<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 Hurler syndrome and explain in detail? [/INST] Hurler syndrome, also known as mucopolysaccharidosis Type IH (MPS-IH), Hurlers disease, and formerly gargoylism, is a genetic disorder that results in the buildup of large sugar molecules called glycosaminoglycans (GAGs) in lysosomes. The inability to break down these molecules results in a wide variety of symptoms caused by damage to several different organ systems, including but not limited to the nervous system, skeletal system, eyes, and heart.
The underlying mechanism is a deficiency of alpha-L iduronidase, an enzyme responsible for breaking down GAGs.: 544  Without this enzyme, a buildup of dermatan sulfate and heparan sulfate occurs in the body. Symptoms appear during childhood, and early death usually occurs. Other, less severe forms of MPS Type I include Hurler-Scheie Syndrome (MPS-IHS) and Scheie Syndrome (MPS-IS).
Hurler syndrome is classified as a lysosomal storage disease. It is clinically related to Hunter syndrome (MPS II); however, Hunter syndrome is X-linked, while Hurler syndrome is autosomal recessive.

Signs and symptoms
Children with Hurler syndrome may appear normal at birth and develop symptoms over the first years of life. Symptoms vary between patients.One of the first abnormalities that may be detected is coarsening of the facial features; these symptoms can begin at 3–6 months of age. The head can be large with prominent frontal bones. The skull can be elongated. The nose can have a flattened nasal bridge with continuous nasal discharge. The eye sockets may be widely spaced, and the eyes may protrude from the skull. The lips can be large, and affected children may hold their jaws open constantly. Skeletal abnormalities occur by about age 6 months, but may not be clinically obvious until 10–14 months. Patients may experience debilitating spine and hip deformities, carpal tunnel syndrome, and joint stiffness. Patients may be normal height in infancy, but stop growing by the age of 2 years. They may not reach a height of greater than 4 feet.Other early symptoms may include inguinal and umbilical hernias. These may be present at birth, or they may develop within the first months of life. Clouding of the cornea and retinal degeneration may occur within the first year of life, leading to blindness. Enlarged liver and spleen are common. There is no organ dysfunction, but GAG deposition in these organs may lead to a massive increase in size. Patients may also have diarrhea. Aortic valve disease may occur.Airway obstruction is frequent, usually secondary to abnormal cervical vertebrae. Upper and lower respiratory tract infections can be frequent.Developmental delay may become apparent by age 1–2 years, with a maximum functional age of 2–4 years. Progressive deterioration follows. Most children develop limited language capabilities. Death usually occurs by age 10.

Genetics
Children with Hurler Syndrome carry two defective copies of the IDUA gene, which has been mapped to the 4p16.3 site on chromosome 4.  This is the gene which encodes for the protein iduronidase.  As of 2018, more than 201 different mutations in the IDUA gene have been shown to cause MPS I.Because Hurler syndrome is an autosomal recessive disorder, affected persons have two nonworking copies of the gene.  A person born with one normal copy and one defective copy is called a carrier. They will produce less α-L-iduronidase than an individual with two normal copies of the gene.  The reduced production of the enzyme in carriers, however, remains sufficient for normal function; the person should not show any symptoms of the disease.

Mechanisms
The IDUA gene is responsible for encoding an enzyme called alpha-L-iduronidase. Through hydrolysis, alpha-L-iduronidase is responsible for breaking down a molecule called unsulfated alpha-L-iduronic acid. This is a uronic acid found in the GAGs dermatan sulfate and heparan sulfate. The alpha-L-iduronidase enzyme is located in lysosomes. Without sufficient enzymatic function, these GAGs cannot be digested properly.

Diagnosis
Diagnosis often can be made through clinical examination and urine tests (excess mucopolysaccharides are excreted in the urine). Enzyme assays (testing a variety of cells or body fluids in culture for enzyme deficiency) are also used to provide definitive diagnosis of one of the mucopolysaccharidoses. Prenatal diagnosis using amniocentesis and chorionic villus sampling can verify if a fetus either carries a copy of the defective gene or is affected with the disorder. Genetic counseling can help parents who have a family history of the mucopolysaccharidoses determine if they are carrying the mutated gene that causes the disorders.

Classification
All members of the mucopolysaccharidosis family are also lysosomal storage diseases. Mucopolysaccharidosis type I (MPS I) is divided into three subtypes based on severity of symptoms. All three types result the absence or decreased functioning of the same enzyme. MPS-IH (Hurler syndrome) is the most severe of the MPS I subtypes. The other two types are MPS-IS (Scheie syndrome) and MPS-IHS (Hurler-Scheie syndrome).Because of the substantial overlap between Hurler syndrome, Hurler-Scheie syndrome, and Scheie syndrome, some sources consider these terms to be outdated. Instead, MPS I may be divided into "severe" and "attenuated" forms.

Treatment
There is currently no cure for Hurler Syndrome. Enzyme replacement therapy with iduronidase (Aldurazyme) may improve pulmonary function and mobility. It can reduce the amount of carbohydrates being improperly stored in organs. Surgical correction of hand and foot deformities may be necessary. Corneal surgery may help alleviate vision problems.Bone marrow transplantation (BMT) and umbilical cord blood transplantation (UCBT) can be used as treatments for MPS I. BMT from siblings with identical HLA genes and from relatives with similar HLA genes can significantly improve survival, cognitive function, and physical symptoms. Patients can develop graft versus host disease; this is more likely in non-sibling donors. In a 1998 study, children with HLA-identical sibling donors had a 5-year survival of 75%; children with non-sibling donors had a 5-year survival of 53%.Children often lack access to a suitable bone marrow donor. In these cases, UCBT from unrelated donors can increase survival, decrease physical signs of the disease, and improve cognition. Complications from this treatment may include graft versus host disease.

Prognosis
A British study from 2008 found a median estimated life expectancy of 8.7 years for patients with Hurler syndrome. In comparison, the median life expectancy for all forms of MPS type I was 11.6 years. Patients who received successful bone marrow transplants had a 2-year survival rate of 68% and a 10-year survival rate of 64%. Patients who did not receive bone marrow transplants had a significantly reduced lifespan, with a median age of 6.8 years.

Epidemiology
Hurler syndrome has an overall frequency of one per 100,000. Combined, all of the mucopolysaccharidoses have a frequency of approximately one in every 25,000 births in the United States.

Research
Gene therapy
A great deal of interest exists in treating MPS I with gene therapy. In animal models, delivery of the iduronidase gene has been accomplished with retrovirus, adenovirus, adeno-associated virus, and plasmid vectors </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 Hunter syndrome and explain in detail? [/INST] Hunter syndrome, or mucopolysaccharidosis type II (MPS II), is a rare genetic disorder in which large sugar molecules called glycosaminoglycans (or GAGs or mucopolysaccharides) build up in body tissues. It is a form of lysosomal storage disease. Hunter syndrome is caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase (I2S). The lack of this enzyme causes heparan sulfate and dermatan sulfate to accumulate in all body tissues. Hunter syndrome is the only MPS syndrome to exhibit X-linked recessive inheritance.The symptoms of Hunter syndrome are comparable to those of MPS I. It causes abnormalities in many organs, including the skeleton, heart, and respiratory system. In severe cases, this leads to death during the teenaged years. Unlike MPS I, corneal clouding is not associated with this disease.

Signs and symptoms
Hunter syndrome may present with a wide variety of phenotypes. It has traditionally been categorized as either "mild" or "severe" depending on the presence of central nervous system symptoms, but this is an oversimplification. Patients with "attenuated" or "mild" forms of the disease may still have significant health issues. For severely affected patients, the clinical course is relatively predictable; patients will normally die at an early age. For those with milder forms of the disease,  a wider variety of outcomes exist. Many live into their 20s and 30s, but some may have near-normal life expectancies. Cardiac and respiratory abnormalities are the usual cause of death for patients with milder forms of the disease.The symptoms of Hunter syndrome (MPS II) are generally not apparent at birth. Often, the first symptoms may include abdominal hernias, ear infections, runny noses, and colds. As the buildup of GAGs continues throughout the cells of the body, signs of MPS II become more visible. Physical appearances of many children with the syndrome include a distinctive coarseness in their facial features, including a prominent forehead, a nose with a flattened bridge, and an enlarged tongue. They may also have a large head, as well as an enlarged abdomen. For severe cases of MPS II, a diagnosis is often made between the ages of 18 and 36 months. In milder cases, patients present similarly to children with Hurler–Scheie syndrome, and a diagnosis is usually made between the ages of 4 and 8 years.The continued storage of GAGs leads to abnormalities in multiple organ systems. After 18 months, children with severe MPS II may experience developmental decline and progressive loss of skills. The thickening of the heart valves and walls of the heart can result in progressive decline in cardiac function. The walls of the airway may become thickened, as well, leading to obstructive airway disease. As the liver and spleen grow larger with time, the abdomen may become distended, making hernias more noticeable. All major joints may be affected by MPS II, leading to joint stiffness and limited motion. Progressive involvement of the finger and thumb joints results in decreased ability to pick up small objects. The effects on other joints, such as hips and knees, can make  walking normally increasingly difficult. If carpal tunnel syndrome develops, a further decrease in hand function can occur. The bones themselves may be affected, resulting in short stature. In addition, pebbly, ivory-colored skin lesions may be found on the upper arms, legs, and upper back of some people with it. These skin lesions are considered pathognomic for the disease. Finally, the storage of GAGs in the brain can lead to delayed development with subsequent intellectual disability and progressive loss of function.The age at onset of symptoms and the presence or absence of behavioral disturbances are predictive factors of ultimate disease severity in very young patients. Behavioral disturbances can often mimic combinations of symptoms of attention deficit hyperactivity disorder, autism, obsessive compulsive disorder, and/or sensory processing disorder, although the existence and level of symptoms differ in each affected child. They often also include a lack of an appropriate sense of danger, and aggression. The behavioral symptoms of MPS II generally precede neurodegeneration and often increase in severity until the mental handicaps become more pronounced. By the time of death, most children with severe MPS II have severe mental disabilities and are completely dependent on their caretakers.

Genetics
Since Hunter syndrome is an X-linked recessive disorder, it preferentially affects male patients. The IDS gene is located on the X chromosome. The IDS gene encodes for an enzyme called iduronate-2-sulfatase (I2S). A lack of this enzyme leads to a buildup of GAGs, which cause the symptoms of MPS II. Females generally have two X chromosomes, whereas males generally have one X chromosome that they inherit from their mother and one Y chromosome that they inherit from their father.If a female inherits one copy of the mutant allele for MPS II, she will usually have a normal copy of the IDS gene which can compensate for the mutant allele. This is known as being a genetic carrier. A male who inherits a defective X chromosome, though,  usually does not have another X chromosome to compensate for the mutant gene. Thus, a female would need to inherit two mutant genes to develop MPS II, while a male patient only needs to inherit one mutant gene. A female carrier can be affected due to X-inactivation, which is a random process.

Pathophysiology
The human body depends on a vast array of biochemical reactions to support critical functions. One of these functions is the breakdown of large biomolecules. The failure of this process is the underlying problem in Hunter syndrome and related storage disorders.The biochemistry of Hunter syndrome is related to a problem in a part of the connective tissue known as the extracellular matrix, which is made up of a variety of sugars and proteins. It helps to form the architectural framework of the body. The matrix surrounds the cells of the body in an organized meshwork and functions as the glue that holds the cells of the body together. One of the parts of the extracellular matrix is a molecule called a proteoglycan. Like many components of the body, proteoglycans need to be broken down and replaced. When the body breaks down proteoglycans, one of the resulting products is mucopolysaccharides (GAGs).In MPS II, the problem concerns the breakdown of two GAGs: dermatan sulfate and heparan sulfate. The first step in the breakdown of dermatan sulfate and heparan sulfate requires the lysosomal enzyme iduronate-2-sulfatase, or I2S. In people with MPS II, this enzyme is either partially or completely inactive. As a result, GAGs build up in cells throughout the body, particularly in tissues that contain large amounts of dermatan sulfate and heparan sulfate. The rate of GAGs buildup is not the same for all people with MPS II, resulting in a wide spectrum of medical problems.

Diagnosis
The first laboratory screening test for an MPS disorder is a urine test for GAGs. Abnormal values indicate that an MPS disorder is likely. The urine test can occasionally be normal even if the child actually has an MPS disorder. A definitive diagnosis of MPS II is made by measuring I2S activity in serum, white blood cells, or fibroblasts from skin biopsy. In some people with MPS II, analysis of the I2S gene can determine clinical severity.Prenatal diagnosis is routinely available by measuring I2S enzymatic activity in amniotic fluid or in chorionic villus tissue. If a specific mutation is known to run in the family, prenatal molecular genetic testing can be performed. DNA sequencing can reveal if someone is a carrier for the disease.

Treatment
Because of the wide variety of phenotypes, the treatment for this disorder is specifically determined for each patient. Until recently,  no effective therapy for MPS II was available, so palliative care was used. Recent advances, though,  have led to medications that can improve survival and well-being in people with MPS II.

Enzyme replacement therapy
Idursulfase, a purified form of the missing lysosomal enzyme, underwent clinical trial in 2006 and was subsequently approved by the United States Food and Drug Administration as an enzyme replacement treatment for MPS II. Idursulfase beta, another enzyme replacement treatment, was approved in Korea by the Ministry of Food and Drug Safety.
Recent advances in enzyme replacement therapy (ERT) with idursulfase have been proven to improve many signs and symptoms of MPS II, especially if started early in the disease. After administration, it can be transported into cells to break down GAGs, but as the medication cannot cross the blood–brain barrier, it is not expected to lead to cognitive improvement in patients with severe central nervous system symptoms. Even with ERT, treatment of various organ problems from a wide variety of medical specialists is necessary.

Bone-marrow and stem-cell transplantation
Bone-marrow transplantation and hematopoietic stem-cell transplantation (HSCT) have been used as treatments in some studies. While transplantation has provided benefits for many organ systems, it has not been shown to improve the neurological symptoms of the disease. Although HSCT has shown promise in the treatment of other MPS disorders, its results have been unsatisfactory so far in the treatment of MPS II. ERT has been shown to lead to better outcomes in MPS II patients.

Gene editing therapy
In February 2019, medical scientists working with Sangamo Therapeutics, headquartered in Richmond, California, announced the first  "in body" human gene editing therapy to permanently alter DNA - in a patient with MPS II.  Clinical trials by Sangamo involving gene editing using zinc finger nuclease  are ongoing as of February 2019.

Prognosis
Earlier onset of symptoms is linked to a worse prognosis. For children who exhibit symptoms between the ages of 2 and 4, death usually occurs by the age of 15 to 20 years. The cause of death is usually due to neurological complications, obstructive airway disease, and cardiac failure </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 Maroteaux–Lamy syndrome and explain in detail? [/INST] Maroteaux–Lamy syndrome, or Mucopolysaccharidosis Type VI (MPS-VI), is an inherited disease caused by a deficiency in the enzyme arylsulfatase B (ARSB). ASRB is responsible for the breakdown of large sugar molecules called glycosaminoglycans (GAGs, also known as mucopolysaccharides). In particular, ARSB breaks down dermatan sulfate and chondroitin sulfate. Because people with MPS-VI lack the ability to break down these GAGs, these chemicals build up in the lysosomes of cells. MPS-VI is therefore a type of lysosomal storage disease.

Signs and symptoms
Unlike other MPS diseases, children with Maroteaux–Lamy syndrome usually have normal intelligence. They share many of the physical symptoms found in Hurler syndrome. Maroteaux–Lamy syndrome has a variable spectrum of severe symptoms. Neurological complications include clouded corneas, deafness, thickening of the dura (the membrane that surrounds and protects the brain and spinal cord), and pain caused by compressed or traumatized nerves and nerve roots.Signs are revealed early in the affected childs life, with one of the first symptoms often being a significantly prolonged age of learning how to walk. Growth begins normally, but children usually stop growing by age 8. By age 10, children often develop a shortened trunk, crouched stance, and restricted joint movement. In more severe cases, children also develop a protruding abdomen and forward-curving spine. Skeletal changes, particularly in the pelvis, are progressive and limit movement. Many children also have umbilical hernia or inguinal hernias. Nearly all children have some form of heart disease, usually involving the heart valves.

Genetics
This disorder is inherited in an autosomal recessive pattern. People with two working copies of the gene are unaffected. People with one working copy are genetic carriers of Maroteaux-Lamy Syndrome. They have no symptoms but may pass down the defective gene to their children. People with two defective copies will have MPS-VI.

Diagnosis
A urinalysis will show elevated levels of dermatan sulfate in the urine. A blood sample may be taken to assess the level of ASRB activity. Dermal fibroblast cells may also be examined for ASRB activity. Molecular genetic testing can give information about the specific mutation causing MPS-VI, but it is only available at specialized laboratories.

Treatment
The treatment of Maroteaux–Lamy syndrome is symptomatic and individually tailored. A variety of specialists may be needed. In 2005, the FDA approved the orphan drug galsulfase (Naglazyme) for the treatment of Maroteaux–Lamy syndrome. Galsulfase is an enzyme replacement therapy (ERT) in which the missing ASRB enzyme is replaced with a recombinant version.In addition to ERT, various procedures can alleviate the symptoms of MPS-VI. Surgery may be necessary to treat abnormalities such as carpal tunnel syndrome, skeletal malformations, spinal cord compression, hip degeneration, and hernias. Some patients may need heart valve replacement. It may be necessary to remove the tonsils and/or adenoids. Severe tracheomalacia may require surgery. Physical therapy and exercise may improve joint stiffness.Hydrocephalus may be treated by the insertion of a shunt to drain excess cerebrospinal fluid. A corneal transplantation can be performed for individuals with severe corneal clouding. A myringotomy, in which a small incision is made in the eardrum, may be helpful for patients with fluid accumulation in the ears. Hearing aids may be useful, and speech therapy may help children with hearing loss communicate more effectively.Certain medications can be used to treat heart abnormalities, asthma-like episodes, and chronic infections associated with MPS-VI. Anti-inflammatory medications may be of benefit. Respiratory insufficiency may require treatment with supplemental oxygen. Aggressive management of airway secretions is necessary as well </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 Sly syndrome and explain in detail? [/INST] Sly syndrome, also called mucopolysaccharidosis type VII (MPS-VII), is an autosomal recessive lysosomal storage disease caused by a deficiency of the enzyme β-glucuronidase. This enzyme is responsible for breaking down large sugar molecules called glycosaminoglycans (AKA GAGs, or mucopolysaccharides). The inability to break down GAGs leads to a buildup in many tissues and organs of the body. The severity of the disease can vary widely.

Signs and symptoms
The most severe cases of Sly syndrome can result in hydrops fetalis, which results in fetal death or death soon after birth. Some people with Sly syndrome may begin to have symptoms in early childhood. Symptoms can include an enlarged head, fluid buildup in the brain, coarse facial features, enlarged tongue, enlarged liver, enlarged spleen, problems with the heart valves, and abdominal hernias. People with Sly syndrome may also suffer from sleep apnea, frequent lung infections, and problems with vision secondary to cloudy corneas. Sly syndrome causes various musculoskeletal abnormalities that worsen with age. These can include short stature, joint deformities, dysostosis multiplex, spinal stenosis, and carpal tunnel syndrome.While some individuals have developmental delay, others may have normal intelligence. However, the accumulation of GAGs in the brain usually leads to the slowing of development from ages 1–3, and then a loss of previously learned skills until death.

Genetics
The defective gene responsible for Sly syndrome is located on chromosome 7.

Diagnosis
Most people with Sly disease will have elevated levels of GAGs seen in the urine. A confirmatory test is necessary for diagnosis </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 Mucormycosis and explain in detail? [/INST] Mucormycosis, also known as black fungus, is a serious fungal infection that comes under fulminant fungal sinusitis, usually in people who are immunocompromised. It is curable only when diagnosed early. Symptoms depend on where in the body the infection occurs. It most commonly infects the nose, sinuses, eye, and brain resulting in a runny nose, one-sided facial swelling and pain, headache, fever, blurred vision, bulging or displacement of the eye (proptosis), and tissue death. Other forms of disease may infect the lungs, stomach and intestines, and skin.It is spread by spores of molds of the order Mucorales, most often through inhalation, contaminated food, or contamination of open wounds. These fungi are common in soils, decomposing organic matter (such as rotting fruit and vegetables), and animal manure, but usually do not affect people. It is not transmitted between people. Risk factors include diabetes with persistently high blood sugar levels or diabetic ketoacidosis, low white cells, cancer, organ transplant, iron overload, kidney problems, long-term steroids or use of immunosuppressants, and to a lesser extent in HIV/AIDS.Diagnosis is by biopsy and culture, with medical imaging to help determine the extent of disease. It may appear similar to aspergillosis. Treatment is generally with amphotericin B and surgical debridement. Preventive measures include wearing a face mask in dusty areas, avoiding contact with water-damaged buildings, and protecting the skin from exposure to soil such as when gardening or certain outdoor work. It tends to progress rapidly and is fatal in about half of sinus cases and almost all cases of the widespread type.Mucormycosis is usually rare, affecting fewer than 2 people per million people each year in San Francisco, but is now ~80 times more common in India. People of any age may be affected, including premature infants.  The first known case of mucormycosis was possibly the one described by Friedrich Küchenmeister in 1855. The disease has been reported in natural disasters; 2004 Indian Ocean tsunami and the 2011 Missouri tornado. During the COVID-19 pandemic, an association between mucormycosis and COVID-19 has been reported. This association is thought to relate to reduced immune function during the course of the illness and may also be related to glucocorticoid therapy for COVID-19. A rise in cases was particularly noted in India.

Classification
Generally, mucormycosis is classified into five main types according to the part of the body affected. A sixth type has been described as mucormycosis of the kidney, or miscellaneous, i.e., mucormycosis at other sites, although less commonly affected.
Sinuses and brain (rhinocerebral); most common in people with poorly controlled diabetes and in people who have had a kidney transplant.
Lungs (pulmonary); the most common type of mucormycosis in people with cancer and in people who have had an organ transplant or a stem cell transplant.
Stomach and intestine (gastrointestinal); more common among young, premature, and low birth weight infants, who have had antibiotics, surgery, or medications that lower the bodys ability to fight infection.
Skin (cutaneous); after a burn, or other skin injury, in people with leukaemia, poorly controlled diabetes, graft-versus-host disease, HIV and intravenous drug use.
Widespread (disseminated); when the infection spreads to other organs via the blood.

Signs and symptoms
Signs and symptoms of mucormycosis depend on the location in the body of the infection. Infection usually begins in the mouth or nose and enters the central nervous system via the eyes.If the fungal infection begins in the nose or sinus and extends to brain, symptoms and signs may include one-sided eye pain or headache, and may be accompanied by pain in the face, numbness, fever, loss of smell, a blocked nose or runny nose. The person may appear to have sinusitis. The face may look swollen on one side, with rapidly progressing "black lesions" across the nose or upper inside of mouth. One eye may look swollen and bulging, and vision may be blurred.Fever, cough, chest pain, and difficulty breathing, or coughing up blood, can occur when the lungs are involved. A stomach ache, nausea, vomiting and bleeding can occur when the gastrointestinal tract is involved. Affected skin may appear as a dusky reddish tender patch with a darkening centre due to tissue death. There may be an ulcer, and it can be very painful.Invasion of the blood vessels can result in thrombosis and subsequent death of surrounding tissue due to a loss of blood supply. Widespread (disseminated) mucormycosis typically occurs in people who are already sick from other medical conditions, so it can be difficult to know which symptoms are related to mucormycosis. People with disseminated infection in the brain can develop changes in mental status or lapse into a coma.

Cause
Mucormycosis is a fungal infection caused by fungi in the order Mucorales. In most cases it is due to an invasion of the genera Rhizopus and Mucor, common bread molds. Most fatal infections are caused by Rhizopus oryzae. It is less likely due to Lichtheimia, and rarely due to Apophysomyces. Others include Cunninghamella, Mortierella, and Saksenaea.The fungal spores are in the environment, can be found on, for instance, moldy bread and fruit, and are breathed in frequently, but cause disease only in some people. In addition to being breathed in to be deposited in the nose, sinuses and lungs, the spores can also enter the skin via blood or directly through a cut or open wound, or grow in the intestine if eaten. Once deposited, the fungus grows branch-like filaments which invade blood vessels, causing clots to form and surrounding tissues to die. Other reported causes include contaminated wound dressings. Mucormycosis has been reported following the use of elastoplast and the use of tongue depressors for holding in place intravenous catheters. Outbreaks have also been linked to hospital bed sheets, negative-pressure rooms, water leaks, poor ventilation, contaminated medical equipment, and building works.

Risk factors
Predisposing factors for mucormycosis include conditions where people are less able to fight infection, have a low neutrophil count or metabolic acidosis. Risk factors include poorly controlled diabetes mellitus (particularly DKA), organ transplant, iron overload, such cancers as lymphomas, kidney failure, long term corticosteroid and immunosuppressive therapy, liver disease and severe malnutrition. Other risk factors include tuberculosis (TB), deferoxamine and to a lesser extent HIV/AIDS. Cases of mucormycosis in fit and healthy people are rare.Corticosteroids are commonly used in the treatment of COVID-19 and reduce damage caused by the bodys own immune response to the virus. They are immunosuppressant and increase blood sugar levels in both diabetic and non-diabetic patients. It is thought that both these effects may contribute to cases of mucormycosis.

Mechanism
Most people are frequently exposed to Mucorales without developing the disease. Mucormycosis is generally spread by breathing in, eating food contaminated by, or getting spores of molds of the Mucorales type in an open wound. It is not transmitted between people.The precise mechanism by which diabetics become susceptible is unclear. In vivo, a high sugar alone does not permit the growth of the fungus, but acidosis alone does. People with high sugars frequently have higher iron levels, also known to be a risk factor for developing mucormycosis. In people on deferoxamine, the iron removed is captured by siderophores on Rhizopus species, which uses the iron to grow.

Diagnosis
There is no blood test that can confirm the diagnosis. Diagnosis requires identifying the mold in the affected tissue by biopsy and confirming it with a fungal culture. Because the causative fungi occur all around, a culture alone is not decisive. Tests may also include culture and direct detection of the fungus in lung fluid, blood, serum, plasma and urine. Blood tests include a complete blood count to look specifically for neutropenia. Other blood tests include iron levels, blood glucose, bicarbonate, and electrolytes. Endoscopic examination of the nasal passages may be needed.

Imaging
Imaging is often performed, such as CT scan of lungs and sinuses. Signs on chest CT scans, such as nodules, cavities, halo signs, pleural effusion and wedge-shaped shadows, showing invasion of blood vessels, may suggest a fungal infection, but do not confirm mucormycosis. A reverse halo sign in a person with a blood cancer and low neutrophil count, is highly suggestive of mucormycosis. CT scan images of mucormycosis can be useful to distinguish mucormycosis of the orbit and cellulitis of the orbit, but images may appear identical to those of aspergillosis. MRI may also be useful. Currently (when?), MRI with gadolinium contrast is the investigation of choice in rhinoorbito cerebral mucormycosis.

Culture and biopsy
To confirm the diagnosis, biopsy samples can be cultured. Culture from biopsy samples does not always give a result as the organism is very fragile. To precisely identify the species requires an expert. The appearance of the fungus under the microscope will determine the genus and species. The appearances can vary but generally show wide, ribbon-like filaments that generally do not have septa and that—unlike in aspergillosis—branch at right angles, resembling antlers of a moose, which may be seen to be invading blood vessels.

Other
Matrix-assisted laser desorption/ionization may be used to identify the species. A blood sample from an artery may be useful to assess for metabolic acidosis.

Differential diagnosis
Other filamentous fungi may however look similar. It may be difficult to differentiate from aspergillosis. Other possible diagnoses include anthrax, cellulitis, bowel obstruction, ecthyma gangrenosum, lung cancer, clot in lungs, sinusitis, tuberculosis and fusariosis.

Prevention
Preventive measures include wearing a face mask in dusty areas, washing hands, avoiding direct contact with water-damaged buildings, and protecting skin, feet, and hands where there is exposure to soil or manure, such as gardening or certain outdoor work. In high risk groups, such as organ transplant patients, antifungal drugs may be given as a preventative.

Treatment
Treatment involves a combination of antifungal drugs, surgically removing infecting tissue and correcting underlying medical problems, such as diabetic ketoacidosis.

Medication
Once mucormycosis is suspected, amphotericin B at an initial dose of 1 mg is initially given slowly over 10–15 minutes into a vein, then given as a once daily dose according to body weight for the next 14 days. It may need to be continued for longer. Isavuconazole and Posaconazole are alternatives.

Surgery
Surgery can be very drastic, and, in some cases of disease involving the nasal cavity and the brain, removal of infected brain tissue may be required. Removal of the palate, nasal cavity, or eye structures can be very disfiguring. Sometimes more than one operation is required.

Other considerations
The disease must be monitored carefully for any signs of reemergence. Treatment also requires correcting sugar levels and improving neutrophil counts. Hyperbaric oxygen may be considered as an adjunctive therapy, because higher oxygen pressure increases the ability of neutrophils to kill the fungus. The efficacy of this therapy is uncertain.

Prognosis
It tends to progress rapidly and is fatal in about half of sinus cases, two thirds of lung cases, and almost all cases of the widespread type. Skin involvement carries the lowest mortality rate of around 15%. Possible complications of mucormycosis include the partial loss of neurological function, blindness, and clotting of blood vessels in the brain or lung.As treatment usually requires extensive and often disfiguring facial surgery, the effect on life after surviving, particularly sinus and brain involvement, is significant.

Epidemiology
The true incidence and prevalence of mucormycosis may be higher than appears. Mucormycosis is rare, affecting fewer than 1.7 people per million population each year in San Francisco. It is around 80 times more prevalent in India, where it is estimated that there are around 0.14 cases per 1000 population, and where its incidence has been rising. Causative fungi are highly dependent on location. Apophysomyces variabilis has its highest prevalence in Asia and Lichtheimia spp. in Europe. It is the third most common serious fungal infection to infect people, after aspergillosis and candidiasis.Diabetes is the main underlying disease in low and middle-income countries, whereas, blood cancers and organ transplantation are the more common underlying problems in developed countries. As new immunomodulating drugs and diagnostic tests are developed, the statistics for mucormycosis have been changing. In addition, the figures change as new genera and species are identified, and new risk factors reported such as tuberculosis and kidney problems.

COVID-19–associated mucormycosis
During the COVID-19 pandemic in India, the Indian government reported that more than 11,700 people were receiving care for mucormycosis as of 25 May 2021. Many Indian media outlets called it "black fungus" because of the black discoloration of dead and dying tissue the fungus causes. Even before the COVID-19 pandemic, rates of mucormycosis in India were estimated to be about 70 times higher than in the rest of the world. Due to its rapidly growing number of cases some Indian state governments have declared it an epidemic. One treatment was a daily injection for eight weeks of anti-fungal intravenous injection of amphotericin B which was in short supply. The injection could be standard amphotericin B deoxycholate or the liposomal form. The liposomal form cost more but it was considered "safer, more effective and [with] lesser side effects".§ The major obstacle of using antifungal drugs in black fungus is the lack of clinical trials.

Recurrence of mucormycosis during COVID-19 second wave in India
Pre-COVID mucormycosis was a very rare infection, even in India. It is so rare that an ENT (ear, nose, throat) doctor would not witness often  a case during their university time. So, the documentation available on the treatment of mucormycosis is limited. In fact, there used to be a couple of mucormycosis expert ENT surgeons for millions of people pre-pandemic. The sudden rise in mucormycosis cases has left a majority of the ENT doctors with no option but to accept mucormycosis cases, as the expert doctors were very much occupied and the patient would die if left untreated. The majority of the ENT doctors had to manage with minimal or no experience on mucormycosis, this has led to the recurrence of mucormycosis in the patients they treated. When a highly experienced doctor in mucormycosis treats a patient even he cannot guarantee that the individual is completely cured and will not have a relapse of mucormycosis; an inexperienced ENT surgeon will definitely have a high number of patients with recurrence due to which there were many recurrent cases of mucormycosis although it did not get the limelight of media or the Indian Government.

History
The first case of mucormycosis was possibly one described by Friedrich Küchenmeister in 1855. Fürbringer first described the disease in the lungs in 1876. In 1884, Lichtheim established the development of the disease in rabbits and described two species; Mucor corymbifera and Mucor rhizopodiformis, later known as Lichtheimia and Rhizopus, respectively. In 1943, its association with poorly controlled diabetes was reported in three cases with severe sinus, brain and eye involvement.In 1953, Saksenaea vasiformis, found to cause several cases, was isolated from Indian forest soil, and in 1979, P. C. Misra examined soil from an Indian mango orchard, from where they isolated Apophysomyces, later found to be a major cause of mucormycosis. Several species of mucorales have since been described. When cases were reported in the United States in the mid-1950s, the author thought it to be a new disease resulting from the use of antibiotics, ACTH and steroids. Until the latter half of the 20th century, the only available treatment was potassium iodide. In a review of cases involving the lungs diagnosed following flexible bronchoscopy between 1970 and 2000, survival was found to be better in those who received combined surgery and medical treatment, mostly with amphotericin B.

Naming
Arnold Paltauf coined the term "Mycosis Mucorina" in 1885, after describing a case with systemic symptoms involving the sinus, brain and gastrointestinal tract, following which the term "mucormycosis" became popular. "Mucormycosis" is often used interchangeably with "zygomycosis", a term made obsolete following changes in classification of the kingdom Fungi. The former phylum Zygomycota included Mucorales, Entomophthorales, and others. Mucormycosis describes infections caused by fungi of the order Mucorales.

COVID-19–associated mucormycosis
COVID-19 associated mucormycosis cases were reported during first and second(delta) wave, with maximum number of cases in delta wave. There were no cases reported during the Omicron wave. A number of cases of mucormycosis, aspergillosis, and candidiasis, linked to immunosuppressive treatment for COVID-19 were reported during the COVID-19 pandemic in India in 2020 and 2021. One review in early 2021 relating to the association of mucormycosis and COVID-19 reported eight cases of mucormycosis; three from the U.S., two from India, and one case each from Brazil, Italy, and the UK. The most common underlying medical condition was diabetes. Most had been in hospital with severe breathing problems due to COVID-19, had recovered, and developed mucormycosis 10–14 days following treatment for COVID-19. Five had abnormal kidney function tests, three involved the sinus, eye and brain, three the lungs, one the gastrointestinal tract, and in one the disease was widespread. In two of the seven deaths, the diagnosis of mucormycosis was made at postmortem. That three had no traditional risk factors led the authors to question the use of steroids and immunosuppressive drugs.  Although, there were cases without diabetes or use of immunosuppressive drugs.  There were cases reported even in children. In May 2021, the BBC reported increased cases in India. In a review of COVID-19-related eye problems, mucormycosis affecting the eyes was reported to occur up to several weeks following recovery from COVID-19. It was observed that people with COVID-19 were recovering from mucormycosis a bit easily when compared to non-COVID-19 patients. This is because unlike non-COVID-19 patients with severe diabetes, cancer or HIV, the recovery time required for the main cause of immune suppression is temporary.Other countries affected included Pakistan, Nepal, Bangladesh, Russia, Uruguay, Paraguay, Chile, Egypt, Iran, Brazil, Iraq, Mexico, Honduras, Argentina Oman, and Afghanistan. One explanation for why the association has surfaced remarkably in India is high rates of COVID-19 infection and high rates of diabetes. In May 2021, the Indian Council of Medical Research issued guidelines for recognising and treating COVID-19–associated mucormycosis. In India, as of 28 June 2021, over 40,845 people have been confirmed to have mucormycosis, and 3,129 have died. From these cases, 85.5% (34,940) had a history of being infected with SARS-CoV-2 and 52.69% (21,523) were on steroids, also 64.11% (26,187) had diabetes.

Society and culture
The disease has been reported in natural disasters and catastrophes; 2004 Indian Ocean tsunami and the 2011 Missouri tornado.  The first international congress on mucormycosis was held in Chicago in 2010, set up by the Hank Schueuler 41 & 9 Foundation, which was established in 2008 for the research of children with leukaemia and fungal infections. A cluster of infections occurred in the wake of the 2011 Joplin tornado. By July 19, 2011, a total of 18 suspected cases of mucormycosis of the skin had been identified, of which 13 were confirmed </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 Multifocal motor neuropathy and explain in detail? [/INST] Multifocal motor neuropathy (MMN) is a progressively worsening condition where muscles in the extremities gradually weaken. The disorder, a pure motor neuropathy syndrome, is sometimes mistaken for amyotrophic lateral sclerosis (ALS) because of the similarity in the clinical picture, especially if muscle fasciculations are present. MMN is thought to be autoimmune. It was first described in the mid-1980s.Unlike ALS, which affects both upper and lower motor neuron pathways, MMN involves only the lower motor neuron pathway, specifically, the peripheral nerves emanating from the lower motor neurons. Definitive diagnosis is often difficult, and many MMN patients labor for months or years under an ALS diagnosis before finally getting a determination of MMN.
MMN usually involves very little pain; however, muscle cramps, spasms and twitches can cause pain for some people. MMN is not fatal, and does not diminish life expectancy. Many patients, once undergoing treatment, only experience mild symptoms over prolonged periods, though the condition remains slowly progressive. MMN can however, lead to significant disability, with loss of function in hands affecting ability to work and perform everyday tasks, and "foot drop" leading to inability to stand and walk; some patients end up using aids like canes, splints and walkers.

Symptoms
Usually beginning in one or both hands, MMN is characterized by weakness, muscle atrophy, cramping, and often profuse fasciculations (muscle twitching). The symptoms are progressive over long periods, often in a stepwise fashion, but unlike ALS are often treatable.Sensory nerves are usually unaffected.Wrist drop and foot drop (leading to trips and falls) are common symptoms. Other effects can include gradual loss of finger extension, leading to a clawlike appearance. Cold & hot temperatures exacerbate MMN symptoms to such an extent, unlike other neuropathies, that this temperature response is being investigated as a diagnostic tool.

Cause
MMN is thought to be caused by alterations in the immune system, such that certain proteins (antibodies) that would normally protect one from viruses and bacteria begin to attack constituents of peripheral nerves. Antibodies may be directed against "GM-1", a ganglioside found at the Nodes of Ranvier. These antibodies have been detected in at least one-third of MMN patients. More recent studies also suggest that newer tests for antibodies directed against GM-1, as well as a number of related gangliosides, are positive in over 80% of MMN patients. There are increasing reasons to believe these antibodies are the cause of MMN.

Diagnosis
The diagnosis of MMN depends on demonstrating that a patient has a purely motor disorder affecting individual nerves, that there are no upper motor neuron (UMN) signs, that there are no sensory deficits, and that there is evidence of conduction block. These criteria are designed to differentiate the disorder from ALS (purely motor but with UMN signs), the Lewis-Sumner Syndrome variant of Chronic inflammatory demyelinating polyneuropathy (CIDP) (similar to MMN but usually with significant sensory loss), and "vasculitis" (a type of multiple mononeuropathy syndrome  caused by inflammatory damage to the blood vessels in nerves that also causes sensory and motor symptoms).A neurologist is usually needed to determine the diagnosis, which is based on the history and physical examination along with the electrodiagnostic study, which includes nerve conduction studies (NCS) and needle electromyography (EMG). The NCS usually demonstrate conduction block.  This can be done by showing that the nerve signal cannot conduct past a "lesion" at some point along the nerve. For example, if the nerve is blocked in the forearm, an electrical impulse can easily get from the wrist to the hand if the stimulus is placed at the wrist. However, the signal will be blocked from reaching the hand if the stimulus is applied at the elbow </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 Necrobiosis lipoidica and explain in detail? [/INST] Necrobiosis lipoidica is a necrotising skin condition that usually occurs in patients with diabetes mellitus but can also be associated with rheumatoid arthritis. In the former case it may be called necrobiosis lipoidica diabeticorum (NLD). NLD occurs in approximately 0.3% of the diabetic population, with the majority of those affected are women (approximately 3:1 females to males affected).
The severity or control of diabetes in an individual does not affect who will or will not get NLD. Better maintenance of diabetes after being diagnosed with NLD will not change how quickly the NLD will resolve.

Signs and symptoms
NL/NLD most frequently appears on the patients shins, often on both legs, although it may also occur on forearms, hands, trunk, and, rarely, nipple, penis, and surgical sites. The lesions are often asymptomatic but may become tender and ulcerate when injured. The first symptom of NL is often a "bruised" appearance (erythema) that is not necessarily associated with a known injury. The extent to which NL is inherited is unknown.
NLD appears as a hardened, raised area of the skin. The center of the affected area usually has a yellowish tint while the area surrounding it is a dark pink. It is possible for the affected area to spread or turn into an open sore </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 Neonatal withdrawal and explain in detail? [/INST] Neonatal withdrawal or neonatal abstinence syndrome (NAS) or neonatal opioid withdrawal syndrome (NOWS) is a withdrawal syndrome of infants after birth caused by in utero exposure to drugs of dependence, most commonly opioids. Common signs and symptoms include tremors, irritability, vomiting, diarrhea, and fever. NAS is primarily diagnosed with a detailed medication history and scoring systems. First-line treatment should begin with non-medication interventions to support neonate growth, though medication interventions may be used in certain situations.In 2017, approximately 7.3 per 1,000 hospitalized infants in the United States were diagnosed with NOWS. Not all opioid-exposed infants will show clinical signs of withdrawal after birth. Clinical signs range from mild to severe, depending on the quantity and type of substance exposure.The most common form on neonatal withdrawal occurs after in utero exposure, however, iatrogenic withdrawal can also occur after medications are used to treat critically ill infants after they are born.

Signs and symptoms
Drug and alcohol use during pregnancy can lead to many health problems in the fetus and infants, including neonatal abstinence syndrome (NAS). The onset of clinical presentation typically appears within 48 to 72 hours of birth but may take up to 8 days. The signs and symptoms of NAS may be different depending on which substance the mother used.Common signs and symptoms in infants with NAS may include:
Signs due to hyperactivity of the central nervous system:
Tremors (trembling)
Irritability (excessive mood crying)
Sleep problems
High-pitched crying
Muscle tightness
Hyperactive reflexes
Seizures (2% to 11%), notably this clinical sign is controversial given it does not occur in other populations experiencing opioid withdrawal.
Signs due to hyperactivity of stomach and intestines:
Poor feeding and sucking reflex
Vomiting
Diarrhea
Signs due to hyperactivity of autonomous nervous system:
Fever
Sweating
Yawning, stuffy nose, and sneezing
Fast breathing

Causes
The drugs involved can include opioids, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitor (SNRIs), tricyclic antidepressants (TCAs), ethanol, and benzodiazepines. Opioids may be more likely to cause NAS than other substances due to an increase in its usage. Exposure to heroin and methadone claimed to be correlated with a 60 to 80% occurrence of neonatal withdrawal, whereas buprenorphine has been associated with a lower risk. Neonatal abstinence syndrome does not happen in prenatal cocaine exposure. Prematurity and exposure to other drugs may instead be the cause of symptoms.The main mechanistic pathway of prescribed and illicit substance-induced NAS is the hyperactivity of the central and autonomic nervous system and gastrointestinal tract There are several potential mechanisms and pathways that have been proposed, which includes the interaction between the neurotransmitters and lack of adequate expression of opioid receptors. However, the main pathophysiology of this syndrome remains unknown. Most of the opioid induced NAS are due to opioid exposure during pregnancy for pain relief, misuse, or abuse of prescribed opioids or other medication-assisted treatment of opioid use disorder.

Diagnosis
The presence of withdrawal in the neonate can be confirmed by taking a detailed medical history from the mother. The medical history should include physical and mental health problems, prescription and non-prescription medication use, nutritional supplement use, history of alcohol and substance use, childhood adversities, cultural and social beliefs, past traumatic experiences, and infectious diseases such as HIV. Since the medical history of the birth giver may not be available immediately after delivery, some testing needs to be done in the infant to confirm possible exposure. Infants urine, meconium, umbilical cord tissue or hair can be used for testing. The timing of urine sample collection is critical because some drugs may become undetectable after they are metabolized and eliminated from the body. Also, urine test results can only confirm if the fetus was exposed to drugs a few days before birth. Meconium testing can be used to confirm drug exposure in earlier stage of pregnancy, but the collecting process is more difficult. Umbilical cord tissue testing is a relatively new testing method and its accuracy is still controversial. The mothers blood and urine sample should also be collected for drug screening. Chest X-rays can confirm or infirm the presence of heart defects.

Assessment
Depending on what hospital setting the infant is in, different scoring systems are used for assessing the severity and the need for medication treatment in neonatal withdrawal syndrome. One challenge with existing clinical predication tools is that they were designed to assess opiate withdrawal only. The Finnegan Neonatal Abstinence Scoring System (FNASS), or its modified version is the most widely used prediction tool currently in the United States. The FNASS tool focuses on 21 signs of neonatal opioid withdrawal, and a score from 0 to 5 is assigned based on the severity of the symptom. The measurement needs to be repeated every two to four hours. The cutoff for initiation, escalation or de-escalation of medication treatment may be varied. A 2019 review shows that "most institutions using the FNASS have protocols that call for starting or increasing pharmacologic treatment after an infant has received three FNASS scores ≥8 or two scores ≥12." However, there are limitations to the FNASS tool. The repeated measurements may delay treatment and result in increased treatment need. In order to assess some of the signs in the measurement process, infants will be stimulated as opposed to minimizing stimulation recommended in non-medication treatment. A study also indicates that the FNASS tool "has not been validated to show utility in improving outcomes for infants with NAS".

Prevention
Neonatal withdrawal is prevented by the mother abstaining from illicit or prescribed substances. In some cases, a prescribed medication may need to be discontinued during the pregnancy to prevent addiction by the infant. Early prenatal care can identify addictive behaviors in the mother and family system. Referrals to treatment centers is appropriate. Some prescribed medicines should not be stopped without medical supervision, or harm may result. Suddenly stopping a medication can result in a premature birth, fetal complications, and miscarriage. It is recommended that pregnant individuals discuss medication, alcohol, and tobacco use with their health-care provider and to seek assistance to abstain when appropriate. She may need medical attention if she is using drugs non-medically, using drugs not prescribed to them, or using alcohol or tobacco.There are several strategies to prevent the incidence of NAS, those include:
Primary Preventions Follow guidance of 2016 CDC Guideline for Prescribing Opioids for Chronic Pain, which addresses the effectiveness of opioid dosing and treatment, the benefits and risks, and strategies to avoid opioid misuse
Utilize prescription drug monitoring programs (PDMPs) to avoid overuse of opioids
Provision of treatment for opioid use disorder among pregnant women
Non-medicine strategies via minimizing environmental stimuliHowever, there are some barriers to prevention which includes lack of consensus to screening tools to identify substance use while pregnant, stigma, provider bias, and legal consequences.

Treatment
Treatment depends on the drug involved, the infants overall health, abstinence scores (FNASS scoring system), and whether the infant was born full-term or premature. It is recommended to observe and provide supportive measure to infants who are at risk of neonatal abstinence syndrome in the hospital. Infants with severe symptoms may require both supportive measures and medicines. Treatment for NAS may require the infant to stay in the hospital for weeks or months after birth.
The goal of treatment is to minimize negative outcomes and promote normal development. Infants may be prescribed a drug similar to the one the mother used during pregnancy, and slowly decrease the dose over time. This helps wean the infant off the drug and relieves some withdrawal symptoms.

Non-medication treatment
First-line treatment should begin with non-medication interventions to support maturation of the neonate. It is not clear if one type of non-medication therapy is better than another. Common non-medication approaches include physical environment adjustments, swaddling, and breastfeeding.

Adjusting physical environments
Infants with NAS symptoms may have hypersensitivity to light and sounds. Techniques such as darkening the room and eliminating surrounding sounds work to lessen the neonates visual and auditory stimuli.

Swaddling
Swaddling (wrapping an infant firmly in a blanket) can help improve sleep, develop nerves and muscles, decrease stress, and improve motor skills.

Breastfeeding
Infants with NAS may have problems with feeding or slow growth, which require higher-calorie feedings that provide greater nutrition.  It is beneficial to give smaller portions more often throughout the day. Breastfeeding promotes infant attachment and bonding, and is associated with a decreased need for medication, may lessen the severity of NAS, and lead to shorter hospital stays.Most pregnant people who are taking buprenorphine or methadone can safely breastfeed their infant. Both buprenorphine and methadone remain in the human milk at low concentrations, which will reduce signs and symptoms of NAS and likely decrease the treatment time. However, there are exclusions in which it is not safe to breastfeed, such as an HIV-positive mother and a mother with history of street drug use or multiple illicit drug use.

Medication treatment
Although non-medication intervention remains first-line treatment, pharmacological intervention, when appropriate and indicated, can improve signs of neonatal withdrawal.Common medication approaches:

Opioids
Opioids have shown to improve symptoms to a clinically safe level but may not affect length of hospital stay. Its common to slowly taper down to wean the infant off.

Sedatives
Sedatives such as phenobarbital or diazepam are less effective at symptom control compared to opioids but can reduce length of hospital stay.

Clonidine
When compared to opioids, clonidine was just as effective at improving clinical symptoms.Additional medication is used to relieve fever, seizures, and weight loss or dehydration </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 Cystinosis and explain in detail? [/INST] Cystinosis is a lysosomal storage disease characterized by the abnormal accumulation of cystine, the oxidized dimer of the amino acid cysteine. It is a genetic disorder that follows an autosomal recessive inheritance pattern. It is a rare autosomal recessive disorder resulting from accumulation of free cystine in lysosomes, eventually leading to intracellular crystal formation throughout the body. Cystinosis is the most common cause of Fanconi syndrome in the pediatric age group. Fanconi syndrome occurs when the function of cells in renal tubules is impaired, leading to abnormal amounts of carbohydrates and amino acids in the urine, excessive urination, and low blood levels of potassium and phosphates.
Cystinosis was the first documented genetic disease belonging to the group of lysosomal storage disease disorders. Cystinosis is caused by mutations in the CTNS gene that codes for cystinosin, the lysosomal membrane-specific transporter for cystine. Intracellular metabolism of cystine, as it happens with all amino acids, requires its transport across the cell membrane. After degradation of endocytosed protein to cystine within lysosomes, it is normally transported to the cytosol. But if there is a defect in the carrier protein, cystine is accumulated in lysosomes. As cystine is highly insoluble, when its concentration in tissue lysosomes increases, its solubility is immediately exceeded and crystalline precipitates are formed in almost all organs and tissues.However, the progression of the disease is not related to the presence of crystals in target tissues. Although tissue damage might depend on cystine accumulation, the mechanisms of tissue damage are not fully understood. Increased intracellular cystine profoundly disturbs cellular oxidative metabolism and glutathione status, leading to altered mitochondrial energy metabolism, autophagy, and apoptosis.Cystinosis is usually treated with cysteamine, which is prescribed to decrease intralysosomal cystine accumulation. However, the discovery of new pathogenic mechanisms and the development of an animal model of the disease may open possibilities for the development of new treatment modalities to improve long-term prognosis.

Symptoms
There are three distinct types of cystinosis each with slightly different symptoms: nephropathic cystinosis, intermediate cystinosis, and non-nephropathic or ocular cystinosis. Infants affected by nephropathic cystinosis initially exhibit poor growth and particular kidney problems (sometimes called renal Fanconi syndrome). The kidney problems lead to the loss of important minerals, salts, fluids, and other nutrients. The loss of nutrients not only impairs growth, but may result in soft, bowed bones (hypophosphatemic rickets), especially in the legs. The nutrient imbalances in the body lead to increased urination, thirst, dehydration, and abnormally acidic blood (acidosis).

By about age two, cystine crystals may also be present in the cornea. The buildup of these crystals in the eye causes an increased sensitivity to light (photophobia). Without treatment, children with cystinosis are likely to experience complete kidney failure by about age ten. With treatment this may be delayed into the patients teens or 20s. Other signs and symptoms that may occur in patients include muscle deterioration, blindness, inability to swallow, impaired sweating, decreased hair and skin pigmentation, diabetes, and thyroid and nervous system problems.
The signs and symptoms of intermediate cystinosis are the same as nephropathic cystinosis, but they occur at a later age. Intermediate cystinosis typically begins to affect individuals around age twelve to fifteen. Malfunctioning kidneys and corneal crystals are the main initial features of this disorder. If intermediate cystinosis is left untreated, complete kidney failure will occur, but usually not until the late teens to mid twenties.
People with non-nephropathic or ocular cystinosis do not usually experience growth impairment or kidney malfunction. The only symptom is photophobia due to cystine crystals in the cornea.

Crystal morphology and identification
Cystine crystals are hexagonal in shape and are colorless. They are not found often in alkaline urine due to their high solubility. The colorless crystals can be difficult to distinguish from uric acid crystals which are also hexagonal </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 Neurocysticercosis and explain in detail? [/INST] Neurocysticercosis  is a specific form of the infectious parasitic disease cysticercosis that is caused by the infection with Taenia solium, a tapeworm found in pigs. Neurocysticercosis occurs when cysts formed by the infection take hold within the brain, causing neurologic syndromes such as epileptic seizures. It is a common cause of seizures worldwide </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 Neurogenic bladder dysfunction and explain in detail? [/INST] Neurogenic bladder dysfunction, or neurogenic bladder, refers to urinary bladder problems due to disease or injury of the central nervous system or peripheral nerves involved in the control of urination. There are multiple types of neurogenic bladder depending on the underlying cause and the symptoms. Symptoms include overactive bladder, urinary urgency, frequency, incontinence or difficulty passing urine. A range of diseases or conditions can cause neurogenic bladder including spinal cord injury, multiple sclerosis, stroke, brain injury, spina bifida, peripheral nerve damage, Parkinsons disease, or other neurodegenerative diseases. Neurogenic bladder can be diagnosed through a history and physical as well as imaging and more specialized testing. Treatment depends on underlying disease as well as symptoms and can be managed with behavioral changes, medications, surgeries, or other procedures. The symptoms of neurogenic bladder, especially incontinence, can have a significant impact on quality of life.

Classification
There are different types of neurogenic bladder depending on the underlying cause. Many of these types may have similar symptoms.

Uninhibited
Uninhibited bladder is usually due to damage to the brain from a stroke or brain tumor. This can cause reduced sensation of bladder fullness, low capacity bladder and urinary incontinence. Unlike other forms of neurogenic bladder, it does not lead to high bladder pressures that can cause kidney damage.

Spastic
In spastic neurogenic bladder (also known as upper motor neuron or hyper-reflexive bladder), the muscle of the bladder (detrusor) and urethral sphincter do not work together and are usually tightly contracted at the same time. This phenomenon is also called detrusor external sphincter dyssynergia (DESD). This leads to urinary retention with high pressures in the bladder that can damage the kidneys. The bladder volume is usually smaller than normal due to increased muscle tone in the bladder. Spastic neurogenic bladder is usually caused by damage to the spinal cord above the level of the 10th thoracic vertebrae (T10).

Flaccid
In flaccid bladder (also known as lower motor neuron or hypotonic bladder), the muscles of the bladder lose ability to contract normally. This can cause the inability to void urine even if the bladder is full and cause a large bladder capacity. The internal urinary sphincter can contract normally, however urinary incontinence is common. This type of neurogenic bladder is caused by damage to the peripheral nerves that travel from the spinal cord to the bladder.

Mixed
Mixed type of neurogenic bladder can cause a combination of the above presentations. In mixed type A, the bladder muscle is flaccid but the sphincter is overactive. This creates a large, low pressure bladder and inability to void, but does not carry as much risk for kidney damage as a spastic bladder. Mixed type B is characterized by a flaccid external sphincter and a spastic bladder causing problems with incontinence.

Signs and symptoms
Neurogenic bladder can cause a range of urinary symptoms including urinary urgency, urinary incontinence or difficulty urinating (urinary retention).  The first sign of bladder dysfunction may be recurrent urinary tract infections (UTIs).

Complications
Neurogenic bladder can cause hydronephrosis (swelling of a kidney due to a build-up of urine), recurrent urinary tract infections, and recurrent kidney stones which may compromise kidney function. This is especially significant in spastic neurogenic bladder that leads to high bladder pressures. Kidney failure was previously a leading cause of mortality in patients with spinal cord injury but is now dramatically less common due to improvements in bladder management.

Causes
Urine storage and elimination (urination) requires coordination between the bladder emptying muscle (detrusor) and the external sphincter of the bladder. This coordination can be disrupted by damage or diseases of the central nervous system, peripheral nerves or autonomic nervous system. This includes any condition that impairs bladder signaling at any point along the path from the urination center in the brain, spinal cord, peripheral nerves and the bladder.

Central nervous system
Damage to the brain or spinal cord is the most common cause of neurogenic bladder. Damage to the brain can be caused by stroke, brain tumors, multiple sclerosis, Parkinsons disease or other neurodegenerative conditions. Bladder involvement is more likely if the damage is in the area of the pons. Damage to the spinal cord can be caused by traumatic injury, demyelinating disease, syringomyelia, cauda equina syndrome, or spina bifida. Spinal cord compression from herniated disks, tumor, or spinal stenosis can also result in neurogenic bladder.

Peripheral nervous system
Damage to the nerves that travel from the spinal cord to the bladder (peripheral nerves) can cause neurogenic bladder, usually the flaccid type. Nerve damage can be caused by diabetes, alcoholism, and vitamin B12 deficiency. Peripheral nerves can also be damaged as a complication of major surgery of the pelvis, such as for removal of tumors.

Diagnosis
The diagnosis of neurogenic bladder is made based on a complete history and physical examination and may require imaging and specialized studies. History should include information on the onset, duration, triggers, severity, other medical conditions and medications (including anticholinergics, calcium channel blockers, diuretics, sedatives, alpha-adrenergic agonist, alpha 1 antagonists). Urinary symptoms may include frequency, urgency, incontinence or recurrent urinary tract infections (UTIs). Questionnaires can be helpful in quantifying symptom burden. In children it is important to obtain a prenatal and developmental history.Ultrasound imaging can give information on the shape of the bladder, post-void residual volume, and evidence of kidney damage such as kidney size, thickness or ureteral dilation. Trabeculated bladder on ultrasound indicates high risk of developing urinary tract abnormalities such as hydronephrosis and stones. A voiding cystourethrography study uses contrast dye to obtain images of the bladder both when it is full and after urination which can show changes in bladder shape consistent with neurogenic bladder.Urodynamic studies are an important component of the evaluation for neurogenic bladder. Urodynamics refers to the measurement of the pressure-volume relationship in the bladder. The bladder usually stores urine at low pressure and urination can be completed without a dramatic pressure rise. Damage to the kidneys is probable if the pressure rises above 40 cm of water during filling. Bladder pressure can be measured by cystometry, during which the bladder is artificially filled with a catheter and bladder pressures and detrusor activity are monitored. Patterns of involuntary detrusor activity as well as bladder flexibility, or compliance, can be evaluated. The most valuable test to test for detrusor sphincter dyssynergia (DESD) is to perform cystometry simultaneously with external sphincter electromyography (EMG). Uroflowmetry is a less-invasive study that can measure urine flow rate and use it to estimate detrusor strength and sphincter resistance. Urethral pressure monitoring is another less-invasive approach to assessing detrusor sphincter dyssynergia. These studies can be repeated at regular intervals, especially if symptoms worsen or to measure response to therapies.Evaluation of kidney function through blood tests such as serum creatinine should be obtained.Imaging of the pelvis with CT scan or magnetic resonance imaging may be necessary, especially if there is concern for an obstruction such as a tumor. The inside of the bladder can be visualized by cystoscopy.

Treatment
Treatment depends on the type of neurogenic bladder and other medical problems. Treatment strategies include catheterization, medications, surgeries or other procedures. The goals of treatment is to keep bladder pressures in a safe range and eliminate residual urine in the bladder after urination (post-void residual volumes).

Catherization
Emptying the bladder with the use of a catheter is the most common strategy for managing urinary retention from neurogenic bladder. For most patients, this can be accomplished with intermittent catherization which involves no surgery or permanently attached appliances. Intermittent catheterization involves using straight catheters (which are usually disposable or single-use products) several times a day to empty the bladder. This can be done independently or with assistance. For people who are unable to use disposable straight catheters, a Foley catheter allows continuous drainage of urine into a sterile drainage bag that is worn by the patient, but such catheters are associated with higher rates of complications.

Medications
Oxybutynin is a common anti-cholinergic medication used to reduce bladder contractions by blocking M3 muscarinic receptors in the detrusor. Its use is limited by side effects such as dry mouth, constipation and decreased sweating. Tolterodine is a longer acting anticholinergic that may have fewer side effects.For urinary retention, cholinergics (muscarinic agonists) like bethanechol can improve the squeezing ability of the bladder. Alpha blockers can also reduce outlet resistance and allow complete emptying if there is adequate bladder muscle function.

Botulinum Toxin
Botulinum toxin (Botox) can be used through two different approaches </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 Neurosyphilis and explain in detail? [/INST] Neurosyphilis refers to infection of the central nervous system in a patient with syphilis. In the era of modern antibiotics the majority of neurosyphilis cases have been reported in HIV-infected patients. Meningitis is the most common neurological presentation in early syphilis. Tertiary syphilis symptoms are exclusively neurosyphilis, though neurosyphilis may occur at any stage of infection.
To diagnose neurosyphilis, patients undergo a lumbar puncture to obtain cerebrospinal fluid (CSF) for analysis. The CSF is tested for antibodies for specific Treponema pallidum antigens. The preferred test is the VDRL test, which is sometimes supplemented by fluorescent treponemal antibody absorption test (FTA-ABS).Historically, the disease was studied under the Tuskegee study, a notable example of unethical human experimentation. The study was done on approximately 400 African-American men with untreated syphilis who were followed from 1932 to 1972 and compared to approximately 200 men without syphilis. The study began without informed consent of the subjects and was continued by the United States Public Health Service until 1972. The researchers failed to notify and withheld treatment for patients despite knowing penicillin was found as an effective cure for neurosyphilis. After four years of follow up, neurosyphilis was identified in 26.1% of patients vs. 2.5% of controls. After 20 years of followup, 14% showed signs of neurosyphilis and 40% had died from other causes.

Signs and symptoms
The signs and symptoms of neurosyphilis vary with the disease stage of syphilis. The stages of syphilis are categorized as primary, secondary, latent, and tertiary. It is important to note that neurosyphilis may occur at any stage of infection.Meningitis is the most common neurological presentation in early syphilis. It typically occurs in the secondary stage, arising within one year of initial infection. The symptoms are similar to other forms of meningitis. The most common associated with neurosyphilitic meningitis is cranial nerve palsy, especially of the facial nerve.Nearly any part of the eye may be involved. The most common form of ocular syphilis is uveitis. Other forms include episcleritis, vitritis, retinitis, papillitis, retinal detachment, and interstitial keratitis.Meningovascular syphilis usually occurs in late syphilis but may affect those with early disease. It is due to inflammation of the vasculature supplying the central nervous system, that results in ischemia. It typically occurs about 6–7 years after initial infection and it may affect those with early disease. It may present as stroke or spinal cord infarct. Signs and symptoms vary with vascular territory involved. The middle cerebral artery is most often affected.Parenchymal syphilis occurs years to decades after initial infection. It presents with the constellation of symptoms known as tabes dorsalis, because of a degenerative process of the posterior columns of the spinal cord. The constellation includes Argyll Robertson pupil, ataxic wide-based gait, paresthesias, bowel or bladder incontinence, loss of position and vibratory sense, loss of deep pain and temperature sensation, acute episodic gastrointestinal pain, Charcot joints, and general paresis.Gummatous disease may also present with destructive inflammation and space-occupying lesions. It is caused by granulomatous destruction of visceral organs. They most often involve the frontal and parietal lobes of the brain.Movement disorders can be found in a small percentage of individuals with neurosyphilis. The abnormal movements already reported were tremor, chorea, parkinsonism, ataxia, myoclonus, dystonia, athetosis, and ballism.

Neuropsychiatric
Although neurosyphilis is a neurological disease, neuropsychiatric symptoms might appear due to overall damage to the brain. These symptoms can make the diagnosis more difficult and can include symptoms of dementia, mania, psychosis, depression, and delirium:These symptoms are not always present, and when they are, they usually appear in more advanced stages of the disease.

Complications
The Jarisch-Herxheimer reaction is an immune-mediated response to syphilis therapy occurring within 2–24 hours. The exact mechanisms of reaction are unclear, however most likely caused by proinflammatory treponemal lipoproteins that are released from dead and dying organisms following antibiotic treatment.  It is typically characterized by fever, headache, myalgia and possibly intensification of skin rash. It most often occurs in early-stage syphilis (up to 50%–75% of patients with primary and secondary syphilis). It is usually self-limiting and managed with antipyretics and nonsteroidal anti-inflammatory medications.

Risk factors
There are several risk factors: high-risk sexual behavior from unprotected sex and multiple sexual partners. The HIV infection antiretroviral therapy (ART) suppresses HIV transmission, but not syphilis transmission. It may also be associated with recreational drug use.

Pathophysiology
The pathogenesis is not fully known, in part due to fact that the organism is not easily cultured. Within days to weeks after initial infection, Treponema pallidum disseminates via blood and lymphatics. The organism may accumulate in perivascular spaces of nearly any organ, including the central nervous system (CNS). It is unclear why some patients develop CNS infection and others do not. Rarely, organisms may invade any structures of the eye (such as cornea, anterior chamber, vitreous and choroid, and optic nerve) and cause local inflammation and edema. In primary or secondary syphilis, invasion of the meninges may result in lymphocytic and plasma cell infiltration of perivascular spaces (Virchow-Robin spaces). The extension of cellular immune response to the brainstem and spinal cord causes inflammation and necrosis of small meningeal vessels.In tertiary syphilis, reactivation of chronic latent infection may result in meningovascular syphilis, arising from endarteritis obliterans of small, medium, or large arteries supplying the CNS. The parenchymal syphilis, presents as tabes dorsalis and general paresis. Tabes dorsalis thought to be due to irreversible degeneration of nerve fibers in posterior columns of the spinal cord involving the lumbosacral and lower thoracic levels. The general paresis is caused by meningeal vascular inflammation and ependymal granulomatous infiltration may lead to neuronal loss, along with astrocytic and microglial proliferation and damage may preferentially occur in the cerebral cortex, striatum, hypothalamus, and meninges.Concurrent infection of T. pallidum with human immunodeficiency virus (HIV) has been found to affect the course of syphilis. Syphilis can lie dormant for 10 to 20 years before progressing to neurosyphilis, but HIV may accelerate the rate of the progress. Also, infection with HIV has been found to cause penicillin therapy to fail more often. Therefore, neurosyphilis has once again been prevalent in societies with high HIV rates and limited access to penicillin.

Diagnosis
To diagnose neurosyphilis, cerebrospinal fluid (CSF) analysis is required. Lumbar puncture ("spinal tap") is used to acquire CSF. The Venereal Disease Research Laboratory test of the CSF is the preferred test for making a diagnosis of neurosyphilis. A positive test confirms neurosyphilis but a negative result does not rule out neurosyphilis. Due to the low sensitivity of the CSF VDRL, fluorescent treponemal antibody absorption test (FTA-ABS) can be used to supplement VDRL. Reported sensitivity is variable. False-negative antibody test result occurring when antibody concentration is so high that agglutination reaction cannot occur, which is typically seen during secondary stage and can be overcome by diluting test sample 1:10 </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 Neurotrophic keratitis and explain in detail? [/INST] Neurotrophic keratitis (NK) is a degenerative disease of the cornea caused by damage of the trigeminal nerve, which results in impairment of corneal sensitivity, spontaneous corneal epithelium breakdown, poor corneal healing and development of corneal ulceration, melting and perforation. This is because, in addition to the primary sensory role, the nerve also plays a role maintaining the integrity of the cornea by supplying it with trophic  factors and regulating tissue metabolism.Neurotrophic keratitis is classified as a rare disease, with an estimated prevalence of less than 5 in 10,000 people in Europe. It has been recorded that on average, 6% of herpetic keratitis cases may evolve to this disease, with a peak of 12.8% of cases of keratitis due to varicella zoster virus.The diagnosis, and particularly the treatment of neurotrophic keratitis are the most complex and challenging aspects of this disease, as a satisfactory therapeutic approach is not yet available.

Causes
The cornea lacks blood vessels and is among the most densely innervated structures of the human body. Corneal nerves are responsible for maintaining the anatomical and functional integrity of the cornea, conveying tactile, temperature and pain sensations, playing a role in the blink reflex, in wound healing and in the production and secretion of tears.Most corneal nerve fibres are sensory in origin and are derived from the ophthalmic branch of the trigeminal nerve. Congenital or acquired ocular and systemic diseases can determine a lesion at different levels of the trigeminal nerve, which can lead to a reduction (hypoesthesia) or loss (anesthesia) of sensitivity of the cornea.
The most common causes of loss of corneal sensitivity are viral infections (herpes simplex and herpes zoster ophthalmicus), chemical burns, physical injuries, corneal surgery, neurosurgery, chronic use of topical medications, or chronic use of contact lenses.Possible causes also include systemic diseases such as diabetes mellitus, multiple sclerosis or leprosy.
Other, albeit less frequent, potential causes of the disease are: intracranial space-occupying lesions such as neuroma, meningioma and aneurysms, which may compress the trigeminal nerve and reduce corneal sensitivity.Conversely, congenital conditions that may lead to this disorder are very rare.

Diagnosis
NK is diagnosed on the basis of the patients medical history and a careful examination of the eye and surrounding area.With regard to the patients medical history, special attention should be paid to any herpes virus infections and possible surgeries on the cornea, trauma, abuse of anaesthetics or chronic topical treatments, chemical burns or, use of contact lenses. It is also necessary to investigate the possible presence of diabetes or other systemic diseases such as multiple sclerosis.
The clinical examination is usually performed through a series of assessments and tools:
General examination of cranial nerves, to determine the presence of nerve damage.
Eye examinations:Complete eye examination: examination of the eyelids, blink rate, presence of inflammatory reactions and secretions, corneal epithelial alterations.
Corneal sensitivity test: performed by placing a cotton wad or cotton thread in contact with the corneal surface: this only allows to determine whether corneal sensitivity is normal, reduced or absent; or using an esthesiometer that allows to assess corneal sensitivity.
Tear film function test, such as Schirmers test, and tear film break-up time.
Fluorescein eye stain test, which shows any damage to the corneal and conjunctival epithelium

Classification
According to Mackies classification, neurotrophic keratitis can be divided into three stages based on severity:

Stage I: characterized by alterations of the corneal epithelium, which is dry and opaque, with superficial punctate keratopathy and corneal oedema. Long-lasting neurotrophic keratitis may also cause hyperplasia of the epithelium, stromal scarring and neovascularization of the cornea.
Stage II: characterized by development of epithelial defects, often in the area near the centre of the cornea.
Stage III: characterized by ulcers of the cornea accompanied by stromal oedema and/or melting that may result in corneal perforation.

Treatment
Early diagnosis, targeted treatment according to the severity of the disease, and regular monitoring of patients with neurotrophic keratitis are critical to prevent damage progression and the occurrence of corneal ulcers, especially considering that the deterioration of the condition is often poorly symptomatic.The purpose of treatment is to prevent the progression of corneal damage and promote healing of the corneal epithelium. The treatment should always be personalized according to the severity of the disease. Conservative treatment is typically the best option.In stage I, the least serious, treatment consists of the administration of preservative-free artificial tears several times a day in order to lubricate and protect the ocular surface, improving the quality of the epithelium and preventing the possible loss of transparency of the cornea.In stage II, treatment should be aimed at preventing the development of corneal ulcers and promoting the healing of epithelial lesions. In addition to artificial tears, topical antibiotics may also be prescribed to prevent possible infections </s>