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Research on Hemangiomas and Sturge-Weber Syndrome

2005 Port Wine Stain Conference Physician Presentation Notes

By Glenda Ethington

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The following are my notes and interpretations of the presentations by Dr. Anne Comi, Dr. Martin Mihm, Jr., and Dr. Milton Waner at the Vascular Birthmarks Foundation 2005 Port Wine Stain Conference in Irvine, California on October 8, 2005. The doctors’ complete presentations can be purchased on CD through the Vascular Birthmarks Foundation:

Sturge-Weber Syndrome
Presented by Dr. Anne Comi
Pediatric neurologist and the Director of the John Hopkins - Kennedy Krieger Institute Sturge-Weber Syndrome Center in Baltimore, Maryland.

Brief history of SWS: Sturge-Weber syndrome (SWS) is the association of abnormal blood vessels in the eye and brain. Patients are born with a port wine stain, which typically occurs on the upper face (forehead and upper/lower eyelid). These signs can indicate an increased risk for complications of eye and brain development over time.

SWS does not run in families. There are cases of multiple family members with port wine stain (familial capillary malformation), but it would be extremely rare for SWS to occur this way. There is no good population based study to indicate how often SWS occurs.

PWS is common and estimates indicate 1 in 50,000 people are born with pws. Of those with pws on the upper 1/3 of the face, approximately 10 – 35% will have eye and brain complications. Factors can include the extent of involvement on the face and if the area affected is bilateral or unilateral (affecting one or both sides). There is no male/female, racial or ethnic predominance associated with SWS.

Dr. Sturge provided the initial description of the association between pws and seizures. Dr. Weber published the first X-ray of calcification on the back part of the brain, seen in SWS.

What is SWS? There are problems and confusion with the definition of SWS. Some list the following associations as markers for SWS: A facial port wine stain in conjunction with either and/or glaucoma/eye issues, abnormal blood vessels in brain/brain issues. Yet others focus on brain involvement as the determining factor for a diagnosis of SWS.

Dr. Comi tends to refer to SWS and its variants in the diagnosis process. A syndrome is usually an association of 2 or more signs, areas or classic findings. If it only occurs in the eye or only occurs in the brain, these are considered SWS variants. Knowing where the abnormal blood vessels and the extent of involvement determines treatment and prognosis.

What causes SWS? Many families ask what causes SWS - why is the upper face and eye involved, and why the brain (typically the back occipital lobe of the brain). Dr Comi points out that there is some thinking that because of this localized area of involvement in pws that sematic mutation might be involved, or other possibilities including a disruption in very early fetal development that produces these abnormalities of blood vessel structure and function. In the case of identical twins, where one has pws and the other does not, this could suggest sematic mutation.

To illustrate a possibility on why the eye and brain are affected, Dr. Comi used the example of a chick embryo. Very early stage embryologic development and the growth structure of blood vessels is very similar to human development. The eyes are located in a lateral position in early development (side of face) and the blood vessels feeding the eye and brain cortex are adjacent to each other. As further development occurs, the eye and the skin surrounding it come around to the front mid-part of the face – thus suggesting some connection between the eye/brain areas in very early development.

There is only indirect data to support the sematic mutation model, but it is only a hypothesis. Sematic mutation is the change in genetic information in the subset of a cell – the rest of the body is not affected. Genetic material is normal, but in this subset of cells the material changes and there is a mutation. The mutation affects the structure and/or function of blood vessels in that localized area, and then produces the pws and abnormal blood vessels of the brain and eye.

Progression vs. Evolution: Does SWS progress? What will happen over time? In issues of progression vs. evolution it often becomes a matter of semantics and how one defines progression or evolution. Dr. Comi suggests that if progression is defined as the risk of developing new and/ or worsening complications of the brain and eye and the function of those structures, then most would agree that progression is a component of SWS. However, the degree, extent and timing is impossible to predict, and varies from patient to patient. Brain and eye involvement can’t be cured, but can be treated and managed - however, to varying extents.

Glaucoma: Increased ocular pressure can occur at any time. The peak times appear to be during infancy, late childhood, and early adulthood. Anyone with pws involving the eyelid is at an increased risk . 50% will develop some degree of glaucoma or increased pressure in the eye. Impaired venous drainage from the eye produces backpressure. This can lead to increased pressure, injuring the optic nerve. Loss of sight can occur. Eye drops are used in treatment, but when they fail to control the pressure sometimes surgery is required. Glaucoma related to SWS is different than other common glaucoma in older or elderly adults.

Buthalmos: The actual enlargement of the eye, or buthalmos, can also occur. Infants need to be seen immediately and often require surgery within the first few days of life.

Seizures: Seizures are a frequent presentation in infants. In 90% of patients with SWS and seizures, the seizures usually appear in the first couple of years of life, but can occur in late childhood or adulthood. Focal neurologic deficits often start the first couple of years of life, and can subtly precede the onset of seizures and become more prominent after a long seizure has occurred (SLE).

Controversy exists as to whether or not seizures are themselves involved in the neurologic process or if they are just symptoms of the injury going on in the brain. Prolonged seizures may not be good. Some seizures are hard to recognize and can last for hours - possibly resulting in prolonged Hemiparesis lasting weeks or months, and if repeated, may not go away. Some feel that aggressive treatment of seizures (the swift stopping of seizures) will help, but there is no evidence to prove that the child would respond if treated differently. Aggressive treatment would include immediate medication or treatment for seizures. In such aggressive treatment, the use of Diastat® (at-home medication for treatment of increased seizures and/or seizures that last longer than 5 minutes) might be needed. In one such case of aggressive treatment, Dr. Comi described an 8 month-old child who exhibited signs of left-handedness (handedness should not occur in an 8-month-old infant). The child was treated aggressively for seizures and the handedness went away and didn’t return.

Some types of seizures associated with SWS are as follows:

  • Focal Seizures: Seizures in SWS are usually focal – twitching shaking, stiffening, or limpness of one side of the body

  • Complex/Partial Seizures: Twitching, shaking, stiffening, associated with impaired consciousness.

  • Other seizures include generalized tonic/clonic, drop seizures, and other kinds of staring seizures.

Stroke-like Episode (SLE): SLE produces prolonged weakness on one side of the body, which can occur after a prolonged seizure in association with migraine headache. SLE usually develops early in life but, but like other SWS symptoms, can occur any time.

Migraine: Migraines frequently start around 8 yrs of life, which is younger than the general population. As patients become older can be associated with SLE and other neurological signs and symptoms.

Developmental Delay: Delays may be apparent very early on, but this is not typical. Typically infant development is normal the first several months to a year or so of life. Then symptoms like early hand preference, evidence visual field cuts, or frequent or prolonged seizures may result (seizures can last for hours in some cases).

Mental Retardation: Dr. Comi commented that literature suggests that mental retardation occurs in around 50% of SWS patients with brain involvement. However, in Dr. Comi’s experience she feels it is less than that. Learning problems with a varying degree such as attention, psychological and mood impairment are common in SWS.

There is still some degree of controversy over what is going on in the brain and answers are incomplete. Research is ongoing. We do know that there are abnormal blood vessels in the brain called leptomeningial angioma (an increased number of dilated blood vessels on the surface of the brain). There is also impaired venous drainage through dilated venous structure draining that area of the brain. SPECT and Profusion studies show that blood flow through the abnormal vessels is not normal. Very early on it is indicated that there can be increased blood flow in pre-symptomatic infants, but once seizures and neurologic symptoms develop, the blood flow decreases. How it occurs, what triggers progressive changes in blood vessel and blood flow still leaves many questions unanswered.

Calcification: There is no evidence that the calcifications themselves are making brain injury. Research indicates that rather calcification is dystrophic change (the progressive degeneration of tissue due to inadequate nourishment to the affected area). Calcium deposits are being made to the area injured or impaired due to the inability of the blood flow to provide the delivery of oxygen and glucose to that area.

Diagnosis of SWS: The diagnosis of SWS brain involvement includes neuro-imaging. This can be problematic, as often the early images taken of infants appears normal. Later, when seizures and other symptoms develop the imaging becomes obvious that there are abnormal blood vessels of the brain. The abnormalities are probably there from the time of fetal development, but properties of blood vessels and/or blood flow have changed, and now they are visible.

Types of imaging used in diagnosis are as follows:

  • MRI: MRI with and without contrast. Contrast is absolutely required, as you can’t see abnormal blood vessels without it.

  • CT Scan: Head CT is still the best way to see calcification, although dense calcification can be seen on the MRI.

  • Profusion Imaging: An MR sequence that allows one to look at both venous and arterial phase of blood flow delivery and drainage from that area.

Anticonvulsants: There are many anticonvulsants for the treatment of seizures. There are no good studies to indicate which is the best or most protective drug. The prevention of prolonged seizures early is thought to be important. The medications typically tired first to control seizures are Tegretol, Carbamezepine, and Phenobarbital. As mentioned previously, Diastat® is used to stop seizures that last longer than 5 minutes. Newer anticonvulsants like Trileptal and Topamax are also used. Depakote and Keppra are other alternatives.

Other Considerations : Dr. Bernard Maria, et al, did a study on patients on low-dose aspirin treatment vs. those patients not on aspirin, and the incidence of SLE was lower in patients on low-dose aspirin. Patients should talk to their doctors about the risk/benefit ratio for regular low-dose aspirin treatment.

Other symptoms and or considerations include the following:

  • Avoid dehydration– especially in cases where vomiting and diarrhea occur.

  • Treat fever, as fever can lower the threshold for seizures.

  • Infection– infection in the inner ear with pws is common and tubes might need to be inserted early on to prevent prolonged illness.

  • Anemia – iron deficiency anemia can be common. Red blood cells carry oxygen to the blood, and since the blood flow is already impaired in SWS patients, this can be a problem.

There is not much data on the treatment of other neurologic symptoms related to SWS. Some of these include:

  • Headaches: Triptans are being used for migraines with some success, although pharmaceutical companies have warned against the use in cases where there are vascular abnormalities of the brain. A study is underway at John Hopkins Kennedy Krieger SWS Center regarding headaches, and participation by SWS patients is encouraged. The study can be accessed online.

  • Attention: 20% of those with SWS have ADD or ADHD. These symptoms need to be distinguished from seizures, and accommodations need to be made at school, and sometimes other medications may be used to help with they symptoms.

  • Depression and Anxiety: This is also common in SWS. There is hardly any data to indicate what might be most effective in treating these symptoms.

Surgery: For children and sometimes adults who experience frequent seizures and medication is not controlling them, these patients need to be examined and studied to see if surgery might be an option (lobectomy or hemispherectomy). More controversial is question of the child with intermittent seizures that are not causing too many problems with daily life, but the child is falling behind developmentally. It could be that the patient is having blood flow issues on the other side of the brain, and early surgery might be an option to prevent further damage. There is less agreement on this issue.

Hope on the Horizon: Through the collaboration of doctors, clinical centers, researchers, companies and clinicians, and the pursuit of research, perhaps better answers can be obtained. Research is going on in all aspects of SWS.

How you can help:

  • Enroll in studies

  • Fill out surveys

  • Donate tissue when appropriate

  • Participate in fundraising efforts to benefit research in this area. This is very important as SWS is not a priority on the national level.

Pathology of Vascular Malformations and Vascular Birthmarks
Presented by Dr. Martin C. Mihm, Jr.
Founder of Albany Medical Center Vascular Anomalies Program and the Massachusetts General Hospital Vascular Anomalies Program (Director of both clinics).

Dr. Mihm acknowledged Dr. Paula North, Chair of Pathology at Milwaukee, who assisted in the research on which his presentation is based, as well as others who have helped with research (Dr. Waner, Dr. Buckmiller, and Dr. Carpintero).

Infantile Hemangioma: This is a lesion that comes on sometimes at birth, but usually perinatal (during the first few weeks of life). It is the most common tumor of infancy. Cellular and juvenile hemangioma are synonyms often used to describe infantile hemangioma. There are other types of lesions and some persist and some will go away rapidly. However, all lesions that are red, congenital, and/or that occur in the perinatal are not always hemangioma or pws, and each has a different pathology.

Often when the lesion occurs for the first time, a white area appears before the lesion come about. This may occur in all lesions but it is difficult to know, as most parents report a scratch or bruise. But the hemangioma appears exactly where the white spot was.

Infantile hemangiomas can be flat or raised with a very large subcutaneous component. When they involute they can leave a fibro fatty residue and rather corrugated skin. These lesions can grow very rapidly (in 3-4 weeks). Lesion such as this, if improperly treated, can cause disfigurement. The old approach was “leave it alone it will go away”, which is taught in medical schools around the country. Linda Shannon (VBF founder and president) wrote to all the medical schools in the US to tell them to change their curriculum.

Treatments are as follows:

  • Embolization– inject vessel causes lesion to shrink or necrose

  • Laser treatment

  • Surgery (or excision)

  • Steroids or some type of anti-metabolite

Topical therapies are needed to apply directly to the skin when these lesions appear.

Pathology: The red part of the lesion is intra-cutaneous, the part of the skin that makes leather in animals. The subcutaneous layer is the fatty layer of the skin. The lesions are composed of spaces in the very early stages and these are blood vessel spaces. Endothelia cells are the lining of blood vessels and a pericyte has smooth muscle-like filaments in them and they keep the blood vessels intact and keeps the endothelia cells in place so the blood can go through them.

There is a similarity between the blood vessels of these lesions and the blood vessels of cancer in that they are not normal vasculature and they both are different than normal vessels. This makes them targets for vaccine therapy. These abnormal cells have different proteins in them from normal cells, and these proteins can be attacked and killed in tumors, such as cancer, and this could work in these lesions also (kill the blood vessel and kill the tumor). These cells have early mitosis or cell division. Cells are dying and dividing at the same time in the early stages, but the rate of division is more than the rate of dying so the lesion grows. As the division tapers off, the rate of cells dying is more and the lesion begins to involute (the lesion may go away entirely or partially go away).

When the lesions involute all the areas that were so cellular begin to get fat and connective tissue between them (connective tissue is the dermis - that makes leather in animals). The cells become smaller, the dying cells become more frequent, and there is more and more connective tissue replacing them. When the end stage occurs what you have is a couple of feeding vessels left, a few vessels of the hemangioma itself, and the large feeding vessels in the subcutaneous fat.

In a hemangioma the blood vessel cells sit in a nerve as if they are part of a nerve, so it looks like they belong there normally. This gave researchers a clue that they should try to find out what are characteristics of places where there are blood vessels and nerves, the most important area being the brain. Researchers looked at components of the barrier between the blood vessel and the brain and found that there was an enzyme (a glucose transporter enzyme). The enzyme transfers energy and sugar to the brain cells so they can keep metabolizing, and they transform ascorbic acid (or vitamin C, which is a rich source of energy). These enzymes occur not only in the blood brain barrier, but occur in other areas throughout the body; including red blood cells, nerve cells and blood vessels at blood tissue barriers like the brain and the placenta. The nerve can be identified as it coats or stains for the enzyme. This became a unique marker for congenital hemangioma (over 565 different vascular lesions were studied to determine the marker).

The question remains as to how hemangiomas occur in children. There are a couple of theories:

  • Metastasis (the spreading of a tumor to a different part of the body from the site of the original tumor by way of tiny cells transported by the blood or lymph) Research studies show that the placenta and hemangioma are identical. There is a constant interchange between the mother’s circulation and the baby’s circulation. The mother’s stem cells are found in the child’s liver.

  • A genetic mutation that makes the cells look like of a placenta. (Dr. Mihm finds this very unlikely, based on research and that there are very common types of hemangiomas. Mutations wouldn’t necessarily be identical in repeated tests. However, 21,000 tests determined that placenta and hemangioma are identical.)

Further studies show that cells in the infantile stage will mark both for blood vessel and lymphatic markers. Also, in embryologic development there is a stage in this development where blood vessels mark for these two markers (blood vessel and lymphatic markers). These are immature cells and different than normal vasculature. In the embryo stage of life these cells occur but in adult life they do not occur, so these are different than normal mature cells in adults and children.

Congenital Hemangioma: This is a fully formed lesion at birth. These sometimes go away very rapidly, or can persist forever. When they do go away, it is in a matter of months after birth, as opposed to infantile hemangioma that can take years to go away. They don’t stain for the glucose transporter enzyme.

Vascular malformations are lesions that are always present at birth. Sometimes they are not visible and the patient may not be aware of them. They can be categorized as follows:

  • Low flow– venous malformation and lymphatic malformation

  • Intermediate flow– port wine stain

  • High flow– arteriovenous malformation

Venous Malformation: These are common lesions. They represent over 50% of lesions referred to vascular centers. They occur in about 1 in 10,000 people. They often occur as a purple-bluish lesion on the lip. They are composed of big, large, abnormal veins. The lesion fills up in the dependent position, and when the patient sits up the lesion will go down. These lesions get clots in them and the clots will calcify, making them feel hard like bb’s. Venous malformations never go away and grow with the patient

Lymphatic Malformation: These are typical lesions that can occur anywhere in the body (referred to as hygroma or cystic hygroma). On the tongue they look like little blisters. The “blisters” have big spaces in them filled with protein and lymph instead of blood. They are malformations of lymph system that drain the lymph nodes. There are large cystic types that are eligible for injection with a protein that will cause them to scar down. The small lesions have little cysts and are more difficult to treat.

Capillary Venular Malformation: These lesions are referred to as port wine stain, and occur in less than 1% of newborns. These lesions are flat, and appear as red to purple color on the skin. They are commonly found on the head and neck, but occur elsewhere on the body. They are made up of capillary vessels. The nerves appear to be decreased in these lesions. It is theorized that a defect in the nerves in port wine won’t allow it to stop dilation.

Some port wine stain lesions start flat, but may begin thickening and develop nodularity (these are different than port wine stains that remain flat). These lesions can have hair follicle benign tumors, abnormal nerve structure and abnormal dermis. These lesions are not eligible for laser therapy

Arteriovenous Malformation (AVM): This is a malformation that has a tiny bed of capillaries that join small veins to small arteries. They are pink, warm lesions and you put your finger on them and feel a pulse. They occur as swellings, and may or may not have a port wine stain covering them. They are composed of abnormal arteries and abnormal veins. AVM’s grow continually and can ulcerate.

In normal capillary circulation there are sphincters that control the circulation, so that you don’t have a continuous flow. In an AVM there are no sphincters, so the flow begins to pool and this is called a nidus. The blood vessels and arteries hypertrophy and begin to grow or enlarge on either side of the nidus. To cure an AVM you have to remove the nidus, or the pooling will continue. Once the nidus is removed, the capillaries return to normal.

Surgical Management of Port Wine Stain
Presented by Dr. Milton Waner
Pediatric facial plastic surgeon and the Director of the Vascular Birthmark Institute at Beth Israel Hospital, New York City.

If a sample was taken of a port wine stain and another area of skin, the number of blood vessels would be the same, only more dilated in the port wine stain area. Studies indicate that there is a deficiency in the nerves that supply the muscle surrounding the blood vessels in a port wine stain. (Nerves supply flow to the muscle that in turn causes the vessel to constrict, but are deficient or not working properly in pws).

There is a direct correlation between the depth of a pws and how well it responds to treatment. A percentage of patients will develop darkening, thickening or cobblestones. Some patients will develop only one of these symptoms, or in a combination with any of the others. However, not every patient develops these symptoms, and it is not known or why some patients present with certain symptoms while others don’t.

All port wine stains will darken due to progressive dilation of blood vessels.

Thickening was first thought to be vascular dilation of blood vessels and increased blood supply. It is now found that thickening of port wine stain involves all layers of tissue (skin, muscle, bone). There seems to be a growth signal abnormality (the lesion doesn’t know when to stop growing). It is possible that once a patient stops growing, the port wine stain doesn’t receive the signal to stop. So once the patient stops growing the thickening becomes more prominent.

In the case of cobblestones, they are treatable by laser in the early stages. The cobblestone is compressible (to the touch) and made up of blood vessels. As cobblestones mature, they become fibrous tissue and have to be surgically excised.

Some patients treated with pulsed dye laser can reach a point of maximum fading, where further treatments fail to diminish the color of the port wine stain. In one such case, the patient reached the point of maximum fading, did not receive laser treatment for a period of time, and the port wine stain darkened again. The records of patients treated over a five-year period were then examined. It was indicated that a percentage of patients with maximum treatment, if the port wine stain was left alone, began to darken again. Dr. Waner found that this theory- that port wine stains, when not completely disappeared and if left alone, will recur - was unpopular amongst many in the medical community. Many believed that port wine stains, once faded, would retain that degree of fading.

The flow rate of port wine stain vessels plays a part in the fading. The smaller vessels have a high rate of blood flow. The larger vessels are less efficient and make it easier for the laser to eradicate them. The smaller vessels then dilate over time, and cause the darkening of the port wine stain.

Not all red stain is port wine stain. Some red stain could indicate arteriovenous malformation (AVM), venous malformation, angel kiss, or stork bite. There seems to be a relationship between port wine stain and AVM. Under the microscope, there is no difference between the two. There may be underlying causes that are the same, but on a different level.

When is it time to operate? Surgery for port wine stain seems to have poor results. Skin grafts don’t seem to produce a match of skin color. When port wine stain remains in the deeper tissue it can thicken and pop up between the layers of skin.

When thickening occurs, doctors were warned that the area was very vascular and that bleeding could be significant. However, the thickening was most often found to be fatty tissue and could be debulked. Also, most cobblestones can be excised.

In summary, surgery can be indicated, but is limited and restricted to the removal of cobblestones, to remove thickened tissue (debulking), and for the realignment of facial features to create symmetry.

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