Вестибулярная шваннома: причины, симптомы и диагностика.

A vestibular schwannoma (VS), also called acoustic neuroma, is a benign tumor that develops on the vestibulocochlear nerve that passes from the inner ear to the brain. The tumor originates when Schwann cells that form the insulating myelin sheath 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, NF2, located on chromosome 22, results in abnormal production of the cell protein named Merlin, 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. 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.

Sporadic VSs originate within the confining bony walls of the small (ca. 2 cm long) internal auditory canal. The most common early symptoms of these intracanalicular (IAC) VSs are gradual hearing loss 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, 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 (facial expression) and trigeminal nerve (facial sensation). Advanced hearing loss and spells of true vertigo may occur. Very large tumors are life threatening when they press on the cerebellum or cause brainstem compression. Late symptoms of very large VS include headache, nausea, vomiting, sleepiness, mental confusion and eventually coma.

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 (NF2), a genetic disorder 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 tumors. The incidence of NF2 is approximately 1 per 60,000 people.

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.

Preliminary diagnostic procedures include ear examination, hearing and vestibular testing. Typical symptoms include unilateral tinnitus, progressive hearing loss and vertigo. Usually diagnostic sensitivity is increased with one or more otological symptom. The rate of VS pick up with unilateral tinnitus alone using MRI has been shown to be <0.1%. The auditory brainstem response test (ABR) is a cost effective test to see if a VS has perhaps compromised the cochlear nerve. 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. 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 is given. A contrasted CT scan of the temporal bone 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, 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.

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 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%).

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/Gy—the measure of energy deposited by ionizing radiation 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.

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. 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.

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 (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," 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."

In 2015, researchers at the Cleveland Clinic 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.

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. In 1895, Thomas Annandale, 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.

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 (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 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 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.

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 rays 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 (1923–2012) pioneered the use of the operating microscope, and (with William Hitselberger) popularized the translabyrinthine and middle fossa 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.

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 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.""

The 1991 NIH Consensus Statement recommended attention to "the development of pharmaceutical and other alternative medical treatments, such as tumor suppressing agents."