<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Crohns disease and can you explain it in depth? [/INST] Crohns disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea (which may be bloody if inflammation is severe), fever, abdominal distension, and weight loss. Complications outside of the gastrointestinal tract may include anemia, skin rashes, arthritis, inflammation of the eye, and fatigue. The skin rashes may be due to infections as well as pyoderma gangrenosum or erythema nodosum. Bowel obstruction may occur as a complication of chronic inflammation, and those with the disease are at greater risk of colon cancer and small bowel cancer.While the precise causes of Crohns disease (CD) are unknown, it is believed to be caused by a combination of environmental, immune, and bacterial factors in genetically susceptible individuals. It results in a chronic inflammatory disorder, in which the bodys immune system defends the gastrointestinal tract, possibly targeting microbial antigens. While Crohns is an immune-related disease, it does not appear to be an autoimmune disease (in that the immune system is not being triggered by the body itself). The exact underlying immune problem is not clear; however, it may be an immunodeficiency state.About half of the overall risk is related to genetics, with more than 70 genes having been found to be involved. Tobacco smokers are twice as likely to develop Crohns disease as nonsmokers. It also often begins after gastroenteritis. Diagnosis is based on a number of findings, including biopsy and appearance of the bowel wall, medical imaging, and description of the disease. Other conditions that can present similarly include irritable bowel syndrome and Behçets disease.There is no known cure for Crohns disease. Treatment options are intended to help with symptoms, maintain remission, and prevent relapse. In those newly diagnosed, a corticosteroid may be used for a brief period of time to rapidly improve symptoms, alongside another medication such as either methotrexate or a thiopurine used to prevent recurrence. Stopping smoking is recommended in people with Crohns disease. One in five people with the disease is admitted to the hospital each year, and half of those with the disease will require surgery for the disease at some point over a ten-year period. While surgery should be used as little as possible, it is necessary to address some abscesses, certain bowel obstructions, and cancers. Checking for bowel cancer via colonoscopy is recommended every few years, starting eight years after the disease has begun.Crohns disease affects about 3.2 per 1,000 people in Europe, North America, and the UK. It is less common in Asia and Africa. It has historically been more common in the developed world. Rates have, however, been increasing, particularly in the developing world, since the 1970s. Inflammatory bowel disease resulted in 47,400 deaths in 2015, and those with Crohns disease have a slightly reduced life expectancy. It tends to start in young adulthood, though it can occur at any age. Males and females are equally affected.

Name
The disease was named after gastroenterologist Burrill Bernard Crohn, who in 1932, together with two colleagues at Mount Sinai Hospital in New York, described a series of patients with inflammation of the terminal ileum of the small intestine, the area most commonly affected by the illness.

Signs and symptoms
Gastrointestinal
Many people with Crohns disease have symptoms for years before the diagnosis. The usual onset is in the teens and twenties, but can occur at any age. Because of the patchy nature of the gastrointestinal disease and the depth of tissue involvement, initial symptoms can be more subtle than those of ulcerative colitis. People with Crohns disease experience chronic recurring periods of flare-ups and remission. The symptoms experienced can change over time as inflammation increases and spreads. Symptoms can also be different depending on which organs are involved. It is generally thought that the presentation of Crohns disease is different for each patient due to the high variability of symptoms, organ involvement, and initial presentation.

Perianal
Perianal discomfort may also be prominent in Crohns disease. Itchiness or pain around the anus may be suggestive of inflammation of the anus, or perianal complications such as anal fissures, fistulae, or abscesses around the anal area. Perianal skin tags are also common in Crohns disease, and may appear with or without the presence of colorectal polyps. Fecal incontinence may accompany perianal Crohns disease.

Intestines
The intestines, especially the colon and terminal ileum, are the most commonly affected areas of the body. Abdominal pain is a common initial symptom of Crohns disease, especially in the lower right abdomen. Flatulence, bloating, and abdominal distension are additional symptoms and may also add to the intestinal discomfort. Pain is often accompanied by diarrhea, which may or may not be bloody. Inflammation in different areas of the intestinal tract can affect the quality of the feces. Ileitis typically results in large-volume, watery feces, while colitis may result in a smaller volume of feces of higher frequency. Fecal consistency may range from solid to watery. In severe cases, an individual may have more than 20 bowel movements per day, and may need to awaken at night to defecate. Visible bleeding in the feces is less common in Crohns disease than in ulcerative colitis, but is not unusual. Bloody bowel movements are usually intermittent, and may be bright red, dark maroon, or even black in color. The color of bloody stool depends on the location of the bleed. In severe Crohns colitis, bleeding may be copious.

Stomach and Esophagus
The stomach is rarely the sole or predominant site of CD. To date there are only a few documented case reports of adults with isolated gastric CD and no reports in the pediatric population. Isolated stomach involvement is very unusual presentation accounting for less than 0.07% of all gastrointestinal CD. Rarely, the esophagus and stomach may be involved in Crohns disease. These can cause symptoms including difficulty swallowing (dysphagia), upper abdominal pain, and vomiting.

Oropharynx (Mouth)
The mouth may be affected by recurrent sores (aphthous ulcers). Recurrent aphthous ulcers are common; however, it is not clear whether this is due to Crohns disease or simply that they are common in the general population. Other findings may include diffuse or nodular swelling of the mouth, a cobblestone appearance inside the mouth, granulomatous ulcers, or pyostomatitis vegetans. Medications that are commonly prescribed to treat CD, such as anti-inflammatory and sulfa-containing drugs, may cause lichenoid drug reactions in the mouth. Fungal infection such as candidiasis is also common due to the immunosuppression required in the treatment of the disease. Signs of anemia such as pallor and angular cheilitis or glossitis are also common due to nutritional malabsorption.People with Crohns disease are also susceptible to Angular Stomatitis, an inflammation of the corners of the mouth, and Pyostomatitis Vegetans.

Systemic
Like many other chronic, inflammatory diseases, Crohns disease can cause a variety of systemic symptoms. Among children, growth failure is common. Many children are first diagnosed with Crohns disease based on inability to maintain growth. As it may manifest at the time of the growth spurt in puberty, up to 30% of children with Crohns disease may have retardation of growth. Fever may also be present, though fevers greater than 38.5 °C (101.3 °F) are uncommon unless there is a complication such as an abscess. Among older individuals, Crohns disease may manifest as weight loss, usually related to decreased food intake, since individuals with intestinal symptoms from Crohns disease often feel better when they do not eat and might lose their appetite. People with extensive small intestine disease may also have malabsorption of carbohydrates or lipids, which can further exacerbate weight loss.

Extraintestinal
Crohns disease can affect many organ systems beyond the gastrointestinal tract.
Visual
Inflammation of the interior portion of the eye, known as uveitis, can cause blurred vision and eye pain, especially when exposed to light (photophobia). Uveitis can lead to loss of vision if untreated.Inflammation may also involve the white part of the eye (sclera) or the overlying connective tissue (episclera), which causes conditions called scleritis and episcleritis, respectively.Other very rare ophthalmological manifestations include: conjunctivitis, glaucoma, and retinal vascular disease.Gallbladder and Liver
Crohns disease that affects the ileum may result in an increased risk of gallstones. This is due to a decrease in bile acid resorption in the ileum, and the bile gets excreted in the stool. As a result, the cholesterol/bile ratio increases in the gallbladder, resulting in an increased risk for gallstones. Although the association is greater in the context of ulcerative colitis, Crohns disease may also be associated with primary sclerosing cholangitis, a type of inflammation of the bile ducts.Liver involvement of Crohns disease can include cirrhosis and steatosis. Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are relatively common and can slowly progress to end-stage liver disease. NAFLD sensitizes the liver to injury and increases the risk of developing acute or chronic liver failure following another liver injury.Other rare hepatobiliary manifestations of Crohns disease include: cholangiocarcinoma, granulomatous hepatitis, cholelithiasis, autoimmune hepatitis, hepatic abscess, and pericholangitis.Renal and Urological
Nephrolithiasis, obstructive uropathy, and fistulization of the urinary tract directly result from the underlying disease process. Nephrolithiasis is due to calcium oxalate or uric acid stones. Calcium oxalate is due to hyperoxaluria typically associated with either distal ileal CD or ileal resection. Oxalate absorption increases in the presence of unabsorbed fatty acids in the colon. The fatty acids compete with oxalate to bind calcium, displacing the oxalate, which can then be absorbed as unbound sodium oxalate across colonocytes and excreted into the urine. Because sodium oxalate only is absorbed in the colon, calcium-oxalate stones form only in patients with an intact colon. Patients with an ileostomy are prone to formation of uric-acid stones because of frequent dehydration. The sudden onset of severe abdominal, back, or flank pain in patients with IBD, particularly if different from the usual discomfort, should lead to inclusion of a renal stone in the differential diagnosis.Urological manifestations in patients with IBD may include ureteral calculi, enterovesical fistula, perivesical infection, perinephric abscess, and obstructive uropathy with hydronephrosis. Ureteral compression is associated with retroperitoneal extension of the phlegmonous inflammatory process involving the terminal ileum and cecum, and may result in hydronephrosis severe enough to cause hypertension.Immune complex glomerulonephritis presenting with proteinuria and hematuria has been described in children and adults with CD or UC. Diagnosis is by renal biopsy, and treatment parallels the underlying IBD.Amyloidosis (see endocrinological involvement) secondary to Crohns disease has been described and is known to affect the kidneys.Pancreatic
Pancreatitis may be associated with both UC and CD. The most common cause is iatrogenic and involves sensitivity to medications used to treat IBD (3% of patients), including sulfasalazine, mesalamine, 6-mercaptopurine, and azathioprine. Pancreatitis may present as symptomatic (in 2%) or more commonly asymptomatic (8–21%) disease in adults with IBD.Cardiovascular and Circulatory
Children and adults with IBD have been rarely (<1%) reported developing pleuropericarditis either at initial presentation or during active or quiescent disease. The pathogenesis of pleuropericarditis is unknown, although certain medications (e.g., sulfasalazine and mesalamine derivatives) have been implicated in some cases. The clinical presentation may include chest pain, dyspnea, or in severe cases pericardial tamponade requiring rapid drainage. Nonsteroidal anti-inflammatory drugs have been used as therapy, although this should be weighed against the hypothetical risk of exacerbating the underlying IBD.In rare cases, cardiomyopathy, endocarditis, and myocarditis have been described.Crohns disease also increases the risk of blood clots; painful swelling of the lower legs can be a sign of deep venous thrombosis, while difficulty breathing may be a result of pulmonary embolism.
Respiratory
Laryngeal involvement in inflammatory bowel disease is extremely rare. Only 12 cases of laryngeal involvement in Crohn disease have been reported until now. Moreover, only one case of laryngeal manifestations in ulcerative colitis has been reported so far. 9 patients complained of difficulty in breathing due to edema and ulceration from the larynx to the hypopharynx Hoarseness, sore throat, and odynophagia are other symptoms of laryngeal involvement of Crohns disease.Considering extraintestinal manifestations of CD, those involving the lung are relatively rare. However, there is a wide array of lung manifestations, ranging from subclinical alterations, airway diseases and lung parenchymal diseases to pleural diseases and drug-related diseases. The most frequent manifestation is bronchial inflammation and suppuration with or without bronchiectasis. There are a number of mechanisms by which the lungs may become involved in CD. These include the same embryological origin of the lung and gastrointestinal tract by ancestral intestine, similar immune systems in the pulmonary and intestinal mucosa, the presence of circulating immune complexes and auto-antibodies, and the adverse pulmonary effects of some drugs. A complete list of known pulmonary manifestations include: Fibrosing alveolitis, Pulmonary vasculitis, Apical fibrosis, Bronchiectasis, Bronchitis, Bronchiolitis, Tracheal stenosis, Granulomatous lung disease, and Abnormal pulmonary function.Musculoskeletal
Crohns disease is associated with a type of rheumatologic disease known as seronegative spondyloarthropathy. This group of diseases is characterized by inflammation of one or more joints (arthritis) or muscle insertions (enthesitis). The arthritis in Crohns disease can be divided into two types. The first type affects larger weight-bearing joints such as the knee (most common), hips, shoulders, wrists, or elbows. The second type symmetrically involves five or more of the small joints of the hands and feet. The arthritis may also involve the spine, leading to ankylosing spondylitis if the entire spine is involved, or simply sacroiliitis if only the sacroiliac joint is involved. The symptoms of arthritis include painful, warm, swollen, stiff joints, and loss of joint mobility or function.Crohns disease increases the risk of osteoporosis or thinning of the bones. Individuals with osteoporosis are at increased risk of bone fractures.

Dermatological
Crohns disease may also involve the skin, blood, and endocrine system. Erythema nodosum is the most common type of skin problem, occurring in around 8% of people with Crohns disease, producing raised, tender red nodules usually appearing on the shins. Erythema nodosum is due to inflammation of the underlying subcutaneous tissue, and is characterized by septal panniculitis.Pyoderma gangrenosum is a less common skin problem, occurring in under 2%, and is typically a painful ulcerating nodule.Clubbing, a deformity of the ends of the fingers, may also be a result of Crohns disease.
Other very rare dermatological manifestations include: Pyostomatitis vegetans, Psoriasis, Erythema multiforme, Epidermolysis bullosa acquista (described in a case report), and Metastatic CD (the spread of Crohns inflammation to the skin). It is unknown if Sweets Syndrome is connected to Crohns disease.Neurological
Crohns disease can also cause neurological complications (reportedly in up to 15%). The most common of these are seizures, stroke, myopathy, peripheral neuropathy, headache, and depression.Central and peripheral neurological disorders are described in patients with IBD and include peripheral neuropathies, myopathies, focal central nervous system defects, convulsions, confusional episodes, meningitis, syncope, optic neuritis, and sensorineural loss. Autoimmune mechanisms are proposed for involvement with IBD. Nutritional deficiencies associated with neurological manifestations, such as vitamin B12 deficiency, should be investigated. Spinal abscess has been reported in both a child and an adult with initial complaints of severe back pain due to extension of a psoas abscess from the epidural space to the subarachnoid space.Psychiatric and psychological
Crohns disease is linked to many psychological disorders, including depression and anxiety, denial of your disease, the need for dependence or dependent behaviors, feeling overwhelmed, and having a poor self-image.Endocrinological or Hematological
Autoimmune hemolytic anemia, a condition in which the immune system attacks the red blood cells, is also more common in Crohns disease and may cause fatigue, a pale appearance, and other symptoms common in anemia.
Secondary amyloidosis (AA) is another rare but serious complication of inflammatory bowel disease (IBD), generally seen in Crohns disease. At least 1% of patients with Crohns disease develop amyloidosis. In the literature, the time lapse between the onset of Crohns disease and the diagnosis of amyloidosis has been reported to range from one to 21 years.
Leukocytosis and thrombocytopenia are usually due to immunosuppressant treatments or sulfasalazine. Plasma erythropoietin levels often are lower in patients with IBD than expected, in conjunction with severe anemia.Thrombocytosis and thromboembolic events resulting from a hypercoagulable state in patients with IBD can lead to pulmonary embolism or thrombosis elsewhere in the body. Thrombosis has been reported in 1.8% of patients with UC and 3.1% of patients with CD. Thromboembolism and thrombosis are less frequently reported among pediatric patients, with 3 patients with UC and 1 with CD described in case reports.In rare cases, hypercoagulation disorders and portal vein thrombosis have been described.Malnutrition Symptoms
People with Crohns disease may develop anemia due to vitamin B12, folate, iron deficiency, or due to anemia of chronic disease. The most common is iron deficiency anemia from chronic blood loss, reduced dietary intake, and persistent inflammation leading to increased hepcidin levels, restricting iron absorption in the duodenum. As Crohns disease most commonly affects the terminal ileum where the vitamin B12/intrinsic factor complex is absorbed, B12 deficiency may be seen. This is particularly common after surgery to remove the ileum. Involvement of the duodenum and jejunum can impair the absorption of many other nutrients including folate. People with Crohns often also have issues with small bowel bacterial overgrowth syndrome, which can produce micronutrient deficiencies.

Complications
Intestinal Damage
Crohns disease can lead to several mechanical complications within the intestines, including obstruction, fistulae, and abscesses. Obstruction typically occurs from strictures or adhesions that narrow the lumen, blocking the passage of the intestinal contents. A fistula can develop between two loops of bowel, between the bowel and bladder, between the bowel and vagina, and between the bowel and skin. Abscesses are walled-off concentrations of infection, which can occur in the abdomen or in the perianal area. Crohns is responsible for 10% of vesicoenteric fistulae, and is the most common cause of ileovesical fistulae.Symptoms caused by intestinal stenosis, or the tightening and narrowing of the bowel, are also common in Crohns disease. Abdominal pain is often most severe in areas of the bowel with stenosis. Persistent vomiting and nausea may indicate stenosis from small bowel obstruction or disease involving the stomach, pylorus, or duodenum.Intestinal granulomas are a walled-off portions of the intestine by macrophages in order to isolate infections. Granuloma formation is more often seen in younger patients, and mainly in the severe, active penetrating disease. Granuloma is considered the hallmark of microscopic diagnosis in Crohns disease (CD), but granulomas can be detected in only 21-60% of CD patients.

Cancer
Crohns disease also increases the risk of cancer in the area of inflammation. For example, individuals with Crohns disease involving the small bowel are at higher risk for small intestinal cancer. Similarly, people with Crohns colitis have a relative risk of 5.6 for developing colon cancer. Screening for colon cancer with colonoscopy is recommended for anyone who has had Crohns colitis for at least eight years.Some studies suggest there is a role for chemoprotection in the prevention of colorectal cancer in Crohns involving the colon; two agents have been suggested, folate and mesalamine preparations. Also, immunomodulators and biologic agents used to treat this disease may promote developing extra-intestinal cancers.Some cancers, such as Acute Myelocytic Leukaemia have been described in cases of Crohns disease. Hepatosplenic T-cell lymphoma (HSTCL) is a rare, lethal disease generally seen in young male patients with inflammatory bowel disease. TNF-α Inhibitor treatments (infliximab, adalimumab, certolizumab, natalizumab, and etanercept) are thought to be the cause of this rare disease.

Major complications
Major complications of Crohns disease include bowel obstruction, abscesses, free perforation, and hemorrhage, which in rare cases may be fatal.

Other Complications
Individuals with Crohns disease are at risk of malnutrition for many reasons, including decreased food intake and malabsorption. The risk increases following resection of the small bowel. Such individuals may require oral supplements to increase their caloric intake, or in severe cases, total parenteral nutrition (TPN). Most people with moderate or severe Crohns disease are referred to a dietitian for assistance in nutrition.Small intestinal bacterial overgrowth (SIBO) is characterized by excessive proliferation of colonic bacterial species in the small bowel. Potential causes of SIBO include fistulae, strictures, or motility disturbances. Hence, patients with Crohns disease are especially predisposed to develop SIBO. As result, CD patients may experience malabsorption and report symptoms such as weight loss, watery diarrhea, meteorism, flatulence, and abdominal pain, mimicking acute flare in these patients.

Pregnancy
Crohns disease can be problematic during pregnancy, and some medications can cause adverse outcomes for the fetus or mother. Consultation with an obstetrician and gastroenterologist about Crohns disease and all medications facilitates preventive measures. In some cases, remission occurs during pregnancy. Certain medications can also lower sperm count or otherwise adversely affect a mans fertility.

Ostomy-related complications
Common complications of an ostomy (a common surgery in Crohns disease) are: Mucosal edema, Peristomal dermatitis, Retraction, Ostomy prolapse, Mucosal/skin detachment, Hematoma, Necrosis, Parastomal hernia, and Stenosis.

Etiology
The etiology of Crohns disease is unknown. Many theories have been disputed, with four main theories hypothesized to be the primary mechanism of Crohns disease. In autoimmune diseases, antibodies and T lymphocytes are the primary mode of inflammation. These cells and bodies are part of the adaptive immune system, or the part of the immune system that learns to fight foreign bodies when first identified. Autoinflammatory diseases are diseases where the innate immune system, or the immune system we are genetically coded with, is designed to attack our own cells. Crohns disease likely has involvement of both the adaptive and innate immune systems.

Autoinflammatory theory
Crohns disease can be described as a multifactorial autoinflammatory disease. The etiopathogenesis of Crohns disease is still unknown. In any event, a loss of the regulatory capacity of the immune apparatus would be implicated in the onset of the disease. In this respect interestingly enough, as for Blaus disease (a monogenic autoinflammatory disease), the NOD2 gene mutations have been linked to Crohns disease. However, in Crohns disease, NOD2 mutations act as a risk factor, being more common among Crohns disease patients than the background population, while in Blaus disease NOD2 mutations are linked directly to this syndrome, as it is an autosomal-dominant disease. All this new knowledge in the pathogenesis of Crohns disease allows us to put this multifactorial disease in the group of autoinflammatory syndromes.Some examples of how the innate immune system affects bowel inflammation have been described. A meta-analysis of CD genome-wide association studies revealed 71 distinct CD-susceptibility loci. Interestingly, three very important CD-susceptibility genes (the intracellular pathogen-recognition receptor, NOD2; the autophagy-related 16-like 1, ATG16L1 and the immunity-related GTPase M, IRGM) are involved in innate immune responses against gut microbiota, while one (the X-box binding protein 1) is involved in regulation of the [adaptive] immune pathway via MHC class II, resulting in autoinflammatory inflammation. Studies have also found that increased ILC3 can overexpress major histocompatibility complex (MHC) II. MHC class II can induce CD4+ T cell apoptosis, thus avoiding the T cell response to normal bowel micro bacteria. Further studies of IBD patients compared with non-IBD patients found that the expression of MHC II by ILC3 was significantly reduced in IBD patients, thus causing an immune reaction against intestinal cells or normal bowel bacteria and damaging the intestines. This can also make the intestines more susceptible to environmental factors, such as food or bacteria.The thinking is, that because Crohns disease has strong innate immune system involvement and has NOD2 mutations as a predisposition, Crohns disease is more likely an autoinflammatory disease than an autoimmune disease.

Immunodeficiency theory
A substantial body of data has emerged in recent years to suggest that the primary defect in Crohns disease is actually one of relative immunodeficiency. This view has been bolstered recently by novel immunological and clinical studies that have confirmed gross aberrations in this early response, consistent with subsequent genetic studies that highlighted molecules important for innate immune function. The suggestion therefore is that Crohns pathogenesis actually results from partial immunodeficiency, a theory that coincides with the frequent recognition of a virtually identical, non-infectious inflammatory bowel disease arising in patients with congenital monogenic disorders impairing phagocyte function.

Causes
While the exact cause or causes are unknown, Crohns disease seems to be due to a combination of environmental factors and genetic predisposition. Crohns is the first genetically complex disease in which the relationship between genetic risk factors and the immune system is understood in considerable detail. Each individual risk mutation makes a small contribution to the overall risk of Crohns (approximately 1:200). The genetic data, and direct assessment of immunity, indicates a malfunction in the innate immune system. In this view, the chronic inflammation of Crohns is caused when the adaptive immune system tries to compensate for a deficient innate immune system.

Genetics
Crohns has a genetic component. Because of this, siblings of known people with Crohns are 30 times more likely to develop Crohns than the general population.The first mutation found to be associated with Crohns was a frameshift in the NOD2 gene (also known as the CARD15 gene), followed by the discovery of point mutations. Over 30 genes have been associated with Crohns; a biological function is known for most of them. For example, one association is with mutations in the XBP1 gene, which is involved in the unfolded protein response pathway of the endoplasmic reticulum. The gene variants of NOD2/CARD15 seem to be related with small-bowel involvement. Other well documented genes which increase the risk of developing Crohns disease are ATG16L1, IL23R, IRGM, and SLC11A1.
There is considerable overlap between susceptibility loci for IBD and mycobacterial infections. Genome-wide association studies have shown that Crohns disease is genetically linked to coeliac disease.Crohns has been linked to the gene LRRK2 with one variant potentially increasing the risk of developing the disease by 70%, while another lowers it by 25%. The gene is responsible for making a protein, which collects and eliminates waste product in cells, and is also associated with Parkinsons disease.

Immune system
There was a prevailing view that Crohns disease is a primary T cell autoimmune disorder; however, a newer theory hypothesizes that Crohns results from an impaired innate immunity. The later hypothesis describes impaired cytokine secretion by macrophages, which contributes to impaired innate immunity and leads to a sustained microbial-induced inflammatory response in the colon, where the bacterial load is high. Another theory is that the inflammation of Crohns was caused by an overactive Th1 and Th17 cytokine response.In 2007, the ATG16L1 gene was implicated in Crohns disease, which may induce autophagy and hinder the bodys ability to attack invasive bacteria. Another study theorized that the human immune system traditionally evolved with the presence of parasites inside the body and that the lack thereof due to modern hygiene standards has weakened the immune system. Test subjects were reintroduced to harmless parasites, with positive responses.

Microbes
It is hypothesized that maintenance of commensal microorganism growth in the GI tract is dysregulated, either as a result or cause of immune dysregulation.There is an apparent connection between Crohns disease, Mycobacterium, other pathogenic bacteria, and genetic markers. A number of studies have suggested a causal role for Mycobacterium avium subspecies paratuberculosis (MAP), which causes a similar disease, Johnes disease, in cattle. In many individuals, genetic factors predispose individuals to Mycobacterium avium subsp. paratuberculosis infection. This bacterium may produce certain compounds containing mannose, which may protect both itself and various other bacteria from phagocytosis, thereby possibly causing a variety of secondary infections.NOD2 is a gene involved in Crohns genetic susceptibility. It is associated with macrophages diminished ability to phagocytize MAP. This same gene may reduce innate and adaptive immunity in gastrointestinal tissue and impair the ability to resist infection by the MAP bacterium. Macrophages that ingest the MAP bacterium are associated with high production of TNF-α.Other studies have linked specific strains of enteroadherent E. coli to the disease. Adherent-invasive Escherichia coli (AIEC), more common in people with CD, have the ability to make strong biofilms compared to non-AIEC strains correlating with high adhesion and invasion indices of neutrophils and the ability to block autophagy at the autolysosomal step, which allows for intracellular survival of the bacteria and induction of inflammation. Inflammation drives the proliferation of AIEC and dysbiosis in the ileum, irrespective of genotype. AIEC strains replicate extensively inside macrophages inducing the secretion of very large amounts of TNF-α.Mouse studies have suggested some symptoms of Crohns disease, ulcerative colitis, and irritable bowel syndrome have the same underlying cause. Biopsy samples taken from the colons of all three patient groups were found to produce elevated levels of a serine protease. Experimental introduction of the serine protease into mice has been found to produce widespread pain associated with irritable bowel syndrome, as well as colitis, which is associated with all three diseases. Regional and temporal variations in those illnesses follow those associated with infection with the protozoan Blastocystis.The "cold-chain" hypothesis is that psychrotrophic bacteria such as Yersinia and Listeria species contribute to the disease. A statistical correlation was found between the advent of the use of refrigeration in the United States and various parts of Europe and the rise of the disease.There is also a tentative association between Candida colonization and Crohns disease.Still, these relationships between specific pathogens and Crohns disease remain unclear.

Environmental factors
The increased incidence of Crohns in the industrialized world indicates an environmental component. Crohns is associated with an increased intake of animal protein, milk protein, and an increased ratio of omega-6 to omega-3 polyunsaturated fatty acids.
Those who consume vegetable proteins appear to have a lower incidence of Crohns disease. Consumption of fish protein has no association.Smoking increases the risk of the return of active disease (flares). The introduction of hormonal contraception in the United States in the 1960s is associated with a dramatic increase in incidence, and one hypothesis is that these drugs work on the digestive system in ways similar to smoking. Isotretinoin is associated with Crohns.Although stress is sometimes claimed to exacerbate Crohns disease, there is no concrete evidence to support such claim. Dietary microparticles, such as those found in toothpaste, have been studied as they produce effects on immunity, but they were not consumed in greater amounts in patients with Crohns. The use of doxycycline has also been associated with increased risk of developing inflammatory bowel diseases. In one large retrospective study, patients who were prescribed doxycycline for their acne had a 2.25-fold greater risk of developing Crohns disease.

Pathophysiology
During a colonoscopy, biopsies of the colon are often taken to confirm the diagnosis. Certain characteristic features of the pathology seen point toward Crohns disease; it shows a transmural pattern of inflammation, meaning the inflammation may span the entire depth of the intestinal wall. Ulceration is an outcome seen in highly active disease. There is usually an abrupt transition between unaffected tissue and the ulcer—a characteristic sign known as skip lesions. Under a microscope, biopsies of the affected colon may show mucosal inflammation, characterized by focal infiltration of neutrophils, a type of inflammatory cell, into the epithelium. This typically occurs in the area overlying lymphoid aggregates. These neutrophils, along with mononuclear cells, may infiltrate the crypts, leading to inflammation (crypititis) or abscess (crypt abscess).Granulomas, aggregates of macrophage derivatives known as giant cells, are found in 50% of cases and are most specific for Crohns disease. The granulomas of Crohns disease do not show "caseation", a cheese-like appearance on microscopic examination characteristic of granulomas associated with infections, such as tuberculosis. Biopsies may also show chronic mucosal damage, as evidenced by blunting of the intestinal villi, atypical branching of the crypts, and a change in the tissue type (metaplasia). One example of such metaplasia, Paneth cell metaplasia, involves the development of Paneth cells (typically found in the small intestine and a key regulator of intestinal microbiota) in other parts of the gastrointestinal system.

Diagnosis
The diagnosis of Crohns disease can sometimes be challenging, and many tests are often required to assist the physician in making the diagnosis. Even with a full battery of tests, it may not be possible to diagnose Crohns with complete certainty; a colonoscopy is approximately 70% effective in diagnosing the disease, with further tests being less effective. Disease in the small bowel is particularly difficult to diagnose, as a traditional colonoscopy allows access to only the colon and lower portions of the small intestines; introduction of the capsule endoscopy aids in endoscopic diagnosis. Giant (multinucleate) cells, a common finding in the lesions of Crohns disease, are less common in the lesions of lichen nitidus.

Classification
Crohns disease is one type of inflammatory bowel disease (IBD). It typically manifests in the gastrointestinal tract and can be categorized by the specific tract region affected. A disease of both the ileum (the last part of the small intestine that connects to the large intestine), and the large intestine, Ileocolic Crohns accounts for fifty percent of cases. Crohns ileitis, manifest in the ileum only, accounts for thirty percent of cases, while Crohns colitis, of the large intestine, accounts for the remaining twenty percent of cases and may be particularly difficult to distinguish from ulcerative colitis.Gastroduodenal Crohns disease causes inflammation in the stomach and the first part of the small intestine called the duodenum. Jejunoileitis causes spotty patches of inflammation in the top half of the small intestine, called the jejunum. The disease can attack any part of the digestive tract, from mouth to anus. However, individuals affected by the disease rarely fall outside these three classifications, with presentations in other areas.Crohns disease may also be categorized by the behavior of disease as it progresses. These categorizations formalized in the Vienna classification of the disease. There are three categories of disease presentation in Crohns disease: stricturing, penetrating, and inflammatory. Stricturing disease causes narrowing of the bowel that may lead to bowel obstruction or changes in the caliber of the feces. Penetrating disease creates abnormal passageways (fistulae) between the bowel and other structures, such as the skin. Inflammatory disease (or nonstricturing, nonpenetrating disease) causes inflammation without causing strictures or fistulae.

Endoscopy
A colonoscopy is the best test for making the diagnosis of Crohns disease, as it allows direct visualization of the colon and the terminal ileum, identifying the pattern of disease involvement. On occasion, the colonoscope can travel past the terminal ileum, but it varies from person to person. During the procedure, the gastroenterologist can also perform a biopsy, taking small samples of tissue for laboratory analysis, which may help confirm a diagnosis. As 30% of Crohns disease involves only the ileum, cannulation of the terminal ileum is required in making the diagnosis. Finding a patchy distribution of disease, with involvement of the colon or ileum, but not the rectum, is suggestive of Crohns disease, as are other endoscopic stigmata.
The utility of capsule endoscopy for this, however, is still uncertain. A "cobblestone"-like appearance is seen in approximately 40% of cases of Crohns disease upon colonoscopy, representing areas of ulceration separated by narrow areas of healthy tissue.

Radiologic tests
A small bowel follow-through may suggest the diagnosis of Crohns disease and is useful when the disease involves only the small intestine. Because colonoscopy and gastroscopy allow direct visualization of only the terminal ileum and beginning of the duodenum, they cannot be used to evaluate the remainder of the small intestine. As a result, a barium follow-through X-ray, wherein barium sulfate suspension is ingested and fluoroscopic images of the bowel are taken over time, is useful for looking for inflammation and narrowing of the small bowel. Barium enemas, in which barium is inserted into the rectum and fluoroscopy is used to image the bowel, are rarely used in the work-up of Crohns disease due to the advent of colonoscopy. They remain useful for identifying anatomical abnormalities when strictures of the colon are too small for a colonoscope to pass through, or in the detection of colonic fistulae (in this case contrast should be performed with iodate substances).CT and MRI scans are useful for evaluating the small bowel with enteroclysis protocols. They are also useful for looking for intra-abdominal complications of Crohns disease, such as abscesses, small bowel obstructions, or fistulae. Magnetic resonance imaging (MRI) is another option for imaging the small bowel as well as looking for complications, though it is more expensive and less readily available. MRI techniques such as diffusion-weighted imaging and high-resolution imaging are more sensitive in detecting ulceration and inflammation compared to CT.

Blood tests
A complete blood count may reveal anemia, which commonly is caused by blood loss leading to iron deficiency or by vitamin B12 deficiency, usually caused by ileal disease impairing vitamin B12 absorption. Rarely autoimmune hemolysis may occur. Ferritin levels help assess if iron deficiency is contributing to the anemia. Erythrocyte sedimentation rate (ESR) and C-reactive protein help assess the degree of inflammation, which is important as ferritin can also be raised in inflammation. Serum iron, total iron binding capacity and transferrin saturation may be more easily interpreted in inflammation. Anemia of chronic disease results in a normocytic anemia.Other causes of anemia include medication used in treatment of inflammatory bowel disease, like azathioprine, which can lead to cytopenia, and sulfasalazine, which can also result in folate deficiency. Testing for Saccharomyces cerevisiae antibodies (ASCA) and antineutrophil cytoplasmic antibodies (ANCA) has been evaluated to identify inflammatory diseases of the intestine and to differentiate Crohns disease from ulcerative colitis. Furthermore, increasing amounts and levels of serological antibodies such as ASCA, antilaminaribioside [Glc(β1,3)Glb(β); ALCA], antichitobioside [GlcNAc(β1,4)GlcNAc(β); ACCA], antimannobioside [Man(α1,3)Man(α)AMCA], antiLaminarin [(Glc(β1,3))3n(Glc(β1,6))n; anti-L] and antichitin [GlcNAc(β1,4)n; anti-C] associate with disease behavior and surgery, and may aid in the prognosis of Crohns disease.Low serum levels of vitamin D are associated with Crohns disease. Further studies are required to determine the significance of this association.

Comparison with ulcerative colitis
The most common disease that mimics the symptoms of Crohns disease is ulcerative colitis, as both are inflammatory bowel diseases that can affect the colon with similar symptoms. It is important to differentiate these diseases, since the course of the diseases and treatments may be different. In some cases, however, it may not be possible to tell the difference, in which case the disease is classified as indeterminate colitis.

Differential diagnosis
Other conditions with similar symptoms as Crohns disease includes intestinal tuberculosis, Behçets disease, ulcerative colitis, nonsteroidal anti-inflammatory drug enteropathy, irritable bowel syndrome and celiac disease. Irritable bowel syndrome is excluded when there are inflammatory changes. Celiac disease cannot be excluded if specific antibodies (anti-transglutaminase antibodies) are negative, nor in absence of intestinal villi atrophy.

Management
There is no cure for Crohns disease and remission may not be possible or prolonged if achieved. In cases where remission is possible, relapse can be prevented and symptoms controlled with medication, lifestyle and dietary changes, changes to eating habits (eating smaller amounts more often), reduction of stress, moderate activity, and exercise. Surgery is generally contraindicated and has not been shown to prevent relapse. Adequately controlled, Crohns disease may not significantly restrict daily living. Treatment for Crohns disease involves first treating the acute problem and its symptoms, then maintaining remission of the disease.

Lifestyle changes
Certain lifestyle changes can reduce symptoms, including dietary adjustments, elemental diet, proper hydration, and smoking cessation.
Patients with Crohns disease are very interested in diet. Recent reviews underlined the importance to adopt diets that are best supported by evidence, even if little is known about the impact of diets on these patients.
Diets that include higher levels of fiber and fruit are associated with reduced risk, while diets rich in total fats, polyunsaturated fatty acids, meat, and omega-6 fatty acids may increase the risk of Crohns. Maintaining a balanced diet with proper portion control can help manage symptoms of the disease. Eating small meals frequently instead of big meals may also help with a low appetite. A food diary may help with identifying foods that trigger symptoms. Despite the recognized importance of dietary fiber for intestinal health, some people should follow a low residue diet to control acute symptoms especially if foods high in insoluble fiber cause symptoms, e.g., due to obstruction or irritation of the bowel. Some find relief in eliminating casein (a protein found in cows milk) and gluten (a protein found in wheat, rye and barley) from their diets. They may have specific dietary intolerances (not allergies), for example, lactose. Fatigue can be helped with regular exercise, a healthy diet, and enough sleep, and for those with malabsorption of vitamin B12 due to disease or surgical resection of the terminal ileum, cobalamin injections. Smoking may worsen symptoms and the course of the disease, and stopping is recommended. Alcohol consumption can also worsen symptoms, and moderation or cessation is advised.

Medication
Acute treatment uses medications to treat any infection (normally antibiotics) and to reduce inflammation (normally aminosalicylate anti-inflammatory drugs and corticosteroids). When symptoms are in remission, treatment enters maintenance, with a goal of avoiding the recurrence of symptoms. Prolonged use of corticosteroids has significant side-effects; as a result, they are, in general, not used for long-term treatment. Alternatives include aminosalicylates alone, though only a minority are able to maintain the treatment, and many require immunosuppressive drugs. It has been also suggested that antibiotics change the enteric flora, and their continuous use may pose the risk of overgrowth with pathogens such as Clostridium difficile.Medications used to treat the symptoms of Crohns disease include 5-aminosalicylic acid (5-ASA) formulations, prednisone, immunomodulators such as azathioprine (given as the prodrug for 6-mercaptopurine), methotrexate, and anti-TNF therapies and monoclonal antibodies, such as infliximab, adalimumab, certolizumab, vedolizumab, ustekinumab, and natalizumab. Hydrocortisone should be used in severe attacks of Crohns disease. Biological therapies are medications used to avoid long-term steroid use, decrease inflammation, and treat people who have fistulas with abscesses. The monoclonal antibody ustekinumab appears to be a safe treatment option, and may help people with moderate to severe active Crohns disease. The long term safety and effectiveness of monoclonal antibody treatment is not known. The monoclonal antibody briakinumab is not effective for people with active Crohns disease and it is no longer being manufactured.The gradual loss of blood from the gastrointestinal tract, as well as chronic inflammation, often leads to anemia, and professional guidelines suggest routinely monitoring for this. Adequate disease control usually improves anemia of chronic disease, but iron deficiency may require treatment with iron supplements. Guidelines vary as to how iron should be administered. Besides, other problems include a limitation in possible daily resorption and an increased growth of intestinal bacteria. Some advise parenteral iron as first line as it works faster, has fewer gastrointestinal side effects, and is unaffected by inflammation reducing enteral absorption.
Other guidelines advise oral iron as first-line with parenteral iron reserved for those that fail to adequately respond as oral iron is considerably cheaper. All agree that severe anemia (hemoglobin under 10g/dL) should be treated with parenteral iron. Blood transfusion should be reserved for those who are cardiovascularly unstable, due to its relatively poor safety profile, lack of long-term efficacy, and cost.

Surgery
Crohns cannot be cured by surgery, as the disease eventually recurs, though it is used in the case of partial or full blockage of the intestine. Surgery may also be required for complications such as obstructions, fistulas, or abscesses, or if the disease does not respond to drugs. After the first surgery, Crohns usually comes back at the site where the diseased intestine was removed and the healthy ends were rejoined; it can also come back in other locations. After a resection, scar tissue builds up, which can cause strictures, which form when the intestines become too small to allow excrement to pass through easily, which can lead to a blockage. After the first resection, another resection may be necessary within five years. For patients with an obstruction due to a stricture, two options for treatment are strictureplasty and resection of that portion of bowel. There is no statistical significance between strictureplasty alone versus strictureplasty and resection in cases of duodenal involvement. In these cases, re-operation rates were 31% and 27%, respectively, indicating that strictureplasty is a safe and effective treatment for selected people with duodenal involvement.Postsurgical recurrence of Crohns disease is relatively common. Crohns lesions are nearly always found at the site of the resected bowel. The join (or anastomosis) after surgery may be inspected, usually during a colonoscopy, and disease activity graded. The "Rutgeerts score" is an endoscopic scoring system for postoperative disease recurrence in Crohns disease. Mild postsurgical recurrences of Crohns disease are graded i1 and i2, moderate to severe recurrences are graded i3 and i4. Fewer lesions result in a lower grade. Based on the score, treatment plans can be designed to give the patient the best chance of managing the recurrence of the disease.Short bowel syndrome (SBS, also short gut syndrome or simply short gut) is caused by the surgical removal of part of the small intestine. It usually develops in those patients who have had half or more of their small intestines removed. Diarrhea is the main symptom, but others may include weight loss, cramping, bloating, and heartburn. Short bowel syndrome is treated with changes in diet, intravenous feeding, vitamin and mineral supplements, and treatment with medications. In some cases of SBS, intestinal transplant surgery may be considered; though the number of transplant centres offering this procedure is quite small and it comes with a high risk due to the chance of infection and rejection of the transplanted intestine.Bile acid diarrhea is another complication following surgery for Crohns disease in which the terminal ileum has been removed. This leads to the development of excessive watery diarrhea. It is usually thought to be due to an inability of the ileum to reabsorb bile acids after resection of the terminal ileum and was the first type of bile acid malabsorption recognized.

Mental health
Crohns may result in anxiety or mood disorders, especially in young people who may have stunted growth or embarrassment from fecal incontinence. Counselling as well as antidepressant or anxiolytic medication may help some people manage.As of 2017 there is a small amount of research looking at mindfulness-based therapies, hypnotherapy, and cognitive behavioural therapy.

Alternative medicine
It is common for people with Crohns disease to try complementary or alternative therapy. These include diets, probiotics, fish oil, and other herbal and nutritional supplements.

Acupuncture is used to treat inflammatory bowel disease in China, and is being used more frequently in Western society. At this time, evidence is insufficient to recommend the use of acupuncture.
A 2006 survey in Germany found that about half of people with IBD used some form of alternative medicine, with the most common being homeopathy, and a study in France found that about 30% used alternative medicine. Homeopathic preparations are not proven with this or any other condition, with large-scale studies finding them to be no more effective than a placebo.
There are contradicting studies regarding the effect of medical cannabis on inflammatory bowel disease, and its effects on management are uncertain.

Prognosis
Crohns disease is a chronic condition for which there is no known cure. It is characterised by periods of improvement followed by episodes when symptoms flare up. With treatment, most people achieve a healthy weight, and the mortality rate for the disease is relatively low. It can vary from being benign to very severe, and people with CD could experience just one episode or have continuous symptoms. It usually reoccurs, although some people can remain disease-free for years or decades. Up to 80% of people with Crohns disease are hospitalized at some point during the course of their disease, with the highest rate occurring in the first year after diagnosis. Most people with Crohns live a normal lifespan. However, Crohns disease is associated with a small increase in risk of small bowel and colorectal carcinoma (bowel cancer).

Epidemiology
The percentage of people with Crohns disease has been determined in Norway and the United States and is similar at 6 to 7.1:100,000. The Crohns and Colitis Foundation of America cites this number as approx 149:100,000; NIH cites 28 to 199 per 100,000. Crohns disease is more common in northern countries, and with higher rates still in the northern areas of these countries. The incidence of Crohns disease is thought to be similar in Europe but lower in Asia and Africa. It also has a higher incidence in Ashkenazi Jews and smokers.Crohns disease begins most commonly in people in their teens and 20s, and people in their 50s through to their 70s. It is rarely diagnosed in early childhood. It usually affects female children more severely than males. However, only slightly more women than men have Crohns disease. Parents, siblings or children of people with Crohns disease are 3 to 20 times more likely to develop the disease. Twin studies find that if one has the disease there is a 55% chance the other will too.The incidence of Crohns disease is increasing in Europe and in newly industrialised countries. For example, in Brazil, there has been an annual increase of 11% in the incidence of Crohns disease since 1990.

History
Inflammatory bowel diseases were described by Giovanni Battista Morgagni (1682–1771) and by Scottish physician T Kennedy Dalziel in 1913.Ileitis terminalis was first described by Polish surgeon Antoni Leśniowski in 1904, although it was not conclusively distinguished from intestinal tuberculosis. In Poland, it is still called Leśniowski-Crohns disease (Polish: choroba Leśniowskiego-Crohna). Burrill Bernard Crohn, an American gastroenterologist at New York Citys Mount Sinai Hospital, described fourteen cases in 1932, and submitted them to the American Medical Association under the rubric of "Terminal ileitis: A new clinical entity". Later that year, he, along with colleagues Leon Ginzburg and Gordon Oppenheimer, published the case series "Regional ileitis: a pathologic and clinical entity". However, due to the precedence of Crohns name in the alphabet, it later became known in the worldwide literature as Crohns disease.

Research
Some evidence supports the hypothesis that the bacterium Mycobacterium avium subspecies paratuberculosis (MAP) is a cause of Crohns disease (see also Johnes disease). As a result, researchers are looking at the eradication of MAP as a therapeutic option. The Crohns MAP Vaccine is an experimental vaccine based on this hypothesis. Treating MAP using specific antibiotics that MAP may be susceptible to has been examined and the results are unclear but tentatively beneficial.Crohns is common in parts of the world where helminthic colonisation is rare and uncommon in those areas where most people carry worms. Infections with helminths may alter the autoimmune response that causes the disease. Trials of extracts from the worm Trichuris suis showed promising results when used in people with IBD. However, these trials (TRUST -I & TRUST -II) failed in Phase 2 clinical trials and were then discontinued after consistent failure in both North America and Europe.There is no good evidence that thalidomide or lenalidomide is useful to bring about or maintain remission.

References
Further reading
Lichtenstein GR, Loftus EV, Isaacs KL, Regueiro MD, Gerson LB, Sands BE (April 2018) </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Idiopathic intracranial hypertension and can you explain it in depth? [/INST] Idiopathic intracranial hypertension (IIH), previously known as pseudotumor cerebri and benign intracranial hypertension, is a condition characterized by increased intracranial pressure (pressure around the brain) without a detectable cause. The main symptoms are headache, vision problems, ringing in the ears, and shoulder pain. Complications may include vision loss.This condition is idiopathic, meaning there is no known cause. Risk factors include being overweight or a recent increase in weight. Tetracycline may also trigger the condition. The diagnosis is based on symptoms and a high opening pressure found during a lumbar puncture with no specific cause found on a brain scan.Treatment includes a healthy diet, salt restriction, and exercise. The medication acetazolamide may also be used along with the above measures. A small percentage of people may require surgery to relieve the pressure.About 2 per 100,000 people are newly affected per year. The condition most commonly affects women aged 20–50. Women are affected about 20 times more often than men. The condition was first described in 1897.

Signs and symptoms
The most common symptom of IIH is headache, which occurs in almost all (92–94%) cases. It is characteristically worse in the morning, generalized in character and throbbing in nature. It may be associated with nausea and vomiting. The headache can be made worse by any activity that further increases the intracranial pressure, such as coughing and sneezing. The pain may also be experienced in the neck and shoulders. Many have pulsatile tinnitus, a whooshing sensation in one or both ears (64–87%); this sound is synchronous with the pulse. Various other symptoms, such as numbness of the extremities, generalized weakness, loss of smell, and loss of coordination, are reported more rarely; none are specific for IIH. In children, numerous nonspecific signs and symptoms may be present.The increased pressure leads to compression and traction of the cranial nerves, a group of nerves that arise from the brain stem and supply the face and neck. Most commonly, the abducens nerve (sixth nerve) is involved. This nerve supplies the muscle that pulls the eye outward. Those with sixth nerve palsy therefore experience horizontal double vision which is worse when looking towards the affected side. More rarely, the oculomotor nerve and trochlear nerve (third and fourth nerve palsy, respectively) are affected; both play a role in eye movements. The facial nerve (seventh cranial nerve) is affected occasionally – the result is total or partial weakness of the muscles of facial expression on one or both sides of the face.The increased pressure leads to papilledema, which is swelling of the optic disc, the spot where the optic nerve enters the eyeball. This occurs in practically all cases of IIH, but not everyone experiences symptoms from this. Those who do experience symptoms typically report "transient visual obscurations", episodes of difficulty seeing that occur in both eyes but not necessarily at the same time. Long-term untreated papilledema leads to visual loss, initially in the periphery but progressively towards the center of vision.Physical examination of the nervous system is typically normal apart from the presence of papilledema, which is seen on examination of the eye with a small device called an ophthalmoscope or in more detail with a fundus camera. If there are cranial nerve abnormalities, these may be noticed on eye examination in the form of a squint (third, fourth, or sixth nerve palsy) or as facial nerve palsy. If the papilledema has been longstanding, visual fields may be constricted and visual acuity may be decreased. Visual field testing by automated (Humphrey) perimetry is recommended as other methods of testing may be less accurate. Longstanding papilledema leads to optic atrophy, in which the disc looks pale and visual loss tends to be advanced.

Causes
"Idiopathic" means of unknown cause. Therefore, IIH can only be diagnosed if there is no alternative explanation for the symptoms. Intracranial pressure may be increased due to medications such as high-dose vitamin A derivatives (e.g., isotretinoin for acne), long-term tetracycline antibiotics (for a variety of skin conditions) and hormonal contraceptives.
There are numerous other diseases, mostly rare conditions, that may lead to intracranial hypertension. If there is an underlying cause, the condition is termed "secondary intracranial hypertension". Common causes of secondary intracranial hypertension include obstructive sleep apnea (a sleep-related breathing disorder), systemic lupus erythematosus (SLE), chronic kidney disease, and Behçets disease.

Mechanism
The cause of IIH is not known. The Monro–Kellie rule states that the intracranial pressure is determined by the amount of brain tissue, cerebrospinal fluid (CSF) and blood inside the bony cranial vault. Three theories therefore exist as to why the pressure might be raised in IIH: an excess of CSF production, increased volume of blood or brain tissue, or obstruction of the veins that drain blood from the brain.The first theory, that of increased production of cerebrospinal fluid, was proposed in early descriptions of the disease. However, there is no experimental data that supports a role for this process in IIH.The second theory posits that either increased blood flow to the brain or increase in the brain tissue itself may result in the raised pressure. Little evidence has accumulated to support the suggestion that increased blood flow plays a role, but recently Bateman et al. in phase contrast MRA studies have quantified cerebral blood flow (CBF) in vivo and suggests that CBF is abnormally elevated in many people with IIH. Both biopsy samples and various types of brain scans have shown an increased water content of the brain tissue. It remains unclear why this might be the case.The third theory suggests that restricted venous drainage from the brain may be impaired resulting in congestion. Many people with IIH have narrowing of the transverse sinuses. It is not clear whether this narrowing is the pathogenesis of the disease or a secondary phenomenon. It has been proposed that a positive biofeedback loop may exist, where raised ICP (intracranial pressure) causes venous narrowing in the transverse sinuses, resulting in venous hypertension (raised venous pressure), decreased CSF resorption via arachnoid granulation and further rise in ICP.

Diagnosis
The diagnosis may be suspected on the basis of the history and examination. To confirm the diagnosis, as well as excluding alternative causes, several investigations are required; more investigations may be performed if the history is not typical or the person is more likely to have an alternative problem: children, men, the elderly, or women who are not overweight.

Investigations
Neuroimaging, usually with computed tomography (CT/CAT) or magnetic resonance imaging (MRI), is used to exclude any mass lesions. In IIH these scans typically appear to be normal, although small or slit-like ventricles, dilatation and buckling of the optic nerve sheaths and "empty sella sign" (flattening of the pituitary gland due to increased pressure) and enlargement of Meckels caves may be seen.
An MR venogram is also performed in most cases to exclude the possibility of venous sinus stenosis/obstruction or cerebral venous sinus thrombosis. A contrast-enhanced MRV (ATECO) scan has a high detection rate for abnormal transverse sinus stenoses. These stenoses can be more adequately identified and assessed with catheter cerebral venography and manometry. Buckling of the bilateral optic nerves with increased perineural fluid is also often noted on MRI imaging.
Lumbar puncture is performed to measure the opening pressure, as well as to obtain cerebrospinal fluid (CSF) to exclude alternative diagnoses. If the opening pressure is increased, CSF may be removed for transient relief (see below). The CSF is examined for abnormal cells, infections, antibody levels, the glucose level, and protein levels. By definition, all of these are within their normal limits in IIH. Occasionally, the CSF pressure measurement may be normal despite very suggestive symptoms. This may be attributable to the fact that CSF pressure may fluctuate over the course of the normal day. If the suspicion of problems remains high, it may be necessary to perform more long-term monitoring of the ICP by a pressure catheter.

Classification
The original criteria for IIH were described by Dandy in 1937.
They were modified by Smith in 1985 to become the "modified Dandy criteria". Smith included the use of more advanced imaging: Dandy had required ventriculography, but Smith replaced this with computed tomography. In a 2001 paper, Digre and Corbett amended Dandys criteria further. They added the requirement that the person is awake and alert, as coma precludes adequate neurological assessment, and require exclusion of venous sinus thrombosis as an underlying cause. Furthermore, they added the requirement that no other cause for the raised ICP is found.
In a 2002 review, Friedman and Jacobson propose an alternative set of criteria, derived from Smiths. These require the absence of symptoms that could not be explained by a diagnosis of IIH, but do not require the actual presence of any symptoms (such as headache) attributable to IIH. These criteria also require that the lumbar puncture is performed with the person lying sideways, as a lumbar puncture performed in the upright sitting position can lead to artificially high pressure measurements. Friedman and Jacobson also do not insist on MR venography for every person; rather, this is only required in atypical cases (see "diagnosis" above).

Treatment
The primary goal in treatment of IIH is the prevention of visual loss and blindness, as well as symptom control. IIH is treated mainly through the reduction of CSF pressure and. IIH may resolve after initial treatment, may go into spontaneous remission (although it can still relapse at a later stage), or may continue chronically.

Lumbar puncture
The first step in symptom control is drainage of cerebrospinal fluid by lumbar puncture. If necessary, this may be performed at the same time as a diagnostic LP (such as done in search of a CSF infection). In some cases, this is sufficient to control the symptoms, and no further treatment is needed.The procedure can be repeated if necessary, but this is generally taken as a clue that additional treatments may be required to control the symptoms and preserve vision. Repeated lumbar punctures are regarded as unpleasant by people, and they present a danger of introducing spinal infections if done too often. Repeated lumbar punctures are sometimes needed to control the ICP urgently if the persons vision deteriorates rapidly.

Medication
The best-studied medical treatment for intracranial hypertension is acetazolamide (Diamox), which acts by inhibiting the enzyme carbonic anhydrase, and it reduces CSF production by six to 57 percent. It can cause the symptoms of hypokalemia (low blood potassium levels), which include muscle weakness and tingling in the fingers. Acetazolamide cannot be used in pregnancy, since it has been shown to cause embryonic abnormalities in animal studies. Also, in human beings it has been shown to cause metabolic acidosis as well as disruptions in the blood electrolyte levels of newborn babies. The diuretic furosemide is sometimes used for a treatment if acetazolamide is not tolerated, but this drug sometimes has little effect on the ICP.Various analgesics (painkillers) may be used in controlling the headaches of intracranial hypertension. In addition to conventional agents such as paracetamol, a low dose of the antidepressant amitriptyline or the anticonvulsant topiramate have shown some additional benefit for pain relief.The use of steroids in the attempt to reduce the ICP is controversial. These may be used in severe papilledema, but otherwise their use is discouraged.

Venous sinus stenting
Venous sinus stenoses leading to venous hypertension appear to play a significant part in relation to raised ICP, and stenting of a transverse sinus may resolve venous hypertension, leading to improved CSF resorption, decreased ICP, cure of papilledema and other symptoms of IIH.A self-expanding metal stent is permanently deployed within the dominant transverse sinus across the stenosis under general anaesthesia. In general, people are discharged the next day. People require double antiplatelet therapy for a period of up to 3 months after the procedure and aspirin therapy for up to 1 year.
In a systematic analysis of 19 studies with 207 cases, there was an 87% improvement in overall symptom rate and 90% cure rate for treatment of papilledema. Major complications only occurred in 3/207 people (1.4%). In the largest single series of transverse sinus stenting there was an 11% rate of recurrence after one stent, requiring further stenting.Due to the permanence of the stent and small but definite risk of complications, most experts will recommend that person with IIH must have papilledema and have failed medical therapy or are intolerant to medication before stenting is undertaken.

Surgery
Two main surgical procedures exist in the treatment of IIH: optic nerve sheath decompression and fenestration and shunting. Surgery would normally only be offered if medical therapy is either unsuccessful or not tolerated. The choice between these two procedures depends on the predominant problem in IIH. Neither procedure is perfect: both may cause significant complications, and both may eventually fail in controlling the symptoms. There are no randomized controlled trials to guide the decision as to which procedure is best.Optic nerve sheath fenestration is an operation that involves the making of an incision in the connective tissue lining of the optic nerve in its portion behind the eye. It is not entirely clear how it protects the eye from the raised pressure, but it may be the result of either diversion of the CSF into the orbit or the creation of an area of scar tissue that lowers the pressure. The effects on the intracranial pressure itself are more modest. Moreover, the procedure may lead to significant complications, including blindness in 1–2%. The procedure is therefore recommended mainly in those who have limited headache symptoms but significant papilledema or threatened vision, or in those who have undergone unsuccessful treatment with a shunt or have a contraindication for shunt surgery.Shunt surgery, usually performed by neurosurgeons, involves the creation of a conduit by which CSF can be drained into another body cavity. The initial procedure is usually a lumboperitoneal (LP) shunt, which connects the subarachnoid space in the lumbar spine with the peritoneal cavity. Generally, a pressure valve is included in the circuit to avoid excessive drainage when the person is erect. LP shunting provides long-term relief in about half the cases; others require revision of the shunt, often on more than one occasion—usually due to shunt obstruction. If the lumboperitoneal shunt needs repeated revisions, a ventriculoatrial or ventriculoperitoneal shunt may be considered. These shunts are inserted in one of the lateral ventricles of the brain, usually by stereotactic surgery, and then connected either to the right atrium of the heart or the peritoneal cavity, respectively. Given the reduced need for revisions in ventricular shunts, it is possible that this procedure will become the first-line type of shunt treatment.It has been shown that in obese people, bariatric surgery (and especially gastric bypass surgery) can lead to resolution of the condition in over 95%.

Prognosis
It is not known what percentage of people with IIH will remit spontaneously, and what percentage will develop chronic disease.IIH does not normally affect life expectancy. The major complications from IIH arise from untreated or treatment-resistant papilledema. In various case series, the long-term risk of ones vision being significantly affected by IIH is reported to lie anywhere between 10 and 25%.

Epidemiology
On average, IIH occurs in about one per 100,000 people, and can occur in children and adults. The median age at diagnosis is 30. IIH occurs predominantly in women, especially in the ages 20 to 45, who are four to eight times more likely than men to be affected. Overweight and obesity strongly predispose a person to IIH: women who are more than ten percent over their ideal body weight are thirteen times more likely to develop IIH, and this figure goes up to nineteen times in women who are more than twenty percent over their ideal body weight. In men this relationship also exists, but the increase is only five-fold in those over 20 percent above their ideal body weight.Despite several reports of IIH in families, there is no known genetic cause for IIH. People from all ethnicities may develop IIH </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Eustachian tube dysfunction and can you explain it in depth? [/INST] Eustachian tube dysfunction (ETD) is a disorder where pressure abnormalities in the middle ear result in symptoms.

Signs and symptoms
Symptoms include aural fullness, ears popping, a feeling of pressure in the affected ear(s), a feeling that the affected ear(s) is clogged, crackling, ear pain, tinnitus, autophony, and muffled hearing.

Diagnosis
While Eustachian tube dysfunction can be hard to diagnose, due to the Eustachian tubes and the nasopharynx not being easily visible, usually a tympanometry is indicated, along with findings on an otoscopy </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Ménières disease and can you explain it in depth? [/INST] Ménières disease (MD) is a disease of the inner ear that is characterized by potentially severe and incapacitating episodes of vertigo, tinnitus, hearing loss, and a fullness in the ear. Typically, only one ear is affected initially, but over time, both ears may become involved. Episodes generally last from 20 minutes to a few hours. The time between episodes varies. The hearing loss and ringing in the ears can become constant over time.The cause of Ménières disease is unclear, but likely involves both genetic and environmental factors. A number of theories exist for why it occurs, including constrictions in blood vessels, viral infections, and autoimmune reactions. About 10% of cases run in families. Symptoms are believed to occur as the result of increased fluid buildup in the labyrinth of the inner ear. Diagnosis is based on the symptoms and a hearing test. Other conditions that may produce similar symptoms include vestibular migraine and transient ischemic attack.No cure is known. Attacks are often treated with medications to help with the nausea and anxiety. Measures to prevent attacks are overall poorly supported by the evidence. A low-salt diet, diuretics, and corticosteroids may be tried. Physical therapy may help with balance and counselling may help with anxiety. Injections into the ear or surgery may also be tried if other measures are not effective, but are associated with risks. The use of tympanostomy tubes, while popular, is not supported.Ménières disease was first identified in the early 1800s by Prosper Ménière. It affects between 0.3 and 1.9 per 1,000 people. It most often starts in people 40 to 60 years old. Females are more commonly affected than males. After 5 to 15 years of symptoms, the episodes of the world spinning sometimes stop and the person is left with loss of balance, poor hearing in the affected ear, and ringing or other sounds in the affected ear or ears.

Signs and symptoms
Ménières is characterized by recurrent episodes of vertigo, fluctuating hearing loss, and tinnitus; episodes may be preceded by a headache and a feeling of fullness in the ears. People may also experience additional symptoms related to irregular reactions of the autonomic nervous system. These symptoms are not symptoms of Menieres disease per se, but rather are side effects resulting from failure of the organ of hearing and balance, and include nausea, vomiting, and sweating, which are typically symptoms of vertigo, and not of Ménières. This includes a sensation of being pushed sharply to the floor from behind. Sudden falls without loss of consciousness (drop attacks) may be experienced by some people.

Causes
The cause of Ménières disease is unclear, but likely involves both genetic and environmental factors. A number of theories exist including constrictions in blood vessels, viral infections, and autoimmune reactions.

Mechanism
The initial triggers of Ménières disease are not fully understood, with a variety of potential inflammatory causes that lead to endolymphatic hydrops (EH), a distension of the endolymphatic spaces in the inner ear. EH, in turn, is strongly associated with developing MD, but not everyone with EH develops MD: "The relationship between endolymphatic hydrops and Menieres disease is not a simple, ideal correlation."Additionally, in fully developed MD, the balance system (vestibular system) and the hearing system (cochlea) of the inner ear are affected, but some cases occur where EH affects only one of the two systems enough to cause symptoms. The corresponding subtypes of MD are called vestibular MD, showing symptoms of vertigo, and cochlear MD, showing symptoms of hearing loss and tinnitus.The mechanism of MD is not fully explained by EH, but fully developed EH may mechanically and chemically interfere with the sensory cells for balance and hearing, which can lead to temporary dysfunction and even to death of the sensory cells, which in turn can cause the typical symptoms of MD – vertigo, hearing loss, and tinnitus.

Diagnosis
The diagnostic criteria as of 2015 define definite MD and probable MD as:
Definite
Two or more spontaneous episodes of vertigo, each lasting 20 minutes to 12 hours
Audiometrically documented low- to medium-frequency sensorineural hearing loss in the affected ear on at least one occasion before, during, or after one of the episodes of vertigo
Fluctuating aural symptoms (hearing, tinnitus, or fullness) in the affected ear
Not better accounted for by another vestibular diagnosisProbable

Two or more episodes of vertigo or dizziness, each lasting 20 minutes to 24 hours
Fluctuating aural symptoms (hearing, tinnitus, or fullness) in the reported ear
Not better accounted for by another vestibular diagnosis
A common and important symptom of MD is hypersensitivity to sounds. This hypersensitivity is easily diagnosed by measuring the loudness discomfort levels (LDLs).Symptoms of MD overlap with migraine-associated vertigo (MAV) in many ways, but when hearing loss develops in MAV, it is usually in both ears, and this is rare in MD, and hearing loss generally does not progress in MAV as it does in MD.People who have had a transient ischemic attack (TIA) or stroke can present with symptoms similar to MD, and in people at risk magnetic resonance imaging  should be conducted to exclude TIA or stroke.Other vestibular conditions that should be excluded include vestibular paroxysmia, recurrent unilateral vestibulopathy, vestibular schwannoma, or a tumor of the endolymphatic sac.

Management
No cure for Ménières disease is known, but medications, diet, physical therapy, and counseling, and some surgical approaches can be used to manage it.

Medications
During MD episodes, medications to reduce nausea are used, as are drugs to reduce the anxiety caused by vertigo. For longer-term treatment to stop progression, the evidence base is weak for all treatments. Although a causal relation between allergy and Ménières disease is uncertain, medication to control allergies may be helpful. To assist with vertigo and balance problems, glycopyrrolate has been found to be a useful vestibular suppressant in patients with Menieres disease.Diuretics, such as the thiazide-like diuretic chlortalidone, are widely used to manage MD on the theory that it reduces fluid buildup (pressure) in the ear. Based on evidence from multiple but small clinical trials, diuretics appear to be useful for reducing the frequency of episodes of dizziness but do not seem to prevent hearing loss.In cases where hearing loss and continuing severe episodes of vertigo occur, a chemical labyrinthectomy, in which a medication such as gentamicin is injected into the middle ear and kills parts of the vestibular apparatus, may be prescribed. This treatment has the risk of worsening hearing loss.

Diet
People with MD are often advised to reduce their sodium intake. Reducing salt intake, however, has not been well studied.Based on the assumption that MD is similar in nature to a migraine, some advise eliminating "migraine triggers" such as caffeine, but the evidence for this is weak. There is no high-quality evidence that changing diet by restricting salt, caffeine or alcohol improves symptoms.

Physical therapy
While use of physical therapy early after the onset of MD is probably not useful due to the fluctuating disease course, physical therapy to help retraining of the balance system appears to be useful to reduce both subjective and objective deficits in balance over the longer term.

Counseling
The psychological distress caused by the vertigo and hearing loss may worsen the condition in some people. Counseling may be useful to manage the distress, as may education and relaxation techniques.

Surgery
If symptoms do not improve with typical treatment, surgery may be considered. Surgery to decompress the endolymphatic sac is one option. A systematic review in 2015 found that three methods of decompression have been used – simple decompression, insertion of a shunt, and removal of the sac. It found some evidence that all three methods were useful for reducing dizziness, but that the level of evidence was low, as trials were not blinded nor were placebo controls used.Another 2015 review found that, on autopsy, shunts used in these surgeries often turn out to be displaced or misplaced, and recommended their use only in cases where the condition is uncontrolled and affecting both ears. A systematic review from 2014 found that in at least 75% of people, EL sac decompression was effective at controlling vertigo in the short term (>1 year of follow-up) and long term (>24 months).An estimated 30% of people with MD have Eustachian tube dysfunction. While a 2005 review found tentative evidence of benefit from tympanostomy tubes for improvement in the unsteadiness associated with the disease, a 2014 review concluded that their use is not supported.Destructive surgeries are irreversible and involve removing entire functionality of most, if not all, of the affected ear; as of 2013, almost no evidence existed with which to judge whether these surgeries are effective. The inner ear itself can be surgically removed via labyrinthectomy, although hearing is always completely lost in the affected ear with this operation. The surgeon can also cut the nerve to the balance portion of the inner ear in a vestibular neurectomy. The hearing is often mostly preserved; however, the surgery involves cutting open into the lining of the brain, and a hospital stay of a few days for monitoring is required.

Poorly supported
As of 2014, betahistine is often used as it is inexpensive and safe; but evidence does not justify its use in MD.
Transtympanic micropressure pulses were investigated in two systematic reviews. Neither found evidence to justify this technique.
Intratympanic steroids were investigated in three systematic reviews. The data were found to be insufficient to decide if this therapy has positive effects.
Evidence does not support the use of alternative medicine such as acupuncture or herbal supplements.

Prognosis
Ménières disease usually starts confined to one ear; it extends to both ears in about 30% of cases. People may start out with only one symptom, but in MD all three appear with time. Hearing loss usually fluctuates in the beginning stages and becomes more permanent in later stages. MD has a course of 5–15 years, and people generally end up with mild disequilibrium, tinnitus, and moderate hearing loss in one ear.

Epidemiology
From 3 to 11% of diagnosed dizziness in neuro-otological clinics are due to MD </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Hirschsprungs disease and can you explain it in depth? [/INST] Hirschsprungs disease (HD or HSCR) is a birth defect in which nerves are missing from parts of the intestine. The most prominent symptom is constipation. Other symptoms may include vomiting, abdominal pain, diarrhea and slow growth. Symptoms usually become apparent in the first two months of life. Complications may include enterocolitis, megacolon, bowel obstruction and intestinal perforation.The disorder may occur by itself or in association with other genetic disorders such as Down syndrome or Waardenburg syndrome. About half of isolated cases are linked to a specific genetic mutation, and about 20% occur within families. Some of these occur in an autosomal dominant manner. The cause of the remaining cases is unclear. If otherwise normal parents have one child with the condition, the next child has a 4% risk of being affected. The condition is divided into two main types, short-segment and long-segment, depending on how much of the bowel is affected. Rarely, the small bowel may be affected, as well. Diagnosis is based on symptoms and confirmed by biopsy.Treatment is generally by surgery to remove the affected section of bowel. The surgical procedure most often carried out is known as a "pull through". Occasionally, an intestinal transplantation may be recommended. Hirschsprungs disease occurs in about one in 5,000 of newborns. Males are more often affected than females. The condition is believed to have first been described in 1691 by Dutch anatomist Frederik Ruysch and is named after Danish physician Harald Hirschsprung following his description in 1888.

Signs and symptoms
Typically, Hirschsprung disease is diagnosed shortly after birth, although it may develop well into adulthood,  because of the presence of megacolon, or because the baby fails to pass the first stool (meconium) within 48 hours of delivery.  Normally, 90% of babies pass their first meconium within 24 hours, and 99% within 48 hours.Other symptoms include symptoms of bowel perforation such as vomiting, constipation, poor feeding, lethargy, and diarrhea. Symptoms of bowel obstruction would include vomiting of bile and abdominal distension. Those who pass stools after 36 to 48 hours after birth should raise suspicion of Hirschsprung disease. Such suspicion can also be risen if there is only passage of stools after suppository, rectal exam, or enema. Children who do not respond to constipation treatment for six months should also raise suspicion of such disease. Enterocolitis, an acute complication of Hirschsprung disease, is characterised by sudden onset of fever, abdominal distension, vomiting, passage of bloody stools or release of explosive gas or stools after rectal examination.Some cases are diagnosed later, into childhood, but usually before age 10. The child may experience fecal retention, constipation, or abdominal distention.

Associated syndromes
Hirschsprungs disease can also present as part of multi system disorders, such as:
Bardet–Biedl syndrome
Cartilage–hair hypoplasia
Congenital central hypoventilation syndrome
MEN2
Mowat–Wilson syndrome
Smith–Lemli–Opitz syndrome
Trisomy 21 (Down syndrome)
Some forms of Waardenburg syndrome

Cause
The disorder may occur by itself or in association with other genetic disorders such as Down syndrome. About half of isolated cases are linked to a specific genetic mutation and about 20% occur within families. Some of these occur in an autosomal dominant manner. The cause of the remaining cases is unclear. If otherwise normal parents have one child with the condition, the next child has a 4% risk of being affected.

Genetics
Several genes and specific regions on chromosomes (loci) have been shown or suggested to be associated with Hirschsprungs disease:
The RET proto-oncogene accounts for the highest proportion of both familial and sporadic cases, with a wide range of mutations scattered along its entire coding region. A proto-oncogene  can cause cancer if it is mutated or overexpressed.

RET proto-oncogene
RET is a gene that codes for proteins that assist cells of the neural crest in their movement through the digestive tract during the development of the embryo.  Those neural crest cells eventually form bundles of nerve cells called ganglions. EDNRB codes for proteins that connect these nerve cells to the digestive tract. Thus, mutations in these two genes could directly lead to the absence of certain nerve fibers in the colon. Research suggests that several genes are associated with Hirschsprungs disease. Also, new research suggests that mutations in genomic sequences involved in regulating EDNRB have a bigger impact on Hirschsprungs disease than previously thought.RET can mutate in many ways and is associated with Down syndrome.  Since Down syndrome is comorbid in 2% of Hirschsprungs cases, a likelihood exists that RET is involved heavily in both Hirschsprungs disease and Down syndrome.  RET is also associated with medullary thyroid cancer and neuroblastoma, which is a type of cancer common in children.  Both of these disorders are more common in Hirschsprungs patients than in the general population.  One function that RET controls is the travel of the neural crest cells through the intestines in the developing fetus. The earlier the RET mutation occurs in Hirschsprungs disease, the more severe the disorder becomes.

Other genes
Common and rare DNA variations in the neuregulin 1 (NRG1) and NRG3 (NRG3) were first shown to be associated with the disease in Chinese patients through a Genome Wide Association Study by the Hong Kong team in 2009  and 2012, respectively Subsequent studies in both Asian and Caucasian patients confirmed the initial findings by the University of Hong Kong. Both rare and common variants in these two genes have been identified in additional Chinese, Thai, Korean, Indonesian, and Spanish patients. These two genes are known to play a role in the formation of the enteric nervous system; thus, they are likely to be involved in the pathology of Hirschsprungs disease, at least in some cases.Another gene associated with this condition is NADPH oxidase, EF-hand calcium binding domain 5 (NOX5). This gene is located on the long arm of chromosome 15 (15q23).

Pathophysiology
During normal prenatal development, cells from the neural crest migrate into the large intestine (colon) to form the networks of nerves called the myenteric plexus (Auerbach plexus) (between the smooth muscle layers of the gastrointestinal tract wall) and the submucosal plexus (Meissner plexus) (within the submucosa of the gastrointestinal tract wall). In Hirschsprung disease, the migration is not complete and part of the colon lacks these nerve bodies that regulate the activity of the colon. The affected segment of the colon cannot relax and pass stool through the colon, creating an obstruction.The most accepted theory of the cause of Hirschsprung is a defect in the craniocaudal migration of neuroblasts originating from the neural crest that occurs during the first 12 weeks of gestation.  Defects in the differentiation of neuroblasts into ganglion cells and accelerated ganglion cell destruction within the intestine may also contribute to the disorder.This lack of ganglion cells in the myenteric and submucosal plexus is well documented in Hirschsprungs disease. With Hirschsprungs disease, the segment lacking neurons (aganglionic) becomes constricted, causing the normal, proximal section of bowel to become distended with feces. This narrowing of the distal colon and the failure of relaxation in the aganglionic segment are thought to be caused by the lack of neurons containing nitric oxide synthase.The most cited feature is absence of ganglion cells: notably in males, 75% have none in the end of the colon (rectosigmoid) and 8% lack ganglion cells in the entire colon. The enlarged section of the bowel is found proximally, while the narrowed, aganglionic section is found distally, closer to the end of the bowel. The absence of ganglion cells results in a persistent overstimulation of nerves in the affected region, resulting in contraction.The equivalent disease in horses is lethal white syndrome.

Diagnosis
Definitive diagnosis is made by suction biopsy of the distally narrowed segment. A histologic examination of the tissue would show a lack of ganglionic nerve cells. Diagnostic techniques involve anorectal manometry, barium enema, and rectal biopsy.
The suction rectal biopsy is considered the current international gold standard in the diagnosis of Hirschsprungs disease.Radiologic findings may also assist with diagnosis. Cineanography (fluoroscopy of contrast medium passing anorectal region) assists in determining the level of the affected intestines.

Treatment
Treatment of Hirschsprungs disease consists of surgical removal (resection) of the abnormal section of the colon, followed by reanastomosis.

Colostomy
The first stage of treatment used to be a reversible colostomy.  In this approach, the healthy end of the large intestine is cut and attached to an opening created on the front of the abdomen. The contents of the bowel are discharged through the hole in the abdomen and into a bag.  Later, when the patients weight, age, and condition are right, the "new" functional end of the bowel is connected with the anus. The first surgical treatment involving surgical resection followed by reanastomosis without a colostomy occurred as early as 1933 by Doctor Baird in Birmingham on a one-year-old boy.

Other procedures
The Swedish-American surgeon Orvar Swenson (1909–2012), who discovered the cause of Hirschsprungs, first performed its surgical treatment, the pull-through surgery, in 1948. The pull-through procedure repairs the colon by connecting the functioning portion of the bowel to the anus. The pull-through procedure is the typical method for treating Hirschsprungs in younger patients. Swenson devised the original procedure, and the pull-through surgery has been modified many times.
Currently,  several different surgical approaches are used, which include the Swenson, Soave, Duhamel, and Boley procedures. The Swenson procedure leaves a small portion of the diseased bowel. The Soave procedure, named after the Italian pediatric surgeon, Franco Soave (1917–1984), leaves the outer wall of the colon unaltered. The Boley procedure, pioneered by the American surgeon, Scott Boley (b. 1941), is a small modification of the Soave procedure, so the term "Soave-Boley" procedure is sometimes used.  The Duhamel procedure, named for the French pediatric surgeon Bernard Duhamel (1917–1996), uses a surgical stapler to connect the good and bad bowel.For the 15% of children who do not obtain full bowel control, other treatments are available. Constipation may be remedied by laxatives or a high-fiber diet. In those patients, serious dehydration can play a major factor in their lifestyles. A lack of bowel control may be addressed by an ileostomy – similar to a colostomy, but uses the end of the small intestine rather than the colon. The Malone antegrade colonic enema (ACE) is also an option. In a Malone ACE, a tube goes through the abdominal wall to the appendix, or if available, to the colon. The bowel is then flushed daily. Children as young as 6 years of age may administer this daily flush on their own.If the affected portion of the lower intestine is restricted to the lower portion of the rectum, other surgical procedures may be performed, such as a posterior rectal myectomy. The prognosis is good in 70% of cases. Chronic postoperative constipation is present in 7 to 8% of the operated cases. Postoperative enterocolitis, a severe manifestation, is present in the 10–20% of operated patients.

Epidemiology
According to a 1984 study conducted in Maryland, Hirschsprungs disease appears in 18.6 per 100,000 live births.  In Japan, it occurs at a similar rate of about one in 5,000 births (20 per 100,000). It is more common in male than female (4.32:1) and in white rather than nonwhite.  Nine percent of the Hirschsprung cases were also diagnosed as having Down syndrome </s>