<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 Scarlet fever and explain in detail? [/INST] Scarlet fever is an infectious disease resulting from a group A streptococcus (group A strep) infection, also known as Streptococcus pyogenes. The signs and symptoms include a sore throat, fever, headaches, swollen lymph nodes, and a characteristic rash. The rash is red and feels like sandpaper and the tongue may be red and bumpy. It most commonly affects children between five and 15 years of age.Scarlet fever affects a small number of people who have strep throat or streptococcal skin infections. The bacteria are usually spread by people coughing or sneezing. It can also be spread when a person touches an object that has the bacteria on it and then touches their mouth or nose. The characteristic rash is due to the erythrogenic toxin, a substance produced by some types of the bacterium. The diagnosis is typically confirmed by culturing the throat.There is no vaccine for scarlet fever. Prevention is by frequent handwashing, not sharing personal items, and staying away from other people when sick. The disease is treatable with antibiotics, which prevent most complications. Outcomes with scarlet fever are typically good if treated. Long-term complications as a result of scarlet fever include kidney disease, rheumatic heart disease, and arthritis. In the early 20th century, before antibiotics were available, it was a leading cause of death in children. An antitoxin was produced before antibiotics; however, it was never made in sufficient quantities, and could not be used to treat any other disease as antibiotics can.There have been signs of antibiotic resistance, and there have been recent outbreaks in Hong Kong in 2011 and in the UK in 2014, with occurrence rising 68% in the UK in the four years up to 2018. Research published in October 2020 has shown that infection of the bacterium by three viruses has led to stronger strains of the bacterium.

Signs and symptoms
Rash which has a characteristic appearance, spreading pattern, and desquamating process e.g.
"Strawberry tongue":

The tongue initially has a white coating on it, while the papillae of the tongue are swollen and reddened. The protrusion of the red papillae through the white coating gives the tongue a "white strawberry" appearance.
A few days later (following the desquamating process, or the shedding of the tissue which created the white coating), the whiteness disappears, and the red and enlarged papillae give the tongue the "red strawberry" appearance. The symptomatic appearance of the tongue is part of the rash that is characteristic of scarlet fever.
Pastias lines
Lines of petechiae, which appear as pink/red areas located in arm pits and elbow pits
Vomiting and abdominal pain

Strep throat
Typical signs and symptoms of streptococcal pharyngitis (also known as strep throat):
Sore throat, painful swallowing
Fever – typically over 39 °C (102.2 °F)
Fatigue
Enlarged and reddened tonsils with yellow or white exudates present (this is typically an exudative pharyngitis)
Enlarged and tender lymph nodes usually located on the front of the neckThe following signs will usually be absent: cough, hoarseness, runny nose, diarrhea, and conjunctivitis. Such symptoms indicate what is more likely a viral infection.

Rash
The rash begins 1–2 days following the onset of symptoms caused by the strep pharyngitis (sore throat, fever, fatigue). This characteristic rash has been denoted as "scarlatiniform", and it appears as a diffuse redness of the skin with small papules, or bumps, which resemble goose bumps. These bumps are what give the characteristic sandpaper texture to the rash. The reddened skin will blanch when pressure is applied to it. The skin may feel itchy, but it will not be painful. The rash generally starts at the flexion of the elbow and other surfaces. It appears next on the trunk and gradually spreads out to the arms and legs. The palms, soles and face are usually left uninvolved by the rash. The face, however, is usually flushed, most prominently in the cheeks, with a ring of paleness around the mouth. After the rash spreads, it becomes more pronounced in creases in the skin, such as the skin folds in the inguinal and axillary regions of the body. Also in those areas, Pastias Lines may appear: petechiae arranged in a linear pattern. Within 1 week of onset, the rash begins to fade followed by a longer process of desquamation, or shedding of the outer layer of skin. This lasts several weeks. The desquamation process usually begins on the face and progresses downward on the body. After the desquamation, the skin will be left with a sunburned appearance.

Mouth
The streptococcal pharyngitis, which is the usual presentation of scarlet fever in combination with the characteristic rash, commonly involves the tonsils. The tonsils will appear swollen and reddened. The palate and uvula are also commonly affected by the infection. The involvement of the soft palate can be seen as tiny red and round spots known as Forchheimer spots.

Variable presentations
The features of scarlet fever can differ depending on the age and race of the person. Children less than 5 years old can have atypical presentations. Children less than 3 years old can present with nasal congestion and a lower grade fever. Infants may present with symptoms of increased irritability and decreased appetite.Children who have darker skin can have a different presentation, as the redness of the skin involved in the rash and the ring of paleness around the mouth can be less obvious. Suspicion based on accompanying symptoms and diagnostic studies are important in these cases.

Course
Following exposure to streptococcus, onset of symptoms occur 12 hours to 7 days later. These may include fever, fatigue, and sore throat. The characteristic scarlatiniform rash appears 12–48 hours later. During the first few days of the rash development and rapid generalization, the Pastias Lines and strawberry tongue are also present. The rash starts fading within 3–4 days, followed by the desquamation of the rash, which lasts several weeks to a month. If the case of scarlet fever is uncomplicated, recovery from the fever and clinical symptoms, other than the process of desquamation, occurs in 5–10 days.

Complications
The complications, which can arise from scarlet fever when left untreated or inadequately treated, can be divided into two categories: suppurative and nonsuppurative.Suppurative complications: These are rare complications that arise either from direct spread to structures that are close to the primary site of infection, or spread through the lymphatic system or blood. In the first case, scarlet fever may spread to the pharynx. Possible problems from this method of spread include peritonsillar or retropharyngeal abscesses, cellulitis, mastoiditis or sinusitis.In the second case, the streptococcal infection may spread through the lymphatic system or the blood to areas of the body further away from the pharynx. A few examples of the many complications that can arise from those methods of spread include endocarditis, pneumonia, or meningitis.Nonsuppurative complications: These complications arise from certain subtypes of group A streptococci that cause an autoimmune response in the body through what has been termed molecular mimicry. In these cases, the antibodies which the persons immune system developed to attack the group A streptococci are also able to attack the persons own tissues. The following complications result, depending on which tissues in the persons body are targeted by those antibodies.
Acute rheumatic fever: This is a complication that results 2–6 weeks after a group A streptococcal infection of the upper respiratory tract. It presents in developing countries, where antibiotic treatment of streptococcal infections is less common, as a febrile illness with several clinical manifestations, which are organized into what is called the Jones criteria. These criteria include arthritis, carditis, neurological issues, and skin findings. Diagnosis also depends on evidence of a prior group A streptococcal infection in the upper respiratory tract (as seen in streptococcal pharyngitis and scarlet fever). The carditis is the result of the immunologic response targeting the persons heart tissue, and it is the most serious sequelae that develops from acute rheumatic fever. When this involvement of the heart tissue occurs, it is called rheumatic heart disease. In most cases of rheumatic heart disease, the mitral valve is affected, ultimately leading to mitral stenosis. The link to rheumatic fever and heart disease is a particular concern in Australia, because of the high prevalence of these diseases in Aboriginal and Torres Strait Islander communities.
Poststreptococcal glomerulonephritis: This is inflammation of the kidney, which presents 1–2 weeks after a group A streptococcal pharyngitis. It can also develop after an episode of Impetigo or any group A streptococcal infection in the skin (this differs from acute rheumatic fever which only follows group A streptococcal pharyngitis). It is the result of the autoimmune response to the streptococcal infection affecting part of the kidney. Persons present with what is called acute nephritic syndrome, in which they have high blood pressure, swelling, and urinary abnormalities. Urinary abnormalities include blood and protein found in the urine, as well as less urine production overall.
Poststreptococcal reactive arthritis: The presentation of arthritis after a recent episode of group A streptococcal pharyngitis raises suspicion for acute rheumatic fever, since it is one of the Jones criteria for that separate complication. But, when the arthritis is an isolated symptom, it is referred to as poststreptococcal reactive arthritis. This arthritis can involve a variety of joints throughout the body, unlike the arthritis of acute rheumatic fever, which primarily affects larger joints such as the knee joints. It can present less than 10 days after the group A streptococcal pharyngitis.

Cause
Strep throat spreads by close contact among people, via respiratory droplets (for example, saliva or nasal discharge). A person in close contact with another person infected with group A streptococcal pharyngitis has a 35% chance of becoming infected. One in ten children who are infected with group A streptococcal pharyngitis will develop scarlet fever.

Pathophysiology
The rash of scarlet fever, which is what differentiates this disease from an isolated group A strep pharyngitis (or strep throat), is caused by specific strains of group A streptococcus which produce a pyrogenic exotoxin, mainly responsible for the skin manifestation of the infection. These toxin-producing strains cause scarlet fever in people who do not already have antitoxin antibodies. Streptococcal pyrogenic exotoxins A, B, and C (speA, speB, and speC) have been identified. The pyrogenic exotoxins are also called erythrogenic toxins and cause the erythematous rash of scarlet fever. The strains of group A streptococcus that cause scarlet fever need specific bacteriophages for there to be pyrogenic exotoxin production. Specifically, bacteriophage T12 is responsible for the production of speA. Streptococcal Pyrogenic Exotoxin A, speA, is the one which is most commonly associated with cases of scarlet fever which are complicated by the immune-mediated sequelae acute rheumatic fever and post-streptococcal glomerulonephritis.These toxins are also known as "superantigens" because they are able to cause an extensive immune response within the body through activation of some of the main cells responsible for the persons immune system. The body responds to these toxins by making antibodies to those specific toxins. However, those antibodies do not completely protect the person from future group A streptococcal infections, because there are 12 different pyrogenic exotoxins possible.

Microbiology
The disease is caused by secretion of pyrogenic exotoxins by the infecting Streptococcus bacteria. Streptococcal pyrogenic exotoxin A (speA) is probably the best studied of these toxins. It is carried by the bacteriophage T12 which integrates into the streptococcal genome from where the toxin is transcribed. The phage itself integrates into a serine tRNA gene on the chromosome.The T12 virus itself has not been placed into a taxon by the International Committee on Taxonomy of Viruses. It has a double-stranded DNA genome and on morphological grounds appears to be a member of the Siphoviridae.The speA gene was cloned and sequenced in 1986. It is 753 base pairs in length and encodes a 29.244 kiloDalton (kDa) protein. The protein contains a putative 30-
amino-acid signal peptide; removal of the signal sequence gives a predicted molecular weight of 25.787 kDa for the secreted protein. Both a promoter and a ribosome binding site (Shine-Dalgarno sequence) are present upstream of the gene. A transcriptional terminator is located 69 bases downstream from the translational termination codon. The carboxy terminal portion of the protein exhibits extensive homology with the carboxy terminus of Staphylococcus aureus enterotoxins B and C1.Streptococcal phages other than T12 may also carry the speA gene.

Diagnosis
Although the presentation of scarlet fever can be clinically diagnosed, further testing may be required to distinguish it from other illnesses. Also, history of a recent exposure to someone with strep throat can be useful in diagnosis. There are two methods used to confirm suspicion of scarlet fever; rapid antigen detection test and throat culture.The rapid antigen detection test is a very specific test but not very sensitive. This means that if the result is positive (indicating that the group A strep antigen was detected and therefore confirming that the person has a group A strep pharyngitis), then it is appropriate to treat the people with scarlet fever with antibiotics. But, if the rapid antigen detection test is negative (indicating that they do not have group A strep pharyngitis), then a throat culture is required to confirm, as the first test could have yielded a false negative result. In the early 21st century, the throat culture is the current "gold standard" for diagnosis.Serologic testing seeks evidence of the antibodies that the body produces against the streptococcal infection, including antistreptolysin-O and antideoxyribonuclease B. It takes the body 2–3 weeks to make these antibodies, so this type of testing is not useful for diagnosing a current infection. But, it is useful when assessing a person who may have one of the complications from a previous streptococcal infection.Throat cultures done after antibiotic therapy can show if the infection has been removed. These throat swabs, however, are not indicated, because up to 25% of properly treated individuals can continue to carry the streptococcal infection while being asymptomatic.

Differential diagnosis
Viral exanthem: Viral infections are often accompanied by a rash which can be described as morbilliform or maculopapular. This type of rash is accompanied by a prodromal period of cough and runny nose in addition to a fever, indicative of a viral process.
Allergic or contact dermatitis: The erythematous appearance of the skin will be in a more localized distribution rather than the diffuse and generalized rash seen in scarlet fever.
Drug eruption: These are potential side effects of taking certain drugs such as penicillin. The reddened maculopapular rash which results can be itchy and be accompanied by a fever.
Kawasaki disease: Children with this disease also present a strawberry tongue and undergo a desquamative process on their palms and soles. However, these children tend to be younger than 5 years old, their fever lasts longer (at least five days), and they have additional clinical criteria (including signs such as conjunctival redness and cracked lips), which can help distinguish this from scarlet fever.
Toxic shock syndrome: Both streptococcal and staphylococcal bacteria can cause this syndrome. Clinical manifestations include diffuse rash and desquamation of the palms and soles. It can be distinguished from scarlet fever by low blood pressure, lack of sandpaper texture for the rash, and multi-organ system involvement.
Staphylococcal scalded skin syndrome: This is a disease that occurs primarily in young children due to a toxin-producing strain of the bacteria Staphylococcus aureus. The abrupt start of the fever and diffused sunburned appearance of the rash can resemble scarlet fever. However, this rash is associated with tenderness and large blister formation. These blisters easily pop, followed by causing the skin to peel.
Staphylococcal scarlet fever: The rash is identical to the streptococcal scarlet fever in distribution and texture, but the skin affected by the rash will be tender.

Prevention
One method is long-term use of antibiotics to prevent future group A streptococcal infections. This method is only indicated for people who have had complications like recurrent attacks of acute rheumatic fever or rheumatic heart disease. Antibiotics are limited in their ability to prevent these infections since there are a variety of subtypes of group A streptococci that can cause the infection.The vaccine approach has a greater likelihood of effectively preventing group A streptococcal infections because vaccine formulations can target multiple subtypes of the bacteria. A vaccine developed by George and Gladys Dick in 1924 was discontinued due to poor efficacy and the introduction of antibiotics. Difficulties in vaccine development include the considerable strain variety of group A streptococci present in the environment and the amount of time and number of people needed for appropriate trials for safety and efficacy of any potential vaccine. There have been several attempts to create a vaccine in the past few decades. These vaccines, which are still in the development phase, expose the person to proteins present on the surface of the group A streptococci to activate an immune response that will prepare the person to fight and prevent future infections.There used to be a diphtheria scarlet fever vaccine. It was, however, found not to be effective. This product was discontinued by the end of World War II.

Treatment
Antibiotics to combat the streptococcal infection are the mainstay of treatment for scarlet fever. Prompt administration of appropriate antibiotics decreases the length of illness. Peeling of the outer layer of skin, however, will happen despite treatment. One of the main goals of treatment is to prevent the child from developing one of the suppurative or nonsuppurative complications, especially acute rheumatic fever. As long as antibiotics are started within nine days, it is very unlikely for the child to develop acute rheumatic fever. Antibiotic therapy has not been shown to prevent the development of post-streptococcal glomerulonephritis. Another important reason for prompt treatment with antibiotics is the ability to prevent transmission of the infection between children. An infected individual is most likely to pass on the infection to another person during the first 2 weeks. A child is no longer contagious (able to pass the infection to another child) after 24 hours of antibiotics.The antibiotic of choice is Penicillin V which is taken by mouth. In countries without a liquid Penicillin V product, children unable to take tablets can be given amoxicillin which comes in a liquid form and is equally effective. Duration of treatment is 10 days. Benzathine penicillin G can be given as a one time intramuscular injection as another alternative if swallowing pills is not possible. If the person is allergic to the family of antibiotics which both penicillin and amoxicillin are a part of (beta-lactam antibiotics), a first generation cephalosporin is used. Cephalosporin antibiotics, however, can still cause adverse reactions in people whose allergic reaction to penicillin is a Type 1 Hypersensitivity reaction. In those cases it is appropriate to choose clindamycin or erythromycin instead. Tonsillectomy, although once a reasonable treatment for recurrent streptococcal pharyngitis, is not indicated, as a person can still be infected with group A streptococcus without their tonsils.

Antibiotic resistance and resurgence
A drug-resistant strain of scarlet fever, resistant to macrolide antibiotics such as erythromycin, but retaining drug-sensitivity to beta-lactam antibiotics such as penicillin, emerged in Hong Kong in 2011, accounting for at least two deaths in that city—the first such in over a decade. About 60% of circulating strains of the group A streptococcus that cause scarlet fever in Hong Kong are resistant to macrolide antibiotics, says Professor Kwok-yung Yuen, head of Hong Kong Universitys microbiology department. Previously, observed resistance rates had been 10–30%; the increase is likely the result of overuse of macrolide antibiotics in recent years.There was also an outbreak in the UK in 2014, and the National Health Service reported a 68% increase in the number of S. pyogenes identified in laboratory reports between 2014 and 2018.New research published in October 2020 in the journal that the bacterium appears to be getting more robust after being infected with viruses, specifically the North-East Asian serotype M12 (emm12) (group A Streptococcus, GAS). They found three new genes, acquired from viruses, leading to the development of "superantigens" targeting white blood cells, leading to a more virulent strain of the bacterium.A vaccine that will protect against the 180 to 200 types of bacteria causing the disease has been worked on for over 20 years, but as of 2020 a safe one had not yet been developed.

Epidemiology
Scarlet fever occurs equally in both males and females. Children are most commonly infected, typically between 5–15 years old. Although streptococcal infections can happen at any time of year, infection rates peak in the winter and spring months, typically in colder climates.The morbidity and mortality of scarlet fever has declined since the 18th and 19th century when there were epidemics caused by this disease. Around 1900 the mortality rate in multiple places reached 25%. The improvement in prognosis can be attributed to the use of penicillin in the treatment of this disease. The frequency of scarlet fever cases has also been declining over the past century. There have been several reported outbreaks of the disease in various countries in the past decade. The reason for these recent increases remains unclear in the medical community. Between 2013 and 2016 population rates of scarlet fever in England increased from 8.2 to 33.2 per 100,000 and hospital admissions for scarlet fever increased by 97%.

History
It is unclear when a description of this disease was first recorded. Hippocrates, writing around 400 BC, described the condition of a person with a reddened skin and fever.The first unambiguous description of the disease in the medical literature appeared in the 1553 book De Tumoribus praeter Naturam by the Sicilian anatomist and physician Giovanni Filippo Ingrassia, where he referred to it as rossalia. He also made a point to distinguish that this presentation had different characteristics from measles. It was redescribed by Johann Weyer during an epidemic in lower Germany between 1564 and 1565; he referred to it as scarlatina anginosa. The first unequivocal description of scarlet fever appeared in a book by Joannes Coyttarus of Poitiers, De febre purpura epidemiale et contagiosa libri duo, which was published in 1578 in Paris. Daniel Sennert of Wittenberg described the classical scarlatinal desquamation in 1572 and was also the first to describe the early arthritis, scarlatinal dropsy, and ascites associated with the disease.In 1675 the term that has been commonly used to refer to scarlet fever, "scarlatina", was written by Thomas Sydenham, an English physician.

In 1827, Richard Bright was the first to recognize the involvement of the renal system in scarlet fever.The association between streptococci and disease was first described in 1874 by Theodor Billroth, discussing people with skin infections. Billroth also coined the genus name Streptococcus. In 1884 Friedrich Julius Rosenbach edited the name to its current one, Streptococcus pyogenes, after further looking at the bacteria in the skin lesions. The organism was first cultured in 1883 by the German surgeon Friedrich Fehleisen from erysipelas lesions.Also in 1884, the German physician Friedrich Loeffler was the first to show the presence of streptococci in the throats of people with scarlet fever. Because not all people with pharyngeal streptococci developed scarlet fever, these findings remained controversial for some time. The association between streptococci and scarlet fever was confirmed by Alphonse Dochez and George and Gladys Dick in the early 1900s.Also in 1884, the worlds first convalescent home for people with scarlet fever was opened at Brockley Hill, Stanmore, founded by Mary Wardell.Nil Filatov (in 1895) and Clement Dukes (in 1894) described an exanthematous disease which they thought was a form of rubella, but in 1900, Dukes described it as a separate illness which came to be known as Dukes disease, Filatovs disease, or fourth disease. However, in 1979, Keith Powell identified it as in fact the same illness as the form of scarlet fever which is caused by staphylococcal exotoxin and is known as staphylococcal scalded skin syndrome.Scarlet fever serum from horses blood was used in the treatment of children beginning in 1900 and reduced mortality rates significantly.In 1906, the Austrian pediatrician Clemens von Pirquet postulated that disease-causing immune complexes were responsible for the nephritis that followed scarlet fever.Bacteriophages were discovered in 1915 by Frederick Twort. His work was overlooked and bacteriophages were later rediscovered by Felix dHerelle in 1917. The specific association of scarlet fever with the group A streptococci had to await the development of Lancefields streptococcal grouping scheme in the 1920s. George and Gladys Dick showed that cell-free filtrates could induce the erythematous reaction characteristic of scarlet fever, proving that this reaction was due to a toxin </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 Hyphema and explain in detail? [/INST] Hyphema is a condition that occurs when blood enters the front (anterior) chamber of the eye between the iris and the cornea. People usually first notice a loss of vision or decrease in vision. The eye may also appear to have a reddish tinge, or it may appear as a small pool of blood at the bottom of the iris or in the cornea. A traumatic hyphema is caused by a hit to the eye from a projected object or a blow to the eye. A hyphema can also occur spontaneously.

Presentation
A decrease in vision or a loss of vision is often the first sign of a hyphema. People with microhyphema may have slightly blurred or normal vision. A person with a full hyphema may not be able to see at all (complete loss of vision). The persons vision may improve over time as the blood moves by gravity lower in the anterior chamber of the eye, between the iris and the cornea. In many people, the vision will improve, however some people may have other injuries related to trauma to the eye or complications related to the hyphema. A microhyphema, where red blood cells are hanging in the anterior chamber of the eye, is less severe. A layered hyphema when fresh blood is seen lower in the anterior chamber is moderately severe. A full hyphema (total hyphema), when blood fills up the chamber completely, is the most severe.

Complications
While the vast majority of hyphemas resolve on their own without issue, sometimes complications occur. Traumatic hyphema may lead to increased intraocular pressure (IOP), peripheral anterior synechiae, atrophy of the optic nerve, staining of the cornea with blood, re-bleeding, and impaired accommodation.Secondary hemorrhage, or rebleeding of the hyphema, is thought to worsen outcomes in terms of visual function and lead to complications such as glaucoma, corneal staining, optic atrophy, or vision loss. Rebleeding occurs in 4–35% of hyphema cases and is a risk factor for glaucoma. Young children with traumatic hyphema are at an increased risk of developing amblyopia, an irreversible condition.

Causes
Hyphemas are frequently caused by injury, and may partially or completely block vision. The most common causes of hyphema are intraocular surgery, blunt trauma, and lacerating trauma.  Hyphemas may also occur spontaneously, without any inciting trauma.  Spontaneous hyphemas are usually caused by the abnormal growth of blood vessels (neovascularization), tumors of the eye (retinoblastoma or iris melanoma), uveitis, or vascular anomalies (juvenile xanthogranuloma). Additional causes of spontaneous hyphema include: rubeosis iridis, myotonic dystrophy, leukemia, hemophilia, and von Willebrand disease.  Conditions or medications that cause thinning of the blood, such as aspirin, warfarin, or drinking alcohol may also cause hyphema. Source of bleeding in hyphema with blunt trauma to eye is circulus iridis major artery.

Treatment
The main goals of treatment are to decrease the risk of re-bleeding within the eye, corneal blood staining, and atrophy of the optic nerve. Small hyphemas can usually be treated on an outpatient basis. There is little evidence that most of the commonly used treatments for hyphema (antifibrinolytic agents [oral and systemic aminocaproic acid, tranexamic acid, and aminomethylbenzoic acid], corticosteroids [systemic and topical], cycloplegics, miotics, aspirin, conjugated estrogens, traditional Chinese medicine, monocular versus bilateral patching, elevation of the head, and bed rest) are effective at improving visual acuity after two weeks </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 Mild cognitive impairment and explain in detail? [/INST] Mild cognitive impairment (MCI) is a neurocognitive disorder which involves cognitive impairments beyond those expected based on an individuals age and education but which are not significant enough to interfere with instrumental activities of daily living. MCI may occur as a transitional stage between normal aging and dementia, especially Alzheimers disease. It includes both memory and non-memory impairments. The cause of the disorder remains unclear, as well as both its prevention and treatment, with some 50 percent of people diagnosed with it going on to develop Alzheimers disease within five years.  The diagnosis can also serve as an early indicator for other types of dementia, although MCI may remain stable or even remit.Mild cognitive impairment has been relisted as mild neurocognitive disorder in DSM-5, and in ICD-11, the latter effective on the 1st of January 2022.

Classification
MCI can present with a variety of symptoms, but is divided generally into two types.Amnestic MCI (aMCI) is mild cognitive impairment with memory loss as the predominant symptom; aMCI is frequently seen as a prodromal stage of Alzheimers disease. Studies suggest that these individuals tend to progress to probable Alzheimers disease at a rate of approximately 10% to 15% per year. It is possible that being diagnosed with cognitive decline may serve as an indicator of MCI.Nonamnestic MCI (naMCI) is mild cognitive impairment in which impairments in domains other than memory (for example, language, visuospatial, executive) are more prominent. It may be further divided as nonamnestic single- or multiple-domain MCI, and these individuals are believed to be more likely to convert to other dementias (for example, dementia with Lewy bodies).The International Classification of Diseases classifies MCI as a "mental and behavioural disorder."

Causes
Mild cognitive impairment (MCI) may be caused due to alteration in the brain triggered during early stages of Alzheimers disease or other forms of dementia. Exact causes of MCI are unknown. It is controversial whether MCI even should be identified as a disorder.Risk factors of both dementia and MCI are considered to be the same: these are aging, genetic (heredity) cause of Alzheimers or other dementia, and cardiovascular disease.Individuals with MCI have increased oxidative damage in their nuclear and mitochondrial brain DNA.

Diagnosis
The diagnosis of MCI requires considerable clinical judgement, and as such a comprehensive clinical assessment including clinical observation, neuroimaging, blood tests and neuropsychological testing are best in order to rule out an alternate diagnosis.
MCI is diagnosed when there is:
Evidence of memory impairment
Preservation of general cognitive and functional abilities
Absence of diagnosed dementia

Neuropathology
Although amnestic MCI patients may not meet criteria for Alzheimers disease, patients may be in a transitional stage of evolving Alzheimers disease.Magnetic resonance imaging can observe deterioration, including progressive loss of gray matter in the brain, from mild cognitive impairment to full-blown Alzheimer disease.  A technique known as PiB PET imaging is used to show the sites and shapes of beta amyloid deposits in living subjects using a 11C tracer that binds selectively to such deposits.

Treatment
As of January 2018, there are no USFDA-approved medications for the treatment of mild cognitive impairment.  Moreover, as of January 2018, there is no high-quality evidence that supports the efficacy of any pharmaceutical drugs or dietary supplements for improving cognitive symptoms in individuals with mild cognitive impairment. A moderate amount of high-quality evidence supports the efficacy of regular physical exercise for improving cognitive symptoms in individuals with MCI. The clinical trials that established the efficacy of exercise therapy for MCI involved twice weekly exercise over a period of six months. A small amount of high-quality evidence supports the efficacy of cognitive training for improving some measures of cognitive function in individuals with mild cognitive impairment.  Due to the heterogeneity among studies which assessed the effect of cognitive training in individuals with MCI, there are no particular cognitive training interventions that have been found to provide greater symptomatic benefits for MCI relative to other forms of cognitive training.The American Academy of Neurologys (AAN) clinical practice guideline on mild cognitive impairment from January 2018 stated that clinicians should identify modifiable risk factors in individuals with MCI, assess functional impairments, provide treatment for any behavioral or neuropsychiatric symptoms, and monitor the individuals cognitive status over time. It also stated that medications which cause cognitive impairment should be discontinued or avoided if possible </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 Mood disorder and explain in detail? [/INST] A mood disorder, also known as an affective disorder, is any of a group of conditions of mental and behavioral disorder where a disturbance in the persons mood is the main underlying feature. The classification is in the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Diseases (ICD).
Mood disorders fall into seven groups, including; abnormally elevated mood, such as mania or hypomania; depressed mood, of which the best-known and most researched is major depressive disorder (MDD) (alternatively known as clinical depression, unipolar depression, or major depression); and moods which cycle between mania and depression, known as bipolar disorder (BD) (formerly known as manic depression). There are several sub-types of depressive disorders or psychiatric syndromes featuring less severe symptoms such as dysthymic disorder (similar to MDD, but longer lasting and more persistent, though often milder) and cyclothymic disorder (similar to but milder than BD).In some cases, more than one mood disorder can be present in an individual, like bipolar disorder and depressive disorder. If a mood disorder and schizophrenia are both present in an individual, this is known as schizoaffective disorder. Mood disorders may also be substance induced, or occur in response to a medical condition.
English psychiatrist Henry Maudsley proposed an overarching category of affective disorder. The term was then replaced by mood disorder, as the latter term refers to the underlying or longitudinal emotional state, whereas the former refers to the external expression observed by others.

Classification
Depressive disorders
Major depressive disorder (MDD), commonly called major depression, unipolar depression, or clinical depression, wherein a person has one or more major depressive episodes. After a single episode, Major Depressive Disorder (single episode) would be diagnosed. After more than one episode, the diagnosis becomes Major Depressive Disorder (Recurrent). Depression without periods of mania is sometimes referred to as unipolar depression because the mood remains at the bottom "pole" and does not climb to the higher, manic "pole" as in bipolar disorder.Individuals with a major depressive episode or major depressive disorder are at increased risk for suicide. Seeking help and treatment from a health professional dramatically reduces the individuals risk for suicide. Studies have demonstrated that asking if a depressed friend or family member has thought of committing suicide is an effective way of identifying those at risk, and it does not "plant" the idea or increase an individuals risk for suicide in any way. Epidemiological studies carried out in Europe suggest that, at this moment, roughly 8.5 percent of the worlds population have a depressive disorder. No age group seems to be exempt from depression, and studies have found that depression appears in infants as young as 6 months old who have been separated from their mothers.Depressive disorder is frequent in primary care and general hospital practice but is often undetected.  Unrecognized depressive disorder may slow recovery and worsen prognosis in physical illness, therefore it is important that all doctors be able to recognize the condition, treat the less severe cases, and identify those requiring specialist care.Diagnosticians recognize several subtypes or course specifiers:Atypical depression (AD) is characterized by mood reactivity (paradoxical anhedonia) and positivity,  significant weight gain or increased appetite ("comfort eating"), excessive sleep or somnolence (hypersomnia), a sensation of heaviness in limbs known as leaden paralysis, and significant social impairment as a consequence of hypersensitivity to perceived interpersonal rejection. Difficulties in measuring this subtype have led to questions of its validity and prevalence.Melancholic depression is characterized by a loss of pleasure (anhedonia) in most or all activities, a failure of reactivity to pleasurable stimuli, a quality of depressed mood more pronounced than that of grief or loss, a worsening of symptoms in the morning hours, early-morning waking, psychomotor retardation, excessive weight loss (not to be confused with anorexia nervosa), or excessive guilt.Psychotic major depression (PMD), or simply psychotic depression, is the term for a major depressive episode, in particular of melancholic nature, wherein the patient experiences psychotic symptoms such as delusions or, less commonly, hallucinations. These are most commonly mood-congruent (content coincident with depressive themes).Catatonic depression is a rare and severe form of major depression involving disturbances of motor behavior and other symptoms. Here, the person is mute and almost stuporose, and either is immobile or exhibits purposeless or even bizarre movements. Catatonic symptoms can also occur in schizophrenia or a manic episode, or can be due to neuroleptic malignant syndrome.Postpartum depression (PPD) is listed as a course specifier in DSM-IV-TR; it refers to the intense, sustained and sometimes disabling depression experienced by women after giving birth. Postpartum depression, which affects 10–15% of women, typically sets in within three months of labor, and lasts as long as three months. It is quite common for women to experience a short-term feeling of tiredness and sadness in the first few weeks after giving birth; however, postpartum depression is different because it can cause significant hardship and impaired functioning at home, work, or school as well as, possibly, difficulty in relationships with family members, spouses, or friends, or even problems bonding with the newborn. In the treatment of postpartum major depressive disorders and other unipolar depressions in women who are breastfeeding, nortriptyline, paroxetine (Paxil), and sertraline (Zoloft) are in general considered to be the preferred medications. Women with personal or family histories of mood disorders are at particularly high risk of developing postpartum depression.Premenstrual dysphoric disorder (PMDD) is a severe and disabling form of premenstrual syndrome affecting 3–8% of menstruating women. The disorder consists of a "cluster of affective, behavioral and somatic symptoms" that recur monthly during the luteal phase of the menstrual cycle. PMDD was added to the list of depressive disorders in the Diagnostic and Statistical Manual of Mental Disorders in 2013. The exact pathogenesis of the disorder is still unclear and is an active research topic. Treatment of PMDD relies largely on antidepressants that modulate serotonin levels in the brain via serotonin reuptake inhibitors as well as ovulation suppression using contraception.Seasonal affective disorder (SAD), also known as "winter depression" or "winter blues", is a specifier. Some people have a seasonal pattern, with depressive episodes coming on in the autumn or winter, and resolving in spring. The diagnosis is made if at least two episodes have occurred in colder months with none at other times over a two-year period or longer. It is commonly hypothesised that people who live at higher latitudes tend to have less sunlight exposure in the winter and therefore experience higher rates of SAD, but the epidemiological support for this proposition is not strong (and latitude is not the only determinant of the amount of sunlight reaching the eyes in winter). It is said that this disorder can be treated by light therapy. SAD is also more prevalent in people who are younger and typically affects more females than males.Dysthymia is a condition related to unipolar depression, where the same physical and cognitive problems are evident, but they are not as severe and tend to last longer (usually at least 2 years). The treatment of dysthymia is largely the same as for major depression, including antidepressant medications and psychotherapy.Double depression can be defined as a fairly depressed mood (dysthymia) that lasts for at least two years and is punctuated by periods of major depression.Unspecified Depressive Disorder is designated by the code 311 for depressive disorders. In the DSM-5, Unspecified Depressive Disorder encompasses symptoms that are characteristic of depressive disorders and cause significant impairment in functioning, but do not meet the criteria for the diagnosis of any specified depressive disorders. In the DSM-IV, this was called Depressive Disorder Not Otherwise Specified.Depressive personality disorder (DPD) is a controversial psychiatric diagnosis that denotes a personality disorder with depressive features. Originally included in the DSM-II, depressive personality disorder was removed from the DSM-III and DSM-III-R. Recently, it has been reconsidered for reinstatement as a diagnosis. Depressive personality disorder is currently described in Appendix B in the DSM-IV-TR as worthy of further study.Recurrent brief depression (RBD), distinguished from major depressive disorder primarily by differences in duration. People with RBD have depressive episodes about once per month, with individual episodes lasting less than two weeks and typically less than 2–3 days. Diagnosis of RBD requires that the episodes occur over the span of at least one year and, in female patients, independently of the menstrual cycle. People with clinical depression can develop RBD, and vice versa, and both illnesses have similar risks.Minor depressive disorder, or simply minor depression, which refers to a depression that does not meet full criteria for major depression but in which at least two symptoms are present for two weeks.

Bipolar disorders
Bipolar disorder (BD) (also called "manic depression" or "manic-depressive disorder"), an unstable emotional condition characterized by cycles of abnormal, persistent high mood (mania) and low mood (depression), which was formerly known as "manic depression" (and in some cases rapid cycling, mixed states, and psychotic symptoms). Subtypes include:Bipolar I is distinguished by the presence or history of one or more manic episodes or mixed episodes with or without major depressive episodes. A depressive episode is not required for the diagnosis of Bipolar I Disorder, but depressive episodes are usually part of the course of the illness.
Bipolar II consisting of recurrent intermittent hypomanic and depressive episodes or mixed episodes.
Cyclothymia is a form of bipolar disorder, consisting of recurrent hypomanic and dysthymic episodes, but no full manic episodes or full major depressive episodes.
Bipolar disorder not otherwise specified (BD-NOS), sometimes called "sub-threshold" bipolar, indicates that the patient has some symptoms in the bipolar spectrum (e.g., manic and depressive symptoms) but does not fully qualify for any of the three formal bipolar DSM-IV diagnoses mentioned above.
It is estimated that roughly 1% of the adult population has bipolar I, a further 1% has bipolar II or cyclothymia, and somewhere between 2% and 5% percent have "sub-threshold" forms of bipolar disorder. Furthermore, the possibility of getting bipolar disorder when one parent is diagnosed with it is 15–30%. Risk, when both parents have it, is 50–75%. Also, while with bipolar siblings the risk is 15–25%, with identical twins it is about 70%.A minority of people with bipolar disorder have high creativity, artistry or a particular gifted talent. Before the mania phase becomes too extreme, its energy, ambition, enthusiasm and grandiosity often bring people with this type of mood disorder lifes masterpieces.

Substance-induced
A mood disorder can be classified as substance-induced if its etiology can be traced to the direct physiologic effects of a psychoactive drug or other chemical substance, or if the development of the mood disorder occurred contemporaneously with substance intoxication or withdrawal. Also, an individual may have a mood disorder coexisting with a substance abuse disorder. Substance-induced mood disorders can have features of a manic, hypomanic, mixed, or depressive episode. Most substances can induce a variety of mood disorders. For example, stimulants such as amphetamine, methamphetamine, and cocaine can cause manic, hypomanic, mixed, and depressive episodes.

Alcohol-induced
High rates of major depressive disorder occur in heavy drinkers and those with alcoholism. Controversy has previously surrounded whether those who abused alcohol and developed depression were self-medicating their pre-existing depression. Recent research has concluded that, while this may be true in some cases, alcohol misuse directly causes the development of depression in a significant number of heavy drinkers. Participants studied were also assessed during stressful events in their lives and measured on a Feeling Bad Scale. Likewise, they were also assessed on their affiliation with  deviant  peers, unemployment, and their partners substance use and criminal offending. High rates of suicide also occur in those who have alcohol-related problems. It is usually possible to differentiate between alcohol-related depression and depression that is not related to alcohol intake by taking a careful history of the patient. Depression and other mental health problems associated with alcohol misuse may be due to distortion of brain chemistry, as they tend to improve on their own after a period of abstinence.

Benzodiazepine-induced
Benzodiazepines, such as alprazolam, clonazepam, lorazepam and diazepam, can cause both depression and mania.Benzodiazepines are a class of medication commonly used to treat anxiety, panic attacks and insomnia, and are also commonly misused and abused. Those with anxiety, panic and sleep problems commonly have negative emotions and thoughts, depression, suicidal ideations, and often have comorbid depressive disorders. While the anxiolytic and hypnotic effects of benzodiazepines disappear as tolerance develops, depression and impulsivity with high suicidal risk commonly persist. These symptoms are "often interpreted as an exacerbation or as a natural evolution of previous disorders and the chronic use of sedatives is overlooked". Benzodiazepines do not prevent the development of depression, can exacerbate preexisting depression, can cause depression in those with no history of it, and can lead to suicide attempts. Risk factors for suicide and suicide attempts while using benzodiazepines include high dose prescriptions (even in those not misusing the medications), benzodiazepine intoxication, and underlying depression.The long-term use of benzodiazepines may have a similar effect on the brain as alcohol, and are also implicated in depression. As with alcohol, the effects of benzodiazepine on neurochemistry, such as decreased levels of serotonin and norepinephrine, are believed to be responsible for the increased depression. Additionally, benzodiazepines can indirectly worsen mood by worsening sleep (i.e., benzodiazepine-induced sleep disorder). Like alcohol, benzodiazepines can put people to sleep but, while asleep, they disrupt sleep architecture: decreasing sleep time, delaying time to REM sleep, and decreasing deep sleep (the most restorative part of sleep for both energy and mood). Just as some antidepressants can cause or worsen anxiety in some patients due to being activating, benzodiazepines can cause or worsen depression due to being a central nervous system depressant—worsening thinking, concentration and problem solving (i.e., benzodiazepine-induced neurocognitive disorder). However, unlike antidepressants, in which the activating effects usually improve with continued treatment, benzodiazepine-induced depression is unlikely to improve until after stopping the medication.In a long-term follow-up study of patients dependent on benzodiazepines, it was found that 10 people (20%) had taken drug overdoses while on chronic benzodiazepine medication despite only two people ever having had any pre-existing depressive disorder. A year after a gradual withdrawal program, no patients had taken any further overdoses.Just as with intoxication and chronic use, benzodiazepine withdrawal can also cause depression. While benzodiazepine-induced depressive disorder may be exacerbated immediately after discontinuation of benzodiazepines, evidence suggests that mood significantly improves after the acute withdrawal period to levels better than during use. Depression resulting from withdrawal from benzodiazepines usually subsides after a few months but in some cases may persist for 6–12 months.

Due to another medical condition
"Mood disorder due to a general medical condition" is used to describe manic or depressive episodes which occur secondary to a medical condition. There are many medical conditions that can trigger mood episodes, including neurological disorders (e.g. dementias), metabolic disorders (e.g. electrolyte disturbances), gastrointestinal diseases (e.g. cirrhosis), endocrine disease (e.g. thyroid abnormalities), cardiovascular disease (e.g. heart attack), pulmonary disease (e.g. chronic obstructive pulmonary disease), cancer, and autoimmune diseases (e.g. multiple sclerosis).

Not otherwise specified
Mood disorder not otherwise specified (MD-NOS) is a mood disorder that is impairing but does not fit in with any of the other officially specified diagnoses. In the DSM-IV MD-NOS is described as "any mood disorder that does not meet the criteria for a specific disorder." MD-NOS is not used as a clinical description but as a statistical concept for filing purposes. The diagnosis of MD-NOS does not exist in the DSM-5, however the diagnoses of unspecified depressive disorder and unspecified bipolar disorder are in the DSM-5.Most cases of MD-NOS represent hybrids between mood and anxiety disorders, such as mixed anxiety-depressive disorder or atypical depression. An example of an instance of MD-NOS is being in minor depression frequently during various intervals, such as once every month or once in three days. There is a risk for MD-NOS not to get noticed, and for that reason not to get treated.

Causes
Meta-analyses show that high scores on the personality domain neuroticism are a strong predictor for the development of mood disorders. A number of authors have also suggested that mood disorders are an evolutionary adaptation (see also evolutionary psychiatry). A low or depressed mood can increase an individuals ability to cope with situations in which the effort to pursue a major goal could result in danger, loss, or wasted effort. In such situations, low motivation may give an advantage by inhibiting certain actions. This theory helps to explain why negative life incidents precede depression in around 80 percent of cases, and why they so often strike people during their peak reproductive years. These characteristics would be difficult to understand if depression were a dysfunction.A depressed mood is a predictable response to certain types of life occurrences, such as loss of status, divorce, or death of a child or spouse. These are events that signal a loss of reproductive ability or potential, or that did so in humans ancestral environment. A depressed mood can be seen as an adaptive response, in the sense that it causes an individual to turn away from the earlier (and reproductively unsuccessful) modes of behavior.A depressed mood is common during illnesses, such as influenza. It has been argued that this is an evolved mechanism that assists the individual in recovering by limiting their physical activity. The occurrence of low-level depression during the winter months, or seasonal affective disorder, may have been adaptive in the past, by limiting physical activity at times when food was scarce. It is argued that humans have retained the instinct to experience low mood during the winter months, even if the availability of food is no longer determined by the weather.Much of what is known about the genetic influence of clinical depression is based upon research that has been done with identical twins. Identical twins have exactly the same genetic code. It has been found that when one identical twin becomes depressed the other will also develop clinical depression approximately 76% of the time. When identical twins are raised apart from each other, they will both become depressed about 67% of the time. Because both twins become depressed at such a high rate, the implication is that there is a strong genetic influence. If it happened that when one twin becomes clinically depressed the other always develops depression, then clinical depression would likely be entirely genetic.Bipolar disorder is also considered a mood disorder and it is hypothesized that it might be caused by mitochondrial dysfunction.

Sex differences
Mood disorders, specifically stress-related mood disorders such as anxiety and depression, have been shown to have differing rates of diagnosis based on sex. In the United States, women are two times more likely than men to be diagnosed with a stress-related mood disorder. Underlying these sex differences, studies have shown a dysregulation of stress-responsive neuroendocrine function causing an increase in the likelihood of developing these affective disorders. Overactivation of the hypothalamic-pituitary-adrenal (HPA) axis could provide potential insight into how these sex differences arise. Neuropeptide corticotropin-releasing factor (CRF) is released from the paraventricular nucleus (PVN) of the hypothalamus, stimulating adrenocorticotropic hormone (ACTH) release into the blood stream. From here ACTH triggers the release of glucocorticoids such as cortisol from the adrenal cortex. Cortisol, known as the main stress hormone, creates a negative feedback loop back to the hypothalamus to deactivate the stress response. When a constant stressor is present, the HPA axis remains overactivated and cortisol is constantly produced. This chronic stress is associated with sustained CRF release, resulting in the increased production of anxiety- and depressive-like behaviors and serving as a potential mechanism for differences in prevalence between men and women.

Diagnosis
DSM-5
The DSM-5, released in May 2013, separates the mood disorder chapter from the DSM-TR-IV into two sections: Depressive and related disorders and bipolar and related disorders. Bipolar disorders fall in between depressive disorders and schizophrenia spectrum and related disorders "in recognition of their place as a bridge between the two diagnostic classes in terms of symptomatology, family history and genetics" (Ref. 1, p 123). Bipolar disorders underwent a few changes in the DSM-5, most notably the addition of more specific symptomology related to hypomanic and mixed manic states. Depressive disorders underwent the most changes, the addition of three new disorders: disruptive mood dysregulation disorder, persistent depressive disorder (previously dysthymia), and premenstrual dysphoric disorder (previously in appendix B, the section for disorders needing further research). Disruptive mood dysregulation disorder is meant as a diagnosis for children and adolescents who would normally be diagnosed with bipolar disorder as a way to limit the bipolar diagnosis in this age cohort. Major depressive disorder (MDD) also underwent a notable change, in that the bereavement clause has been removed. Those previously exempt from a diagnosis of MDD due to bereavement are now candidates for the MDD diagnosis.

Treatment
There are different types of treatments available for mood disorders, such as therapy and medications. Behaviour therapy, cognitive behaviour therapy and interpersonal therapy have all shown to be potentially beneficial in depression. Major depressive disorder medications usually include antidepressants; a combination of antidepressants and cognitive behavioral therapy has shown to be more effective than one treatment alone. Bipolar disorder medications can consist of antipsychotics, mood stabilizers, anticonvulsants and/or lithium. Lithium specifically has been proven to reduce suicide and all causes of mortality in people with mood disorders. If mitochondrial dysfunction or mitochondrial diseases are the cause of mood disorders like bipolar disorder, then it has been hypothesized that N-acetyl-cysteine (NAC), acetyl-L-carnitine (ALCAR), S-adenosylmethionine (SAMe), coenzyme Q10 (CoQ10), alpha-lipoic acid (ALA), creatine monohydrate (CM), and melatonin could be potential treatment options. In determining treatment, there are many types of depression scales that are used. One of the depression scales is a self-report scale called Beck Depression Inventory (BDI). Another scale is the Hamilton Depression Rating Scale (HAMD). HAMD is a clinical rating scale in which the patient is rated based on clinician observation. The Center for Epidemiologic Studies Depression Scale (CES-D) is a scale for depression symptoms that applies to the general population. This scale is typically used in research and not for self-reports. The PHQ-9 which stands for Patient-Health Questionnaire-9 questions, is a self-report as well. Finally, the Mood Disorder Questionnaire (MDQ) evaluates bipolar disorder.

Epidemiology
According to a substantial number of epidemiology studies conducted, women are twice as likely to develop certain mood disorders, such as major depression.  Although there is an equal number of men and women diagnosed with bipolar II disorder, women have a slightly higher frequency of the disorder.The prevalence of depressive symptoms has increased over the years with recent generations reporting a 6% increase in symptoms of depression compared to individuals from older generations.In 2011, mood disorders were the most common reason for hospitalization among children aged 1–17 years in the United States, with approximately 112,000 stays. Mood disorders were top principal diagnosis for Medicaid super-utilizers in the United States in 2012. Further, a study of 18 States found that mood disorders accounted for the highest number of hospital readmissions among Medicaid patients and the uninsured, with 41,600 Medicaid patients and 12,200 uninsured patients being readmitted within 30 days of their index stay—a readmission rate of 19.8 per 100 admissions and 12.7 per 100 admissions, respectively. In 2012, mood and other behavioral health disorders were the most common diagnoses for Medicaid-covered and uninsured hospital stays in the United States (6.1% of Medicaid stays and 5.2% of uninsured stays).A study conducted in 1988 to 1994 amongst young American adults involved a selection of demographic and health characteristics. A population-based sample of 8,602 men and women ages 17–39 years participated. Lifetime prevalence were estimated based on six mood measures:

major depressive episode (MDE) 8.6%,
major depressive disorder with severity (MDE-s) 7.7%,
dysthymia 6.2%,
MDE-s with dysthymia 3.4%,
any bipolar disorder 1.6%, and
any mood disorder 11.5%.

Research
Kay Redfield Jamison and others have explored the possible links between mood disorders – especially bipolar disorder – and creativity. It has been proposed that a "ruminating personality type may contribute to both [mood disorders] and art."Jane Collingwood notes an Oregon State University study that

"looked at the occupational status of a large group of typical patients and found that those with bipolar illness appear to be disproportionately concentrated in the most creative occupational category. They also found that the likelihood of engaging in creative activities on the job is significantly higher for bipolar than nonbipolar workers".In Liz Patereks article "Bipolar Disorder and the Creative Mind" she wrote

"Memory and creativity are related to mania. Clinical studies have shown that those in a manic state will rhyme, find synonyms, and use alliteration more than controls. This mental fluidity could contribute to an increase in creativity. Moreover, mania creates increases in productivity and energy. Those in a manic state are more emotionally sensitive and show less inhibition about attitudes, which could create greater expression. Studies performed at Harvard looked into the amount of original thinking in solving creative tasks. Bipolar individuals, whose disorder was not severe, tended to show greater degrees of creativity".The relationship between depression and creativity appears to be especially strong among poets.

See also
Personality disorder

References
Cited textsAmerican Psychiatric Association (2000). Diagnostic and statistical manual of mental disorders, Fourth Edition, Text Revision: DSM-IV-TR. Washington, DC: American Psychiatric Publishing, Inc. ISBN 978-0-89042-025-6.
American Psychiatric Association (2013). Diagnostic and statistical manual of mental disorders, Fifth Edition, Text Revision: DSM-5. Washington, DC: American Psychiatric Association, Inc. ISBN 978-0-89042-554-1.
Carlson, Neil R.; Heth, C. Donald (2007). Psychology the science of behaviour (4th ed.). Pearson Education Inc. ISBN 978-0-205-64524-4.
Collier, Judith; Longmore, Murray (2003). "4".  In Scally, Peter (ed.). Oxford Handbook of Clinical Specialties (6th ed.). Oxford University Press. ISBN 978-0-19-852518-9.
Nesse, Randolphe M.; Williams, George C. (1994). Why We Get Sick: The New Science of Darwinian Medicine. Vintage Books. ISBN 0-8129-2224-7.
Nolen-Hoeksema, S (2013). Abnormal Psychology (6th ed.). McGraw-Hill Higher Education. ISBN 9780077499693. Retrieved 5 December 2014.
Parker, Gordon; Hadzi-Pavlovic, Dusan; Eyers, Kerrie (1996). Melancholia: A disorder of movement and mood: a phenomenological and neurobiological review. Cambridge: Cambridge University Press. ISBN 978-0-521-47275-3.
Sadock, Benjamin J.; Sadock, Virginia A. (2002). Kaplan and Sadocks Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry (9th ed.). Lippincott Williams & Wilkins. ISBN 978-0-7817-3183-6.
Semple, David; Smyth, Roger; Burns, Jonathan; Darjee, Rajan; McIntosh, Andrew (2007) [2005]. "13". Oxford Handbook of Psychiatry. Oxford University Press </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 Lymphangioleiomyomatosis and explain in detail? [/INST] Lymphangioleiomyomatosis (LAM) is a rare, progressive and systemic disease that typically results in cystic lung destruction. It predominantly affects women, especially during childbearing years. The term sporadic LAM is used for patients with LAM not associated with tuberous sclerosis complex (TSC), while TSC-LAM refers to LAM that is associated with TSC.

Signs and symptoms
The average age of onset is the early to mid 30s. Exertional dyspnea (shortness of breath) and spontaneous pneumothorax (lung collapse) have been reported as the initial presentation of the disease in 49% and 46% of patients, respectively.Diagnosis is typically delayed 5 to 6 years. The condition is often misdiagnosed as asthma or chronic obstructive pulmonary disease. The first pneumothorax, or lung collapse, precedes the diagnosis of LAM in 82% of patients. The consensus clinical definition of LAM includes multiple symptoms:
Fatigue
Cough
Coughing up blood (rarely massive)
Chest pain
Chylous complications arising from lymphatic obstruction, including
Chylothorax
Chylous ascites
Chylopericardium
Chyloptysis
Chyluria
Chyle in vaginal discharge
Chyle in stool.
Angiomyolipomas (fatty kidney tumors) are present in about 30% of patients with sporadic LAM and up to 90% of patients with TSC-LAM. Angiomyolipomas can sometimes spontaneously bleed, causing pain or low blood pressure.
Cystic lymphangiomas or lymph nodes with hypodense centers, which mimic necrotizing lymphomas, ovarian or renal cancers, or other malignancies can occur in the retroperitoneum, pelvis or mediastinum.Lung destruction in LAM is a consequence of diffuse infiltration by neoplastic smooth muscle-like cells that invade all lung structures including the lymphatics, airway walls, blood vessels and interstitial spaces. The consequences of vessel and airway obstruction include chylous fluid accumulations, hemoptysis, airflow obstruction and pneumothorax. The typical disease course displays progressive dyspnea on exertion, spaced by recurrent pneumothoraces and in some patients, chylous pleural effusions or ascites.Most people have dyspnea on exertion with daily activities by 10 years after symptom onset. Many patients require supplemental oxygen over that interval.

Genetics
LAM occurs in two settings: in the disease tuberous sclerosis complex (TSC-LAM) and in a sporadic form, in women who do not have TSC (sporadic LAM). In both settings, genetic evidence indicates that LAM is caused by inactivating or “loss of function” mutations in the TSC1 or TSC2 genes, which were cloned in 1997 and 1993 respectively. The TSC1 gene is located on the long arm of chromosome 9 (9q34) and the TSC2 gene is located on the short arm of chromosome 16 (16p13). TSC-LAM occurs in women who have germline mutations in either the TSC1 or the TSC2 gene.Sporadic LAM is primarily associated with somatic TSC2 gene mutations. Germline and somatic mutations in LAM include many types of mutations spread across the genes, with no clear “hot spots,” including missense changes, in-frame deletions and nonsense mutations. Because of the large size of the genes (together they have more than 60 exons) and because mutations can be located virtually anywhere within the genes, mutation detection is often challenging.On a cellular basis, LAM cells carry bi-allelic inactivation of the TSC2 genes, consistent with the “two-hit” tumor suppressor gene model. The second hit event in LAM cells is often loss of the chromosomal region containing the wild-type copy of the TSC2 gene; this is referred to as loss of heterozygosity or LOH. LOH can be detected in microdissected LAM cells, in angiomyolipomas and lymph nodes from women with LAM, and in circulating LAM cells (cells in blood and urine).Angiomyolipomas and pulmonary LAM cells from women with the sporadic form of LAM carry identical mutations in TSC2. This, together with the fact that recurrent LAM after lung transplantation carries the same TSC2 mutations as the original LAM, has led to the "benign metastasis" hypothesis that LAM cells can migrate or metastasize from one site to another.

Pathophysiology
A variable percentage of cells within the LAM lesion contain mutational inactivation of the tuberous sclerosis complex (TSC1 or TSC2) tumor suppressor genes. TSC1 mutations cause a less severe clinical phenotype than TSC2 mutations. The discovery of TSC1/2 gene function as negative regulator of the mammalian target of rapamycin complex 1 (mTORC1) led to successful use of rapamycin analog sirolimus in clinical trials and FDA approval of sirolimus for treatment of LAM.
TSC1 and TSC2 form a tumor suppressor complex that regulates mammalian target of rapamycin (mTOR) signaling complex by directly controlling the activity of the small GTPase Rheb via the GTPase activating protein (GAP) domain of TSC2. Rheb binds to Raptor and controls the activity of mTOR complex 1 (mTORC1) that directly phosphorylates p70 S6 kinase (S6K1) and 4E-BP1. mTOR forms two physically and functionally distinct multiprotein complexes: the rapamycin-sensitive mTORC1 and the rapamycin-insensitive mTORC2. MTORC1 consists of five proteins including Raptor that positively regulate mTOR activity. MTORC2 consists of six proteins including mTOR and Rictor, which defines the activation level of mTORC2 and modulates the assembly of the actin cytoskeleton through Rho GTPases, and Rac1 is required for mTOR activation. In TSC2-null and human LAM cells, Rho GTPase activity is required for cell adhesion, motility, proliferation and survival. Loss of TSC1/TSC2 in LAM induces uncontrolled LAM cell growth and increases LAM cell viability. Upregulation of STAT1 and STAT3 and autophagy are known mediators of LAM cell viability and survival.
LAM cells behave, in many ways, like metastatic tumor cells. LAM cells appear to arise from an extrapulmonary source and migrate to the lung. Increased LAM cell migration and invasiveness is rescued by TSC2 re-expression. The cellular and molecular mechanisms of neoplastic transformation and lung parenchymal destruction by LAM cells remain unknown. Lung remodeling may be mediated by an imbalance between matrix degrading metalloproteinases (MMPs) and their endogenous inhibitors TIMPs. The invasive cell phenotype in LAM is associated with TIMP-3 downregulation and TSC2-dependent upregulation of MMPs.Clinical and histopathological evidence demonstrate the lymphatic involvement in LAM. The prevailing hypothesis is that LAM lesions secrete the lymphangiogenic factor VEGF-D, recruit lymphatic endothelial cells (LECs) that form lymphatic vessels and induce lung cysts. VEGF-D serum levels are increased in LAM compared to other cystic lung diseases, including pulmonary Langerhans cell histiocytosis, emphysema, Sjögrens syndrome, or Birt–Hogg–Dubé syndrome. VEGF-D levels correlate with the severity of LAM, evaluated as a measure of CT grade (the abundance of chylous effusions and lymphatic involvement). VEGF-D is a secreted homodimeric glycoprotein and a member of the VEGF family of growth factors, is known for its role in cancer lymphangiogenesis and metastasis. Proteolytic processing of VEGF-D affects cognate binding to VEGFR3. Histopathologically, LAM lesions are surrounded by cells that stain for VEGFR3, the lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) and podoplanin. VEGF-D binds to the receptor protein tyrosine kinases VEGFR-2 and VEGFR-349 in humans, and to VEGFR3 in mice. Surprisingly, knock-out of VEGF-D in mice has little effect on lymphatic system development. Nevertheless, during tumorigenesis VEGF-D promotes formation of tumor lymphatic vessels and facilitates metastatic spread of cancer cells. However, little is known about a role of abnormal lymphatics and VEGF-D in LAM pathogenesis.

Diagnosis
LAM can come to medical attention in several ways, most of which trigger a chest CT. Thin-walled cystic change in the lungs may be found incidentally on CT scans of the heart, chest or abdomen (on the cuts that include lung bases) obtained for other purposes. HRCTs of TSC patients reveals that about 20% of women have cystic change by age 20 and about 80% of women have cystic changes after age 40. LAM is sometimes revealed by chest CT in patients who present with an apparent primary spontaneous pneumothorax, but more often CT scanning is not ordered (in the United States) until recurrences occur. Progressive dyspnea on exertion without the exacerbations and remissions that are characteristic of asthma or COPD sometimes prompt a chest CT. A review of the CT by an expert familiar with LAM may increase diagnostic accuracy. Chylothorax can also bring LAM to attention.
In some cases, a LAM diagnosis can be made with confidence on clinical grounds (without biopsy) in patients with typical cystic changes on high resolution CT scanning of the lung and findings of tuberous sclerosis, angiomyolipoma, lymphangioleiomyoma, chylothorax or serum VEGF-D > 800 pg/ml.If none of these clinical features are present, a biopsy may be necessary to make the diagnosis. Video-assisted thoracoscopic lung biopsy is the most definitive technique, but transbronchial biopsy has a yield of over 50% and can also be effective. The safety of the latter procedure in patients with diffuse cystic disease and the profusion of cystic change that predicts an informative biopsy are incompletely understood, however. Cytology of chylous fluids, aspirated abdominal nodes or lymphatic masses can also be diagnostic.
Diagram 1 outlines a proposed algorithm for the diagnosis of LAM.

Chest radiograph
The chest radiograph may appear relatively normal, even late in the disease, or may suggest hyperinflation only. As the disease progresses, the chest radiograph often demonstrates diffuse, bilateral and symmetric reticulonodular opacities, cysts, bullae or a "honeycomb" (i.e., pseudo fibrotic) appearance. Pleural effusion and pneumothorax may be apparent. Preservation of lung volumes in the presence of increased interstitial markings is a radiographic hallmark of LAM that helps distinguish it from most other interstitial lung diseases, in which alveolar septal and interstitial expansion tend to increase the lungs elastic recoil properties and decreased lung volumes.

Computed tomography
The high-resolution computed tomography (HRCT) chest scan is better than the chest radiograph to detect cystic parenchymal disease and is almost always abnormal at the time of diagnosis, even when the chest radiograph and pulmonary function assessments are normal. The typical CT shows diffuse round, bilateral, thin-walled cysts of varying sizes ranging from 1 to 45 mm in diameter. The numbers of cysts varies in LAM from a few to almost complete replacement of normal lung tissue. The profusion of cysts tends to be milder in patients with TSC-LAM than S-LAM, perhaps explained in part because TSC-LAM patients typically receive earlier screening. Pleural effusions are seen on CT in 12% of patients with S-LAM and 6% of patients with TSC-LAM. Other CT features include linear densities (29%), hilar or mediastinal lymphadenopathy (9%), pneumothorax, lymphangiomyoma, and thoracic duct dilation. Ground-glass opacities (12%) suggest the presence of interstitial edema due to lymphatic congestion. In patients with TSC, nodular densities on HRCT may represent multifocal micronodular pneumocyte hyperplasia (MMPH) made up of clusters of hyperplastic type II pneumocytes. MMPH may be present in males or females with TSC in the presence or absence of LAM, but not in patients with S-LAM. MMPH is not typically associated with physiologic or prognostic consequences, but one case of respiratory failure due to MMPH has been reported.

Ventilation-perfusion scans
In one study ventilation-perfusion scans were abnormal in 34 of 35 LAM patients. The most common abnormality was nonspecific diffuse heterogeneity, usually grossly matched. These authors also described an “unusual,” “speckling pattern” on the perfusion images in 74% of patients, consisting of “small, often peripheral collections of radioisotope.”

Positron emission tomography
LAM and AML lesions do not typically exhibit increased uptake of 18F-fluorodeoxyglucose on positron emission tomography (PET) scanning. Other neoplasms (or sources of inflammation) should therefore be considered in known or suspected LAM cases in which FDG-PET results are positive.

Abdominal imaging
Abnormalities on abdominal imaging, such as renal AML and enlarged lymphatic structures, are also common in LAM. Fat density within a renal mass is pathognomonic of AMLs. AMLs are more prevalent and more frequently bilateral and large in patients with TSC-LAM than in patients with S-LAM. AML size correlates with the prevalence of pulmonary cysts in patients with TSC. One study CT imaged 256 patients with S-LAM and 67 with TSC-LAM. Renal AMLs were present in 32% of patients with S-LAM and 93% of patients with TSC-LAM. Hepatic AMLs were present in 2% of patients with S-LAM and 33% of patients with TSC-LAM. Ascites was uncommon, seen in fewer than 10% of patients with LAM. Abdominal lymphangiomatosis, often containing both cystic and solid components, were seen in 29% of patients with S-LAM and 9% of patients with TSC-LAM.

Central nervous system imaging
Central nervous system abnormalities, such as cortical or subependymal tubers and astrocytomas, are common in patients with TSC, including those with TSC-LAM, but are not found in women with S-LAM. Moss and associates reported that women with S-LAM and TSC-LAM may have an increased incidence of meningioma, but the significance of that finding has been challenged.

Pulmonary function studies
Pulmonary function testing in patients with LAM may be normal or may reveal obstructive, restrictive or mixed patterns. Obstructive physiology is the most common abnormality. Quality-controlled lung function data were collected prospectively by the NHLBI Registry, a 5-year study of patients with LAM in centers around the United States. Spirometry revealed obstructive changes in about 57% of patients and normal results in 34%. Restriction, defined as a total lung capacity less than the lower limit of normal, was seen in 11%. Hyperinflation was present in about 6%. The average residual volume was 125% of predicted when measured by plethysmography, but was only 103% of predicted determined with gas dilution methods, suggesting significant air trapping in noncommunicating airspaces. Approximately 25% of patients with obstructive physiology may demonstrate bronchodilator responsiveness but may be less in more severe obstruction. The obstructive physiologic defect in LAM is primarily attributable to airflow obstruction. The earliest change in initial pulmonary function testing in various case series was abnormal gas transfer, as assessed by the diffusing capacity for carbon monoxide (DLCO), described in 82% to 97% of patients. It is not unusual for DLCO to be reduced out of proportion to forced expiratory volume in 1 second (FEV1). Reduction in DLCO and increase in residual volume are generally considered to be LAMs earliest physiologic manifestations.Cardiopulmonary exercise testing in a much larger cohort of patients with LAM revealed a reduced maximal oxygen consumption (VO2 max) and anaerobic threshold in 217 patients. Exercise-induced hypoxemia was found even in patients who did not have resting abnormalities in FEV1 and DLCO. In most patients, exercise was thought to be ventilation limited, owing to airflow obstruction and increased dead-space ventilation.Disease progression is usually accompanied by a progressive obstructive ventilatory defect. Decline in FEV1 is the most commonly used parameter to monitor disease progression. Although resting pulmonary hypertension appears to be unusual in LAM, pulmonary arterial pressure often rises with low levels of exercise, related in part to hypoxemia. One study reported an increase in intraparenchymal shunts in dyspneic patients with LAM, which may contribute to resting and exercise hypoxemia.

Pathology
Grossly, LAM lungs are enlarged and diffusely cystic, with dilated air spaces as large as several centimeters in diameter. Microscopic examination of the lung reveals foci of smooth muscle-like cell infiltration of the lung parenchyma, airways, lymphatics, and blood vessels associated with areas of thin-walled cystic change. LAM lesions often contain an abundance of lymphatic channels, forming an anastomosing meshwork of slit-like spaces lined by endothelial cells. LAM cells generally expand interstitial spaces without violating tissue planes but have been observed to invade the airways, the pulmonary artery, the diaphragm, aorta, and retroperitoneal fat, to destroy bronchial cartilage and arteriolar walls, and to occlude the lumen of pulmonary arterioles.There are two major cell morphologies in the LAM lesion: small spindle-shaped cells and cuboidal epithelioid cells. LAM cells stain positively for smooth muscle actin, vimentin, desmin, and, often, estrogen and progesterone receptors. The cuboidal cells within LAM lesions also react with a monoclonal antibody called HMB-45, developed against the premelanosomal protein gp100, an enzyme in the melanogenesis pathway. This immunohistochemical marker is very useful diagnostically, because other smooth muscle–predominant lesions in the lung do not react with the antibody. The spindle-shaped cells of the LAM lesion are more frequently proliferating cell nuclear antigen positive than the cuboidal cells, consistent with a proliferative phenotype. Compared with cigar-shaped normal smooth muscle cells, spindle-shaped LAM cells contain less abundant cytoplasm and are less eosinophilic. Estrogen and progesterone receptors are also present in LAM lesions, but not in adjacent normal lung tissue. LAM lesions express lymphatic markers LYVE-1, PROX1, podoplanin and VEGFR-3. The smooth muscle–like cells of AMLs are morphologically and immunohistochemically similar to LAM cells, including reactivity with antibodies directed against actin, desmin, vimentin, and HMB-45 as well as estrogen and progesterone receptors. Unlike the dilated airspaces in emphysema, the cystic spaces found in LAM may be partially lined with hyperplastic type II cells.

Treatment
An FDA-approved drug for treatment of LAM, the mTOR inhibitor sirolimus, is available for stabilization of lung function decline. Lung transplant remains the last resort for patients with advanced disease.

Pneumothorax
Pneumothoraces in LAM patients tend to recur, especially after conservative management such as observation, aspiration or simple tube thoracostomy. Over 65% of LAM patients develop pneumothorax during the course of their illness, averaging 3.5 pneumothoraces in those who have at least one pneumothorax. The LAM Foundation Pleural Consensus Group advocated the use of a pleural symphysis procedure with the first pneumothorax, given the greater than 70% chance of recurrence. Chemical sclerosis, mechanical abrasion, talc poudrage and pleurectomy have been effective in patients with LAM, but mechanical abrasion is preferred for those who may require pulmonary transplantation in the future. About half of LAM patients who have undergone transplant have had a prior pleurodesis procedure, and more than 75% of those had had prior bilateral pleurodesis. Although pleurodesis is not a contraindication to transplantation, it can result in increased perioperative bleeding.

Chylothorax
Chyle does not generally cause pleural inflammation or fibrosis. Small stable chylous effusions rarely require intervention once the LAM diagnosis is made. Shortness of breath may mandate possibly repeated drainage. Sirolimus is effective for chylous effusions and most experts believe it should be used as the first line of therapy. Imaging the source of the leak with heavy T2-weighted MRI or contrast lymphangiography is an advised for refractory effusions. Some leaks are amenable to embolization through catheters threaded from groin lymph nodes into the thoracic duct. Thoracic duct ligation can be considered, but since thoracic effusions sometimes originate from ascites that are siphoned into the chest by the bellows action of the thorax, it is important to rule out an abdominal source before considering this option. Pleural symphysis may be required to prevent nutritional and lymphocyte deficiencies that can result from repeated taps or persistent drainage. Chemical pleurodesis is generally an effective therapy for chylothorax, as is mechanical abrasion and talc poudrage.

Angiomyolipoma
Renal angiomyolipomas (AMLs) may require embolization or cauterization for control of bleeding, a complication that is thought to be more common when tumor diameter exceeds 4 cm. The extent of aneurysmal change may determine bleeding risk. Serial abdominal imaging should be performed to assess AML size at 6- to 12-month intervals, at least until trends in growth are clear. Nephron sparing partial resections may be considered for very large tumors. Nephrectomy is sometimes required for tumors with intravascular extension or other reasons, but is rarely the approach of choice for AMLs that can be managed by less invasive means. Everolimus is approved by the U.S. Food and Drug Administration (FDA) for AML treatment.

Lymphangioleiomyoma
Lymphangioleiomyomatoses are fluid-filled hypodense structures present in the retroperitoneal regions of the abdomen and pelvis in about 30% of LAM patients. They generally do not require intervention. Biopsy or resection can lead to prolonged leakage. mTOR inhibitors are effective at shrinking the size of lymphangioleiomyomatosis, and can lead to total resolution.

Management-other
Estrogen-containing medications can exacerbate LAM and are contraindicated. Agents that antagonize the effects of estrogen have not been proven to be effective for treatment, but no proper trials have been done. A trial of bronchodilators should be considered in LAM patients, because up to 17% to 25% have bronchodilator-responsive airflow obstruction. Oxygen should be administered to maintain oxyhemoglobin saturations of greater than 90% with rest, exercise and sleep. Bone densitometry should be considered in all patients who are immobilized and/or on antiestrogen therapies, and appropriate therapy instituted for osteoporotic patients. Proper attention should be paid to cardiovascular health following natural or induced menopause. Immunizations for pneumococcus and influenza should be kept up to date. Pulmonary rehabilitation seems to be particularly rewarding in young, motivated patients with obstructive lung disease, but studies to assess this interventions effect on exercise tolerance, conditioning and quality of life have not been done.

Medication
Sirolimus is an mTOR inhibitor that stabilizes lung function and improves some measures of life in LAM patients. It is approved by the FDA  for use in LAM, based on the results of the Multicenter International LAM Efficacy and Safety of Sirolimus (MILES) Trial. MILES data supports the use of sirolimus in patients who have abnormal lung function (i.e. FEV1<70% predicted). Whether the benefits of treatment outweigh the risks for asymptomatic LAM  patients with normal lung function is not clear, but some physicians consider treatment for declining patients who are approaching the abnormal range for FEV1. Sirolimus also appears to be effective for the treatment chylous effusions and lymphangioleiomyomatosis. The benefits of sirolimus only persist while treatment continues. The safety of long term therapy has not been studied.Potential side effects from mTOR inhibitors include swelling in the ankles, acne, oral ulcers, dyspepsia, diarrhea, elevation of cholesterol and triglycerides, hypertension and headache. Sirolimus pneumonitis and latent malignancy are more serious concerns, but occur infrequently. Sirolimus inhibits wound healing. It is important to stop therapy with the drug for 1–2 weeks before and after elective procedures that require optimal wound healing. Precautions must be taken to avoid prolonged sun exposure due to increased skin cancer risk.Treatment with another mTOR inhibitor, everolimus, was reported in a small, open-label trial to be associated with improvement in FEV1 and six-minute walk distance. Serum levels of VEGF-D and collagen IV were reduced by treatment. Adverse events were generally consistent with those known to be associated with mTOR inhibitors, although some were serious and included peripheral edema, pneumonia, cardiac failure and Pneumocystis jirovecii infection. Escalating doses of everolimus were used, up to 10 mg per day; higher than what is typically used clinically for LAM.
Serum VEGF-D concentration is useful, predictive and prognostic biomarker. Higher baseline VEGF-D levels predicts more rapid disease progression and a more robust treatment response.
Hormonal approaches to treatment have never been tested in proper trials. In the absence of proven benefit, therapy with progesterone, GnRh agonists (e.g., leuprorelin, goserelin) and tamoxifen are not routinely recommended. Doxycycline had no effect on the rate of lung function decline in a double blind trial.Sirolimus is often effective as first-line management for chylothorax. If chylous leakage or accumulations persist despite treatment, imaging with heavy T2 weighted MRI, MRI lymphangiography or thoracic duct lymphangiography can be considered. Pleural fusion procedures can be considered in refractory cases.

Prognosis
Survival estimates vary, dependent on mode of presentation or ascertainment, and have generally trended upward, probably due to earlier recognition through more widespread use of CT scanning. In a recent population-based cohort survey, median survival was found to be 29 years.  Data from earlier, large case series indicated that 38% to 78% of patients were alive at 8.5 years from the time of disease onset.Patients typically develop progressive airflow obstruction. In a cohort of patients in the United Kingdom, 10 years after symptom onset, 55% of 77 patients were breathless walking on flat ground and 10% were housebound. The average annual rate of decline in FEV1 and DLCO in 275 patients studied in a single pulmonary function laboratory at the NHLBI was 75 ± 9 mL, and 0.69 ± 0.07 mL/min/mm Hg, respectively. In other series from Europe, the rate of decline in FEV1 was considerably higher, estimated at approximately 100 to 120 mL/yr. In the MILES trial, patients in the placebo group lost 134 cc/yr. There was some evidence in these studies that rate of decline in lung function correlates with initial DLCO, with menopausal status and high baseline VEGF-D.
Estimates of median survival vary from 10 to 30 years, depending on whether hospital-based or population-based cohorts are studied.

Epidemiology
LAM is almost completely restricted to women. While lung cysts consistent with LAM are reported in some men with tuberous sclerosis, very few of these men develop symptoms. The prevalence of LAM is estimated using data from registries and patient groups and is between 3.4 and 7.8/million women. The number of new cases each year is between 0.23 and 0.31/million women/year in the US, UK and Switzerland. The variation between countries and between adjacent states in the US, suggest that a significant number of women with LAM remain either undiagnosed or their symptoms are attributed to other diseases. Adult women with tuberous sclerosis are more likely to develop LAM than women without tuberous sclerosis. Cohorts of patients with tuberous sclerosis have been screened for LAM using CT scanning. In a retrospective study of adults with tuberous sclerosis, CT demonstrated lung cysts in 42% of 95 women and 13% of 91 men. In general, lung cysts were larger and more numerous in women than in men. In a further retrospective study of women with TSC who underwent CT scanning to detect LAM, 25% of those in their 20s had lung cysts whereas 80% of women in their 40s were affected, suggesting that the development of LAM is age dependent at least in tuberous sclerosis-related LAM. Although the prevalence of tuberous sclerosis at 1 in 6000 births is much greater than that of LAM, most pulmonary clinics see more cases of sporadic than tuberous sclerosis-LAM: probably due to a combination of low levels of screening for LAM in tuberous sclerosis and in many, the absence of symptoms.Female sex and tuberous sclerosis are the only known risk factors. Although use of supplemental estrogen is not associated with development of LAM, one study suggested that use of estrogen-containing contraceptive pills was associated with earlier onset.It occurs in more than 30% of women with tuberous sclerosis complex (TSC-LAM), a heritable syndrome that is associated with seizures, cognitive impairment and benign tumors in multiple tissues. Most LAM patients who present for medical evaluation have the sporadic form of the disease (S-LAM), however, which is not associated with other manifestations of tuberous sclerosis complex.
Mild cystic changes consistent with LAM have been described in 10–15% of men with TSC, but symptomatic LAM in males is rare. Sporadic LAM occurs exclusively in women, with one published exception to date. Both TSC-LAM and S-LAM are associated with mutations in tuberous sclerosis genes.

Pregnancy
Pregnancy has been reported to exacerbate LAM in some cases. However, the risk has not been rigorously studied </s>