<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Wilsons disease and can you explain it in depth? [/INST] Wilsons disease is a genetic disorder in which excess copper builds up in the body. Symptoms are typically related to the brain and liver. Liver-related symptoms include vomiting, weakness, fluid build up in the abdomen, swelling of the legs, yellowish skin and itchiness. Brain-related symptoms include tremors, muscle stiffness, trouble in speaking, personality changes, anxiety, and psychosis.Wilsons disease is caused by a mutation in the Wilson disease protein (ATP7B) gene. This protein transports excess copper into bile, where it is excreted in waste products. The condition is autosomal recessive; for a person to be affected, they must inherit a mutated copy of the gene from both parents. Diagnosis may be difficult and often involves a combination of blood tests, urine tests and a liver biopsy. Genetic testing may be used to screen family members of those affected.Wilsons disease is typically treated with dietary changes and medication. Dietary changes involve eating a low-copper diet and not using copper cookware. Medications used include chelating agents such as trientine and d-penicillamine and zinc supplements. Complications of Wilsons disease can include liver failure, liver cancer and kidney problems. A liver transplant may be helpful to those for whom other treatments are not effective or if liver failure occurs.Wilsons disease occurs in about 1 in 30,000 people. Symptoms usually begin between the ages of 5 and 35 years. It was first described in 1854 by a German pathologist Friedrich Theodor von Frerichs and is named after British neurologist Samuel Wilson.

Signs and symptoms
The main sites of copper accumulation are the liver and the brain, and consequently liver disease and neuropsychiatric symptoms are the main features that lead to diagnosis. People with liver problems tend to come for medical attention earlier, generally as children or teenagers, than those with neurological and psychiatric symptoms, who tend to be in their twenties or older. Some are identified only because relatives have been diagnosed with Wilsons disease; many of these, when tested, turn out to have been experiencing symptoms of the condition but have not received a diagnosis.

Liver disease
Liver disease may present itself as tiredness, increased bleeding tendency or confusion (due to hepatic encephalopathy) and portal hypertension. The latter, a condition in which the pressure in the portal vein is markedly increased, leads to esophageal varices, blood vessels in the esophagus that may bleed in a life-threatening fashion, as well as enlargement of the spleen (splenomegaly) and accumulation of fluid in the abdominal cavity (ascites). On examination, signs of chronic liver disease such as spider angiomata (small distended blood vessels, usually on the chest) may be observed. Chronic active hepatitis has caused cirrhosis of the liver in most by the time they develop symptoms. While most people with cirrhosis have an increased risk of hepatocellular carcinoma (liver cancer), this risk is relatively very low in Wilsons disease.About 5% of all people are diagnosed only when they develop fulminant acute liver failure, often in the context of a hemolytic anemia (anemia due to the destruction of red blood cells). This leads to abnormalities in protein production (identified by deranged coagulation) and metabolism by the liver. The deranged protein metabolism leads to the accumulation of waste products such as ammonia in the bloodstream. When these irritate the brain, the person develops hepatic encephalopathy (confusion, coma, seizures and finally life-threatening swelling of the brain).

Neuropsychiatric symptoms
About half of the people with Wilsons disease have neurological or psychiatric symptoms. Most initially have mild cognitive deterioration and clumsiness, as well as changes in behavior. Specific neurological symptoms usually then follow, often in the form of parkinsonism (cogwheel rigidity, bradykinesia or slowed movements and a lack of balance are the most common parkinsonian features) with or without a typical hand tremor, masked facial expressions, slurred speech, ataxia (lack of coordination) or dystonia (twisting and repetitive movements of part of the body). Seizures and migraine appear to be more common in Wilsons disease. A characteristic tremor described as "wing-beating tremor" is encountered in many people with Wilsons; this is absent at rest but can be provoked by abducting the arms and flexing the elbows toward the midline.Cognition can also be affected in Wilsons disease. This comes in two, not mutually exclusive, categories: frontal lobe disorder (may present as impulsivity, impaired judgement, promiscuity, apathy and executive dysfunction with poor planning and decision making) and subcortical dementia (may present as slow thinking, memory loss and executive dysfunction, without signs of aphasia, apraxia or agnosia). It is suggested that these cognitive involvements are related and closely linked to psychiatric manifestations of the disease.Psychiatric problems due to Wilsons disease may include behavioral changes, depression, anxiety disorders, and psychosis. Psychiatric symptoms are commonly seen in conjunction with neurological symptoms and are rarely manifested on their own. These symptoms are often poorly defined and can sometimes be attributed to other causes. Because of this, diagnosis of Wilsons disease is rarely made when only psychiatric symptoms are present.

Other organ systems
Medical conditions have been linked with copper accumulation in Wilsons disease:

Eyes: Kayser–Fleischer rings (KF rings), a pathognomonic sign, may be visible in the cornea of the eyes, either directly or on slit lamp examination as deposits of copper form a ring around the cornea. This is due to copper deposition in Descemets membrane. These rings can be either dark brown, golden, or reddish-green, are 1 to 3 mm wide, and appear at the corneal limbus. They do not occur in all people with Wilsons disease. Wilsons disease is also associated with sunflower cataracts exhibited by brown or green pigmentation of the anterior and posterior lens capsule. Neither causes significant visual loss. KF rings occur in approximately 66% of diagnosed cases (more often in those with neurological symptoms rather than with liver problems).
Kidneys: renal tubular acidosis (Type 2), a disorder of bicarbonate handling by the proximal tubules leads to nephrocalcinosis (calcium accumulation in the kidneys), a weakening of bones (due to calcium and phosphate loss), and occasionally aminoaciduria (loss of essential amino acids needed for protein synthesis).
Heart: cardiomyopathy (weakness of the heart muscle) is a rare but recognized problem in Wilsons disease; it may lead to heart failure (fluid accumulation due to decreased pump function) and cardiac arrhythmias (episodes of irregular and/or abnormally fast or slow heart beat).
Hormones: hypoparathyroidism (failure of the parathyroid glands leading to low calcium levels), infertility, and recurrent miscarriage.

Genetics
The Wilsons disease gene (ATP7B) is on chromosome 13 (13q14.3) and is expressed primarily in the liver, kidney, and placenta. The gene codes for a P-type (cation transport enzyme) ATPase that transports copper into bile and incorporates it into ceruloplasmin. Mutations can be detected in 90% of cases. Most (60%) are homozygous for ATP7B mutations (two abnormal copies), and 30% have only one abnormal copy. Ten percent have no detectable mutation.Although 300 mutations of ATP7B have been described, in most populations the cases of Wilsons disease are due to a small number of mutations specific for that population. For instance, in Western populations the H1069Q mutation (replacement of a histidine by a glutamine at position 1069 in the protein) is present in 37–63% of cases, while in China this mutation is very uncommon and R778L (arginine to leucine at 778) is found more often. Relatively little is known about the relative impact of various mutations, although the H1069Q mutation seems to predict later onset and predominantly neurological problems, according to some studies. A comprehensive clinically annotated resource, WilsonGen provides clinical classification for the variants as per the recent ACMG & AMP guidelinesA normal variation in the PRNP gene can modify the course of the disease by delaying the age of onset and affecting the type of symptoms that develop. This gene produces prion protein, which is active in the brain and other tissues and also appears to be involved in transporting copper. A role for the ApoE gene was initially suspected but could not be confirmed.The condition is inherited in an autosomal recessive pattern. In order to inherit it, both of the parents of an individual must carry an affected gene. Most have no family history of the condition. People with only one abnormal gene are called carriers (heterozygotes) and may have mild, but medically insignificant, abnormalities of copper metabolism.Wilsons disease is the most common from a group of hereditary diseases that cause copper overload in the liver. All can cause cirrhosis at a young age. The other members of the group are Indian childhood cirrhosis (ICC), endemic Tyrolean infantile cirrhosis and idiopathic copper toxicosis. These are not related to ATP7B mutations: for example, ICC has been linked to mutations in the KRT8 and the KRT18 gene.

Pathophysiology
Copper is needed by the body for a number of functions, predominantly as a cofactor for a number of enzymes such as ceruloplasmin, cytochrome c oxidase, dopamine β-hydroxylase, superoxide dismutase and tyrosinase.Copper enters the body through the digestive tract. A transporter protein on the cells of the small bowel, copper membrane transporter 1 (Ctr1; SLC31A1), carries copper inside the cells, where some is bound to metallothionein and part is carried by ATOX1 to an organelle known as the trans-Golgi network. Here, in response to rising concentrations of copper, an enzyme called ATP7A (Menkes protein) releases copper into the portal vein to the liver. Liver cells also carry the CMT1 protein, and metallothionein and ATOX1 bind it inside the cell, but here it is ATP7B that links copper to ceruloplasmin and releases it into the bloodstream, as well as removing excess copper by secreting it into bile. Both functions of ATP7B are impaired in Wilsons disease. Copper accumulates in the liver tissue; ceruloplasmin is still secreted, but in a form that lacks copper (termed apoceruloplasmin) and is rapidly degraded in the bloodstream.When the amount of copper in the liver overwhelms the proteins that normally bind it, it causes oxidative damage through a process known as Fenton chemistry; this damage eventually leads to chronic active hepatitis, fibrosis (deposition of connective tissue) and cirrhosis. The liver also releases copper into the bloodstream that is not bound to ceruloplasmin. This free copper precipitates throughout the body but particularly in the kidneys, eyes and brain. In the brain, most copper is deposited in the basal ganglia, particularly in the putamen and globus pallidus (together called the lenticular nucleus); these areas normally participate in the coordination of movement as well as playing a significant role in neurocognitive processes such as the processing of stimuli and mood regulation. Damage to these areas, again by Fenton chemistry, produces the neuropsychiatric symptoms seen in Wilsons disease.It is not clear why Wilsons disease causes hemolysis, but various lines of evidence suggest that a high level of free (non-ceruloplasmin bound) copper has a direct effect on either oxidation of hemoglobin, inhibition of energy-supplying enzymes in the red blood cell, or direct damage to the cell membrane.

Diagnosis
Wilsons disease may be suspected on the basis of any of the symptoms mentioned above, or when a close relative has been found to have Wilsons. Most have slightly abnormal liver function tests such as a raised aspartate transaminase, alanine transaminase and bilirubin level. If the liver damage is significant, albumin may be decreased due to an inability of damaged liver cells to produce this protein; likewise, the prothrombin time (a test of coagulation) may be prolonged as the liver is unable to produce proteins known as clotting factors. Alkaline phosphatase levels are relatively low in those with Wilsons-related acute liver failure. If there are neurological symptoms, magnetic resonance imaging (MRI) of the brain is usually performed; this shows hyperintensities in the part of the brain called the basal ganglia in the T2 setting. MRI may also demonstrate the characteristic "face of the giant panda" pattern.There is no totally reliable test for Wilsons disease, but levels of ceruloplasmin and copper in the blood, as well of the amount of copper excreted in urine during a 24-hour period, are together used to form an impression of the amount of copper in the body. The gold standard—or most ideal test—is a liver biopsy.

Ceruloplasmin
Levels of ceruloplasmin are abnormally low (<0.2 g/L) in 80–95% of cases.  It can, however, be present at normal levels in people with ongoing inflammation as it is an acute phase protein. Low ceruloplasmin is also found in Menkes disease and aceruloplasminemia, which are related to, but much rarer than Wilsons disease.The combination of neurological symptoms, Kayser–Fleischer rings and a low ceruloplasmin level is considered sufficient for the diagnosis of Wilsons disease. In many cases, however, further tests are needed.

Serum and urine copper
Serum copper is low, which may seem paradoxical given that Wilsons disease is a disease of copper excess. However, 95% of plasma copper is carried by ceruloplasmin which is often low in Wilsons disease. Urine copper is elevated in Wilsons disease and is collected for 24 hours in a bottle with a copper-free liner. Levels above 100 μg/24h (1.6 μmol/24h) confirm Wilsons disease, and levels above 40 μg/24h (0.6 μmol/24h) are strongly indicative. High urine copper levels are not unique to Wilsons disease; they are sometimes observed in autoimmune hepatitis and in cholestasis (any disease obstructing the flow of bile from the liver to the small bowel).In children, the penicillamine test may be used. A 500 mg oral dose of penicillamine is administered, and urine collected for 24 hours. If this contains more than 1600 μg (25 μmol), it is a reliable indicator of Wilsons disease. This test has not been validated in adults.

Liver biopsy
Once other investigations have indicated Wilsons disease, the ideal test is the removal of a small amount of liver tissue through a liver biopsy. This is assessed microscopically for the degree of steatosis and cirrhosis, and histochemistry and quantification of copper are used to measure the severity of the copper accumulation. A level of 250 μg of copper per gram of dried liver tissue confirms Wilsons disease. Occasionally, lower levels of copper are found; in that case, the combination of the biopsy findings with all other tests could still lead to a formal diagnosis of Wilsons.In the earlier stages of the disease, the biopsy typically shows steatosis (deposition of fatty material), increased glycogen in the nucleus, and areas of necrosis (cell death). In more advanced disease, the changes observed are quite similar to those seen in autoimmune hepatitis, such as infiltration by inflammatory cells, piecemeal necrosis and fibrosis (scar tissue). In advanced disease, finally, cirrhosis is the main finding. In acute liver failure, degeneration of the liver cells and collapse of the liver tissue architecture is seen, typically on a background of cirrhotic changes. Histochemical methods for detecting copper are inconsistent and unreliable, and taken alone are regarded as insufficient to establish a diagnosis.

Genetic testing
Mutation analysis of the ATP7B gene, as well as other genes linked to copper accumulation in the liver, may be performed. Once a mutation is confirmed, it is possible to screen family members for the disease as part of clinical genetics family counseling. Regional distributions of genes associated with Wilsons disease are important to follow, as this can help clinicians design appropriate screening strategies. Since mutations of the WD gene vary between populations, research and genetic testing done in countries like the USA or United Kingdom can pose problems as they tend to have more mixed populations.

Treatment
Diet
In general, a diet low in copper-containing foods is recommended with the avoidance of mushrooms, nuts, chocolate, dried fruit, liver, sesame seeds and sesame oil, and shellfish.

Medication
Medical treatments are available for Wilsons disease. Some increase the removal of copper from the body, while others prevent the absorption of copper from the diet.
Generally, penicillamine is the first treatment used. This binds copper (chelation) and leads to excretion of copper in the urine. Hence, monitoring of the amount of copper in the urine can be done to ensure a sufficiently high dose is taken. Penicillamine is not without problems: about 20% experience a side effect or complication of penicillamine treatment, such as drug-induced lupus (causing joint pains and a skin rash) or myasthenia (a nerve condition leading to muscle weakness). In those who presented with neurological symptoms, almost half experience a paradoxical worsening in their symptoms. While this phenomenon is observed in other treatments for Wilsons, it is usually taken as an indication for discontinuing penicillamine and commencing second-line treatment. Those intolerant to penicillamine may instead be commenced on trientine hydrochloride, which also has chelating properties. Some recommend trientine as first-line treatment, but experience with penicillamine is more extensive. A further agent, under clinical investigation by Wilson Therapeutics, with known activity in Wilsons disease is tetrathiomolybdate.  This is regarded as experimental, though some studies have shown a beneficial effect.Once all results have returned to normal, zinc (usually in the form of a zinc acetate prescription called Galzin) may be used instead of chelators to maintain stable copper levels in the body. Zinc stimulates metallothionein, a protein in gut cells that binds copper and prevents their absorption and transport to the liver. Zinc therapy is continued unless symptoms recur or if the urinary excretion of copper increases.In rare cases where none of the oral treatments are effective, especially in severe neurological disease, dimercaprol (British anti-Lewisite) is occasionally necessary. This treatment is injected intramuscularly (into a muscle) every few weeks and has unpleasant side effects such as pain.People who are asymptomatic (for instance, those diagnosed through family screening or only as a result of abnormal test results) are generally treated, as the copper accumulation may cause long-term damage in the future. It is unclear whether these people are best treated with penicillamine or zinc acetate.

Physical and occupational therapies
Physiotherapy and occupational therapy are beneficial for patients with the neurologic form of the disease. The copper chelating treatment may take up to six months to start working, and these therapies can assist in coping with ataxia, dystonia, and tremors, as well as preventing the development of contractures that can result from dystonia.

Transplantation
Liver transplantation is an effective cure for Wilsons disease but is used only in particular scenarios because of the risks and complications associated with the procedure. It is used mainly in people with fulminant liver failure who fail to respond to medical treatment or in those with advanced chronic liver disease. Liver transplantation is avoided in severe neuropsychiatric illness, in which its benefit has not been demonstrated.

Prognosis
Left untreated, Wilsons disease tends to become progressively worse and is eventually fatal. With early detection and treatment, most of those affected can live relatively normal lives </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Cavernous sinus thrombosis and can you explain it in depth? [/INST] Cavernous sinus thrombosis (CST) is the formation of a blood clot within the cavernous sinus, a cavity at the base of the brain which drains deoxygenated blood from the brain back to the heart. This is a rare disorder and can be of two types–septic cavernous thrombosis and aseptic cavernous thrombosis. The most common form is septic cavernous sinus thrombosis. The cause is usually from a spreading infection in the nose, sinuses, ears, or teeth. Staphylococcus aureus and Streptococcus are often the associated bacteria.Cavernous sinus thrombosis symptoms include: decrease or loss of vision, chemosis, exophthalmos (bulging eyes), headaches, and paralysis of the cranial nerves which course through the cavernous sinus. This infection is life-threatening and requires immediate treatment, which usually includes antibiotics and sometimes surgical drainage. Aseptic cavernous sinus thrombosis is usually associated with trauma, dehydration, anemia, and other disorders.

Signs and symptoms
The clinical presentation of CST can be varied. Both acute, fulminant disease, and indolent, subacute presentations have been reported in the literature.
The most common signs of CST are related to anatomical structures affected within the cavernous sinus, notably cranial nerves III-VI, as well as symptoms resulting from impaired venous drainage from the orbit and eye.
Classic presentations are abrupt onset of unilateral periorbital edema, headache, photophobia, and bulging of the eye (exophthalmos).Other common signs and symptoms include:
Ptosis, chemosis, cranial nerve palsies (III, IV, V, VI). Sixth nerve palsy is the most common. Sensory deficits of the ophthalmic and maxillary branch of the fifth nerve are common. Periorbital sensory loss and impaired corneal reflex may be noted. Papilledema, retinal hemorrhages, and decreased visual acuity and blindness may occur from venous congestion within the retina. Fever, tachycardia and sepsis may be present. Headache with nuchal rigidity (neck stiffness) may occur. One or both pupils may be dilated and sluggishly reactive. Infection can spread to contralateral cavernous sinus within 24–48 hours of initial presentation.

Cause
Septic CST most commonly results from contiguous spread of infection from a nasal furuncle (50%), sphenoidal or ethmoidal sinuses (30%) and dental infections (10%). Less common primary sites of infection include tonsils, soft palate, middle ear, or orbit (orbital cellulitis). The highly anastomotic venous system of the paranasal sinuses allows retrograde spread of infection to the cavernous sinus via the superior and inferior ophthalmic veins. It was previously thought that veins in the area were valveless and that this was the major cause of the retrograde spread, but studies have since shown that the ophthalmic and facial veins are not valveless.Staphylococcus aureus is the most common infectious microbe, found in 70% of the cases. Streptococcus is the second leading cause. Gram-negative rods and anaerobes may also lead to cavernous sinus thrombosis. Rarely, Aspergillus fumigatus and mucormycosis cause CST.Aseptic cavernous sinus thrombosis is much less common and is usually associated with other disorders including trauma, circulatory problems, nasopharynx cancers and other tumors of the skull base, dehydration, and anemia.

Diagnosis
The diagnosis of cavernous sinus thrombosis is made clinically, with imaging studies to confirm the clinical impression. Proptosis, ptosis, chemosis, and cranial nerve palsy beginning in one eye and progressing to the other eye establish the diagnosis. Cavernous sinus thrombosis is a clinical diagnosis with laboratory tests and imaging studies confirming the clinical impression.

Laboratory tests
CBC, ESR, blood cultures and sinus cultures help establish and identify an infectious primary source. Lumbar puncture is necessary to rule out meningitis.

Imaging studies
Sinus films are helpful in the diagnosis of sphenoid sinusitis. Opacification, sclerosis, and air-fluid levels are typical findings.  Contrast-enhanced CT scan may reveal underlying sinusitis, thickening of the superior ophthalmic vein, and irregular filling defects within the cavernous sinus; however, findings may be normal early in the disease course. An MRI using flow parameters and an MR venogram are more sensitive than a CT scan and are the imaging studies of choice to diagnose cavernous sinus thrombosis. Findings may include deformity of the internal carotid artery within the cavernous sinus, and an obvious signal hyperintensity within thrombosed vascular sinuses on all pulse sequences. Cerebral angiography can be performed, but it is invasive and not very sensitive </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Meniscus tear and can you explain it in depth? [/INST] A tear of a meniscus is a rupturing of one or more of the fibrocartilage strips in the knee called menisci. When doctors and patients refer to "torn cartilage" in the knee, they actually may be referring to an injury to a meniscus at the top of one of the tibiae. Menisci can be torn during innocuous activities such as walking or squatting. They can also be torn by traumatic force encountered in sports or other forms of physical exertion. The traumatic action is most often a twisting movement at the knee while the leg is bent. In older adults, the meniscus can be damaged following prolonged wear and tear. Especially acute injuries (typically in younger, more active patients) can lead to displaced tears which can cause mechanical symptoms such as clicking, catching, or locking during motion of the joint. The joint will be in pain when in use, but when there is no load, the pain goes away.
A tear of the medial meniscus can occur as part of the unhappy triad, together with a tear of the anterior cruciate ligament and medial collateral ligament.

Signs and symptoms
The common signs and symptoms of a torn meniscus are knee pain, particularly along the joint line, and swelling. These are worse when the knee bears more weight (for example, when running). Another typical complaint is joint locking, when the affected person is unable to straighten the leg fully. This can be accompanied by a clicking feeling. Sometimes, a meniscal tear also causes a sensation that the knee gives way.A person with a torn meniscus can sometimes remember a specific activity during which the injury was sustained. A tear of the meniscus commonly follows a trauma that involves rotation of the knee while it was slightly bent. These maneuvers also exacerbate the pain after the injury; for example, getting out of a car is often reported as painful.

Causes
There are two menisci in the knee. They sit between the thigh bone and the shin bone. While the ends of the thigh bone and the shin bone have a thin covering of soft hyaline cartilage, the menisci are made of tough fibrocartilage and conform to the surfaces of the bones they rest on. One meniscus rests on the medial tibial plateau; this is the medial meniscus. The other meniscus rests on the lateral tibial plateau; this is the lateral meniscus.These menisci act to distribute body weight across the knee joint. Without the menisci, the weight of the body would be unevenly applied to the bones in the legs (the femur and tibia). This uneven weight distribution would cause the development of abnormal excessive forces leading to early damage of the knee joint. The menisci also contribute to the stability of the joint.The menisci are nourished by small blood vessels but have a large area in the center with no direct blood supply (avascular). This presents a problem when there is an injury to the meniscus, as the avascular areas tend not to heal. Without the essential nutrients supplied by blood vessels, healing cannot take place.The two most common causes of a meniscal tear are traumatic injury (often seen in athletes) and degenerative processes, which are the most common tear seen in all ages of patients. Meniscal tears can occur in all age groups. Traumatic tears are most common in active people aged 10–45. Traumatic tears are usually radial or vertical in the meniscus and more likely to produce a moveable fragment that can catch in the knee and therefore require surgical treatment.A meniscus can tear due to an internally or externally rotated knee in a flexed position, with the foot in a flexed position. It is not uncommon for a meniscal tear to occur along with injuries to the anterior cruciate ligament ACL and the medial collateral ligament MCL — these three problems occurring together are known as the "unhappy triad," which is seen in sports such as football when the player is hit on the outside of the knee. Individuals who experience a meniscal tear usually experience pain and swelling as their primary symptoms. Another common complaint is joint locking, or the inability to completely straighten the joint. This is due to a piece of the torn cartilage preventing the normal functioning of the knee joint.Degenerative tears are most common in people from age 40 upward but can be found at any age, especially with obesity. Degenerative meniscal tears are thought to occur as part of the aging process when the collagen fibers within the meniscus start to break down and lend less support to the structure of the meniscus. Degenerative tears are usually horizontal, producing both an upper and a lower segment of the meniscus. These segments do not usually move out of place and are therefore less likely to produce mechanical symptoms of catching or locking.

Risk factors
The meniscus is made of cartilage, a viscoelastic material, which makes it more susceptible to rate of loading injuries. Repetitive loading can also lead to injury. Recent studies have shown people who experience rapid rate of loading and/or repetitive loading to be the most susceptible to meniscus tears. People over the age of 60 who have working conditions in which squatting and kneeling are common are more susceptible to degenerative meniscal tears. Athletes who constantly experience a high rate of loading (e.g. soccer, rugby) are also susceptible to meniscus tears. Studies have also shown with increasing time between ACL injury and ACL reconstruction, there is an increasing chance of meniscus tears. This study showed meniscus tears occurring at a rate of 50–70% depending on how long after the ACL injury the surgery occurred. Meniscal ramp lesions (tears of the medial meniscus posterior horn at the menisco-capsular junction) occur in approximately 25% of ACL-injured knees. Lateral meniscal root tears occur in approximately 7% of ACL injured knees

Pathophysiology
The force distribution is across the knee joint, increasing force concentration on the cartilage and other joint structures.Damage to the meniscus due to rotational forces directed to a flexed knee (as may occur with twisting sports) is the usual underlying mechanism of injury. A valgus force applied to a flexed knee with the foot planted and the femur rotated externally can result in a lateral meniscus tear. A varus force applied to the flexed knee when the foot is planted and the femur rotated internally result in a tear of the medial meniscus.Tears produce rough surfaces inside the knee, which cause catching, locking, buckling, pain, or a combination of these symptoms. Abnormal loading patterns and rough surfaces inside the knee, especially when coupled with return to sports, significantly increase the risk of developing arthritis if not already present.

Anatomy
The menisci are C-shaped wedges of fibrocartilage located between the tibial plateau and femoral condyles. The menisci contain 70% type I collagen. The larger semilunar medial meniscus is attached more firmly than the loosely fixed, more circular lateral meniscus. The anterior and posterior horns of both menisci are secured to the tibial plateaus. Anteriorly, the transverse ligament connects the 2 menisci; posteriorly, the meniscofemoral ligament helps stabilize the posterior horn of the lateral meniscus to the femoral condyle. The coronary ligaments connect the peripheral meniscal rim loosely to the tibia. Although the lateral collateral ligament (LCL) passes in close proximity, the lateral meniscus has no attachment to this structure.The joint capsule attaches to the entire periphery of each meniscus but adheres more firmly to the medial meniscus. An interruption in the attachment of the joint capsule to the lateral meniscus, forming the popliteal hiatus, allows the popliteus tendon to pass through to its femoral attachment site. Contraction by the popliteus during knee flexion pulls the lateral meniscus posteriorly, avoiding entrapment within the joint space. The medial meniscus does not have a direct muscular connection. The medial meniscus may shift a few millimeters, while the less stable lateral meniscus may move at least 1 cm.In 1978, Shrive et al. reported that the collagen fibers of the menisci are oriented in a circumferential pattern. When a compressive force is applied in the knee joint, a tensile force is transmitted to the menisci. The femur attempts to spread the menisci anteroposteriorly in extension and mediolaterally in flexion. Shrive et al. further studied the effects of a radial cut in the peripheral rim of the menisci during loading. In joints with intact menisci, the force was applied through the menisci and articular cartilage; however, a lesion in the peripheral rim disrupted the normal mechanics of the menisci and allowed it to spread when a load was applied. The load now was distributed directly to the articular cartilage. In light of these findings, it is essential to preserve the peripheral rim during partial meniscectomy to avoid irreversible disruption of the structures hoop tension capability.

Diagnosis
Physical examination
After noting symptoms, a physician can perform clinical tests to determine if the pain is caused by compression and impingement of a torn meniscus. The knee is examined for swelling. In meniscal tears, pressing on the joint line on the affected side typically produces tenderness. The McMurray test involves pressing on the joint line while stressing the meniscus (using flexion–extension movements and varus or valgus stress). Similar tests are the Steinmann test (with the patient sitting) and the Apley grind test (a grinding maneuver while the person lies prone and the knee is bent 90°) and the Thessaly test (flexing the affected knee to 20 degrees, pivoting on the knee to see if the pain is reproduced). Bending the knee (into hyperflexion if tolerable), and especially squatting, is typically a painful maneuver if the meniscus is torn. The range of motion of the joint is often restricted.
Coopers sign is present in over 92% of tears. It is a subjective symptom of pain in the affected knee when turning over in bed at night. Osteoarthritic pain is present with weightbearing, but the meniscal tear causes pain with a twisting motion of the knee as the meniscal fragment gets pinched, and the capsular attachment gets stretched causing the complaint of pain.

Radiology
X-ray images (normally during weightbearing) can be obtained to rule out other conditions or to see if the patient also has osteoarthritis. The menisci themselves cannot be visualised with plain radiographs. If the diagnosis is not clear from the history and examination, the menisci can be imaged with magnetic resonance imaging (an MRI scan). This technique has replaced previous arthrography, which involved injecting contrast medium into the joint space. In straightforward cases, knee arthroscopy allows quick diagnosis and simultaneous treatment. Recent clinical data shows that MRI and clinical testing are comparable in sensitivity and specificity when looking for a meniscal tear.

Classification
A meniscal tear can be classified in various ways, such as by anatomic location or by proximity to blood supply. Various tear patterns and configurations have been described. These include:

Radial tears
Flap or parrot-beak tears
Peripheral, longitudinal tears
Bucket-handle tears
Horizontal cleavage tears
Complex, degenerative tearsThese tears can then be further classified by their proximity to the meniscus blood supply, namely whether they are located in the “red-red,” “red-white,” or “white-white” zones.
The functional importance of these classifications, however, is to ultimately determine whether a meniscus is repairable. The repairability of a meniscus depends on a number of factors. These include:

Age/strength
Activity level
Tear pattern
Chronicity of the tear
Associated injuries (anterior cruciate ligament injury)
Healing potential

Prevention
Tear of a meniscus is a common injury in many sports. The menisci hold 30–50% of the body load in standing position. Some sports where a meniscus tear is common are American football, association football, ice hockey and tennis.  Regardless of what the activity is, it is important to take the correct precautions to prevent a meniscus tear from happening.

Footwear
There are three major ways of preventing a meniscus tear. The first of these is wearing the correct footwear for the sport and surface that the activity is taking place on. This means that if the sport being played is association football, cleats are an important item in reducing the risk of a meniscus tear. The proper footwear is imperative when engaging in physical activity because one off-balanced step could mean a meniscus tear.
It is highly advised that cleats contain a sole that molds around the foot, no fewer than fourteen cleats per shoe, no lower than a half inch diameter of the cleat tip, and at most, a three-eighths inch of cleat length.

Stretches
The second way to prevent a meniscus tear is to strengthen and stretch the major leg muscles.  Those muscles include the hamstrings, quadriceps, and calf muscles. One popular exercise used to strengthen the hamstrings is the leg curl.  It is also important to properly stretch the hamstrings; doing standing toe touches can do this.  Seated leg extensions strengthen the quadriceps and doing the quadriceps stretch will help loosen the muscles. Toe raises are used to strengthen and stretch the calves.
Adequate muscle mass and strength may also aid in maintaining healthy knees.  The use of the parallel squat increases much needed stability in the knee if executed properly.  Execution of the parallel squat will develop the lower body muscles that will strengthen the hips, knees, and ankles.

Technique
The last major way to prevent a tear in the meniscus is learning proper technique for the movement that is taking place. For the sports involving quick powerful movements it is important to learn how to cut, turn, land from a jump, and stop correctly. It is important to take the time out to perfect these techniques when used. These three major techniques will significantly prevent and reduce the risk of a meniscus tear.

Treatment
Presently, treatments make it possible for quicker recovery. If the tear is not serious, physical therapy, compression, elevation and icing the knee can heal the meniscus. Meniscus tears are more likely to heal on their own if they are in what physicians call the "red zone," or the outer edge of the meniscus where blood supply is present. More serious tears may require surgical procedures. Surgery, however, does not appear to be better than non-surgical care. In the long term, degenerative meniscal tears are often associated with osteoarthritis. This leads to poor outcomes regardless of treatment type. In the short term, studies have shown arthroscopic partial meniscectomy (APM) is a more effective treatment with regards to function and pain management.

Conservative treatments
Initial treatment may include physical therapy, bracing, anti-inflammatory drugs, or corticosteroid injections to increase flexibility, endurance, and strength.Common anti-inflammatory drugs and painkillers prescribed for meniscus tears include acetaminophen, non-steroidal inflammatory drugs, and corticosteroids.Exercises can strengthen the muscles around the knee, especially the quadriceps. Stronger and bigger muscles will protect the meniscus cartilage by absorbing a part of the weight. The patient may be given paracetamol or anti-inflammatory medications.
For patients selecting non-surgical treatment, physical therapy may reduce symptoms of pain and swelling. This type of rehabilitation focuses on maintenance of full range of motion and functional progression without aggravating symptoms. Physical therapists can employ electric stimulation, cold therapy, and ultrasonography.
Accelerated rehabilitation programs can be as successful as the conservative program. The program reduces the time the patient spends using crutches and allows weight bearing activities. The less conservative approach allows the patient to apply a small amount of stress while protecting range of motion. It is likely that a patient with a peripheral tear can pursue the accelerated program, while a patient with a larger tear adopts the conservative program.
The use of platelet rich plasma (PRP) to aid in the healing process has become widely accepted among US athletes. Although the procedure has grown in popularity, studies assessing the efficacy of PRP treatment have yielded contradictory results.

Surgery
Arthroscopy is a surgical technique in which a joint is operated on using an endoscopic camera as opposed to open surgery on the joint. The meniscus can either be repaired or completely removed. Surgery is not appropriate for a degenerative meniscus tear, absent locking or catching of the knee, recurrent effusion or persistent pain. Evidence suggests that it is no better than conservative management in those with and without osteoarthritis. Surgery appears to offer no benefit to adults who have mild arthritis.An independent international guideline panel recommended against arthroscopy for degenerative meniscus tears; this conclusion derived from evidence of no lasting benefit and that less than 15% of patients experience even a short-term benefit. Disadvantages include a two to six week recovery time and rare but serious adverse effects that can occur, including blood clots in the legs, surgical site infections, and nerve damage. The BMJ Rapid Recommendation includes infographics and shared decision-making tools to facilitate a conversation between doctors and patients about the risks and benefits of arthroscopic surgery.If the injury is isolated, then the knee would be relatively stable. However, if an injury such as an anterior cruciate ligament injury (torn ACL) is coupled with a torn meniscus, then an arthroscopy is recommended. A meniscal repair has a higher success rate given an adequate blood supply to the peripheral rim. The interior of the meniscus is avascular, but the blood supply can penetrate up to about 6 millimetres (0.24 in). Therefore, meniscus tears that occur near the peripheral rim are able to heal after a meniscal repair. One study found that repair is better than removal (meniscectomy). The amount of rehabilitation time required for a repair is longer, but removing the meniscus can induce osteoarthritis. Meniscectomy rehab requires four to six weeks. Repair requires four to six months. If conservative treatment is ineffective, surgical intervention may be required. Younger patients are typically more resilient and respond well to this treatment, while older, more sedentary patients do not have a favorable outcome after a repair.

Transplants
Meniscus transplants are regularly successful, although the procedure is not common and many questions surrounding its use remain. Side effects of meniscectomy include:

The knee loses its ability to transmit and distribute load and absorb mechanical shock.
Persistent and significant swelling and stiffness in the knee.
The knee may be not be fully mobile; there may be the sensation of knee locking or buckling in the knee.
The full knee may be in full motion after tear of meniscus.
Increases progression of arthritis and time to knee replacement.

Implants
Another treatment approach in development is a meniscus implant or "artificial meniscus." While many artificial joints and bionic body parts are available, including arms, legs, joints and other body parts, a prosthetic meniscus replacement.The first to be implanted in humans is called the NUsurface Meniscus Implant. The implant is made from medical grade plastic and is designed not to require fixation to bone or soft tissue. The implant could be a good option for younger, active patients who are considered too young for knee replacement because that surgery lasts only about 10 years. The implant has been used in clinical trials in Europe since 2008. The first surgery as part of US clinical trials took place in January 2015 at Ohio State Universitys Wexner Medical Center. Two FDA-approved clinical trials evaluating the implant completed enrollment in June 2018. In September 2019, the manufacturer received breakthrough designation from the U.S. Food and Drug Administration, and the company expected to file for regulatory approval  within the following year. In November 2019, the implant became commercially available in Israel.Other implants include TRAMMPOLIN and Orthonika.Scientists are working to grow an artificial meniscus in the lab. Scientists from Cornell and Columbia universities grew a meniscus inside the knee joint of a sheep using a 3-D printer and the sheeps stem cells. Similarly, researchers at Scripps Research Shiley Center for Orthopaedic Research and Education reported growing a meniscus.

Post-surgical rehabilitation
After a successful surgery for treating the destroyed part of the meniscus, patients must follow a rehabilitation program to have the best result. The rehabilitation following a meniscus surgery depends on whether the entire meniscus was removed or repaired.
If the destroyed part of the meniscus was removed, patients can usually start walking using a crutch a day or two after surgery. Although each case is different, patients return to their normal activities on average after a few weeks (2 or 3). Still, a completely normal walk will resume gradually, and its not unusual to take 2–3 months for the recovery to reach a level where a patient will walk totally smoothly. Many meniscectomy patients dont ever feel a 100% functional recovery, but even years after the procedure they sometimes feel tugging or tension in a part of their knee. There is little medical follow-up after meniscectomy and official medical documentation tends to ignore the imperfections and side-effects of this procedure.
If the meniscus was repaired, the rehabilitation program that follows is a lot more intensive. After the surgery, a hinged knee brace is sometimes placed on the patient. This brace allows controlled movement of the knee. The patient is encouraged to walk using crutches from the first day, and most of the times can put partial weight on the knee.
Improving symptoms, restoring function, and preventing further injuries are the main goals when rehabilitating.  By the end of rehabilitation, normal range of motion, function of muscles and coordination of the body are restored. Personalized rehabilitation programs are designed considering the patients surgery type, location repaired (medial or lateral), simultaneous knee injuries, type of meniscal tear, age of patient, condition of the knee, loss of strength and ROM, and the expectations and motivations of the patient.

Phase I
There are three phases that follow meniscal surgery. Each phase consists of rehabilitation goals, exercises, and criteria to move on to the next phase. Phase I starts immediately following surgery to 4–6 weeks or until the patient is able meet progression criteria. The goals are to restore normal knee extension, reduce and eliminate swelling, regain leg control, and protect the knee (Fowler, PJ and D. Pompan, 1993). During the first 5 days following the surgery, a passive continuous motion machine is used to prevent a prolonged period of immobilization which leads to muscular atrophy and delays functional recovery. During the 4–6 weeks post-surgical, active and passive non-weight bearing motions which flex the knee up to 90° are recommended. For patients with meniscal transplantation, further knee flexion can damage the allograft because of the increased shear forces and stresses. If any weight-bearing exercises are applied, a controlled brace should be worn on the knee to keep the knee at near (<10°) or full extension.
The suggested exercises target increasing the patients ROM, muscular and neuromuscular strength, and cardiovascular endurance. Aquatic therapy, or swimming, can be used to rehab patients because it encompasses ROM, strength, and cardiovascular exercises while relieving stress on the body. It has also been shown to significantly improve dependent edema and pain symptoms.  No pain gait without crutches, swelling and 4–6 weeks after surgery are the criteria to begin the next phase (Ulrich G.S., and S Aroncyzk, 1993).

Phase II
This phase of the rehabilitation program is 6 to 14 weeks after the surgery. The goals for Phase II include being able to restore full ROM, normalized gait, and performing functional movements with control and no pain (Fowler, PJ and D. Pompan, 1993). Also, muscular strengthening and neuromuscular training are emphasized using progressive weight bearing and balance exercises. Exercises in this phase can increase knee flexion for more than 90°.  Advised exercises include stationary bicycle, standing on foam surface with two and one leg, abdominal and back strengthening, and quadriceps strengthening. The proposed criteria include normal gait on all surfaces and single leg balance longer than 15 seconds (Ulrich G.S., and S Aroncyzk, 1993).

Phase III
Patients begin exercises in phase III 14 to 22 weeks after surgery. Phase IIIs goal and final criterion is to perform sport/work specific movements with no pain or swelling (Fowler, PJ and D. Pompan, 1993).  Drills for maximal muscle control, strength, flexibility, movements specific to patients work/sport, low to high rate exercises, and abdominal and back strengthening exercises are all recommended exercises (Ulrich G.S., and S Aroncyzk, 1993). Exercises to increase cardiovascular fitness are also applied to fully prepare the patients to return to their desired activities.
If the progression criteria are met, the patient can gradually return to "high-impact" activities (like running). However, "heavier activities", like running, skiing, basketball etc., generally any activities where knees bear sudden changes of the direction of movement can lead to repeated injuries. When planning sport activities it makes sense to consult a physical therapist and check how much impact the sport will have on the knee.

Epidemiology
The meniscal tear is the most common knee injury. It tends to be more frequent in sports that have rough contact or pivoting sports such as soccer. It is more common in males than females, with a ratio of about two and a half males to one female. Males between the ages of 31 and 40 tend to tear their meniscus more frequently than younger men </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Amphetamine dependence and can you explain it in depth? [/INST] Amphetamine dependence refers to a state of psychological dependence on a drug in the amphetamine class. Stimulants such as amphetamines and cocaine do not cause physical dependence.Signs of amphetamine intoxication manifest themselves in euphoria, hypersexuality, tachycardia, diaphoresis, and intensifications of the train of thought, speech, and movement. Over time, neurodegenerative changes become apparent in the form of altered behavior, reduced cognitive functions, and signs of neurological damage, such as a decrease in the levels of dopamine transporters (DAT) and serotonin transporters (SERT) in the brain. Amphetamine use within teenagers can have lasting effects on their brain, in particular the prefrontal cortex. Amphetamine use is rising among students due to the ability to easily access prescribed stimulants like Adderall </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Laryngeal cancer and can you explain it in depth? [/INST] Laryngeal cancers are mostly squamous-cell carcinomas, reflecting their origin from the epithelium of the larynx.
Cancer can develop in any part of the larynx. The prognosis is affected by the location of the tumour. For the purposes of  staging, the larynx is divided into three anatomical regions: the glottis (true vocal cords, anterior and posterior commissures); the supraglottis (epiglottis, arytenoids and aryepiglottic folds, and false cords); and the subglottis.
Most laryngeal cancers originate in the glottis, with supraglottic and subglottic tumours being less frequent.
Laryngeal cancer may spread by: direct extension to adjacent structures, metastasis to regional cervical lymph nodes, or via the blood stream. The most common site of distant metastases is the lung. Laryngeal cancer occurred in 177,000 people in 2018, and resulted in 94,800 deaths (an increase from 76,000 deaths in 1990). Five-year survival rates in the United States are 60.3%.

Signs and symptoms
The symptoms of laryngeal cancer depend on the size and location of the tumour. Symptoms may include the following:
Hoarseness or other voice changes
A lump in the neck
A sore throat or feeling that something is stuck in the throat
Persistent cough
Stridor - a high-pitched wheezing sound indicative of a narrowed or obstructed airway
Bad breath
Earache (due to referred pain)
Difficulty swallowingAdverse effects of treatment can include changes in appearance, difficulty eating, dry mouth, or loss of voice that may require learning alternate methods of speaking.

Risk factors
The most important risk factor for laryngeal cancer is tobacco smoking. Death from laryngeal cancer is 20 times more likely for the heaviest smokers than for their non-smoking peers. Heavy chronic consumption of alcohol, particularly alcoholic spirits, is also a significant risk factor. When present in combination, the usages of alcohol and tobacco appear to have a synergistic effect. Other reported risk factors include being of low socioeconomic status, male sex, or age greater than 55 years.Occupational exposure to environmental factors such as wood dust, paint fumes, and certain chemicals used in the metalworking, petroleum, plastics, and textile industries is also believed to be a risk factor for laryngeal cancers. Infections by some strains of Papillomaviridae carry some risk of laryngeal carcinoma.People with a history of head and neck cancer are known to be at higher risk (about 25%) of developing a second, separate cancer of the head, neck, or lung. This is likely due to chronic exposure to the carcinogenic effects of alcohol and tobacco. In this situation, a field change effect may occur, where the epithelial tissues start to become diffusely dysplastic with a reduced threshold for malignant change. This risk may be reduced by quitting alcohol and tobacco.

Diagnosis
Diagnosis is made by the doctor on the basis of a medical history, physical examination, and special investigations which may include a chest x-ray, CT or MRI scans, and tissue biopsy. The examination of the larynx requires some expertise, which may require specialist referral.The physical exam includes a systematic examination of the whole patient to assess general health and to look for signs of associated conditions and metastatic disease. The neck and supraclavicular fossa are palpated to feel for cervical adenopathy, other masses, and laryngeal crepitus. The oral cavity and oropharynx are examined under direct vision. The larynx may be examined by indirect laryngoscopy using a small angled mirror with a long handle (akin to a dentists mirror) and a strong light. Indirect laryngoscopy can be highly effective, but requires skill and practice for consistent results. For this reason, many specialist clinics now use fibre-optic nasal endoscopy where a thin and flexible endoscope, inserted through the nostril, is used to clearly visualise the entire pharynx and larynx. Nasal endoscopy is a quick and easy procedure performed in clinic. Local anaesthetic spray may be used.If there is a suspicion of cancer, biopsy is performed, usually under general anaesthetic. This provides histological proof of cancer type and grade. If the lesion appears to be small and well localised, the surgeon may undertake excision biopsy, where an attempt is made to completely remove the tumour at the time of first biopsy. In this situation, the pathologist will not only be able to confirm the diagnosis, but can also comment on the completeness of excision, i.e., whether the tumour has been completely removed. A full endoscopic examination of the larynx, trachea, and esophagus is often performed at the time of biopsy.For small glottic tumours further imaging may be unnecessary. In most cases, tumour staging is completed by scanning the head and neck region to assess the local extent of the tumour and any pathologically enlarged cervical lymph nodes.
The final management plan will depend on the site, stage (tumour size, nodal spread, distant metastasis), and histological type. The overall health and wishes of the patient must also be taken into account. A prognostic multigene classifier has been shown to be potentially useful for the distinction of laryngeal cancer of low or high risk of recurrence and might influence the treatment choice in future.

Staging
Laryngeal tumours are classified according to the guidelines set by academic organisations such as the National Comprehensive Cancer Network (NCCN) . Overall classification, also known as "staging", can help predict treatment options for patients. Staging consists of three separate evaluations. The first is of the tumour/cancer itself ("T"). The second is the extent to which adjacent lymph nodes are involved in the tumour/cancers spread ("N"). The third is the presence or absence of any distant metastases ("M). The specific “staging” criteria for laryngeal cancer, as utilised in the NCCN’s 2019 Guidelines for Head and Neck Cancers, are:

T
TX: Unable to assess
Tis: Carcinoma in situ

Supraglottis
T1: Tumour present in only one subsite of the supraglottis. Vocal cords have normal mobility.
T2: Tumour invades mucosa. There is no fixation of the larynx.
T3: Tumour causes fixation of the vocal cords, with or without invasion of neighbouring areas.
T4:

T4A – Tumour invades at least one of the following: the outer cortex of the thyroid cartilage, extra-laryngeal tissue
T4B – Tumour invades at least one of the following: the pre-vertebral space, any structures of the mediastinum, the carotid sheath, or the structures within the carotid sheath.

Glottis
T1: Tumour only involves the vocal cords. Vocal cords have normal mobility.

T1A – One vocal cord
T1B – Both vocal cordsT2: Tumour meets at least one of the following criteria:

extends to supra- or sub-glottis
impairs vocal cord mobilityT3: Tumour meets at least one of the following criteria:

causes fixation of the vocal cords
invades the paraglottic space
involves the thyroid cartilage’s inner cortexT4: Same as “Supraglottis”

Subglottis
T1: Tumour is only in the subglottis
T2: Tumour involves both subglottis and vocal cords (regardless of cord mobility)
T3: Same as “Glottis”
T4: Same as “Supraglottis”

N
If Using Clinical (Non-Pathological) Diagnosis
NX: Unable to assess
N0: No involvement of neighbouring lymph nodes
N1: Tumour meets ALL of the following criteria:

involves single lymph node
involved lymph node on the same side of the body as tumour
involved lymph node less than 3 cm in “greatest dimension”
lacks extension beyond the lymph nodeN2: Tumour meets ANY of the following criteria

N2A – Same as N1, except size can be between 3–6 cm
N2B – Same as N2A, except lymph nodes can be  multiple, and there is no minimum size
N2C – Same as N2B, except lymph nodes can be on any side of the bodyN3: Tumour meets ANY of the following criteria:

N3A – Same as N1, except size is greater than 6 cm
N3B – Tumour obviously extends beyond the lymph node border (regardless of number, size, or location of lymph nodes)If Using Pathological Diagnosis
NX: Same as “Clinical Diagnosis – NX”
N0:  Same as “Clinical Diagnosis – N0”
N1:  Same as “Clinical Diagnosis – N1”
N2: Tumour meets ANY of the following criteria

N2A – Same as “Clinical Diagnosis – N2A”, except tumour can extend beyond the involved lymph node
N2B – Same as “Clinical Diagnosis – N2B”
N2C – Same as “Clinical Diagnosis – N2C”N3: Tumour meets ANY of the following criteria:

N3A – Same as “Clinical Diagnosis – N3A”
N3B – Any provable presence of tumour extension beyond the lymph node

M
M0: No evidence of distant metastasis
M1: Evidence of distant metastasis

Treatment
Specific treatment depends on the location, type, and stage of the tumour </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Ductal carcinoma in situ and can you explain it in depth? [/INST] Ductal carcinoma in situ (DCIS), also known as intraductal carcinoma, is a pre-cancerous or non-invasive cancerous lesion of the breast. DCIS is classified as Stage 0. It rarely produces symptoms or a breast lump one can feel, typically being detected through screening mammography. It has been diagnosed in a significant percentage of men (see male breast cancer).In DCIS, abnormal cells are found in the lining of one or more milk ducts in the breast. In situ means "in place" and refers to the fact that the abnormal cells have not moved out of the mammary duct and into any of the surrounding tissues in the breast ("pre-cancerous" refers to the fact that it has not yet become an invasive cancer). In some cases, DCIS may become invasive and spread to other tissues, but there is no way of determining which lesions will remain stable without treatment, and which will go on to become invasive. DCIS encompasses a wide spectrum of diseases ranging from low-grade lesions that are not life-threatening to high-grade (i.e. potentially highly aggressive) lesions.
DCIS has been classified according to the architectural pattern of the cells (solid, cribriform, papillary, and micropapillary), tumor grade (high, intermediate, and low grade), the presence or absence of comedo histology, or the cell type forming the lesion in the case of the apocrine cell-based in situ carcinoma, apocrine ductal carcinoma in situ. DCIS can be detected on mammograms by examining tiny specks of calcium known as microcalcifications. Since suspicious groups of microcalcifications can appear even in the absence of DCIS, a biopsy may be necessary for diagnosis.
About 20–30% of those who do not receive treatment develop breast cancer. It is the most common type of pre-cancer in women. There is some disagreement on its status as a cancer; some bodies include DCIS when calculating breast cancer statistics, while others do not.

Terminology
Ductal carcinoma in situ (DCIS) literally means groups of "cancerous" epithelial cells which remained in their normal location (in situ) within the ducts and lobules of the mammary gland. Clinically, it is considered a premalignant (i.e. potentially malignant) condition, because the biologically abnormal cells have not yet crossed the basement membrane to invade the surrounding tissue. When multiple lesions (known as "foci" of DCIS) are present in different quadrants of the breast, this is referred to as "multicentric" disease.For statistical purposes, some count DCIS as a "cancer", whereas others do not. When classified as a cancer, it is referred to as a non-invasive or pre-invasive form. The National Cancer Institute describes it as a "noninvasive condition".

Signs and symptoms
Most of the women who develop DCIS do not experience any symptoms. The majority of cases (80-85%) are detected through screening mammography. The first signs and symptoms may appear if the cancer advances. Because of the lack of early symptoms, DCIS is most often detected at screening mammography.
In a few cases, DCIS may cause:

A lump or thickening in or near the breast or under the arm
A change in the size or shape of the breast
Nipple discharge or nipple tenderness; the nipple may also be inverted, or pulled back into the breast
Ridges or pitting of the breast; the skin may look like the skin of an orange
A change in the way the skin of the breast, areola, or nipple looks or feels such as warmth, swelling, redness or scaliness.

Causes
The specific causes of DCIS are still unknown. The risk factors for developing this condition are similar to those for invasive breast cancer.Some women are however more prone than others to developing DCIS. Women considered at higher risks are those who have a family history of breast cancer, those who have had their periods at an early age or who have had a late menopause. Also, women who have never had children or had them late in life are also more likely to get this condition.
Long-term use of estrogen-progestin hormone replacement therapy (HRT) for more than five years after menopause, genetic mutations (BRCA1 or BRCA2 genes), atypical hyperplasia, as well as radiation exposure or exposure to certain chemicals may also contribute in the development of the condition. Nonetheless, the risk of developing noninvasive cancer increases with age and it is higher in women older than 45 years.

Diagnosis
80% of cases in the United States are detected by mammography screening. More definitive diagnosis is made by breast biopsy for histopathology.

Treatment
There are different opinions on the best treatment of DCIS. Surgical removal, with or without additional radiation therapy or tamoxifen, is the recommended treatment for DCIS by the National Cancer Institute. Surgery may be either a breast-conserving lumpectomy or a mastectomy (complete or partial removal of the affected breast). If a lumpectomy is used it is often combined with radiation therapy. Tamoxifen may be used as hormonal therapy if the cells show estrogen receptor positivity. Research shows that survival is the same with lumpectomy as it is with mastectomy, whether or not a woman has radiation after lumpectomy. Chemotherapy is not needed for DCIS since the disease is noninvasive.While surgery reduces the risk of subsequent cancer, many people never develop cancer even without treatment and the associated side effects. There is no evidence comparing surgery with watchful waiting and some feel watchful waiting may be a reasonable option in certain cases.

Radiation therapy
Use of radiation therapy after lumpectomy provides equivalent survival rates to mastectomy, although there is a slightly higher risk of recurrent disease in the same breast in the form of further DCIS or invasive breast cancer. Systematic reviews (including a Cochrane review) indicate that the addition of radiation therapy to lumpectomy reduces recurrence of DCIS or later onset of invasive breast cancer in comparison with breast-conserving surgery alone, without affecting mortality. The Cochrane review did not find any evidence that the radiation therapy had any long-term toxic effects. While the authors caution that longer follow-up will be required before a definitive conclusion can be reached regarding long-term toxicity, they point out that ongoing technical improvements should further restrict radiation exposure in healthy tissues </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Vestibular schwannoma and can you explain it in depth? [/INST] 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 tumors 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 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 Ménières disease, an abnormality of the inner ear that also has tinnitus as a symptom. The brains 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.

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 (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.

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 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. Large VS will expand the size of internal acoustic meatus (IAC), thus associated with poor hearing function because the nerves within the IAC are compressed, particularly the cochlear nerve. However, facial nerve is less commonly affected. The main advantage of CT scan is to assess the extent of bony involvement by VS. VS enhances when iodinated contrast is given. Contrasted CT scan of temporal bone can done if the subject is unsuitable to undergo MRI scan.MRI scan is the imaging of choice because it can more accurately differentiate the mass from other tumours 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 tumour 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 were 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 was a major factor in determining approach selection. Adjunctive use of the endoscope for enhanced visualization during surgery for IAC tumors gained attention as an emerging technique with advancing technology. For large tumors, a facial nerve sparing surgery evolved offering 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.
Structured surgical training of neurosurgeons and official accreditation replaced the ages-old informal apprenticeship model. Advances in microsurgical instrumentation, the refinement of operative techniques including the introduction of intraoperative facial and cochlear nerve monitoring, and the development of multidisciplinary team-based patient care reduced the incidence of complications related to treatment. There was a trend toward the emergence of high-patient-volume centers for VS surgery where good outcomes and routine patient discharges could become commonplace. The mortality rate for VS surgery fell to less than 1%. In 1991 the NIH Consensus Statement for Acoustic Neuroma observed: "The best published surgical outcomes in the treatment of vestibular schwannoma are from medical centers that have highly organized and dedicated teams with a specific interest in these tumors and sufficient continuing experience to develop, refine and maintain proficiency."ref>Sweeney A, Breen JT, Vrabec JT (2019). "Chapter 29: Training in Vestibular Schwannoma Surgery".  In Carlson ML, Link MJ, Driscoll CL,  et al. (eds.). Comprehensive Management of Vestibular Schwannoma. New York. ISBN 978-1-62623-332-4.</ref>

Radiosurgery and radiotherapy
The 1991 NIH Consensus Statement recognized radiation therapy as "a treatment option limited in current practice primarily to patients unable or unwilling to undergo otherwise indicated surgery." The beneficiaries of radiation therapy soon greatly exceeded this limited clientele. 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. A failed radiosurgery is uncommon. Radiation doses are calculated in terms of Gray/Gy—the measure of energy deposited by ionizing radiation per kilogram of matter -- "named after the British physicist Louis Harold Gray (1905–1965), a pioneer in the measurement of X-ray and radium radiation and their effects on living tissue."  Since VSs are noninvasive and well-demarcated from surrounding tissues, as is apparent on MRI scans, 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
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. These pathways that drive VS formation (tumorigenesis) 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 named VEGF (vascular endothelial growth factor) that initiates proliferation was discovered. An anti-VEGF drug named bevacizumab (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 and impaired wound healing. 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.
To date, there is no fully efficacious medical therapy for VS. The complexity of the molecular biology research involved is truly challenging. The development of a new generation of drugs may become a secondary therapy in view of advances in genome editing during the 1990s that led to the invention of CRISPR in 2009. CRISPR has become the preferred genome editing tool whereby diseases may be treated by correcting causative mutations directly in a patients genome.

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 (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) 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
The U.S. National Institutes of Health (NIH) consensus statement for Acoustic Neuroma in 1991 estimated that 2–3,000 cases of VS were diagnosed in the U.S. annually—an incidence rate of about 10 per million of population per year. 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.

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, the co-founder with the botanist Matthias Schleiden of the critically important cell theory that all living things are composed of cells. 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. His achievement was exceptional. 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 (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.

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-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. Houses 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 was definitely the predominant management strategy for VS. The consensus conferences 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 was also becoming an attractive option for VS patients. At the Karolinska Institute in Stockholm, Sweden, Lars Leksell (1907–1986) pioneered Gamma Knife radiosurgery </s>