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A vestibular schwannoma (VS), also called acoustic neuroma, is a benign tumor that develops on the vestibulocochlear nerve that passes from the
inner ear The inner ear (internal ear, auris interna) is the innermost part of the vertebrate ear. In vertebrates, the inner ear is mainly responsible for sound detection and balance. In mammals, it consists of the bony labyrinth, a hollow cavity in th ...
to the brain. The tumor originates when
Schwann cells Schwann cells or neurolemmocytes (named after German physiologist Theodor Schwann) are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory en ...
that form the insulating
myelin sheath Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be l ...
on the nerve malfunction. Normally, Schwann cells function beneficially to protect the nerves which transmit balance and sound information to the brain. However, sometimes a mutation in the
tumor suppressor gene A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or re ...
, NF2, located on chromosome 22, results in abnormal production of the cell protein named ''
Merlin Merlin ( cy, Myrddin, kw, Marzhin, br, Merzhin) is a mythical figure prominently featured in the legend of King Arthur and best known as a mage, with several other main roles. His usual depiction, based on an amalgamation of historic and leg ...
'', and Schwann cells multiply to form a tumor. The tumor originates mostly on the vestibular division of the nerve rather than the cochlear division, but hearing as well as balance will be affected as the tumor enlarges. The great majority of these VSs (95%) are unilateral, in one ear only. They are called "sporadic" (i.e., by-chance, non-hereditary). Although non-cancerous, they can do harm or even become life-threatening if they grow to press on other cranial nerves and vital structures such as the
brainstem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is ...
. Variations in the mutation determine the nature of the tumor's development. The only environmental exposure that has been definitely associated with the growth of a VS is therapeutic radiation exposure to the head.


Symptoms of Sporadic VS

Sporadic VSs originate within the confining bony walls of the small (ca. 2 cm long)
internal auditory canal The internal auditory meatus (also meatus acusticus internus, internal acoustic meatus, internal auditory canal, or internal acoustic canal) is a canal within the petrous part of the temporal bone of the skull between the posterior cranial fos ...
. The most common early symptoms of these intracanalicular (IAC) VSs are gradual
hearing loss Hearing loss is a partial or total inability to hear. Hearing loss may be present at birth or acquired at any time afterwards. Hearing loss may occur in one or both ears. In children, hearing problems can affect the ability to acquire spoken l ...
and a feeling of fullness in the affected ear, some imbalance or dizziness, and tinnitus (ringing or other noise in the ear). Gradual single-sided hearing loss in the high frequencies is the first most obvious symptom for the great majority of patients. Headache as a presenting symptom of VS specifically is rare; facial symptoms (facial numbness, weakness) usually occur only as the tumor grows out of the canal and/or after therapeutic treatment. Delayed diagnosis and misdiagnosis are not unusual. Initial hearing loss is usually subtle and may be attributed mistakenly to aging, earwax buildup, or perhaps exposure to some loud environmental noise. A sudden hearing loss, which is uncommon, might be misdiagnosed as
Ménière's disease Ménière's disease (MD) is a disease of the inner ear that is characterized by potentially severe and incapacitating episodes of vertigo, tinnitus, hearing loss, and a feeling of fullness in the ear. Typically, only one ear is affected initi ...
, an abnormality of the inner ear that also has tinnitus as a symptom. The brain's vestibular system usually compensates for early balance problems. There have been cases of tumors that were actually asymptomatic until very large and at a critical stage. Tumor growth rates are highly variable: some small VSs (perhaps 50%) do not grow at all; some few grow for a time and then shrink; some appear dormant but suddenly grow rapidly. In general, although studies differ, VSs that grow are slow-growing at an average rate of 1.2 to 1.9 mm per year. IAC tumors that grow beyond 1.5 cm in diameter expand into the relatively empty space of the cerebellopontine angle, taking on the characteristic 'ice-cream-cone' appearance seen on MRIs. As 'space-occupying-lesions,' the tumors can reach 3 to 4 cm or more in size and infringe on the
facial nerve The facial nerve, also known as the seventh cranial nerve, cranial nerve VII, or simply CN VII, is a cranial nerve that emerges from the pons of the brainstem, controls the muscles of facial expression, and functions in the conveyance of taste ...
(facial expression) and
trigeminal nerve In neuroanatomy, the trigeminal nerve ( lit. ''triplet'' nerve), also known as the fifth cranial nerve, cranial nerve V, or simply CN V, is a cranial nerve responsible for sensation in the face and motor functions such as biting and che ...
(facial sensation). Advanced hearing loss and spells of true
vertigo Vertigo is a condition where a person has the sensation of movement or of surrounding objects moving when they are not. Often it feels like a spinning or swaying movement. This may be associated with nausea, vomiting, sweating, or difficulties w ...
may occur. Very large tumors are life-threatening when they press on the
cerebellum The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebe ...
or cause brainstem compression. Late symptoms of very large VS include headache, nausea, vomiting, sleepiness, mental confusion and eventually coma.


Neurofibromatosis Type 2 (NF2)

For the most part, unilateral sporadic vestibular schwannomas are readily treated successfully by modern medical techniques. Having bilateral VSs is a more troublesome condition. Bilateralism is considered to be the hallmark and main diagnostic criterion of
Neurofibromatosis Type II Neurofibromatosis type II (also known as MISME syndrome – multiple inherited schwannomas, meningiomas, and ependymomas) is a genetic condition that may be inherited or may arise spontaneously, and causes benign tumors of the brain, spinal cord, ...
(NF2), a
genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
that is heritable, progressive, difficult to manage, and has a 1 in 2 chance of being passed on to each offspring. NF2 patients tend to have a more severe mutation, although there are mild mosaic cases in which only some cells carry the mutation. Genetic testing confirming mutation of the NF2 gene is recommended. About 50% of people with NF2 have a ''de novo'' mutation, and about 50% of these new mutations will be mild mosaic cases which are less likely to be passed on. NF2 patients may develop other cranial and spine tumors. NF2 develops during the teens or early adulthood, whereas sporadic VSs are diagnosed mostly in patients between the ages of 40–60 years. Both varieties of VS (sporadic and NF2) are very rare, accounting for only about 8% of all primary
brain tumor A brain tumor occurs when abnormal cells form within the brain. There are two main types of tumors: malignant tumors and benign (non-cancerous) tumors. These can be further classified as primary tumors, which start within the brain, and seco ...
s. The incidence of NF2 is approximately 1 per 60,000 people.


Tumor sizes

Patient surveys in the U.S. by the national Acoustic Neuroma Association (1998, 2007–08, 2012, 2014) showed that the percentage of diagnosed tumors 1.5 cm or less increased significantly from 23% to 47%. Researchers in Denmark reported (2004): "The size of diagnosed tumors has decreased from a median of 35 mm in 1979 to 10 mm in 2001." In general, tumor size (diameter) is described as small (less than 1.5 cm), medium (1.5 to 2.5 cm), large (2.5 to 4.0 cm) and giant (more than 4.0 cm). (Note: 1 inch = 2.54 cm) Radiologists reporting on MRI scans use the Koos Grading Scale which relates tumor size to its proximity to the brainstem and nearby cranial nerves. Thus Koos grade 1 is a purely intrameatal (IAC) tumor, 1–10 mm in size; Koos grade 2, 10–20 mm, has extended into the cerebellopontine angle (CPA), but with no brainstem contact; Koos grade 3, 20–30 mm, fills the CPA space and touches on the brainstem, but without compression; and Koos grade 4, more than 30 mm in size, compresses the brainstem and nearby nerves, and displaces critical arteries.


Diagnosis

Preliminary diagnostic procedures include ear examination, hearing and vestibular testing. The
auditory brainstem response The auditory brainstem response (ABR), also called brainstem evoked response audiometry (BERA), is an auditory evoked potential extracted from ongoing electrical activity in the brain and recorded via electrodes placed on the scalp. The measured ...
test (ABR) is a cost-effective test to see if a VS has perhaps compromised the
cochlear nerve The cochlear nerve (also auditory nerve or acoustic nerve) is one of two parts of the vestibulocochlear nerve, a cranial nerve present in amniotes, the other part being the vestibular nerve. The cochlear nerve carries auditory sensory information ...
. Computed tomography (CT scan) of the head will detect moderate to large sized VS but can miss small sized VS. VS appears as isodense to surrounding brain parenchyma on CT. VS does not have calcifications in it. A large VS may expand the size of internal acoustic meatus (IAC) and may compromise hearing function because the nerves within the IAC are compressed, particularly the
cochlear nerve The cochlear nerve (also auditory nerve or acoustic nerve) is one of two parts of the vestibulocochlear nerve, a cranial nerve present in amniotes, the other part being the vestibular nerve. The cochlear nerve carries auditory sensory information ...
. However, the facial nerve is less commonly affected. The main advantage of a CT scan is to assess the extent of bony involvement by VS. VS enhances when
iodinated contrast Iodinated contrast is a form of intravenous radiocontrast agent containing iodine, which enhances the visibility of vascular structures and organs during radiographic procedures. Some pathologies, such as cancer, have particularly improved visib ...
is given. A contrasted CT scan of the
temporal bone The temporal bones are situated at the sides and base of the skull, and lateral to the temporal lobes of the cerebral cortex. The temporal bones are overlaid by the sides of the head known as the temples, and house the structures of the ears. ...
can done if the patient is unable to undergo MRI scan. MRI scan is the imaging of choice because it can more accurately differentiate the mass from other tumors such as
meningioma Meningioma, also known as meningeal tumor, is typically a slow-growing tumor that forms from the meninges, the membranous layers surrounding the brain and spinal cord. Symptoms depend on the location and occur as a result of the tumor pressing ...
, facial nerve schwannoma, epidermoid cyst, arachnoid cyst, aneurysm, and brain metastasis. MRI scan also helps in surgical planning and follow-up of the tumor after surgery. VC is usually isointense on T1 weighted images, hyperintense on T2 weighted images, and enhances after given gadolinium contrast.


Management


Microsurgery for Sporadic VS

The ''Guidelines on the Treatment of Adults with Vestibular Schwannoma'' issued in 2018 by the Congress of Neurological Surgeons in the U.S. looked at the long-term evolution of treatments for VS. The Introduction to the Guidelines stated: "The evolution in treatment over the last century has ultimately led to an environment where functional outcome has taken precedence over disease eradication. With multiple noninvasive management options available, the tolerance of cranial neuropathy in patients with small and medium-sized tumors is low. Today, hearing preservation, facial nerve function, and tumor control remain the primary benchmarks used to evaluate treatment effectiveness and compare outcomes." In other words, tumor management was able to give greater attention to preserving quality of life. The three main surgical approaches to the tumor are the translabyrinthine (incision behind the ear to reach the bony labyrinth), the retrosigmoid (incision behind the ear to reach cerebellopontine angle) and the middle cranial fossa (incision in front of the ear to access the IAC from above). Tumor size is a major factor in determining approach selection. Adjunctive use of the
endoscope An endoscope is an inspection instrument composed of image sensor, optical lens, light source and mechanical device, which is used to look deep into the body by way of openings such as the mouth or anus. A typical endoscope applies several modern t ...
for enhanced visualization during surgery for IAC tumors has gained attention as an emerging technique with advancing technology. For large tumors, a 'facial nerve sparing surgery' offers partial removals, to be followed (as needed) by stereotactic radiosurgery or radiotherapy for 'residuals'. The rate of 'tumor control' appeared to be similar to that for gross total removal surgeries. For small to medium size tumors, the appropriateness of so-called 'hearing preservation surgery' via either the Middle Fossa or Retrosigmoid approach remained controversial. Data from Denmark indicated that primary observation offered the best chance to preserve good hearing the longest. But preserving good hearing in the affected ear remained an elusive goal. Even during observation, although tumors showed no significant growth, hearing deterioration occurred. Stangerup et al. reported (2010) that most patients with 100% speech discrimination at diagnosis had the best chance of maintaining good hearing after ten years of observation. The overall mortality rate for VS surgery is around 0.2% - 0.5%. The most common complications include facial nerve disorder (25.0%), cerebrospinal fluid leakage (8.5%) and postoperative neurological complications (8.4%).


Radiosurgery and radiotherapy

The 'Patient Survey' in the U.S. in 2014 by the national Acoustic Neuroma Association showed that 29% of VS patients reported radiosurgery (17%) or radiotherapy (12%) as their treatment of choice. Radiosurgery is the delivery to the VS of a concentrated high radiation dose in a one-day session, whereas radiotherapy involves multiple treatment sessions where the total radiation dose is spread out in fractions over a few days or 3–4 weeks. The main objective in either case is 'tumor control' by damaging tumor cell DNA and stopping blood vessel proliferation (angiogenesis) needed for tumor growth. Tumors may swell following radiation, but this increase in size is transient and does not signal a failed procedure. The average success rate for stereotactic radiosurgery is reported to be 95.5%. Radiation doses are calculated in terms of
Gray Grey (more common in British English) or gray (more common in American English) is an intermediate color between black and white. It is a neutral or achromatic color, meaning literally that it is "without color", because it can be compose ...
/Gy—the measure of energy deposited by
ionizing radiation Ionizing radiation (or ionising radiation), including nuclear radiation, consists of subatomic particles or electromagnetic waves that have sufficient energy to ionize atoms or molecules by detaching electrons from them. Some particles can travel ...
per kilogram of matter. Since VSs are noninvasive and well-demarcated from surrounding tissues, radiosurgeons are able to target the tumor volume closely and minimize normal tissue damage. Multisession radiotherapy recommends the advantage of giving time between sessions for biological repair of any damage to normal tissues that may occur, and allows for radiation of the tumor at different times in the cell growth cycle. The CyberKnife radiation system introduced in 1994 recommends a protocol of three sessions known as hypofractionation. Radiation dosages overall were reduced over the years as experience showed that excellent tumor control rates could be maintained even as dosages were lowered to benefit hearing preservation and facial nerve function. Generally, single-session Gamma Knife radiosurgery is limited in use to VSs less than 3 cm in diameter to avoid possible complications with facial nerves, brainstem and the cochlea apparatus. The risk of radiation-induced secondary tumors is very small, in the range of 0.01-0.02%. The risk for NF2 patients appears to be slightly higher.


Medical and gene therapies

To date, there is no fully efficacious medical therapy for VS. The complexity of the molecular biology research involved is truly challenging. Clinical trials are in progress for other drugs such as everolimus, lapatinib and
mifepristone Mifepristone, also known as RU-486, is a medication typically used in combination with misoprostol to bring about a medical abortion during pregnancy and manage early miscarriage. This combination is 97% effective during the first 63 days of ...
''.'' Common aspirin has been studied as a low-risk therapeutic option, but emerging evidence suggests that aspirin and other NSAID use may not prevent VS tumor growth.


Observation of Small VS

The 1991 NIH Consensus Statement observed: "There is evidence that some patients with unilateral vestibular schwannoma and a subgroup of patients with NF2 may have tumors that fail to progress rapidly, resulting in stable neurologic function for a long time. The use of MRI with contrast enhancement has resulted in the identification of patients with very small, relatively asymptomatic vestibular schwannomas for whom the natural history is unknown. Conservative management may be appropriate for these patients." At the time,
conservative management Conservative management is a type of medical treatment defined by the avoidance of invasive measures such as surgery or other invasive procedures, usually with the intent to preserve function or body parts. For example, in appendicitis, conservati ...
(i.e., observation, 'wait-and-watch'/'wait-and-scan') was reserved mainly for elderly or infirm patients. Data on tumor sizes at diagnosis and tumor growth behavior was sparse or contradictory and mainly short-term. The Central Brain Tumor Registry of the U.S., established in 1992, only began to keep records for benign tumors like VS in 2004. In 2006, a landmark study from Denmark, entitled "The Natural History of Vestibular Schwannoma," initiated a significant trend toward observation for managing small VS. Researchers in Copenhagen had the advantage that data for all Danish patients diagnosed with VS since 1976 was entered into a national database. The 2006 study by Stangerup et al. looked at the data for 1,818 patients (1976–2004) comparing intrameatal VS (in the
auditory canal The ear canal (external acoustic meatus, external auditory meatus, EAM) is a pathway running from the outer ear to the middle ear. The adult human ear canal extends from the pinna to the eardrum and is about in length and in diameter. Stru ...
) and extrameatal VS (into the cerebellopontine angle). Remarkably, for the 729 patients having observation management via interval MRI scans, tumor growth was observed in only 17% of intrameatal tumors and 29% of extrameatal tumors. The mean observation time was 3.6 years (range 1–15 years). The researchers concluded: "VS growth occurs within the first 5 years after diagnosis in a limited number of tumors, primarily in tumors with an extrameatal extension. These findings justify primary observation of small tumors." The medical community and VS patients responded positively to these findings. 'Patient Surveys' in the U.S. by the national Acoustic Neuroma Association showed an increase in "Wait-and-Watch" from 4% of respondents in 1998 to 20% in 2012. An important study in 2015 entitled "The Changing Landscape of Vestibular Schwannoma Management in the United States – A Shift Toward Conservatism," predicted that half of all cases of VS would be managed initially with observation by 2026. Stangerup et al. have urged caution (2019): "Most studies show that if tumor growth occurs, it is usually detected within the first few years of diagnosis. However, long-term observational studies are desperately needed to guide the development of evidence-based surveillance algorithms designed to detect late tumor progression." Also (see Medical and Gene Therapies, above): "Basic science and identification of genes, molecular pathways, and networks related to tumor growth are likely to change our approach to treatment including conservative management."


Incidence of Sporadic VS

In 2015, researchers at the
Cleveland Clinic Cleveland Clinic is a nonprofit American academic medical center based in Cleveland, Ohio. Owned and operated by the Cleveland Clinic Foundation, an Ohio nonprofit corporation established in 1921, it runs a 170-acre (69 ha) campus in Cleveland, ...
in Ohio used population-based data of the Central Brain Tumor Registry of the U.S. to calculate an incidence of 10.9 per million of population, or about 3,300 cases of VS per year. A higher incidence up to 29.3 per million of population was found for the 65-74 year-old age group. There was no significant difference in incidence by gender. Incidence was higher in Asian Pacific Islanders, and lower in African Americans and Hispanics. The annual number of diagnosed VS increased significantly worldwide by the early 1990s with the introduction of magnetic resonance imaging (MRI). Notably, epidemiologists in Denmark (population of 5.7 million in 2015) reported 193 cases of VS for 2015—an incidence of 34 per million of population per year. The first MRI scanner in Denmark was functional in 1989, and by 2015 the number increased to approximately 100.


History


Early descriptions

In 1777, Eduard Sandifort of Leiden, the Netherlands, wrote a postmortem first description of a vestibular schwannoma. He observed "a certain hard body adherent to the auditory nerve," and concluded this cause of deafness was beyond the reach of medication or surgery and was therefore incurable. The Schwann cells that multiply to form a VS on the vestibulocochlear nerve were identified 60 years later in 1838 by the German physiologist
Theodor Schwann Theodor Schwann (; 7 December 181011 January 1882) was a German physician and physiologist. His most significant contribution to biology is considered to be the extension of cell theory to animals. Other contributions include the discovery of ...
. In 1895,
Thomas Annandale Thomas Annandale, FRCS FRSE (1838–1907) was a Scottish surgeon who conducted the first repair of the meniscus and the first successful removal of an acoustic neuroma, and introduced the pre-peritoneal approach to inguinal hernia repair. He ...
, a general surgeon at the Royal Infirmary in Edinburgh, Scotland, was the first to successfully localize and surgically remove a VS. Finger dissection of VS to 'shell out' the tumor was typical. The main goal when dealing with large tumors was preservation of life.


Early surgeries

In the early 1900s the mortality rate for VS surgery was in the range of 75 to 85%. Surgeons typically delayed invasive intervention as long as possible as a last resort.
Harvey Cushing Harvey Williams Cushing (April 8, 1869 – October 7, 1939) was an American neurosurgeon, pathologist, writer, and draftsman. A pioneer of brain surgery, he was the first exclusive neurosurgeon and the first person to describe Cushing's disease ...
(1869–1939) is known as 'the father of neurosurgery for VS.' His basic study published in 1917 was entitled ''Tumors of the Nervus Acusticus and the Syndrome of the Cerebellopontine Angle.'' Cushing perfected the retrosigmoid surgical approach, and by doing suboccipital
craniotomy A craniotomy is a surgical operation in which a bone flap is temporarily removed from the skull to access the brain. Craniotomies are often critical operations, performed on patients who are suffering from brain lesions, such as tumors, blood clot ...
and subtotal removals he was able to reduce mortality to 4% by 1931. Cushing worked at Brigham Hospital in Boston. An equally famous specialist for VS at
Johns Hopkins Johns Hopkins (May 19, 1795 – December 24, 1873) was an American merchant, investor, and philanthropist. Born on a plantation, he left his home to start a career at the age of 17, and settled in Baltimore, Maryland where he remained for most ...
in Baltimore was Walter E. Dandy (1886–1946), a former pupil of Cushing who advocated total tumor removals. In 1931, he reported a complete removal with preservation of the facial nerve.


Imaging

A major problem for the pioneers in VS neurosurgery was the lack of adequate imaging for spotting small tumors. Treating tumors that grew overly large in the cerebellopontine angle resulted in poor outcomes for the goals of facial nerve and hearing preservation. For imaging, conventional
X-ray An X-ray, or, much less commonly, X-radiation, is a penetrating form of high-energy electromagnetic radiation. Most X-rays have a wavelength ranging from 10 picometers to 10  nanometers, corresponding to frequencies in the range 30&nb ...
s began to be used in the 1920s and CT scanners were introduced in the 1960s, but all were superseded by 'gold standard' MRIs in the 1980s. Facial nerve monitoring was added in 1979.
William F. House William Fouts House (December 1, 1923 in Kansas City, Missouri – December 7, 2012 in Aurora, Oregon) was an American otologist, physician and medical researcher who developed and invented the cochlear implant. The cochlear implant is considered ...
(1923–2012) pioneered the use of the operating microscope, and (with William Hitselberger) popularized the translabyrinthine and
middle fossa The middle cranial fossa, deeper than the anterior cranial fossa, is narrow medially and widens laterally to the sides of the skull. It is separated from the posterior fossa by the clivus and the petrous crest. It is bounded in front by the po ...
surgery approaches for VS. The operating microscope would be used in virtually all operations by 1998. House's son, John W. House, proposed (1983) and, with Derald E. Brackmann, developed the House-Brackmann grading system for reporting facial nerve outcomes following VS surgery.


Treatment


Surgical treatment

In 1986, at a meeting for neurosurgeons in San Francisco, the House group endorsed a guideline for the surgical treatment of VS: "The best opportunity for successful removal of an acoustic neuroma is when it is small: when first diagnosed." At the time of the NIH Consensus Development Conference for ''Acoustic Neuroma'' in 1991,
microsurgery Microsurgery is a general term for surgery requiring an operating microscope. The most obvious developments have been procedures developed to allow anastomosis of successively smaller blood vessels and nerves (typically 1 mm in diameter) whic ...
was definitely the predominant management strategy for VS. The consensus conference's panel of experts reported: "Currently, the ideal treatment for symptomatic patients with vestibular schwannoma is the total excision of the tumor in a single stage with minimal morbidity and mortality and with preservation of neurological function." Total surgical removal was not, however, the only treatment indicated at the time. Partial removals were in use to debulk very large VSs threatening to compress vital structures. And long-term observation management was deemed appropriate as MRI scans began to reveal more and more small tumors with stable neurological symptoms.


Radiosurgery

By the 1980s,
radiation therapy Radiation therapy or radiotherapy, often abbreviated RT, RTx, or XRT, is a therapy using ionizing radiation, generally provided as part of cancer treatment to control or kill malignant cells and normally delivered by a linear accelerator. Rad ...
was also becoming an attractive option for VS patients. At the
Karolinska Institute The Karolinska Institute (KI; sv, Karolinska Institutet; sometimes known as the (Royal) Caroline Institute in English) is a research-led medical university in Solna within the Stockholm urban area of Sweden. The Karolinska Institute is consist ...
in Stockholm, Sweden, Lars Leksell (1907–1986) pioneered Gamma Knife radiosurgery. In 1951, he published his landmark scientific paper, "The Stereotaxic Method and Radiosurgery of the Brain," defining radiosurgery as "the destruction of intracranial targets without opening the skull using very high doses of ionizing radiation in stereotactically directed beams." The first Gamma Knife machine was operable in Sweden in 1969, and the first Gamma Knife in the U.S. was installed in 1987 at the Presbyterian University Hospital in Pittsburgh, PA. Departments of radiation oncology at major medical centers began to modify X-ray linear accelerators (linacs) to do single-session radiosurgery and multiple-session radiotherapy. In 1991, the U.S. National Institutes of Health convened a Consensus Development Conference (December 11–13, 1991) for Acoustic Neuroma (Vestibular Schwannoma) to evaluate management of the disorder and recommend areas for future activity and research."


Medical and gene therapies

The 1991 NIH Consensus Statement recommended attention to "the development of pharmaceutical and other alternative medical treatments, such as tumor suppressing agents." Ideally, a drug could be found to permanently shrink or eradicate VSs, with minimal side effects. A key step forward in 1993 was the identification of the NF2 gene and its protein product ''Merlin'', which modulates the complex molecular signaling pathways that control
cell proliferation Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation r ...
. These pathways that drive VS formation (
tumorigenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...
) and growth are currently under investigation. A second important field of study in molecular biology investigates ways to stop the formation (angiogenesis) of the new blood vessels that are needed to support tumor growth by supplying nutrients and oxygen. In 1998, the
glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glyco ...
named
VEGF Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors ...
(vascular endothelial growth factor) that initiates proliferation was discovered. An anti-VEGF drug named
bevacizumab Bevacizumab, sold under the brand name Avastin among others, is a medication used to treat a number of types of cancers and a specific eye disease. For cancer, it is given by slow injection into a vein (intravenous) and used for colon cancer, ...
(Avastin) was developed and showed promise in stopping this vascular proliferation. Unfortunately, when tested for NF2 tumors, the therapy required prolonged treatment resulting in
hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high b ...
and impaired wound healing. The development of a new generation of drugs may become a secondary therapy in view of advances in
genome editing Genome editing, or genome engineering, or gene editing, is a type of genetic engineering in which DNA is inserted, deleted, modified or replaced in the genome of a living organism. Unlike early genetic engineering techniques that randomly inserts ...
during the 1990s that led to the invention of
CRISPR CRISPR () (an acronym for clustered regularly interspaced short palindromic repeats) is a family of DNA sequences found in the genomes of prokaryotic organisms such as bacteria and archaea. These sequences are derived from DNA fragments of bact ...
in 2009. CRISPR has become the preferred genome editing tool whereby diseases may be treated by correcting causative mutations directly in a patient's genome.


Notable people

American actor, director, humanitarian, social activist and film producer
Mark Ruffalo Mark Alan Ruffalo (; born November 22, 1967) is an American actor and producer best known for playing Bruce Banner / Hulk since 2012 in the superhero franchise of the Marvel Cinematic Universe, and in the television series '' She-Hulk: Attorne ...
was diagnosed with vestibular schwannoma in 2001 which resulted in a period of partial facial paralysis. He recovered from the paralysis; however, he became deaf in his left ear as a result of the tumor. Guitarist/composer/producer
David Torn David M. Torn (born May 26, 1953) is an American guitarist, composer, and producer. He is known for combining electronic and acoustic instruments and for his use of looping. Background Torn has contributed to recordings by artists as diverse ...
was diagnosed with an acoustic neuroma in 1992. It required intricate surgery that left him deaf in the right ear and burdened by many other health obstacles. American actress and designer Tara Subkoff was diagnosed with schwannoma in 2009. She successfully underwent surgery, but was left with permanent nerve damage and deafness in her right ear.
Tionne Watkins Tionne Tenese Watkins (born April 26, 1970), better known by her stage name T-Boz, is an American singer and actress. Born in Des Moines, Iowa, Watkins rose to fame in the early 1990s as a member of the girl-group TLC. She has won four Grammy ...
, better known by her stage name T-Boz, R&B singer from the R&B/hip-hop group TLC, was diagnosed with a strawberry-sized acoustic neuroma on her vestibular nerve in 2006. Many physicians refused to remove the tumor due to her
sickle-cell Sickle cell disease (SCD) is a group of blood disorders typically inherited from a person's parents. The most common type is known as sickle cell anaemia. It results in an abnormality in the oxygen-carrying protein haemoglobin found in red blo ...
-related complications, leaving her alternatives grim. Ultimately, she underwent surgery at
Cedars-Sinai Hospital Cedars-Sinai Medical Center is a nonprofit, tertiary, 886-bed teaching hospital and multi-specialty academic health science center located in Los Angeles, California. Part of the Cedars-Sinai Health System, the hospital employs a staff of over 2 ...
in Los Angeles. English comedian, artist, surrealist, musician, actor, and television presenter Vic Reeves revealed that he was diagnosed with a grape-sized vestibular schwannoma at age 62. He has lost all hearing in the left ear as a result.


See also

*
Cerebellopontine angle syndrome The cerebellopontine angle syndrome is a distinct neurological syndrome of deficits that can arise due to the closeness of the cerebellopontine angle to specific cranial nerves.Rolak LA. ''Neurology Secrets'', 4th Ed. Chapter 10, "Cerebellar Dis ...


References


Further reading

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External links

* {{DEFAULTSORT:Vestibular Schwannoma PNS neoplasia Rare diseases