<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Glycogen storage disease type I and explain in detail? [/INST] Glycogen storage disease type I (GSD I) is an inherited disease that results in the liver being unable to properly break down stored glycogen. This impairment disrupts the livers ability to break down stored glycogen that is necessary to maintain adequate blood sugar levels. GSD I is divided into two main types, GSD Ia and GSD Ib, which differ in cause, presentation, and treatment. GSD Ia is caused by a deficiency in the enzyme glucose-6-phosphatase, while GSD Ib is caused a deficiency in the enzyme glucose-6-phosphate translocase. Since glycogenolysis is the principal metabolic mechanism by which the liver supplies glucose to the body during periods of fasting, both deficiencies cause severe low blood sugar and, over time, excess glycogen storage in the liver and (in some cases) the kidneys.
GSD I patients typically present with an enlarged liver from non-alcoholic fatty liver disease as the result of this glycogen buildup. Other functions of the liver and kidneys are initially intact in GSD I, but are susceptible to a variety of other problems. Without proper treatment, GSD I gives rise to chronic low blood sugar, which can result in derangements including excessive levels of lactic acid and abnormally high levels of lipids in the bloodstream. Frequent feedings of cornstarch or other carbohydrates are the principal treatment for all forms of GSD I.
GSD Ib also features chronic neutropenia due to a dysfunction in the production of neutrophils in the bone marrow. This immunodeficiency, if untreated, makes GSD Ib patients susceptible to infection. The principal treatment for this feature of GSD Ib is filgrastim; however, patients often still require treatment for frequent infections, and a chronically enlarged spleen is a common side effect. GSD Ib patients often present with inflammatory bowel disease.It is the most common of the glycogen storage diseases. GSD I has an incidence of approximately 1 in 100,000 births in the American population, and approximately 1 in 20,000 births among Ashkenazi Jews. The disease was named after German doctor Edgar von Gierke, who first described it in 1929.

Signs and symptoms
Early research into GSD I identified numerous clinical manifestations falsely thought to be primary features of the genetic disorder. However, continuing research has revealed that these clinical features are the consequences of only one (in GSD Ia) or two (in GSD Ib) fundamental abnormalities:

impairment in the livers ability to convert stored glycogen into glucose through glycogenolysis
in GSD Ib, impairment of the neutrophils ability to take up glucose, resulting in neutrophil dysfunction and neutropeniaThese fundamental abnormalities give rise to a small number of primary clinical manifestations, which are the features considered in diagnosis of GSD I:

Low blood sugar (hypoglycemia), due to impairment of glycogen breakdown (glycogenolysis) causing insufficient fasting blood glucose
hepatomegaly of non-alcoholic fatty liver disease, due to impairment of glycogenolysis causing glycogen accumulation in the liver
in GSD Ib, increased infection risk, due to neutropenia and neutrophil dysfunctionAffected people commonly present with secondary clinical manifestations, linked to one or more of the primary clinical manifestations:

High levels of uric acid in the blood and attendant risk of gout or kidney damage, caused by low serum insulin levels in prolonged hypoglycemia
High levels of lactic acid in the blood, in extreme cases leading to lactic acidosis, caused by prolonged hypoglycemia
hepatic adenomas developing in adulthood and attendant risk of anemia, suspected to be caused by blood glucose dysregulation in the presence of non-alcoholic fatty liver disease
in GSD Ib, inflammatory bowel disease and attendant risk of anemia, caused by neutrophil dysfunction and exacerbated by the increased carbohydrate intake required to prevent hypoglycemiaIn addition, there are several clinical manifestations that often result from the treatment of the primary clinical manifestations:

pancreatic hypertrophy, due to increased carbohydrate intake causing frequent engagement of the insulin response
in GSD Ib, splenomegaly, due to the long-term use of filgrastim to treat neutropenia causing sequestration of blood factors in the spleen
in GSD Ib, an abnormally low number of platelets in the blood may occur, due to long-term use of filgrastim causing sequestration of platelets in the spleen
in GSD Ib, anemia, due to long-term use of filgrastim causing sequestration of hemoglobin in the spleen, potentially exacerbated by uncontrolled inflammatory bowel disease

Hypoglycemia
Low blood sugar (hypoglycemia) is the primary clinical symptom common to both GSD Ia and GSD Ib and most often prompts initial diagnosis of the disease. During fetal development in utero, maternal glucose transferred across the placenta prevents hypoglycemia. However, after birth, the inability to maintain blood glucose from stored glycogen in the liver causes measurable hypoglycemia in no more than 1–2 hours after feedings. Without proper dietary treatment after birth, prolonged hypoglycemia often leads to sudden lactic acidosis that can induce primary respiratory distress in the newborn period, as well as ketoacidosis.Neurological manifestations of hypoglycemia are less severe in GSD I than in other instances. Rather than acute hypoglycemia, GSD I patients experience persistent mild hypoglycemia. The diminished likelihood of neurological manifestations is due to the habituation of the brain to mild hypoglycemia. Given the reduced blood glucose level, the brain adapts to using alternative fuels like lactate. These gradual metabolic adaptations during infancy make severe symptoms like unconsciousness or seizure uncommon before diagnosis.In the early weeks of life, undiagnosed infants with GSD I tolerate persistent hypoglycemia and compensated lactic acidosis between feedings without symptoms. Without consistent carbohydrate feeding, infant blood glucose levels typically measure between 25 and 50 mg/dL (1.4 to 2.8 mmol/L). After weeks to months without treatment with consistent oral carbohydrates, infants will progress to show clear symptoms of hypoglycemia and lactic acidosis. Infants may present with paleness, clamminess, irritability, respiratory distress, and an inability to sleep through the night even in the second year of life. Developmental delay is not an intrinsic effect of GSD I, but is common if the diagnosis is not made in early infancy.

Genetics
GSD I is inherited in an autosomal recessive manner. People with one copy of the faulty gene are carriers of the disease and have no symptoms. As with other autosomal recessive diseases, each child born to two carriers of the disease has a 25% chance of inheriting both copies of the faulty gene and manifesting the disease. Unaffected parents of a child with GSD I can be assumed to be carriers. Prenatal diagnosis has been made by fetal liver biopsy at 18–22 weeks of gestation, but no fetal treatment has been proposed. Prenatal diagnosis is possible with fetal DNA obtained by chorionic villus sampling when a fetus is known to be at risk.The most common forms of GSD I are designated GSD Ia and GSD Ib, the former accounting for over 80% of diagnosed cases and the latter for less than 20%. A few rarer forms have been described.

GSD Ia results from mutations of G6PC, the gene for glucose-6-phosphatase, located on chromosome 17q21.
GSD Ib results from mutations of the gene for SLC37A4 or "G6PT1", the glucose-6-phosphate transporter.
GSD Ic results from mutations of SLC17A3 or SLC37A4.Glucose-6-phosphatase is an enzyme located on the inner membrane of the endoplasmic reticulum. The catalytic unit is associated with a calcium binding protein, and three transport proteins (T1, T2, T3) that facilitate movement of glucose-6-phosphate (G6P), phosphate, and glucose (respectively) into and out of the enzyme.

Pathophysiology
Normal carbohydrate balance and maintenance of blood glucose levels
Glycogen in liver and (to a lesser degree) kidneys serves as a form of stored, rapidly accessible glucose, so that the blood glucose level can be maintained between meals. For about 3 hours after a carbohydrate-containing meal, high insulin levels direct liver cells to take glucose from the blood, to convert it to glucose-6-phosphate (G6P) with the enzyme glucokinase, and to add the G6P molecules to the ends of chains of glycogen (glycogen synthesis). Excess G6P is also shunted into production of triglycerides and exported for storage in adipose tissue as fat.
When digestion of a meal is complete, insulin levels fall, and enzyme systems in the liver cells begin to remove glucose molecules from strands of glycogen in the form of G6P. This process is termed glycogenolysis. The G6P remains within the liver cell unless the phosphate is cleaved by glucose-6-phosphatase. This dephosphorylation reaction produces free glucose and free PO4 anions. The free glucose molecules can be transported out of the liver cells into the blood to maintain an adequate supply of glucose to the brain and other organs of the body. Glycogenolysis can supply the glucose needs of an adult body for 12–18 hours.
When fasting continues for more than a few hours, falling insulin levels permit catabolism of muscle protein and triglycerides from adipose tissue. The products of these processes are amino acids (mainly alanine), free fatty acids, and lactic acid. Free fatty acids from triglycerides are converted to ketones, and to acetyl-CoA. Amino acids and lactic acid are used to synthesize new G6P in liver cells by the process of gluconeogenesis. The last step of normal gluconeogenesis, like the last step of glycogenolysis, is the dephosphorylation of G6P by glucose-6-phosphatase to free glucose and PO4.
Thus glucose-6-phosphatase mediates the final, key, step in both of the two main processes of glucose production during fasting. The effect is amplified because the resulting high levels of glucose-6-phosphate inhibit earlier key steps in both glycogenolysis and gluconeogenesis.

Pathophysiology
The principal metabolic effects of deficiency of glucose-6-phosphatase are hypoglycemia, lactic acidosis, hypertriglyceridemia, and hyperuricemia.

The hypoglycemia of GSD I is termed "fasting", or "post-absorptive", usually about 4 hours after the complete digestion of a meal. This inability to maintain adequate blood glucose levels during fasting results from the combined impairment of both glycogenolysis and gluconeogenesis. Fasting hypoglycemia is often the most significant problem in GSD I, and typically the problem that leads to the diagnosis. Chronic hypoglycemia produces secondary metabolic adaptations, including chronically low insulin levels and high levels of glucagon and cortisol.
Lactic acidosis arises from impairment of gluconeogenesis. Lactic acid is generated both in the liver and muscle and is oxidized by NAD+ to pyruvic acid and then converted via the gluconeogenic pathway to G6P. Accumulation of G6P inhibits conversion of lactate to pyruvate. The lactic acid level rises during fasting as glucose falls. In people with GSD I, it may not fall entirely to normal even when normal glucose levels are restored.
Hypertriglyceridemia resulting from amplified triglyceride production is another indirect effect of impaired gluconeogenesis, amplified by chronically low insulin levels. During fasting, the normal conversion of triglycerides to free fatty acids, ketones, and ultimately acetyl-CoA is impaired. Triglyceride levels in GSD I can reach several times normal and serve as a clinical index of "metabolic control".
Hyperuricemia results from a combination of increased generation and decreased excretion of uric acid, which is generated when increased amounts of G6P are metabolized via the pentose phosphate pathway. It is also a byproduct of purine degradation. Uric acid competes with lactic acid and other organic acids for renal excretion in the urine. In GSD I increased availability of G6P for the pentose phosphate pathway, increased rates of catabolism, and diminished urinary excretion due to high levels of lactic acid all combine to produce uric acid levels several times normal. Although hyperuricemia is asymptomatic for years, kidney and joint damage gradually accrue.

Elevated lactate and lactic acidosis
High levels of lactic acid in the blood are observed in all people with GSD I, due to impaired gluconeogenesis. Baseline elevations generally range from 4 to 10 mol/mL, which will not cause any clinical impact. However, during and after an episode of low blood sugar, lactate levels will abruptly rise to exceed 15 mol/mL, the threshold for lactic acidosis. Symptoms of lactic acidosis include vomiting and hyperpnea, both of which can exacerbate hypoglycemia in the setting of GSD I. In cases of acute lactic acidosis, patients need emergency care to stabilize blood oxygen, and restore blood glucose. Proper identification of lactic acidosis in undiagnosed children presents a challenge, since the first symptoms are typically vomiting and dehydration, both of which mimic childhood infections like gastroenteritis or pneumonia. Moreover, both of these common infections can precipitate more severe hypoglycemia in undiagnosed children, making diagnosis of the underlying cause difficult.
As elevated lactate persists, uric acid, ketoacids, and free fatty acids further increase the anion gap. In adults and children, the high concentrations of lactate cause significant discomfort in the muscles. This discomfort is an amplified form of the burning sensation a runner may feel in the quadriceps after sprinting, which is caused by a brief buildup of lactic acid. Proper control of hypoglycemia in GSD I eliminates the possibility for lactic acidosis.

Elevated urate and complications
High levels of uric acid often present as a consequence of elevated lactic acid in GSD I patients. When lactate levels are elevated, blood-borne lactic acid competes for the same kidney tubular transport mechanism as urate, limiting the rate that urate can be cleared by the kidneys into the urine. If present, increased purine catabolism is an additional contributing factor. Uric acid levels of 6 to 12 mg/dl (530 to 1060 umol/L) are common among GSD I patients, if the disease is not properly treated. In some affected people, the use of the medication allopurinol is necessary to lower blood urate levels. Consequences of hyperuricemia among GSD I patients include the development of kidney stones and the accumulation of uric acid crystals in joints, leading to kidney disease and gout, respectively.

Hyperlipidemia and plasma effects
Elevated triglycerides in GSD I result from low serum insulin in patients with frequent prolonged hypoglycemia. It may also be caused by intracellular accumulation of glucose-6-phosphate with secondary shunting to pyruvate, which is converted into Acetyl-CoA, which is transported to the cytosol where the synthesis of fatty acids and cholesterol occurs. Triglycerides above the 3.4 mmol/L (300 mg/dL) range may produce visible lipemia, and even a mild pseudohyponatremia due to a reduced aqueous fraction of the blood plasma. In GSD I, cholesterol is typically only mildly elevated compared to other lipids.

Hepatomegaly
Impairment in the livers ability to perform gluconeogenesis leads to clinically apparent hepatomegaly. Without this process, the body is unable to liberate glycogen from the liver and convert it into blood glucose, leading to an accumulation of stored glycogen in the liver. Hepatomegaly from the accumulation of stored glycogen in the liver is considered a form of non-alcoholic fatty liver disease. GSD I patients present with a degree of hepatomegaly throughout life, but severity often relates to the consumption of excess dietary carbohydrate. Reductions in the mass of the liver are possible, since most patients retain residual hepatic function that allows for the liberation of stored glycogen at a limited rate.
GSD I patients often present with hepatomegaly from the time of birth. In fetal development, maternal glucose transferred to the fetus prevents hypoglycemia, but the storage of glucose as glycogen in the liver leads to hepatomegaly. There is no evidence that this hepatomegaly presents any risk to proper fetal development.
Hepatomegaly in GSD type I generally occurs without sympathetic enlargement of the spleen. GSD Ib patients may present with splenomegaly, but this is connected to the use of filgrastim to treat neutropenia in this subtype, not comorbid hepatomegaly. Hepatomegaly will persist to some degree throughout life, often causing the abdomen to protrude, and in severe cases may be palpable at or below the navel. In GSD-related non-alcoholic fatty liver disease, hepatic function is usually spared, with liver enzymes and bilirubin remaining within the normal range. However, liver function may be affected by other hepatic complications in adulthood, including the development of hepatic adenomas.

Hepatic adenomas
The specific etiology of hepatic adenomas in GSD I remains unknown, despite ongoing research. The typical GSD I patient presenting with at least one adenoma is an adult, though lesions have been observed in patients as young as fourteen. Adenomas, composed of heterogeneous neoplasms, may occur individually or in multiples. Estimates on the rate of conversion of a hepatocellular adenoma into hepatocellular carcinoma in GSD I range from 0% to 11%, with the latter figure representing more recent research. One reason for the increasing estimate is the growing population of GSD I patients surviving into adulthood, when most adenomas develop.
Treatment standards dictate regular observation of the liver by MRI or CT scan to monitor for structural abnormalities. Hepatic adenomas may be misidentified as focal nodular hyperplasia in diagnostic imaging, though this condition is rare. However, hepatic adenomas in GSD I uniquely involve diffuse Mallory hyaline deposition, which is otherwise commonly observed in focal nodular hyperplasia. Unlike common hepatic adenomas related to oral contraception, hemorrhaging in GSD I patients is rare.
While the reason for the high prevalence of adenomas in GSD I is unclear, research since the 1970s has implicated serum glucagon as a potential driver. In studies, patients that have been put on a dietary regimen to keep blood sugar in a normal range spanning 72 to 108 mg/dL (4.0 to 6.0 mmol/L) have shown a decreased likelihood of developing adenomas. Moreover, patients with well controlled blood glucose have consistently seen a reduction in the size and number of hepatic adenomas, suggesting that adenomas may be caused by imbalances of hepatotropic agents like serum insulin and especially serum glucagon in the liver.

Osteopenia
Patients with GSD I will often develop osteopenia. The specific etiology of low bone mineral density in GSD is not known, though it is strongly associated with poor metabolic control. Osteopenia may be directly caused by hypoglycemia, or the resulting endocrine and metabolic sequelae. Improvements in metabolic control have consistently been shown to prevent or reverse clinically relevant osteopenia in GSD I patients. In cases where osteopenia progresses with age, bone mineral density in the ribs is typically more severe than in the vertebrae. In some cases bone mineral density T-score will drop below -2.5, indicating osteoporosis. There is some evidence that osteopenia may be connected with associated kidney abnormalities in GSD I, particularly glomular hyperfiltration. The condition also seems responsive to calcium supplementation. In many cases bone mineral density can increase and return to the normal range given proper metabolic control and calcium supplementation alone, reversing osteopenia.

Kidney effects
The kidneys are usually 10 to 20% enlarged with stored glycogen. In adults with GSD I, chronic glomerular damage similar to diabetic nephropathy may lead to kidney failure. GSD I may present with various kidney complications. Renal tubular abnormalities related to hyperlactatemia are seen early in life, likely because prolonged lactic acidosis is more likely to occur in childhood. This will often present as Fanconi syndrome with multiple derangements of renal tubular reabsorption, including tubular acidosis with bicarbonate and phosphate wasting. These tubular abnormalities in GSD I are typically detected and monitored by urinary calcium. Long term these derangements can exacerbate uric acid nephropathy, otherwise driven by hyperlactatemia. In adolescence and beyond, glomerular disease may independently develop, initially presenting as glomerular hyperfiltration indicated by elevated urinary eGFR.

Splenomegaly
Enlargement of the spleen (splenomegaly) is common in GSD I and has two primary causes. In GSD Ia, splenomegaly may be caused by a relation between the liver and the spleen which causes either to grow or shrink to match the relative size of the other, to a lessened degree. In GSD Ib, it is a side effect of the use of filgrastim to treat neutropenia.

Bowel effects
Intestinal involvement can cause mild malabsorption with greasy stools (steatorrhea), but usually requires no treatment.

Infection risk
Neutropenia is a distinguishing feature of GSD Ib, absent in GSD Ia. The microbiological cause of neutropenia in GSD Ib is not well understood. Broadly, the problem arises from compromised cellular metabolism in the neutrophil, resulting in accelerated neutrophil apoptosis. The neutropenia in GSD is characterized by both a decrease in absolute neutrophil count and  diminished neutrophil function. Neutrophils use a specific G6P metabolic pathway which relies on the presence of G6Pase-β or G6PT to maintain energy homeostasis within the cell. The absence of G6PT in GSD Ib limits this pathway, leading to endoplasmic reticulum stress, oxidative stress within the neutrophil, triggering premature apoptosis. Granulocyte colony-stimulating factor (G-CSF), available as filgrastim, can reduce the risk of infection. In some cases, G-CSF formulated as pegfilgrastim, sold under the trade name Neulasta, may be used as a slow-acting alternative, requiring less frequent dosing.

Thrombocytopenia and blood clotting problems
Impaired platelet aggregation is an uncommon consequence of chronic hypoglycemia, seen in GSD I patients. Research has demonstrated decreased platelet function, characterized by decreased prothrombin consumption, abnormal aggregation reactions, prolonged bleeding time, and low platelet adhesiveness. Severity of platelet dysfunction typically correlates with clinical condition, with the most severe cases correlating with lactic acidosis and severely lipidemia. It may cause clinically significant bleeding, especially epistaxis. Additionally, GSD I patients may present with thrombocytopenia as a consequence of splenomegaly. In the setting of splenomegaly various hematologic factors may be sequestered in the tissues of the spleen as blood is filtered through the organ. This can diminish levels of platelets available in the bloodstream, leading to thrombocytopenia.

Developmental effects
Developmental delay is a potential secondary effect of chronic or recurrent hypoglycemia, but is at least theoretically preventable. Normal neuronal and muscle cells do not express glucose-6-phosphatase, and are thus not impacted by GSD I directly. However, without proper treatment of hypoglycemia, growth failure commonly results from chronically low insulin levels, persistent acidosis, chronic elevation of catabolic hormones, and calorie insufficiency (or malabsorption). The most dramatic developmental delays are often the cause of severe (not just persistent) episodes of hypoglycemia.

Diagnosis
Several different problems may lead to the diagnosis, usually by two years of age:

seizures or other manifestations of severe fasting hypoglycemia
hepatomegaly with abdominal protuberance
hyperventilation and apparent respiratory distress due to metabolic acidosis
episodes of vomiting due to metabolic acidosis, often precipitated by minor illness and accompanied by hypoglycemiaOnce the diagnosis is suspected, the multiplicity of clinical and laboratory features usually makes a strong circumstantial case. If hepatomegaly, fasting hypoglycemia, and poor growth are accompanied by lactic acidosis, hyperuricemia, hypertriglyceridemia, and enlarged kidneys by ultrasound, GSD I is the most likely diagnosis. The differential diagnosis list includes glycogenoses types III and VI, fructose 1,6-bisphosphatase deficiency, and a few other conditions (page 5), but none are likely to produce all of the features of GSD I.
The next step is usually a carefully monitored fast. Hypoglycemia often occurs within six hours. A critical blood specimen obtained at the time of hypoglycemia typically reveals a mild metabolic acidosis, high free fatty acids and  beta-hydroxybutyrate, very low insulin levels, and high levels of glucagon, cortisol, and growth hormone. Administration of intramuscular or intravenous glucagon (0.25 to 1 mg, depending on age) or epinephrine produces little rise of blood sugar.
The diagnosis is definitively confirmed by liver biopsy with electron microscopy and assay of glucose-6-phosphatase activity in the tissue and/or specific gene testing, available in recent years.

Treatment
The primary treatment goal is prevention of hypoglycemia and the secondary metabolic derangements by frequent feedings of foods high in glucose or starch (which is readily digested to glucose). To compensate for the inability of the liver to provide sugar, the total amount of dietary carbohydrate should approximate the 24-hour glucose production rate. The diet should contain approximately 65–70% carbohydrate, 10–15% protein, and 20–25% fat. At least a third of the carbohydrates should be supplied through the night, so that a young child goes no more than 3–4 hours without carbohydrate intake.
Once a diagnosis is made, the priority in GSD I treatment is to maintain an adequate blood glucose. Patients aim to maintain a blood glucose above the 72 mg/dL (4.0 mmol/L) cutoff for hypoglycemia. GSD Ib patients have an additional treatment priority relating to neutropenia. Proper management of blood glucose in GSD I is critical in avoiding the more severe effects of high leves of lactic acid and uric acid in the blood, and the development of hepatic adenomas.
In the last 30 years, two methods have been used to achieve this goal in young children: (1) continuous nocturnal gastric infusion of glucose or starch; and (2) night-time feedings of uncooked cornstarch. An elemental formula, glucose polymer, and/or cornstarch can be infused continuously through the night at a rate supplying 0.5–0.6 g/kg/h of glucose for an infant, or 0.3–0.4 for an older child. This method requires a nasogastric or gastrostomy tube and pump. Sudden death from hypoglycemia has occurred due to malfunction or disconnection, and periodic cornstarch feedings are now preferred to continuous infusion.
Cornstarch is an inexpensive way to provide gradually digested glucose. One tablespoon contains nearly 9 g carbohydrate (36 calories). Although it is safer, less expensive, and requires no equipment, this method does require that parents arise every 3–4 hours to administer the cornstarch. A typical requirement for a young child is 1.6 g/kg every 4 hours.
Long-term management should eliminate hypoglycemic symptoms and maintain normal growth. Treatment should achieve normal glucose, lactic acid, and electrolyte levels, and only mild elevations of uric acid and triglycerides.

Avoidance of other sugars
Intake of carbohydrates which must be converted to G6P to be utilized (e.g., galactose and fructose) should be minimized. Although elemental formulas are available for infants, many foods contain fructose or galactose in the forms of sucrose or lactose. Adherence becomes a contentious treatment issue after infancy.

Other therapeutic measures
Persistent elevation of uric acid above 6.5 mg/dl warrants treatment with allopurinol to prevent uric acid deposition in kidneys and joints.
Because of the potential for impaired platelet function, coagulation ability should be checked and the metabolic state normalized before surgery. Bleeding time may be normalized with 1–2 days of glucose loading, and improved with ddavp. During surgery, IV fluids should contain 10% dextrose and no lactate.
A patient with GSD, type 1b was treated with a liver transplant at UCSF Medical Center in 1993 that resulted in the resolution of hypoglycemic episodes and the need for the patient to stay away from natural sources of sugar. Other patients have undergone this procedure as well with positive results. Although a liver transplant resulted in the resolution of hypoglycemia it did not however resolve the chronic neutropenia and the risk of infection among patients.

Treatment of acute metabolic acidosis episodes
The most significant acute problem in childhood is a vulnerability to episodes of metabolic acidosis precipitated by minor illnesses </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Wilsons disease and explain in detail? [/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 helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Cavernous sinus thrombosis and explain in detail? [/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 helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Meniscus tear and explain in detail? [/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 helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Amphetamine dependence and explain in detail? [/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 helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Laryngeal cancer and explain in detail? [/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>