of the brain (intraparenychmal hemorrhage), but also may be subarachnoid (outer or under surfaces of the brain), or within the fluid filled spaces of the brain (intraventricular), or just under the leather covering of the brain (subdural).

Some tendencies regarding hemorrhage are the following (subject to debate): the hemorrhage rate may be higher in the following: (i) kids; (ii) AVMs located in the back portion of the brain (hindbrain, posterior fossa); (iii) smaller AVMs (?higher pressure in these); (iv) pregnancy.

Hemorrhage rates: The average (annual) rate of hemorrhage for a newly diagnosed AVM that has not bled before is somewhere between 2-4% per year. The mean time between diagnosis of an AVM and first hemorrhage is somewhere around 7-8 years, but this obviously varies from person to person. The chance of death with a newly diagnosed AVM is approximately 1% per year, much higher after hemorrhage as mentioned above.

The risk of hemorrhage from the AVM itself after treatment with radiation (e.g., stereotactic radiosurgery such as GammaKnife or LINAC) is not reduced, in fact may be slightly higher than normal AVM hemorrhage rates, till the AVM is completely obliterated by such treatment (which can take 2-3 years).

Rehemorrhage rates: Depending on what you read, the (annual) rehemorrhage rate from an AVM (i.e., the chance of second bleed) is somewhere between 6-18% in the first year following diagnosis. Over the next few years, this rate decreases to somewhere around 3-4% per year. As mentioned above, rehemorrhage carries a very high rate of death and permanent disability.

As described in the Brain Aneurysm section ( take me to the Brain Aneurysm section now), the American Heart Association (AHA) and its Stroke Council coined the term "brain attack" ( take me to the Brain Attack section) to describe the brain equivalent of the common "heart attack". This term is an important one, aimed at increasing community awareness of this important and potentially life-threatening brain condition. The term encompasses the symptoms of a stroke (many of which were mentioned above), although the stroke itself may arise from blood vessel blockage (which is the most common cause), or from the rupture of an arteriovenous malformation blood vessel (or an aneurysm associated with an AVM).

6. What are the complications of an arteriovenous malformation?

For any AVM, the biggest problem or most dangerous consequence (i.e., "complication") is that it may rupture. However, many unrupturd AVMs present with seizures too, and the development of a seizure disorder (epilepsy) can certainly occur after rupture of an AVM. So, seizure disorder is regarded a second major problem associated with AVMs, be they unruptured or ruptured. In fact, the younger the patient at the time of AVM diagnosis, the higher the risk of developing a seizure disorder. Overall, this the seizure risk lies somewhere between 1-2%/yr following diagnosis, but varies according to age and whether or not the AVM has ruptured.

If an AVM (or an aneurysm associated with it) ruptures, the main complications are death and serious disability from the initial rupture itself (see above) or due to events occurring after the initial rupture. Of these events, the most important one is "rebleeding" of the AVM (i.e., it, or an aneurysm associated with it, re-ruptures and bleeds again), resulting in further permanent brain tissue injury (i.e., "infarction"). Occasionally, "cerebral vasospasm" (i.e., where, following hemorrhage, brain arteries go into severe spasm; i.e., they shut down, depriving the nearby brain tissue of oxygen and other nutrients) can occur after AVM hemorrhage (especially if the hemorrhage involves the subarachnoid space; take me to the section on Cerebral Vasospasm now). In persons surviving these complications, other complications may arise. For example, there may be some degree of obstruction (or blockage) of normal cerebrospinal fluid (CSF) flow in the brain (i.e., resulting in high-pressure build up in the brain referred to as "hydrocephalus"). This is caused by the blood clot or blood products clogging up the CSF drainage system following rupture, and it can lead to progressive, permanent brain injury. Also, following AVM rupture, parts of the brain can become electrically irritated, resulting in seizures.

Another complication that can occur after surgery for AVMs is hemorrhage not from the AVM itself (which should have been removed by surgery), but rather from abormal leakiness from the vessels surrounding the recently removed AVM, particlularly if the blood pressure of the patient is running relatively on the high side. This phenomenon is known as Normal Perfusion Pressure Breakthrough (NPPB). The chance of it occurring (approximately 10%) can generally be reduced by tight control of the blood pressure in the few days surrounding surgery (most of these hemorrhages occur within the first week after surgery).

7. How is an arteriovenous malformation detected?

Sadly, many AVMs are detected only after they have ruptured.

The gold-standard for detection of an AVM is cerebral angiography. Here, a contrast dye is first injected through a catheter device inserted usually in a thigh (femoral) artery. From here, the dye eventually enters one or more of the main brain arteries, where it is X-ray imaged. An AVM often appears early during the injection as an abnormal number of expanded and tortuous (windy) vessels. There maybe one or more aneurysms associated with the AVM as mentioned above, and these can appear as sacs or balloons (variable size and number) coming off the parent arteries or within the tight coil of the AVM nidus itself.

Other X-ray based advanced imaging methods for detecting AVMs are magnetic resonance imaging (MRI) and its associated methods referred to as magnetic resonance angiography (MRA) and magnetic resonance venography (MRV). The advantages of these methods are that they are less invasive than cerebral angiography, in that they do not involve femoral (thigh) artery puncture and insertion and navigation of a long catheter through the arteries. They also provide excellent information regarding where exactly the AVM is located (i.e., which part of the brain, which importance brain functions may be involved, what critical structurs lie nearby, and how best to approach the AVM when considering a treatment option). However, MRI/A/V may not detect the smallest of aneurysms associated with AVMs as well as cerebral angiography can, and (due to problems with magnetic attraction and interference; ferromagnetism) MRI/A/V may not able to be used in certain patients in whom metallic hardware has been placed. Of course, some patients with certain metallic (nonferromagnetic, e.g., titanium) hardware can still be safely and effectively imaged by this method. Check with your physicians first.

Ordinary computer-assisted tomographic (CAT or CT) scanning is another way to detect AVMs. This method is not as sensitive (i.e., can't quite pick up the smallest AVMs or aneurysms associated with them) or as specific (i.e., can't really be sure it's an AVM that's been detected) compared with cerebral angiography. Ultrasound (e.g., Duplex-Doppler) plays no real role in the detection of AVMs in clinical practice. Common X-rays are not used for aneurysm detection, although highly calcified AVMs may show up as curvilinear lesions on a plain skull x-ray (and in neurosurgery resident examinations!).

A combination of CT scanning and angiography (referred to as CT-angiography, CTA; where an intravenous dye is introduced into the patient at the time of CT scanning) is currently gaining popularity as a good alternative for studying AVMs, and may one day replace conventional cerebral angiography (with the obvious advantages that CT-angiography is so much quicker, cheaper, and less invasive compared with conventional angiography). The ability to create high-resolution and color 3-dimensional images with CTA is very useful for surgeons planning to operate these lesions.

At present there is no single blood test that can reliably predict brain AVM formation or rupture by genetic means.

8. How is an arteriovenous malformation treated?

There are three basic ways of treating a brain AVM after it is diagnosed. The bottom line is that each case of AVM should be treated on an individualized basis, taking into consideration the age of the patient, copresence of significant medical conditions, the site (especially the "eloquence" of brain involved by the AVM; see below) and size of the AVM, whether there is a history of previous AVM hemorrhage in that patient, the skill and experience of the treating physician or surgeon, and the type and risk(s) of treatment option most suitable for that AVM and person.

To neurosurgeons, the Spetzler-Martin AVM Grading System is a very intuitive and useful tool for predicting the risks of surgical intervention associated with AVMs. This System gives an AVM score of 1 to 5, with the surgical risks increasing as the score increases. The grading system is based three things: the size of the core (nidus) of the AVM (scores 1, 2 or 3 as the nidus size increases); the "eloquence" (i.e., degree of functional importance) of the brain tissue/region the AVM is found in (scores 0 for noneloquent, or 1 for eloquent brain); and the pattern of venous drainage [i.e., whether the AVM draining veins drain deep in the brain (scores 1) or just superficially - on the brain surface only (scores 0)].

For AVMs, the options are either surgical or nonsurgical. Of the nonsurgical options, the main therapeutic option is a radiation-based intervention (basically, focussed radiotherapy also known as steretactic radiosurgery or SRS). The second nonsurgical option does not strictly cure the AVM, but helps to reduce it's arterial supply, and this option is neuroradiological or "endovascular".

1. Surgery: The goal of surgery is the complete removal (resection) of the AVM in one operation. It can be carried out before rupture of an AVM, and is recommended especially after rupture of an AVM, particlularly if the AVM is more amenable (suitable) to safe and effective surgery (Spetlzer Martin Grades 1-3). It is my (personal) opinion that, whenever possible, surgery should be carried out by an experienced neurosurgeon, especially one with advanced Cerebrovascular Fellowship training. The advantages of surgery are the immediate elimination of the hemorrhage and rehemorrhage risk of an AVM, and improvement in seizure control if the AVM itself is generating the seizures. The basic method is to carry out a bony opening in the skull (craniotomy), followed by meticulous identification, isolation and disconnection of the arterial branches feeding the AVM, followed by meticulous identification, isolation and disconnection of the main veins draining the AVM. This way, the AVM is carefully shelled out in one piece. Postoperative care involves many things of course, but particular attention to tight blood pressure regulation is paramount to avoide secondary hemorrhage from NPPB (see above). In the best hands, surgery for Spetzler-Martin Grades 1-3 AVMs carries a 1-10% chance (respectively) of significant neurological complications.

2. Stereotactic Radiosurgery (SRS): SRS, either in the form of GammaKnife or Linear Accelerator (Linac), involves delivery of a focused beam of radiation to the nidus of the AVM. It may involve one or a few treatments. It is painless and generally well tolerated by patients. In some patients, it can cause secondary tumors (rare), impairment of brain function (especially important in kids whose brains are more rapidly developing), and delayed swelling (brain edema) or cystic radiation necrosis (not common, but a problem when it occurs). SRS is certainly a good option for treating AVMs when those AVMs are located in very deep regions of the brain (e.g., brainstem, thalamus), or those which are Spetzler-Martin grades 3 or higher. Of course, SRS can be used to treat any AVM, but it is my bias that AVMs that can be safely and readily accessed surgically, should be removed by an appropriately trained neurosurgeon. This is because such lesions are readily curable via surgery, and the AVM-rebleeding risk is immediately eliminated by successful surgery. Note that SRS does not immediately eliminate the AVM-bleeding risk, because it takes on average 2-3 years (following the first radiation treatment) for the AVM to be cured (and not all AVMs are curable with SRS). The rebleeding risk in these first 2-3 years following SRS is possibly lower than the usual rebleeding risk for untreated ruptured AVMs (see above). However, there still remains a significantly higher rate of rebleeding among AVMs treated with SRS compared with AVMs treated surgically.

3. Endovascular Therapy: This generally involves placement of metallic (e.g., titanium) microcoil or "glue" (or a similar composite) in the lumen of arteries feeding the AVM in order to slow the flow of blood in the feeder artery lumen, encouraging AVM feeder arteries to clot off. These therapies can also be used to treat aneurysms associated with the AVM, especially those on parent (feeder) arteries (pedicle aneurysms). Endovascular therapy itself rarely cures an AVM, it is best thought of as a helpful adjunct (supportive measure) for subsequent open surgery or SRS. Endovascular therapy is very helpful in high-flow/high-shunt AVMs, and also in AVMs whose feeder arteries may be difficult to reach surgically (because they are on the deep/underside of the AVM compared with the surgical approach). Endovascular therapy ("pre-operative" or "pre-radiosurgical" embolization) carries its own set of risks, just like any other treatment option. Overall, the risk of death or significant neurological disablilty associated with this option is about 4-5% in total. Disability may be from parent vessel rupture or blockage (by the embolic material - microcoil or glue) or tearing (dissection).

In the ideal circumstance, the decision as to how to best treat an AVM is made in joint consultation between the patient, a neurosurgeon and a neuroradiologist, taking into careful consideration the specific circumstances of the patient and aneurysm.

9. Some radiological images of an arteriovenous malformation (AVM).

The image to the left is a CAT scan image that shows hemorrhage into the brain (arrow heads). The cause of the hemorrhage was not known at the time that this image was obtained. Because of the patient's neurological deterioration, surgery was immediately carried out to remove the blood clot. At the time of surgery, an arteriovenous malformation (AVM) was found. The patient was then taken to the angiogram suite where formal cerebral angiography showed the roadmap representing the AVM (see below). This valuable information was then used by the surgeons to safely and effectively remove (resect) the AVM.
The image to the left is from a cerebral angiogram showing the arteriovenous malformation (AVM) described earlier. The internal carotid artery (ICA) gives rise to the middle cerebral artery (MCA) deep at the base of the brain. This image shows MCA (arterial) branches feeding the AVM, whose nidus is marked by the arrow heads. Note the large draining vein (DV). The two arrows show direction of blood flow to and from the AVM. Owing to the risk of rehemorrhage, this AVM was successfully removed by surgeons.

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