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NF-1 AND NF-2 NEUROSURGERY
Ann-Marie Yost, M.D.
Department of Neurosurgery
George Washington University Medical Center
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Mary Ann Wilson: George Washington University Hospital still has its affiliation with
Children's National Medical Center which is the pediatric unit of George Washington University.
Our chapter has a long standing relationship with George Washington University. One thing you
may have realized in thinking about medical care for someone with neurofibromatosis (NF) is that
you might not really know when a neurosurgeon should be called in to be part of the team. We
thought it might be helpful to know just what a neurosurgeon does. It is different with NF1 and
different with NF2. Dr. Yost will be talking about both NF 1 and NF2.
Dr. Yost: I want to thank you for the opportunity to pinch-hit for
Dr. Martuza. He has some really big shoes to fill. I am not going to deal
with the areas of genetic research and genetic therapy. I will just talk to
you about what we as neurosurgeons have to offer for the patients with
NF1 and NF2.
I'll start with NF1. I assume that most of you are familiar with the criteria
for diagnosis. NF1, which was known as Peripheral Neurofibromatosis, is much more
common than NF2. It occurs in 1/4000 births, whereas NF2 occurs in 1/40,000. They
both have an autosomal dominant form of genetic transmission. This means that a
child has a 50% chance of inheriting the disease if one parent has it and that
inheriting the gene definitely means getting the disease. The abnormality in
NF1 is found on a very large gene on chromosome 17 which has a very high mutation rate.
Although in both NF1 and NF2, 100% of the people who have the genes are affected by the
disorder, there is a much higher degree of variability in the symptoms of NF 1, because
the mutations can occur in different spots on the larger gene (variable penetrance).
In terms of the surgical issues in NF1: 15% of patients get tumors in the brain or in
the spinal cord. The most common type of tumor is a glioma, which is a class of tumors
composed of astrocytes, the neural cells of the brain and spinal cord. They can also get
meningiomas which are more common in NF2, but still occur at a higher than baseline level
in NF1. 15% of NF 1 patients will also get optic nerve gliomas. People with NF1 also get
cutaneous and subcutaneous neurofibromas. Approximately 3-5% of these neurofibromas will
transform from the benign to the malignant form. NF 1 patients also can develop
hydrocephalus, a buildup of the cerebrospinal fluid in the brain. This most commonly
results from a condition called aqueductal stenosis (a narrowing or obliteration of
the aqueduct of Sylvius which drains cerebrospinal fluid from the front to the back of
the head). The blockage can also occur from optic nerve gliomas. In some cases, patients
with hydrocephalus will have to have a ventriculo-peritoneal shunt inserted. This
is silicon tubing with a valve that drains the excess fluid from the head to the abdomen.
Patients with NF1 also have a tendency to develop abnormal blood vessels that are smaller
than normal and can clot off and cause strokes. The risk of this is higher risk if the
patient has received radiation therapy in the past for another problem.
Fifty percent of patients with NF1 will have some form of learning disability. Only
8.4% have mental retardation. Even those with a normal IQ, however, may require
some special accommodations in school.
Precocious puberty may involve neurosurgeons. Approximately 5-10% of NF1 patients have
tumors in the region of the hypothalamus, which is the area of the brain that controls
sex hormone production.
The orthopedic surgeons may be needed because of the high percentage of
scoliotic (S shaped curve A) or kyphotic (bent over) deformities of the spine.
These deformities may become most apparent during puberty and the growth spurt, but
pediatricians should screen for this earlier in children diagnosed with NF1. Scoliosis
or kyphosis may require wearing a brace or surgery to help avoid compressing the
spinal cord. Individuals with NF2 can also develop these problems.
Patients with NF1 have cutaneous neurofibromas as well as cafe au lait spots and Lisch
nodules ( seen on the iris of the eyes with a slit lamp). The relative importance of
these lesions for diagnosis can be seen in the NIH diagnostic criteria.
Dr. Edward R Laws, Jr. while at the Mayo Clinic conducted a study of 104 cases of optic
nerve glioma between 1914 and 1978. Optic nerve glioma is another of the diagnostic
criteria for NF1. Dr. Laws' study indicated that they are relatively rare tumors and
it took quite a while to accumulate 104 cases. Twenty-seven percent of those cases
are patients with NF1. Forty percent of the tumors were anterior, which means that they
occur before the optic nerves cross. Sixty percent of them occur posterior to the
crossing of the nerves, an area called the optic chiasm. The posterior lesions are
less common in NF 1, but are more of a problem surgically and require more adjuvant
therapy because they are close to dangerous areas on which to operate. NF1 patients
tend to develop anterior optic nerve gliomas, but they tend to be bilateral. In the Mayo
Clinic series, the female:male ratio is about 2: 1. The tumors show up relatively early
in life, which is consistent with the pathology of NF1. They usually develop before
10 years of age. Relatively speaking, these are benign tumors and the patients
often need no therapy. There is little mortality from these tumors. In NF1, 2/3's of
optic nerve gliomas will be asymptomatic and not cause any problems with vision.
Only 1/3 will become symptomatic and perhaps require therapy.
NF1 patients usually have symptoms from optic nerve gliomas by 1O years of age and
no later than 15 years old. There is controversy over whether NF1 patients should
have screening MRI scans. Most authorities feel that a negative scan
(no optic nerve gliomas seen) by age five: means that the patient will likely not
develop an optic glioma. However, the Children's National Medical
Center in DC performs screening MRI yearly on all NF1 patients with optic gliomas.
The optic chiasm is where the optic nerves cross. The pituitary gland (secretor of
hormones controlling lactation, the thyroid gland: sexual function, and growth)
is beneath the chiasm and the hypothalamus (area that controls the pituitary as
well as hunger, thirst and sexual desire) is the area behind it. When optic nerve
gliomas occur posteriorly, they can cause precocious puberty because of pressure on the
hypothalamus. This will manifest as young children starting to look
like adults and experiencing puberty years too early. They will also cease to grow.
A large percentage of NF 1 patients have short stature: but it is not thought
to be related to a hormonal effect of these tumors. The cause of the short stature
is not really understood.
The indications for surgery are pretty much the same for NF1 patients as they are for the
general population with optic nerve gliomas. Keep in mind that 66% of patients will not
need any therapy at all. The reason to operate on the anterior tumors is progressive
proptosis (bulging of the eye). The tumor pushing the eyeball forward can cause problems
with appearance, vision, movement of the eye and can cause pain as well. Progressive
visual loss followed with serial scans may show the tumor growing back toward the
chiasm and more dangerous areas of the brain.
The tumors that are posterior can sometimes be meningiomas or other tumors. It may be
necessary to biopsy the tumor to confirm that it is an optic nerve glioma. As I
mentioned before, the tumors that are posterior can block the cerebrospinal fluid
pathways and cause obstructive hydrocephalus. In some cases, the tumor can be
operated on to allow the cerebrospinal fluid to drain normally. Another way to relieve
the blockage is to insert a ventriculoperitoneal shunt.
Some of these tumors form a large fluid filled cyst and evacuating the fluid will
alleviate the pressure on the brain in that area.
The Mayo Clinic proposal for management of optic nerve gliomas, including NF1 patients
is to follow the patient closely with visual exams and MRI scans (not CT scans) and
take out the tumor if necessary. Visual symptoms are more of ten caused by the
posterior tumors and these are thus more often caused by the posterior tumors and
these are thus more likely to require surgery and subsequent radiotherapy. The incision
would be hidden behind the hairline. The survival is very good with these lesions.
The posterior ones tend to be a higher grade (less benign) than the
anterior ones. Most NF1 patients with optic gliomas have a grade II astrocytoma which
is a relatively benign tumor and has a 90% long term survival.
The optic nerves are diffusely enlarged and a bit shaggy looking. They do not tend to
become symptomatic. It is the policy at Children's Hospital to perform MRI scans
yearly once these tumors have been diagnosed. As I mentioned, this is a controversial area.
Some experts argue that, because so few patients' tumors change, that scans shouldn't
be done again until the patient becomes symptomatic. This camp doesn't feel that
the expense and anxiety of a yearly MRI are justified in the asymptomatic patient.
I think that this is something best decided between an educated patient and his
physician on an individual basis. There have not been any studies to show that it makes
a difference either way to detect these lesions before they become symptomatic.
Another factor in the debate over screening MRIs is "UBO's". Patients with NF1 can
develop changes in their myelin, the coating over the nerves that allows rapid
transmission of electrical impulses. The change is known as spongioform encephalopathy.
This is what causes UBO's or "Unidentified Bright Objects" on MRI. UBO's are seen on the
MRI scans of 60% of children with NF1. The UBO's tend to appear in the deep areas of
the brain, the basal ganglion (the deep gray matter) and the deep white matter tracts
that carry information back and forth between different levels of the brain and between
the brain and the spinal cord. UBO's appear to be a developmental phenomenon and are
very rare in adults. They appear to have no clinical significance
(don't cause any symptoms).
A UBO in the brain stem, making it fat, is an area that you would worry about
initially because children can develop tumors in this area. However, a UBO
usually disappears on subsequent scans.
Children with NF1 get tumors in other areas besides the optic nerves. One percent of
children with NF1 will get low grade astrocytomas in the brain stem or the cerebellum
(back of the brain controlling coordination) or in the cerebral hemispheres. The
tumors can compress the brain stem, wrap around it or thin it out. Tumors near the
brain stem can also block the cerebrospinal fluid pathways and cause hydrocephalus.
The tumors occurring outside of the optic nerves are usually of a benign type that
can be completely removed (except when they occur in the brain stem). These pilocytic
astrocytoma can be cured by surgery. These tumors are resectable and can
also occur in children without NF1.
Normally the vessels coming off one of the two internal carotid arteries (the main
supply to the front of the brain) would be more impressive. Moya Moya means
"puff of smoke" in Japanese. The blood vessels in Moya Moya disease are small
and not really adequate to feed their vascular territories. Much of the brain is being
fed by collaterals from other vessels. Some patients develop some strokes because of
inadequate blood flow. There are operations for this. I was not able to find any
statistics about whether surgery is more difficult or has a lesser success rate in
patients with NF1. It's possible to take a vein graft, like they do for cardiac bypass
surgery, and tie it into the internal carotid artery and bring it up to one of these
vessels (a branch of the middle cerebral artery). There is another procedure where
a vascularized substance like the fascia under the scalp or some muscle is laid over
the brain to try to encourage new vessels to grow into the brain from the supply
in the muscle or fascia.
Another finding that occurs with greater frequency in NF1 patients is arachnoid cysts.
These are developmental anomalies of the arachnoid, one of the layers covering the brain.
They fill with cerebrospinal fluid. In most patients, they are an incidental discovery.
Some patients may have headaches or seizures, and the cyst may be noted to be increasing
in size over time on CT or MRI scans. Occasionally, it is necessary to shunt the fluid
from the cyst into the abdomen with silicon tubing. Although they are more common in
the NF1 population, they are not symptomatic at a greater rate than that of the non NF1
population.
Tumors that arise from the neural sheath are the schwannomas, neurofiromas, and the
malignant nerve sheath tumors. Neurofiromas comprise 66% of nerve sheath tumors. 33% of
patients with these tumors have NF and the remainder are sporadic (an isolated
mutation in that individual). Schwannomas comprise 20% of nerve sheath tumors and malignant
neutral sheath tumors form 10% of the soft tissue sarcomas seen. 50% of malignant
neural sheath tumors occur in patients with NF1. Previous radiation therapy
increases the risk of malignant degeneration of neurofibromas. Schwannomas do not
undergo malignant degeneration. Only 5% of neurofibromas become malignant.
The important thing to take away from this is when you should seek surgical advice
and when these tumors would need to be operated on. Neurofiromas are usually
asymptomatic and as you know, they can number in the thousands and be very small in
NF1 patients. They can present with pain and are more likely to do so than schwannomas.
Neurofibromas can be solitary or plexiform (a mass that runs along the nerve and
can grow very large). Neurofibromas can also grow in plexi of nerves like the
brachial plexus in the underarm that supplies all of the sensory and motor nerves
to the arm. They may be difficult to distinguish from schwannomas on MRI. The surgical
indications are pretty much the same for both tumors. Development of progressive
neurological deficit or intractable pain would lead to surgery. A neurofibroma
that is rapidly becoming larger or causing pain or neurological changes
should be suspected to be undergoing malignant degeneration and should be checked
immediately. The 5% of neurofibromas in NF1 tend to occur earlier than those
seen in the general population and can increase in number or size during
puberty or pregnancy without undergoing malignant degeneration at that time.
Schwannomas can occur in NF Type I and II, but are much more common in NF2. In NF2,
they appear at a younger age than would be seen in the baseline population and are
more likely to be multiple. Both neurofibromas and schwannomas can appear in the
spinal cord where they tend to occur on the sensory (posterior) roots. They can occur
in the peripheral nerves (nerves away from the spinal cord) and when they do, they tend
to occur along the flexor surfaces (inside of arms, back of legs).
They can also appear in the chest cavity or in the pelvis. Schwannomas are
less likely to present with pain or neurological deficit, but the indications for
surgery are the same: growth or new symptoms. (Schwannomas in the central nervous
system occur on the cranial nerves and usually present with a deficit and will be
discussed later.)
Schwannomas tend to develop from one fascicle of many fascicles in the nerve. The tumor
pushes the other fascicles to the side. Surgically, it is easy to get into this plane
and get the schwannoma away from the rest of the nerve without hurting the other
fascicles. Small, solitary neurofibromas will develop along the same lines. As
neurofibromas grow, or occur on bigger nerves, or in plexi, the capsule of the
tumor surrounds several fascicles and compresses those fascicles and causes damage.
The compression in what leads to the pain and neurological changes (usually sensory).
The fascides can be all through the neurofibroma. Neurofibromas are usually
very difficult to separate from normal nerve. The surgeon must use a nerve
stimulator and test each of the fascicles to see which are functional and which
are not, which can be resected and
which should be spared to avoid deficit.
Hemihypertrophy (disproportionate soft tissue growth) can occur in an
extremity or any part of the body because of developing neurofibromas.
There are quite a number of nerves that run in the brachial plexus, making
it difficult to remove a neurofibroma in this region. The tumor will often damage
the plexus as it grows.
The neurofibroma can be focal or can grow along a long length of the nerve,
compressing it all the way. This is part of the difficulty with resecting
peripheral neurofibromas. If I were to insert an instrument here (on a slide
of a schwannoma), I could peel the fascicles off of the tumor to
either side. But the neurofibroma can enveloped everything. In this case,
the surgeon would need to use the nerve stimulator and find normal nerve on
either side of the tumor. If the nerve is a functionally important one, then
grafting may be performed to attempt to preserve some of its function. A sensory
nerve is taken from the lower leg and used to replace the section that has
been removed with the tumor. However, neurofibromas often involve a long section of nerve,
which creates a poor situation for grafting. (It is difficult to find a long section
of nerve to use for the graft and results are poor if the graft is on stretch.) So,
it may not always be possible to use a nerve graft. However, it is often still necessary
to sacrifice the nerve to remove the tumor. Given this, you can understand that a
solitary neurofibroma involving only one fascicle can have good results, but those
involving more than one, often have poor results.
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