<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 Pseudomyxoma peritonei and can you explain it in depth? [/INST] Pseudomyxoma peritonei (PMP) is a clinical condition caused by cancerous cells (mucinous adenocarcinoma) that produce abundant mucin or gelatinous ascites. The tumors cause fibrosis of tissues and impede digestion or organ function, and if left untreated, the tumors and mucin they produce will fill the abdominal cavity.  This will result in compression of organs and will destroy the function of the colon, small intestine, stomach, or other organs. Prognosis with treatment in many cases is optimistic, but the disease is lethal if untreated, with death occurring via cachexia, bowel obstruction, or other types of complications.
This disease is most commonly caused by an appendiceal primary cancer (cancer of the appendix); mucinous tumors of the ovary have also been implicated, although in most cases ovarian involvement is favored to be a metastasis from an appendiceal or other gastrointestinal source. Disease is typically classified as low- or high-grade (with signet ring cells).  When disease presents with low-grade histologic features the cancer rarely spreads through the lymphatic system or through the bloodstream.

Signs and symptoms
Signs and symptoms of pseudomyxoma peritonei may include abdominal or pelvic pain and/or bloating, distension, digestive disorders, weight changes, increased girth, and infertility.

Cause
The primary tumor appears to arise from the MUC2 expressing goblet cells and most commonly from these cells in the appendix. The K-Ras and p53 genes may be involved in the oncogenesis. It may be diagnosed with a range of conditions. While the majority of these cases are associated with appendiceal carcinomas, other conditions may also be found, including disseminated peritoneal adenomucinosis (DPAM), peritoneal carcinomas, several mucinous tumors (mucinous adenocarcinoma, mucinous cystadenoma, and mucinous cystadenocarcinoma), as well as other disease states. Other primary sites that have been reported include colon, rectum, stomach, gallbladder, bile ducts, small intestine, urinary bladder, lung, breast, fallopian tubes, and the pancreas.

Diagnosis
This disease is often discovered during surgery for other conditions, e.g., hernia repair, following which an experienced pathologist can confirm the diagnosis. Advanced stages may present as tumors palpable on the abdomen or distention of the belly ("jelly belly" is sometimes used as a slang term for the condition).  Due to the rarity of this disease, it is important to obtain an accurate diagnosis so that appropriate treatment may be obtained from a Gastro intestinal cancer surgeon.  Diagnostic tests may include CT scans, examination of tissue samples obtained through laparoscopy, and the evaluation of tumor markers. In most cases a colonoscopy is unsuitable as a diagnostic tool because in most cases appendix cancer invades the abdominal cavity but not the colon (however, spread inside the colon is occasionally reported). PET scans may be used to evaluate high-grade mucinous adenocarcinoma, but this test is not reliable for detecting low-grade tumors because those do not take up the dye which shows up on scans.  New MRI procedures are being developed for disease monitoring, but standard MRIs are not typically used as a diagnostic tool.  Diagnosis is confirmed through pathology.

Classification
There is substantial debate regarding histopathologic classification of pseudomyxoma peritonei. In 1995, Ronnett et al. proposed separating pseudomyxoma peritonei cases into two diagnostic categories: adenoma (disseminated peritoneal adenomucinosis, DPAM) or carcinoma (peritoneal mucinous carcinomatosis, PMCA) with a third category reserved for cases with intermediate features.  In this classification system, cases of DPAM were characterized by peritoneal lesions composed of abundant extracellular mucin containing scant simple to focally proliferative mucinous epithelium with little cytologic atypia or mitotic activity (in other words, most cells looked fairly normal and there was no evidence of mitosis which would indicate that cells were rapidly dividing), with or without an associated appendiceal mucinous adenoma.  Cases of PMCA were characterized by peritoneal lesions composed of more abundant mucinous epithelium with the architectural and cytologic features of carcinoma (irregular cells, evidence that cells were rapidly dividing, and other criteria), with or without an associated primary mucinous adenocarcinoma.  Bradley et al. (2007) argued that continued use of non-malignant terms, i.e., adenoma, for those frequent cases with low-grade features (such as DPAM), is misleading because pseudomyxoma peritonei is a disease state that results from invasion of the abdominal cavity by cells with uncontrolled growth.  Bradley states that an adenoma, by definition, is a tumor confined to the appendiceal mucosa with absolutely no evidence of invasion beyond the muscularis mucosae.
The term mucinous adenocarcinoma is used in different contexts depending on the reference material used by the pathologist for disease classification.  For example, neoplasms characterized by high-grade features, invasive glands and or signet ring cells, are termed adenocarcinoma in pathology literature. However, some pathologists (e.g., Odze and Goldblum, Surgical Pathology of the GI Tract, Liver, Biliary Tract and Pancreas, 2nd ed.) also use the term mucinous adenocarcinoma when referring to low-grade, well-differentiated tumors lacking high-grade features.  Low-grade mucinous adenocarcinoma is used by the American Joint Committee on Cancer and World Health Organization and is nearly or completely synonymous with the DPAM designation. For low-grade mucinous adenocarcinoma, disease may be designated as "benign" because tumors do not invade deeply into tissue and rarely metastasize to parenchyma of organs; this designation may be misleading and confusing to the layperson because pseudomyxoma peritonei is not a harmless condition, fatal if untreated.  High-grade or poorly differentiated mucinous adenocarcinoma has a generally poorer prognosis, though surgical treatment with heated intra-peritoneal chemotherapy (HIPEC) is yielding promising outcomes (see surgical treatment).

Immunohistochemistry
Immunohistochemical features:

Diffuse expression of SATB2, CK20, CDX2, and mCEA
Sometimes patchy CK7; negative PAX8
High-grade neoplasms may show loss of DPC4 (10%)

Treatment
Treatment is variable, both due to its rarity and to its frequently slow-growing nature. Treatment ranges from watchful waiting to debulking and hyperthermic intraperitoneal chemotherapy (HIPEC, also called intraperitoneal hyperthermic chemotherapy, IPHC) with cytoreductive surgery.

Surgical
The standard of care for mucinous adenocarcinoma with clinical condition PMP involves cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC), performed by surgical oncologists who specialize in treating PMP.  Some surgeons also apply early post-operative intraperitonial chemotherapy (EPIC), adjunct to surgical cytoreduction and HIPEC.  In situations where surgery is not required immediately, patients can be monitored via CT scans, tumor marker laboratory tests, and physical symptoms, to determine when, and if, surgery is warranted. Although some surgical procedures may be rather extensive, patients can and do recover from surgery, and the majority of these patients can and do live productive lives.In debulking, the surgeon attempts to remove as much tumor as possible. CRS or cytoreductive surgery involves surgical removal of the peritoneum and any adjacent organs which appear to have tumor seeding. Since the mucus tends to pool at the bottom of the abdominal cavity, it is common to remove the ovaries, fallopian tubes, uterus, and parts of the large intestine.  Depending upon the spread of the tumor, other organs might be removed, including but not limited to the gallbladder, spleen, and portions of the  small intestine and/or stomach.  For organs that cannot be removed safely (like the liver), the surgeon strips off the tumor from the surface.

Chemotherapy
Chemotherapy (typically utilising the chemotherapeutic agent Mitomycin C) may be infused directly into the abdominal cavity after cytoreductive surgery (surgery removing all visible disease to kill remaining microscopic cancerous tumors and free floating cells). The heated chemotherapy (HIPEC) is perfused throughout the abdominal cavity for an hour or two as the last step in the surgery, or ports are installed to allow circulation and/or drainage of the chemicals for one to five days after surgery, known as early postoperative intraperitoneal chemotherapy (EPIC). EPIC may be given in multiple cycles for several months after surgery.Systemic chemotherapy may be administered as additional or adjuvant treatment </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 Pronator teres syndrome and can you explain it in depth? [/INST] Pronator teres syndrome is a compression neuropathy of the median nerve at the elbow.
It is rare compared to compression at the wrist (carpal tunnel syndrome) or isolated injury of the anterior interosseous branch of the median nerve (anterior interosseous syndrome).

Symptoms
Compression of the median nerve in the region of the elbow or proximal part of the forearm can cause pain and/or numbness in the distribution of the distal median nerve, and weakness of the muscles innervated by the anterior interosseous nerve: the flexor pollicis longus ("FPL"), the flexor digitorum profundus of the index finger ("FDP IF"), and the pronator quadratus ("PQ").
The pain tends to be at the wrist joint, in the distribution of the terminal branch of the anterior interosseous nerve, and is exacerbated by sustained pronation (i.e., wrist down).
The weakness of the FPL and FDP IF is painless, but causes people to "drop things" and have a sense of loss of dexterity </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 Variegate porphyria and can you explain it in depth? [/INST] Variegate porphyria, also known by several other names, is an autosomal dominant porphyria that can have acute (severe but usually not long-lasting) symptoms along with symptoms that affect the skin. The disorder results from low levels of the enzyme responsible for the seventh step in heme production. Heme is a vital molecule for all of the bodys organs. It is a component of hemoglobin, the molecule that carries oxygen in the blood.

Signs and symptoms
When symptoms occur, they can include acute attacks (similar to acute intermittent porphyria) or skin damage. Acute attacks usually begin in adulthood and cause abdominal pain, vomiting, diarrhoea and constipation. During an attack, a person may also experience muscle weakness, seizures, and mental changes such as anxiety and hallucinations. These signs and symptoms are triggered by nongenetic factors such as certain drugs, dieting or fasting, certain hormones and stress.Some people with variegate porphyria have skin that is overly sensitive to sunlight (photosensitive). Areas of skin exposed to the sun develop severe blistering, scarring, changes in pigmentation, and increased hair growth. Exposed skin becomes fragile and is easily damaged.Rarely, the signs and symptoms of variegate porphyria can begin in infancy or early childhood. In such cases, the signs and symptoms are usually more severe than those starting later in life.

Genetics
Mutations in the PPOX gene cause variegate porphyria. The PPOX gene makes a membrane bound mitochondrial enzyme called protoporphyrinogen oxidase, which is critical to the chemical process that leads to heme production </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 Mauriac syndrome and can you explain it in depth? [/INST] Mauriac syndrome is a rare complication of type 1 diabetes characterized by extreme liver enlargement due to glycogen deposition, along with growth failure and delayed puberty. It occurs in some children and adolescents with type 1 diabetes irrespective of their glycemic control.

History
Mauriac syndrome was first described in 1930 by Pierre Mauriac. It was described as a syndrome of growth failure and delayed puberty in children with poorly-controlled type I diabetes.

Signs and symptoms
Patients with Mauriac syndrome may present with obesity, hepatomegaly, cushingoid facies, and elevated liver enzymes. Patients usually have growth failure and delayed puberty, which should warn the physician about insufficient management of the patients diabetes. These symptoms can be reversed with good glycemic control.

Genetics
Abnormally high blood sugar levels are relatively common among patients with type I diabetes, but Mauriac syndrome is rare </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 Anonychia and can you explain it in depth? [/INST]  </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 Dextrocardia and can you explain it in depth? [/INST] Dextrocardia (from Latin dextro, meaning "right hand side," and Greek kardia, meaning "heart") is a rare congenital condition in which the apex of the heart is located on the right side of the body, rather than the more typical placement towards the left. There are two main types of dextrocardia:  dextrocardia of embryonic arrest (also known as isolated dextrocardia) and dextrocardia situs inversus.  Dextrocardia situs inversus is further divided.

Classification
Dextrocardia of embryonic arrest
In this form of dextrocardia, the heart is simply placed further right in the thorax than is normal.  It is commonly associated with severe defects of the heart and related abnormalities including pulmonary hypoplasia.

Dextrocardia situs solitus
Dextrocardia refers to a heart positioned in the right side of the chest </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 Natural killer cell enteropathy and can you explain it in depth? [/INST] Natural killer cell enteropathy, also termed  NK cell enteropathy (NKCE), and a closely related disorder, lymphomatoid gastropathy (LG), are non-malignant diseases in which one type of lymphocyte, the natural killer cell (i.e. NK cell), proliferates excessively in  the gastrointestinal tract (GI tract). This proliferation causes red, sore-like spots, raised lesions, erosions, and ulcers in the mucosal layer surrounding the GI tract lumen. Both disorders cause either no or only vague symptoms of GI tract disturbances such as nausea, vomiting, and bleeding.In 2006, a persistent but apparently benign disease that involved the proliferation of NK cells at multiple sites throughout the intestines was described. This disorder appeared similar to and easily mistaken for a highly malignant disease, extranodal NK/T-cell lymphoma, nasal type. In 2010, a similarly non-malignant disorder that involved the proliferation of NK cells in the stomach was described. The disease mimicked gastrointestinal lymphomas. Since these first descriptions, several case series and case reports have been published on these enteropathies.The two NK cell proliferation diseases have been termed NK cell enteropathy and lymphomatoid gastropathy with NKCE being seen mostly in the United States and Korea and LG being seen mostly in Japan. Besides this geographical difference, the only other critical difference between the two diseases is that the lesions in NKCE occur in the small intestine, colon, stomach, and/or esophagus while those of LG are limited to the stomach. Since the pathophysiological features of the two diseases are virtually identical, NKCE and LG are now commonly viewed as manifestations of the same disease.Only 36 patients with NKCE or LG have been reported as of January 2019. Nonetheless, these diseases are emerging as important clinical entities because they 1) are newly described and likely to be diagnosed more often as they become better known and 2) have been mistaken for, and treated as, various types of pre-malignant and malignant lymphomas of the GI tract. Given the radical differences in the prognoses and treatments of NKCE and LG compared to the lymphomas that they can mimic, the evaluation of many lymphocyte-proliferating disorders of the GI tract must consider and rule out the possibility that they are NKCE or LG rather than a pre-malignant disorder or malignant lymphoma.

Presentation
Most cases of NKCE and LG have been reported in middle-aged or older individuals. Patients diagnosed with NKCE (medium age 46 years) have presented with vague abdominal pain, indigestion, vomiting, diarrhea, constipation, weight loss, anemia, and/or GI bleeding. Two patients complained of biliary colic (i.e. gallbladder pain) and were found to have typical lesions of NKCE in their cystic ducts. These two cases indicate that NKCE involvement is not totally limited to the alimentary canal. Three of 15 individuals diagnosed with NKCE disease reported no symptoms, their disease being found on endoscopy conducted for screening purposes. Typically, patients diagnosed with LG (medium age 58 years) have been asymptomatic at presentation with their disease being detected during GI tract examinations done for other reasons. Three of twenty patients diagnosed with LG complained of pain or discomfort in the upper abdominal region. Symptomatic individuals with either disease generally have a long history of persistent or intermittent symptoms.

Pathophysiology
NK cells normally occupy the GI tract where they contribute to innate immunity by becoming active in killing pathogen-infected and cancerous cells. The proliferating lymphocytes in NKCE and LG express CD56 and CD7 proteins on their cell surface membrane, CD3γ protein in their cytoplasm, and granzyme B, perforin, and T-cell intracellular antigen-1 cytotoxic proteins within their cytoplasmic granules. This pattern of protein expression identifies these cells as NK cells that, because of their expression of the cytotoxic granule-bound proteins, have been activated. However, the cause(s) for the activation of these cells as wells as for their rapid proliferation to produce NKCE and LG is unknown. To date, no evidence of NK cell clonality (i.e. cells developing from a single precursor) or for these cells to bear gene mutations or chromosome abnormalities have been reported in NKCE or LG. These findings help distinguish LB and NKCE from many lymphomas and support the conclusion that neither disease is malignant. The NK cells in LG and NKCE are not infected with the Epstein-Barr virus (EBV), as evidenced by their failure to express this viruss latency proteins and latency ncRNAs. This finding indicates that EBV is not the cause for the NK cell activation and excessive proliferation seen in NKCE and LG and distinguishes these diseases from malignant diseases they can mimic such as extranodal NK/T-cell lymphoma, nasal type. In isolated reports, LG has occurred in individuals with Helicobacter pylori infection of the stomach or a history of stomach cancer, while NKCE has been reported to occur in patients with gluten sensitivity or circulating anti-gliadin antibodies. Both of the latter conditions are associated with the development of GI tract lymphomas. However, the relationship of any of these findings to the etiology of LB and NKCE is unclear.

Histology
Biopsies of NKCE tissues reveal atypical medium to large lymphocytes identified by immunohistochemistry to be NK cells that are multiplying at a moderately rapid rate and that lack evidence of being infected by the Epstein-Barr virus. These cells are located primarily in the lamina propria, i.e. loose connective tissue lying just below the epithelium lining the GI tract. There is generally little invasion of these cells into the epithelium, submucosa, or glands of the GI tract, and the lesions almost always show a complete absence of vascular injury due to invasion by these cells. The lesions in LG closely resemble those of NKCE.

Diagnosis
The diagnoses of NKCE and LG depends on clinical and pathological findings indicating that the two diseases: a) are indolent and non-malignant; b) usually manifested by mild, vague, or no symptoms; c) localize to the GI tract without involvement of the head, neck, or organs such as the liver and spleen; d) consist of one or more lesions localized primarily to the lamina propria of the esophagus, stomach, small intestine, and/or large intestine (for NKCE} or to the stomach (for LG); and e) involve lesions which contain medium-to large-sized, atypical, and non-clonal lymphocytes that are activated NK cells (see Pathophysiology section) which proliferate at moderately rapid rates (as gauged by, e.g. analysis of their Ki-67 protein levels), lack evidence of Epstein-Barr virus infection, gene mutations, or chromosome abnormalities, and show little evidence of centering around, and destroying, blood vessels.

Differential diagnosis
In early studies, aggressive chemotherapy with or without bone marrow translanton and gastric resections were used to treat NKCE and LG, respectively, based on the assumptions that these diseases were malignant </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 Dysgraphia and can you explain it in depth? [/INST] Dysgraphia is a learning disability of written expression, that affects the ability to write, primarily handwriting, but also coherence. It is a specific learning disability (SLD) as well as a transcription disability, meaning that it is a writing disorder associated with impaired handwriting, orthographic coding and finger sequencing (the movement of muscles required to write). It often overlaps with other learning disabilities and neurodevelopmental disorders such as speech impairment, attention deficit hyperactivity disorder (ADHD) or developmental coordination disorder (DCD).In the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), dysgraphia is characterized as a learning disability in the category of written expression, when ones writing skills are below those expected given a persons age measured through intelligence and age-appropriate education. The DSM is unclear in whether writing refers only to the motor skills involved in writing, or if it also includes orthographic skills and spelling.Dysgraphia should be distinguished from agraphia (sometimes called acquired dysgraphia), which is an acquired loss of the ability to write resulting from brain injury, progressive illness, or a stroke.The prevalence of dysgraphia throughout the world is not known, due to difficulties in diagnosis and lack of research.

Etymology
The word dysgraphia comes from the Greek words dys meaning "impaired" and γραφία graphía meaning "writing by hand".

Development
There are at least two stages in the act of writing: the linguistic stage and the motor-expressive-praxic stage. The linguistic stage involves the encoding of auditory and visual information into symbols for letters and written words. This is mediated through the angular gyrus, which provides the linguistic rules which guide writing. The motor stage is where the expression of written words or graphemes is articulated. This stage is mediated by Exners writing area of the frontal lobe.The condition can cause individuals to struggle with feedback and anticipating and exercising control over rhythm and timing throughout the writing process.People with dysgraphia can often write on some level and may experience difficulty with other activities requiring reciprocal movement of their fingers and other fine motor skills, such as; tying shoes, fastening buttons or playing certain musical instruments. However, dysgraphia does not affect all fine motor skills. People with dysgraphia often have unusual difficulty with handwriting and spelling which in turn can cause writing fatigue. Unlike people without transcription disabilities, they tend to fail to preserve the size and shape of the letters they produce if they cannot look at what they are writing. They may lack basic grammar and spelling skills (for example, having difficulties with the letters p, q, b, and d), and often will write the wrong word when trying to formulate their thoughts on paper. The disorder generally emerges when the child is first introduced to writing. There is accumulating evidence that in many cases individuals with SLDs and DCD do not outgrow their disorders. Accordingly, it has been found that adults, teenagers, and children alike are all subject to dysgraphia.  Studies have shown that higher education students with developmental dysgraphia still experience significant difficulty with hand writing, fine motor skills and motor-related daily functions when compared to their peers without neurodevelopmental disorders.

Classification
Dysgraphia is nearly always accompanied by other learning disabilities and/or neurodevelopmental disorders such as dyslexia, attention deficit disorder or oral and written language learning disability (OWL LD)  and this can impact the type of dysgraphia a person has. Tourette syndrome, ASD and dyspraxia are also common diagnoses among dysgraphic individuals. Developmental dysgraphia was originally described as being a disorder that occurs solely in dyslexic individuals. Dysgraphia was not studied as a separate entity until mid-20th century when researchers discovered there were different types that occur without dyslexia. Dyslexics and dysgraphics experience similar synchronization difficulties and issues with spelling. However, dyslexia does not seem to impair physical writing ability or dramatically impact fine motor skills and dysgraphia does not impact reading comprehension. Methods for evaluating, managing and remedying dysgraphia are still evolving, but there are three principal subtypes of dysgraphia that are recognized. There is little information available about different types of dysgraphia and there are likely more subtypes than the ones listed below. Some people may have a combination of two or more of these, and individual symptoms may vary in presentation from what is described here. Most common presentation is a motor agraphia resulting from damage to some part of the motor cortex in the parietal lobes.

Dyslexic
There are several features that distinguish dyslexic-dysgraphia (sometimes called linguistic dysgraphia) from the other types. People with dyslexic-dysgraphia typically have poor oral and written spelling that is typically phonemic in nature. Their spontaneously written work is often illegible, has extra or deleted syllables or letters, and contains unnecessary capitalization or large spaces in the middle of words which can make each individual word unrecognizable. They may also insert symbols that do not resemble any letter of the alphabet. Writing production generally requires long periods of contemplation and correction.Dyslexic-dysgraphic individuals have fairly good copied work, and their ability to draw is also preserved. Their finger tapping speed (a method for identifying fine motor problems) is normal, indicating that the deficit does not likely stem from cerebellar damage. Impaired verbal executive functioning has also been related to this form of the disorder.One study found that boys with ADHD and dysgraphia struggle primarily with motor planning rather than have a linguistic impairment but the prevalence of linguistic/dyslexic-dysgraphia compared to other subtypes is uncertain.

Motor
Motor dysgraphia (sometimes called peripheral dysgraphia) is due to deficient fine motor skills, poor dexterity, poor muscle tone or unspecified motor clumsiness. Motor dysgraphia impairs both motor patterns and motor memory. Letter formation may be acceptable in very short samples of writing, but this requires extreme effort and an unreasonable amount of time to accomplish, and it cannot be sustained for a significant length of time, as it can cause arthritis-like tensing of the hand. Overall, their written work is poor to illegible even if copied by sight from another document, and drawing is impaired. Oral spelling for these individuals is normal, and their finger tapping speed is below normal. This shows that there are problems within the fine motor skills of these individuals. People with developmental coordination disorder may be dysgraphic and motor-dysgraphia may serve as a marker of dyspraxia. Motor-dysgraphics struggle with proper finger grip and writing is often slanted due to holding a pen or pencil incorrectly. Average writing speed is slower than that of non-dysgrapic individuals, but this seems to improve with age. Motor skill deficits appears to be a common cause of dysgraphia; 78% of children with the disorder present kinematic difficulties, while 58% of them display issues with pressure skills.

Spatial
A person with spatial dysgraphia has a defect in the understanding of space. This impaired spatial perception causes illegible spontaneously written work, illegible copied work, abnormal spacing between letters and majorly impaired drawing abilities. They have normal oral spelling and normal finger tapping speed, suggesting that this subtype is not fine motor based. Symptoms in actuality may vary in presentation from what is listed here. Spatial dysgraphia may develop in individuals with lesions on the right hemisphere of the brain.

Miscellaneous
Other subtypes and informal classification systems have been proposed by researchers; this includes but is not limited to phonological dysgraphia, deep dysgraphia and surface dysgraphia.

Signs and symptoms
The symptoms to dysgraphia are often overlooked or attributed to the student being lazy, unmotivated, careless or anxious. The condition may also be dismissed as simply being an expression of attention deficiency or having delayed visual-motor processing. In order to be diagnosed with dysgraphia, one must have a cluster, but not necessarily all, of the following symptoms:

The symptoms of dysgraphia can change as one ages.  Dysgraphia may cause students emotional trauma often due to the fact that no one can read their writing, and they are aware that they are not performing to the same level as their peers. Emotional problems that may occur alongside dysgraphia include impaired self-esteem, lowered self-efficacy, reduced motivation, poorer social functioning, heightened anxiety, and depression. They may put in extra efforts in order to have the same achievements as their peers, but often get frustrated because they feel that their hard work does not pay off. Dysgraphia is a hard disorder to detect as it does not affect specific ages, gender, or intelligence. The main concern in trying to detect dysgraphia is that people hide their disability behind their verbal fluency/comprehension and strong syntax coding  because they are ashamed that they cannot achieve the same goals as their peers. Having dysgraphia is not related to a lack of cognitive ability, and it is not uncommon in intellectually gifted individuals, but due to dysgraphia their intellectual abilities are often not identified.

Associated conditions
There are some common problems not related to dysgraphia but often associated with dysgraphia, the most common of which is stress. Developing an aversion to writing is another common issue. Often children (and adults) with dysgraphia will become extremely frustrated with the task of writing specially on plain paper (and spelling); younger children may cry, pout, or refuse to complete written assignments. This frustration can cause the student a great deal of stress and can lead to stress-related illnesses. This can be a result of any symptom of dysgraphia.

Causes
The underlying causes of the disorder are not fully understood  But dysgraphia is as well known to be a biologically based disorder with genetic and brain bases. More specifically, it is a working memory problem caused by specific neurodevelopmental dysfunction. In dysgraphia, individuals fail to develop normal connections among different brain regions needed for writing. People with dysgraphia have difficulty in automatically remembering and mastering the sequence of motor movements required to write letters or numbers. Dysgraphia is also in part due to underlying problems in orthographic coding, the orthographic loop, and graphmotor output (the movements that result in writing) by ones hands, fingers and executive functions involved in letter writing. The orthographic loop is when written words are stored in the minds eye, connected through sequential finger movement for motor output through the hand with feedback from the eye.Family history of specific learning disabilities may play a role. Children with developmental dysphasia, developmental dysgraphia and developmental dyslexia may be more likely to have family members with one of these conditions. Genetic studies suggest that verbal executive function tasks, orthographic skills, and spelling ability may have a genetic basis. Genes on chromosomes 6 and 15 may play some role with SLDs as they have linked to poorer reading, poorer spelling and lower phonemic awareness.

Diagnosis
Unlike specific learning disabilities and neurodevelopmental disorders that have been more extensively studied, there is no gold standard for diagnosing dysgraphia. This is likely due to writing systems often differing substantially between countries and languages and there being considerable heterogeneity among the therapists who are charged with diagnosing dysgraphia. Consequently, there are several tests that are used to diagnose dysgraphia like Ajuriaguerra scale, BHK for children or teenagers, the Minnesota Handwriting Assessment, ETCH, SCRIPT, DASH and HHE scale.With devices like drawing tablets, it is now possible to measure the position, tilt, and pressure in real time. From these features, it is possible to compute automatic features like speed and shaking and train a classifier to diagnose automatically children with atypical writing. The features extracted have different importances in the classification through development and allow to characterize different subtypes of dysgraphia that could have different origins, outcomes and could require different remediation strategies.It is not uncommon for dysgraphic individuals to be intellectually gifted, possess a rich vocabulary and have strong comprehension of language when speaking or reading, though their disorder is often not detected or treated; which may also be in part to developmental dyslexia receiving far more academic and medical attention than developmental dysgraphia. In addition, gifted children with transcription disabilities seldom receive programming for their intellectual talents due to their difficulties in completing written assignments.

Treatment
Treatment for dysgraphia varies and may include treatment for motor disorders to help control writing movements. Helping dysgraphic students overcome writing avoidance and accept the purpose and necessity of writing may be needed. The use of occupational therapy can be effective in the school setting, and teachers should be well informed about dysgraphia to aid in carry-over of the occupational therapists interventions. Treatments may address impaired memory or other neurological problems. Some physicians recommend that individuals with dysgraphia use computers to avoid the problems of handwriting. Dysgraphia can sometimes be partially overcome with appropriate and conscious effort and training. The International Dyslexia Association suggests the use of kinesthetic memory through early training by having the child overlearn how to write letters and to later practice writing with their eyes closed or averted to reinforce the feel of the letters being written. They also suggest teaching the students cursive writing as it has fewer reversible letters and can help lessen spacing problems, at least within words, because cursive letters are generally attached within a word.

Prevalence
It has been estimated that up to 10% of children in the world are affected by disabilities like dysgraphia, dyslexia, dyscalculia and dyspraxia. Estimates on the true prevalence of dysgraphia are not available due to lack of research on the disorder.

School
There is no special education category for students with dysgraphia; in the United States, The National Center for Learning Disabilities suggests that children with dysgraphia be handled in a case-by-case manner with an Individualized Education Program, or provided individual accommodation to provide alternative ways of submitting work and modify tasks to avoid the area of weakness. Students with dysgraphia often cannot complete written assignments that are legible, appropriate in length and content, or within given time. It is suggested that students with dysgraphia receive specialized instructions that are appropriate for them. Children will mostly benefit from explicit and comprehensive instructions, help translating across multiple levels of language, and review and revision of assignments or writing methods. Direct, explicit instruction on letter formation and guided practice will help students achieve automatic handwriting performance before they use letters to write words, phrases, and sentences. Some older children may benefit from the use of a personal computer or a laptop in class so that they do not have to deal with the frustration of falling behind their peers.It is also suggested by Berninger that teachers with dysgraphic students decide if their focus will be on manuscript writing (printing) or keyboarding. In either case, it is beneficial that students are taught how to read cursive writing as it is used daily in classrooms by some teachers </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 Necrobiotic xanthogranuloma and can you explain it in depth? [/INST]  </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 Laryngopharyngeal reflux and can you explain it in depth? [/INST] Laryngopharyngeal reflux (LPR) is the retrograde flow of gastric contents into the larynx, oropharynx and/or the nasopharynx. LPR causes respiratory symptoms such as cough and wheezing and is often associated with head and neck complaints such as dysphonia, globus pharyngis, and dysphagia.  LPR may play a role in other diseases, such as sinusitis, otitis media, and rhinitis, and can be a comorbidity of asthma.  While LPR is commonly used interchangeably with gastroesophageal reflux disease (GERD), it presents with a different pathophysiology.LPR reportedly affects approximately 10% of the U.S. population. However, LPR occurs in as many as 50% of individuals with voice disorders.

Signs and symptoms
Extraesophageal symptoms result from exposure of the upper aerodigestive tract to gastric contents. This causes a variety of symptoms, including hoarseness, postnasal drip, sore throat, difficulty swallowing, indigestion, wheezing, globus pharyngeus, and chronic throat-clearing. Some people with LPR have heartburn, while others have little to no heartburn as refluxed stomach contents do not remain in the esophagus long enough to irritate the surrounding tissue. Individuals with more severe forms of LPR may experience abrasion of tooth enamel due to intermittent presence of gastric contents in the oral cavity.Additionally, LPR can cause inflammation in the vocal tract which results in the symptom of dysphonia or hoarseness. Hoarseness is considered to be one of the primary symptoms of LPR and is associated with complaints such as strain, vocal fatigue, musculoskeletal tension, and hard glottal attacks, all of which can reduce a persons ability to communicate effectively.  Moreover, LPR patients may try to compensate for their hoarseness by increasing muscular tension in their vocal tract. This hyper-functional technique adopted in response to the inflammation caused by LPR can lead to a condition called muscle tension dysphonia and may persist even after the hoarseness and inflammation has disappeared. A speech-language pathologist will often need to be involved to help resolve this maladaptive, compensatory pattern through the implementation of voice therapy.LPR presents as a chronic and intermittent disease in children. LPR in children and infants tends to manifest with a unique set of symptoms.  Symptoms seen in children with LPR include a cough, hoarseness, stridor, sore throat, asthma, vomiting, globus sensation, wheezing, aspiration and recurrent pneumonia. Common symptoms of LPR in infants include wheezing, stridor, persistent or recurrent cough, apnea, feeding difficulties, aspiration, regurgitation, and failure to thrive. Moreover, LPR in children is commonly concomitant with laryngeal disorders such as laryngomalacia, subglottic stenosis, and laryngeal papillomatosis.

Relationship to GERD
LPR is often regarded as a subtype of GERD that occurs when stomach contents flow upward through the esophagus and reach the level of the larynx and pharynx. However, LPR is associated with a distinct presentation of symptoms. LPR and GERD frequently differ in the relative prevalence of heartburn and throat clearing. While heartburn is present in over 80% of GERD cases, it occurs in only 20% of LPR cases. Throat clearing shows the opposite prevalence pattern, occurring in approximately 87% of LPR cases and in fewer than 5% of GERD cases. Unlike GERD, LPR also poses a risk for bronchitis or pneumonitis as reflux of stomach acid to the level of the larynx can result in aspiration. LPR is also commonly associated with erythema, or redness, as well as edema in the tissues of the larynx that are exposed to gastric contents. In contrast, most cases of GERD are nonerosive, with no apparent injury to the mucosal lining of the esophageal tissue exposed to the refluxed material.Differences in the molecular structure of the epithelial tissue lining the laryngopharyngeal region may be partly responsible for the different symptomatic manifestations of LPR in comparison to GERD. In contrast to the resistant stratified squamous epithelium lining the esophagus, the larynx is lined by ciliated respiratory epithelium, which is more fragile and susceptible to damage. While the epithelium lining the esophagus is capable of withstanding as many as 50 instances of exposure to gastric contents each day, which is the uppermost estimate considered to be within the range of normal physiologic functioning, injury to laryngeal epithelium can occur following exposure to only small amounts of acidic gastric contents.

Diagnosis
LPR presents with non-specific symptoms and signs that make differential diagnosis difficult to achieve. Furthermore, symptoms of the disorder overlap greatly with symptoms of other disorders. Therefore, LPR is under-diagnosed and under-treated. As there are multiple potential etiologies for the respiratory and laryngeal symptoms of LPR, diagnosing LPR based on symptoms alone is unreliable. Laryngoscopic findings such as erythema, edema, laryngeal granulomas, and interarytenoid hypertrophy have been used to establish the diagnosis; however, these findings are nonspecific and have been described in the majority of asymptomatic subjects undergoing laryngoscopy. Response to acid-suppression therapy has been suggested as a diagnostic tool for confirming diagnosis of LPR, but studies have shown that the response to empirical trials of such therapy (as with proton-pump inhibitors) in these patients is often disappointing. Several studies have emphasized the importance of measuring proximal esophageal, or ideally pharyngeal acid exposure, in patients with clinical symptoms of LPR to document reflux as the cause of the symptoms.Additionally, several potential biomarkers of LPR have been investigated. These include inflammatory cytokines, carbonic anyhydrase, E-cadherin and mucins; however, their direct implications in LPR are still being established. The presence of pepsin, an enzyme produced in the stomach, in the hypopharynx has also become an increasingly researched biomarker for LPR. Research suggests that the stomach enzyme pepsin plays a crucial role in the complex mechanism behind LPR. Once present in the larynx pepsin is active at a low pH, but persists even when inactive.  Pepsin can manifest both extracellularly and intracellularly; however, damage is realized differently in these two environments. Intracellularly, pepsin enters the laryngeal tissue through endocytosis and causes damage that accumulates over time. Pepsin has implications on cellular transcription and therefore, gene expression, which subsequently leads to the recruitment of inflammatory cells, but inhibition of protective mechanisms such as growth factors. Structurally, pepsin plays a role in increasing viscosity of the vibratory portion of the vocal folds and decreasing cellular water retention, which reduces the overall thickness of the vocal folds. These morphological changes result in decreased vibratory amplitude, increasing demands for initiating vibration and ultimately, impacting voice quality.Before a diagnosis can be made, a physician will need to record the patients medical history and ask for details about the presenting symptoms. Questionnaires such as the Reflux Symptom Index (RSI), Quality-of-Life Index (QLI) for LPR, Glottal Closure/Function Index (GCI) and Voice Handicap Index (VHI) can be administered to gain information about the patients medical history as well as their symptomatology. A physical examination will then need to be performed with particular concentration around the head and neck. A scope with a specialized camera lens made of fiber optic strands is gently fed down the throat and feeds back images to a monitor. This provides a clear view of the throat and larynx. Signs of LPR include redness, swelling, and obvious irritation. Other, more invasive tests, such as fibre-optic transnasal laryngoscopy, 24-hour ambulatory dual probe pHmetry, pharyngeal pHmetry, transnasal esophagoscopy (TNE) and biopsy may be used. A noninvasive test for diagnosis of LPR is the collection of refluxate where the refluxed material is collected and analyzed. Another noninvasive diagnostic test that can be used is an empirical trial of proton-pump inhibitor therapy; however, this test is mostly successful in diagnosing GERD.There is no agreed-upon assessment technique to identify LPR in children. Of the debated diagnostic tools, multichannel intraluminal impedance with pH monitoring (MII-pH) is used as it recognizes both acid and non-acid reflux. A more common technique that is used is 24-hour dual probe pH monitoring. Both of these tools are expensive and are therefore not widely used.

Treatment
Management of symptoms for patients within this subgroup of the GERD spectrum is difficult. Once these patients are identified, behavioural and dietary changes are advised. Dietary modifications may include limiting the intake of chocolate, caffeine, acidic food and liquids, gaseous beverages and foods high in fat. Behavioral changes may include weight loss, cessation of smoking, limiting alcohol consumption and avoiding the ingestion of food shortly before bed. Lifestyle changes in children diagnosed with LPR include dietary modifications to avoid foods that will aggravate reflux (e.g., chocolate or acidic and spicy food), altering positioning (e.g., sleeping on your side), modifying the textures of foods (e.g., thickening feeds to heighten awareness of the passing bolus), and eliminating the intake of food before bed.Proton pump inhibitors (PPIs) are the leading pharmaceutical intervention chosen for the relief and reduction of LPR and are typically recommended for ongoing use twice a day for a period of 3–6 months. PPIs have been shown to be ineffective in very young children and are of uncertain efficacy in older children, for whom their use has been discouraged.
While PPIs may provide limited clinical benefits in some adults, there is insufficient evidence to support routine use. Many studies show that PPIs are not more effective than placebos in treating LPR.When medical management fails, Nissen fundoplication can be offered. However, patients should be advised that surgery may not result in complete elimination of LPR symptoms and even with immediate success, recurrence of symptoms later on is still possible.One way to assess treatment outcomes for LPR is through the use of voice quality measures. Both subjective and objective measures of voice quality can be used to assess treatment outcomes </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 Hyperlysinemia and can you explain it in depth? [/INST]  </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 Verrucous perforating collagenoma and can you explain it in depth? [/INST]  </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 Aarskog–Scott syndrome and can you explain it in depth? [/INST] Aarskog–Scott syndrome is a rare disease inherited as X-linked and characterized by short stature, facial abnormalities, skeletal and genital anomalies. This condition mainly affects males, although females may have mild features of the syndrome.

Signs and symptoms
People with Aarskog–Scott syndrome often have distinctive facial features, such as widely spaced eyes (hypertelorism), a small nose, a long area between the nose and mouth (philtrum), and a widows peak hairline. They frequently have mild to moderate short stature during childhood, but their growth usually catches up with that of their peers during puberty. Hand abnormalities are common in this syndrome and include short fingers (brachydactyly), curved pinky fingers (fifth finger clinodactyly), webbing of the skin between some fingers (cutaneous syndactyly), and a single crease across the palm. Other abnormalities in people with Aarskog–Scott syndrome include heart defects and a split in the upper lip (cleft lip) with or without an opening in the roof of the mouth (cleft palate).Most males with Aarskog–Scott syndrome have a shawl scrotum, in which the scrotum surrounds the penis instead of hanging below. Less often, they have undescended testes (cryptorchidism) or a soft out-pouching around the belly-button (umbilical hernia) or in the lower abdomen (inguinal hernia).The intellectual development of people with Aarskog–Scott syndrome varies widely. Some may have mild learning and behavior problems, while others have normal intelligence. In rare cases, severe intellectual disability has been reported.

Genetics
Mutations in the FGD1 gene are the only known genetic cause of Aarskog-Scott syndrome. The FGD1 gene provides instructions for making a protein that turns on (activates) another protein called Cdc42, which transmits signals that are important for various aspects of development before and after birth.Mutations in the FGD1 gene lead to the production of an abnormally functioning protein. These mutations disrupt Cdc42 signaling, leading to the wide variety of abnormalities that occur in people with Aarskog-Scott syndrome.Only about 20 percent of people with this disorder have identifiable mutations in the FGD1 gene. The cause of Aarskog-Scott syndrome in other affected individuals is unknown.

Pathophysiology
The Aarskog–Scott syndrome is due to mutation in the FGD1 gene. FGD1 encodes a guanine nucleotide exchange factor (GEF) that specifically activates Cdc42, a member of the Rho (Ras homology) family of the p21 GTPases. By activating Cdc42, FGD1 protein stimulates fibroblasts to form filopodia, cytoskeletal elements involved in cellular signaling, adhesion, and migration. Through Cdc42, FGD1 protein also activates the c-Jun N-terminal kinase (JNK) signaling cascade, a pathway that regulates cell growth, apoptosis, and cellular differentiation.Within the developing mouse skeleton, FGD1 protein is expressed in precartilaginous mesenchymal condensations, the perichondrium and periosteum, proliferating chondrocytes, and osteoblasts. These results suggest that FGD1 signaling may play a role in the biology of several different skeletal cell types including mesenchymal prechondrocytes, chondrocytes, and osteoblasts. The characterization of the spatiotemporal pattern of FGD1 expression in mouse embryos has provided important clues to the understanding of the pathogenesis of Aarskog–Scott syndrome.It appears likely that the primary defect in Aarskog–Scott syndrome is an abnormality of FGD1/Cdc42 signaling resulting in anomalous embryonic development and abnormal endochondral and intramembranous bone formation.

Diagnosis
Genetic testing may be available for mutations in the FGDY1 gene. Genetic counseling is indicated for individuals or families who may carry this condition, as there are overlapping features with fetal alcohol syndrome.Other examinations or tests can help with diagnosis. These can include:

detailed family history
conducting a detailed physical examination to document morphological features
testing for genetic defect in FGDY1
x-rays can identify skeletal abnormalities
echo cardiogram can screen for heart abnormalities
CT scan of the brain for cystic development
X-ray of the teeth
Ultrasound of abdomen to identify undescended testis

Treatment
Similar to all genetic diseases Aarskog–Scott syndrome cannot be cured, although numerous treatments exist to increase the quality of life.Surgery may be required to correct some of the anomalies, and orthodontic treatment may be used to correct some of the facial abnormalities. Trials of growth hormone have been effective to treat short stature in this disorder.

Prognosis
Some people may have some mental slowness, but children with this condition often have good social skills. Some males may have problems with fertility.

History
The syndrome is named for Dagfinn Aarskog, a Norwegian pediatrician and human geneticist who first described it in 1970, and for Charles I. Scott, Jr., an American medical geneticist who independently described the syndrome in 1971.

References
Jones, Kenneth Lyons (2005). Smiths Recognizable Patterns of Human Malformation (6th ed.). Philadelphia: WB Saunders </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 Remitting seronegative symmetrical synovitis with pitting edema and can you explain it in depth? [/INST] Remitting seronegative symmetrical synovitis with pitting edema (or sometimes RS3PE) is a rare syndrome identified by symmetric polyarthritis, synovitis, acute pitting edema (swelling) of the back of the hands and/or feet, and a negative serum rheumatoid factor. If no underlying disorder can be identified (idiopathic RS3PE), this entity has an excellent prognosis and responds well to treatment.RS3PE typically involves the joints of the extremities, specifically the metacarpophalangeal and proximal interphalangeal joints, wrists, shoulders, elbows, knees and ankles.
It is more common in older adults, with the mean age between 70 and 80 years in most studies.
It occurs more often in men than in women with a 2:1 ratio.
It is unknown how common this condition is.

Signs and symptoms
Individuals affected by RS3PE typically have repeated episodes of inflammation of the lining of their synovial joints and swelling of the end portion of the limbs. The arms and hands are more commonly affected than the legs and feet. Both sides are usually involved though RS3PE can affect only one side in certain cases.

Causes
RS3PE is a constellation of symptoms that can be caused by many other conditions </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 Uveitic glaucoma and can you explain it in depth? [/INST] Uveitic glaucoma (or uveitis glaucoma, or anterior uveitic glaucoma, or anterior noninfectious uveitic glaucoma, or uveitis associated with glaucoma, or iritic glaucoma) is most commonly a progression stage of noninfectious anterior uveitis or iritis.
Noninfectious anterior uveitis is an inflammation of the anterior (front) part of the eye and is instigated by autoimmune or other noninfectious causes (noninfectious uveitis can also affect the posterior segments of the eye, and then is called posterior, pan or intermediate uveitis). The onset of noninfectious uveitis occurs in patients in their thirties, with up to 10% of cases diagnosed in children under the age of 16. The condition may persist as a chronic disease.
Noninfectious uveitis is the most common form of uveitis in developed countries. Approximately 30% of uveitis patients develop glaucoma as a result of the inflammation that occurs in uveitis, as a complication of steroid treatment or a combination of both.Uveitis, as well as steroid treatment for uveitis, can cause an increased resistance to the flow of aqueous humour (the clear liquid suspended between the lens and the cornea) from the eye. This leads to an excess of fluid buildup, which exerts elevated pressure on the inside parts of the eye, or elevated intraocular pressure (IOP). Elevated intraocular pressure can in turn lead to optic nerve damage and glaucoma.
Based on epidemiological studies of uveitis, approximately 34-94/100,000 people will develop uveitic glaucoma (see Epidemiology section). Uveitic glaucoma patients are at significantly higher risk for visual field loss in the long term compared to patients who only have uveitis. Patients with uveitic glaucoma also experience a particularly high burden of care.

Signs and symptoms
Because uveitic glaucoma is a progressive stage of anterior non infectious uveitis, uveitic glaucoma involves signs and symptoms of both glaucoma and uveitis.
Patients with acute non infectious anterior uveitis may experience the following symptoms: pain, blurry vision, headache, photophobia (discomfort or pain due to light exposure), or the observance of haloes around lights.
An ophthalmologist may be able to observe the main sign of active noninfectious anterior uveitis, which is the presence of immune cells (anterior chamber cells, or ACCs) floating within the anterior segment of the eye (see "Noninfectious anterior uveitis" in Diagnosis section). The ophthalmologist also may observe peripheral anterior synechiae (PAS), or adhesions between the iris and trabecular meshwork, the tissue responsible for draining aqueous humour from the eye.Patients with uveitis who also experience symptoms of glaucoma may have uveitic glaucoma.
In an eye with uveitic glaucoma, the following glaucoma signs may be observed: elevated intraocular pressure, scotomas in the field of vision, defects in the fiber layer of the retinal nerve, and/or excavation (a regional deformation or depression of the optic nerve). Pupillary blocks, or the obstruction of "the flow of aqueous humor from the posterior chamber to the anterior chamber" due to a "functional block between the pupillary portion of the iris and the lens" may also be detected. Finally, the ophthalmologist may observe peripheral anterior synechiae (PAS), or adhesions between the iris and trabecular meshwork.The dual presence of glaucoma and uveitis symptoms points to a diagnosis of uveitic glaucoma.

Causes
Uveitic glaucoma is a progressive stage of anterior noninfectious uveitis. Patients diagnosed with anterior noninfectious uveitis may also develop glaucoma; in this case the condition is termed uveitic glaucoma. Uveitic glaucoma can arise from the inflammation that occurs in uveitis; from steroid treatment for uveitis; or a combination of both.

Uveitis inflammation
The inflammatory response associated with uveitis may lead to glaucoma. Active anterior uveitis flare-ups may develop quickly; in these cases, the inflammation can damage the tissues in the front part of the eye. Anterior uveitis may also be chronic; in these cases, repeated inflammation can cause progressive, accumulating damage to the eye tissues.
In all cases — acute one-time episodes, recurrent chronic inflammation or acute-on-chronic inflammation — damage to the eye tissues can cause increased resistance to the outflow of aqueous humour from the eye, which then increases the pressure inside the eye. In some chronic uveitis cases, the pressure inside the eye waxes and wanes due to the uveitis flare-ups.Elevated pressure inside the eye can lead to irreversible optic nerve damage and glaucoma.

Steroid treatment for uveitis
Topical corticosteroids are the first-line treatment for an active flare-up of noninfectious anterior uveitis, and the only effective treatment available for active inflammation. However, steroid treatment for uveitis can lead to uveitic glaucoma. Corticosteroids increase the fluid pressure inside the eye by increasing resistance to the outflow of aqueous humour, which can cause optic nerve damage and glaucoma. Steroid treatment can therefore cause or worsen uveitic glaucoma.Elevated pressure inside the eye typically develops 2 to 6 weeks after starting corticosteroid therapy, but can occur at any time during corticosteroid therapy and may continue for weeks after steroid use has been stopped. According to the Glaucoma Research Foundation, the risk of developing chronic steroid-induced glaucoma increases with every week of steroid use.Around 90% of patients with open angle glaucoma experience a steroid response of elevated intraocular pressure following steroid treatment. Therefore, once uveitis patients have developed uveitic glaucoma, they should ideally avoid steroids wherever possible.

Combination of uveitis inflammation and steroid treatment
In some cases, uveitis inflammation and steroid treatment both contribute to elevated pressure inside the eye, which leads to optic nerve damage and glaucoma.

Pathogenesis
Uveitic glaucoma as a result of recurring uveitic inflammation
Uveitic glaucoma can develop as a complication of anterior uveitis resulting from the inflammatory response associated with the disease. The inflammatory response can be characterized by occlusion of the trabecular meshwork, or blocking of the tissue that is responsible for draining aqueous humour from the eye. Another characteristic that presents in some patients is peripheral anterior synechiae (PAS), or adhesions between the iris and trabecular meshwork. These two characteristics of the inflammatory uveitic response can lead to an increase in intraocular pressure, and consequently to irreversible optic nerve damage and glaucoma.
Noninfectious uveitis is characterized by an inflammatory process that may be acute, recurrent, chronic or acute-on-chronic. Uveitic glaucoma is associated with an aggressive disease course caused by very high levels of intraocular pressure that wax and wane. When uveitis is acute, the onset of inflammation is rapid, with obstruction of intertrabecular spaces. When uveitis is chronic, recurrent bouts lead to tissue destruction from direct inflammation. Obstruction of the intertrabecular spaces characteristic of acute onset uveitis, as well as the repeated inflammation characteristic to chronic uveitis, can lead to elevated intraocular pressure. This can consequently cause optic nerve damage and glaucoma.

Uveitic glaucoma as a response to steroid treatment of uveitis
Uveitic glaucoma can also develop as a response to steroid treatment of uveitis. Corticosteroids cause a rise in the fluid pressure inside the eye. While the pathogenesis of corticosteroid-induced ocular hypertension is not fully understood, it likely involves swelling and remodeling (alterations to the extracellular matrix) of the trabecular meshwork, which leads to increased resistance to aqueous humour outflow and an increase in intraocular pressure. Another possible mechanism by which corticosteroids increase fluid pressure inside the eye is as follows:

Corticosteroids inhibit (partly prevent and slow) the breakdown of glycosaminoglycans (GAGs) in the trabecular meshwork.
GAGs accumulate in the meshwork.
Fluid drainage is decreased.
Fluid pressure in the eye is increased.It has also been suggested that corticosteroids may be capable of modifying the trabecular meshwork cells, modulating their size as well as their cytoskeletal arrangement, which in turn could limit fluid drainage.

Diagnosis
Uveitic glaucoma is a progression stage of noninfectious acute anterior uveitis. In order to diagnose uveitic glaucoma, a dual diagnosis of non-infectious anterior uveitis and glaucoma is required. A thorough examination of the eye by an ophthalmologist is performed in order to diagnose uveitic glaucoma.

Noninfectious anterior uveitis
[Main article: Uveitis]

The main diagnostic sign of noninfectious acute anterior uveitis is the presence of anterior chamber cells (ACCs), or immune cells, in the anterior, or front, chamber of the eye. The anterior chamber of healthy eyes does not contain any immune cells, hence the main indicator of noninfectious anterior uveitis is the presence of immune blood cells inside the anterior chamber of the eye. The more cells found floating in the anterior chamber, the more severe the uveitis.The quantity of immune cells present in the anterior chamber can be determined via a slit lamp examination.In 2005, an International Working Group on SUN (Standardization of Uveitis Nomenclature) took steps towards standardizing the methods for reporting clinical data in the field of uveitis. One of their products was a grading scheme for anterior chamber cells.
In 2021, a new slit lamp–based ACC assessment method, TGIS (Tarsier Grading Image Scale), was developed. TGIS uses a visual analog scale to enable pattern recognition-based evaluation of ACC density during a uveitic flare-up. This is achieved by graphically representing a high-power field slit beam through the anterior chamber, from the cornea to the lens surface.
Another important clinical measurement of ocular inflammation is flare. Flare is the leakage of various proteins (such as fibrin and cytokines) into the ocular anterior chamber, as a manifestation of inflammation. It will usually have a "milky" appearance. Flare can also be observed via slit lamp examination.

Glaucoma
[Main article: Glaucoma]
Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss.Glaucoma is challenging to diagnose and relies on several different methods of assessment to determine the level of optic nerve damage. These may include tonometry, a procedure to determine pressure inside the eye; a visual field test, which assesses peripheral vision; and imaging tests of the optic nerve.

Treatment
Treatment for uveitic glaucoma requires addressing the noninfectious anterior uveitis as well as the glaucoma present in uveitic glaucoma patients. Most urgently, the inflammation associated with uveitis must be identified and treated, to ensure as little damage to the eye as possible. Secondly, the elevated intraocular pressure associated with glaucoma must be treated. Steroid treatment may be discouraged because of the associated side effects.

Treatment of noninfectious anterior uveitis
Topical corticosteroid eyedrops are first-line treatment for uveitis and represent the only approved topical treatment for active non-infectious anterior uveitis. They are the only effective treatment for the short term available today. Corticosteroids can also be administered via periocular injection or intravitreal (IVT) injection. In more severe cases, treatment may be administered systemically via oral or intravenous corticosteroids.
Other treatments, including systemic immunosuppressive agents — which require close monitoring — may be considered where corticosteroids are ineffective or if there are concerns regarding side effects. Immunosuppressive agents include T-cell inhibitors such as cyclosporine and tacrolimus; antimetabolites such as azathioprine, methotrexate, mycophenolate mofetil, and leflunomide; alkylating agents such as cyclophosphamides and chlorambucil; and biological drugs such as adalimumab.
Most uveitis patients are treated with local steroids in the acute phase but may also need long-term treatment with lower-dose steroids as a preventive measure between flare-ups. This precaution is employed in order to minimize the use of topical corticosteroids, due to their severe ocular side effects.
Despite significant advances in therapeutics, the prevalence of blindness secondary to uveitis has not been reduced in the U.S. for the past 30 years.

Challenges related to steroid treatment of noninfectious anterior uveitis
Steroid treatment for uveitis can lead to uveitic glaucoma. Corticosteroids increase the fluid pressure inside the eye (by increasing the resistance to the outflow of aqueous humour), which can cause optic nerve damage and glaucoma. Steroid treatment can therefore cause or worsen uveitic glaucoma.Studies show that 40% to 50% of patients treated with the corticosteroid triamcinolone via intravitreal injection developed clinically significant ocular hypertension. Corticosteroid-induced ocular hypertension typically develops 2 to 6 weeks after starting therapy but can occur at any time during corticosteroid therapy and may persist for weeks after corticosteroids have been discontinued. According to the Glaucoma Research Foundation, "every week of steroid use averaged over a lifetime leads to a 4% increased risk of chronic steroid[-induced] glaucoma".In addition, around 90% of patients with pre-existing open angle glaucoma develop an additional adverse response to steroid treatment.

Treatment of uveitic glaucoma
Glaucoma medications, glaucoma surgery and steroids are the primary options for addressing uveitic glaucoma. Approximately 30% of uveitic glaucoma patients require surgical intervention due to insufficient intraocular pressure control while on maximum medicinal therapy.Available surgical interventions to treat the glaucoma in uveitic glaucoma patients pose a high risk to the eye, with a lower success rate compared to glaucoma surgeries in non-uveitic eyes. Steroids for treating uveitic glaucoma patients also carry high risks.
Because of the risks inherent in steroid treatment and the ineffectiveness of surgical interventions for uveitic glaucoma, there is currently no approved treatment for uveitic patients who also have glaucoma.
A steroid-free medication for uveitis in uveitic glaucoma patients, formulated by Tarsier Pharma, is currently undergoing clinical trials [see Research section].

Challenges related to surgical treatment of uveitic glaucoma
Uveitic glaucoma patients respond poorly to glaucoma surgery; surgery in uveitic glaucoma patients commonly has complications. These complications are caused by either the surgical wound healing improperly or unhealthy levels of pressure inside the eye.Glaucoma surgery usually leads to increased levels of inflammation in the eyes. This is an undesirable consequence, especially in uveitis patients, who already have a high tendency to develop inflammation. Because of this, 80% of uveitis experts report that glaucoma surgeries for uveitic glaucoma patients are likely to fail. Surgery in an eye with uveitis is associated with a higher complication rate, and in some cases surgeries such as valve implantation are too complicated to perform.

Prognosis for  uveitic glaucoma patients
About 30% of uveitis patients also develop uveitic glaucoma. Uveitic glaucoma patients are at significantly higher risk for visual field loss in the long term (>5 years) compared to patients who only have uveitis. A patient who only has glaucoma (without uveitis) will, on average, become blind in one eye within 20 years of glaucoma onset </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 Generalized epilepsy with febrile seizures plus and can you explain it in depth? [/INST] Generalized epilepsy with febrile seizures plus (GEFS+) is a syndromic autosomal dominant disorder where affected individuals can exhibit numerous epilepsy phenotypes. GEFS+ can persist beyond early childhood (i.e., 6 years of age). GEFS+ is also now believed to encompass three other epilepsy disorders: severe myoclonic epilepsy of infancy (SMEI), which is also known as Dravets syndrome, borderline SMEI (SMEB), and intractable  epilepsy of childhood (IEC). There are at least six types of GEFS+, delineated by their causative gene. Known causative gene mutations are in the sodium channel α subunit genes SCN1A, an associated β subunit SCN1B, and in a GABAA receptor γ subunit gene, in GABRG2 and there is another gene related with calcium channel the PCDH19 which is also known as Epilepsy Female with Mental Retardation. Penetrance for this disorder is estimated at 60%.

Signs and symptoms
Individuals with GEFS+ present with a range of epilepsy phenotypes. These include febrile seizures that end by age 6 (FS), such seizures extending beyond age 6 that may include afebrile tonic-clonic, myoclonic, absence, atonic seizures and myoclonic-astatic epilepsy. Individuals may also present with SMEI, characterized by generally tonic-clonic seizures, impaired psychomotor development, myoclonic seizures, ataxia, and poor response to many anticonvulsants.

Pathophysiology
Type 1
GEFS+ type 1 is a subtype of GEFS+ in which there are mutations in SCN1B, a gene encoding a sodium channel β subunit. The β subunit is required for proper channel inactivation. There are two known mutations in SCN1B that lead to GEFS+ (Figure 1). The first and best characterized of these mutations is C121W. This mutation alters a cysteine involved in a disulfide bond in the extracellular N-terminus of the protein. This extracellular region is similar to the cell adhesion molecule contactin and other cell adhesion molecules. It is believed that the disulfide bond disrupted by the C121W mutation is required for the proper folding of this N-terminus motif. Coexpression of SCN1B with sodium channel α subunits in oocytes and other cells results in channels that inactivate more slowly. Expression of C121W mutant along with wild-type α subunits produces current indistinguishable from that through α subunits alone. Further investigation of this mutation has indicated that it results in decreased frequency dependent rundown and, thus, likely hyperexcitability when compared to cells expressing the wild-type subunit. This mutation also disrupts the subunits ability to induce cellular aggregation. The importance of this last fact is unclear, though it is presumed that proper channel aggregation within cells and cell-cell contact are required for normal neuronal function.A second mutation has been found in one kindred with GEFS+ type 1. This mutation is in a splice acceptor site of exon 3. The loss of this acceptor site reveals a downstream cryptic acceptor site and a protein missing 5 amino acids in the N-terminus (I70_E74del). This mutation has not been further characterized.

Type 2
A second subtype of GEFS+, type 2, is the result of mutations in SCN1A, a gene encoding a sodium channel α subunit. There are currently almost 90 known mutations in the SCN1A gene throughout the entirety of the channel (see table 1). These mutations result in almost any imaginable mutation type in the gene, short of duplications. The results of these mutations are highly variable, some producing functional channels while others result in non-functional channels. Some functional channels result in membrane hyperexcitability while others result in hypoexcitability. Most of the functional mutant channels result in hyperexcitability due to decreased frequency dependent rundown. An example of this is the D188V mutation. A 10 Hz stimulation of wild-type channels causes current to decrease to approximately 70% of maximum whereas the same stimulation of mutant channels results in rundown to 90% of maximum. This is caused by an expedited recovery from inactivation for mutant channels versus wild-type. The D188V mutant, for example, recovers to 90% maximal current in 200ms while wild-type channels are unable to recover to this degree in >1000ms. Some other functional mutations that lead to hyperexcitability do so by other means, such as decreasing the rate of entrance into the slow inactivated state.Some of the other functional mutations are believed to result in hypoexcitability. The R859C mutation, for example, has a more depolarized voltage dependence of activation, meaning that the membrane must be more depolarized for the channel to open. This mutant also recovers more slowly from inactivation. The nonfunctional channels are believed to produce similar changes in cell excitability. Likewise, many of the nonsense mutations likely result in nonfunctional channels and hypoexcitability, though this has yet to be tested. It is also unclear how this membrane hypoexcitability leads to the GEFS+ phenotype.

Type 3
Patients with GEFS+ type 3 have mutations in the GABRG2 gene, which encodes the GABAA γ2 subunit (figure 2). The first mutation discovered in GABRG2 was K289M, in the extracellular region linking membrane-spanning domains M2 and M3. Oocytes injected with α1, β2, and γ2 subunits produce large GABA inducible currents whereas those injected with K289M mutant instead of wild-type subunits produce currents much smaller (about 10% of wild-type). This abnormal current is not the result of non-incorporation of mutant subunits since mutant containing receptors are still sensitive to benzodiazepines, a property for which functional γ subunits are required. Because of these results, it is believed that the GEFS+ phenotype in these individuals is a result of hyperexcitability.Concurrent with the previous mutation, a second group found a second mutation in GABRG2 associated with GEFS+. This mutation, R43Q, is located in the one of two benzodiazepine binding-sites located in the extracellular N-terminus. Benzodiazepines, such as Diazepam, potentiate GABA induced current. This potentiation is abolished in cells expressing the R43Q mutant subunit instead of the wild-type γ subunit. This mutation does not affect the subunits ability to coassemble into function receptors as it still confers resistance to GABA current blockade by zinc. As with the previous mutation, this mutation is expected to result in neuronal hyperexcitability.The final known GEFS+ type 3 mutation is a nonsense mutation, Q351X, located in the intracellular  region linking the third and fourth membrane spanning segments. When this mutant subunit is expressed in cells with wild-type α and β subunits it produces non-functional receptors. Since wild-type α and β subunits expressed alone are able to produce GABA inducible current this indicates that the mutation either prevents both coassembly of the mutant and wild-type subunits but also coassembly of the wild-type α and β subunits or prevents proper trafficking of the formed receptor to the membrane. Fusion of GFP onto this mutated subunit has indicated that it is localized to the endoplasmic reticulum instead of the cell membrane </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 Anterior cerebral artery syndrome and can you explain it in depth? [/INST] Anterior cerebral artery syndrome is a condition whereby the blood supply from the anterior cerebral artery (ACA) is restricted, leading to a reduction of the function of the portions of the brain supplied by that vessel: the medial aspects of the frontal and parietal lobes, basal ganglia, anterior fornix and anterior corpus callosum.Depending upon the area and severity of the occlusion, signs and symptoms may vary within the population affected with ACA syndrome. Blockages to the proximal (A1) segment of the vessel produce only minor deficits due to the collateral blood flow from the opposite hemisphere via the anterior communicating artery. Occlusions distal to this segment will result in more severe presentation of ACA syndrome. Contralateral hemiparesis and hemisensory loss of the lower extremity is the most common symptom associated with ACA syndrome.

Signs and symptoms
Hemiparesis or hemiplegia contralaterally, involving primarily the lower limbs and pelvic floor musculature
Sensory deficits contralaterally, involving primarily the leg and perineum
Apraxia (due to branches to the supplementary motor area and corpus callosum)
Disconnection syndrome (due to callosal branches)
Anosmia (due to branches of the olfactory bulb and olfactory tract)
Urinary incontinence
Grasp reflex and or sucking reflex contralaterally (if circle of Willis compromised)

Diagnosis
Once an acute ischemic stroke is suspected, the standard evaluation includes performing routine airway, breathing and circulation assessment, checking blood glucose, performing a validated stroke severity scale assessment and accurate, focused history regarding the time of symptom onset or last known well or at baseline. The National Institutes of Health Stroke Scale (NIHSS) is a standardized method for quantifiable assessment of stroke symptoms. It is the preferred scoring system, and scores range from 0 to 42. A patient with a higher score on this scale is more likely to be considered disabled; however, the definition of "disabling" depends on age, occupation, underlying life-limiting comorbidities, advance directives.
The crucial step in the evaluation of stroke patients is to obtain brain imaging to ascertain the type and characteristics of the stroke. In this regard, non-contrast CT of the head is the imaging modality of choice. Ischemic changes may classify as acute, subacute, and chronic, depending on the time in which they present after the onset of stroke. CT scan can also rule out intracranial hemorrhage.[18] If an intracranial hemorrhage is present, aneurysmal rupture should be investigated given its association with arterial vasospasm resulting in stroke.[3] Anterior cerebral artery strokes could be missed on imaging studies depending on their location or size. One case series found that 37.5% (6 of 16) of ACA infarcts evaluated by CT were identifiable only after using contrast injection or angiography. If the area of hypodensity is small and localized over a sulcus, the infarct could be overlooked.[1] [13]  Noncontrast head CT should be quickly followed by CT angiography of the head and neck to expedite identification of intracranial large vessel occlusion.
The finding of a hyperdense lesion in the ACA on CT scan aid in the diagnosis of stroke in its acute phase, particularly when it may be otherwise difficult to establish. The frequency of this sign in ACA infarcts is similar to that in the territories of the middle cerebral artery and the posterior circulation.[19]
As in strokes involving other areas of the brain, magnetic resonance imaging is also of critical value in the diagnosis of ACA strokes. MRI with diffusion-weight imaging is a highly useful modality, which facilitates the demarcation of ischemic boundaries in the territory of the ACA.[3] [18] MR angiography can be a helpful adjunct in the evaluation of stroke mechanisms.[7] The goal of completing head CT or MRI should be 25 min or less within patient arrival.
The National Institutes of Neurological Disorders and Stroke (NINDS) established time frame goals in the evaluation of stroke patients: door to physician less than 10 min, door to stroke team less than 15 min, door to CT scan less than 25 min, door to drug less than 60 min.[20]
Along with accurate history and early imaging, laboratory studies including capillary blood glucose, complete blood count with platelets, chemistries, coagulation studies, hemoglobin A1c, lipid panel, and markers of hypercoagulability or inflammation can be useful in identifying the risk factors or establishing the etiology of stroke. The medication checklist is an integral part of the evaluation, specifically recent use of anticoagulants, as contraindications to thrombolytic therapy should undergo rapid assessment. Cardiac sources of embolism can be evaluated as part of the work up with EKG monitoring and echocardiogram.

Management
Pulse oximetry can guide the use of supplemental oxygen to maintain oxygen saturation greater than 94%. Hyperoxia should be avoided as may be detrimental in stroke. Hypertension is common in an acute ischemic stroke. A low BP is uncommon and may indicate symptoms exacerbation of a previous stroke due to poor perfusion. Blood pressure of 220/120 mmHg should receive treatment. There is a consensus approach of allowing permissive hypertension up to 220/120 mmHg for patients that are not candidates for thrombolysis.[21]
However, for a patient that is a potential candidate for alteplase, attempt to control BP should be made immediately as goal BP for initiation of IV alteplase is 185/110 mmHg. Usually, titratable short-acting intravenous hypotensive agents are recommended to avoid dropping the BP too much once the patient is at goal. Hypotensive agents that can be options include labetalol, nicardipine, clevidipine, hydralazine, enalaprilat.[21]
For the patients that present within the therapeutic window, the decision to treat with intravenous recombinant tissue plasminogen (less than 4.5 hours from symptom onset) or endovascular treatment with mechanical thrombectomy should be made. Initiation of IV alteplase treatment in the 3 to 4.5-hour window is the current recommendation for patients less than 80 years of age, no history of both diabetes mellitus and prior stroke, use of anticoagulants, and NIHSS score of less than 25.  Only patients with disabling symptoms are considered eligible for thrombolytic treatment. Eligibility and absolute and relative contraindications should undergo rapid assessment. Randomized controlled trials have shown that intravenous administration of recombinant tissue plasminogen activator (alteplase) decrease functional disability with an absolute reduction risk of 7%-13% relative to placebo.[21]
Unfortunately, over half of patients arrive after this time window has closed and are not eligible for thrombolysis. Treatment delays may result from failure to ascribe a patients symptoms to stroke, and furthermore, the risk of harm increases with time elapsed from symptom onset.[21] This situation could be of particular concern in ACA strokes, given their sometimes atypical presentation.
Endovascular treatment with mechanical thrombectomy (MT) is another proven treatment modality in the management of patients with acute stroke suffering a large vessel occlusion, although treatment efficacy is highly time-dependent.  The procedure is available in tertiary hospitals as requires stroke team with the expertise to use timely imaging and intervention. One study evaluating MT in ACA stroke patients found that while recanalization rates were high, the outcomes were otherwise unsatisfactory. The latter was attributed to larger infarct volumes and longer times to recanalization.[22] [23].
New guidelines recommend that in patients with acute ischemic stroke within 6 to 24 hours from last known well and who have large vessel occlusion in anterior circulation, obtaining CTP, DW-MRI, or MRI perfusion is recommended to aid in selection for mechanical thrombectomy. However, this is only with the strict application of imaging or other eligibility criteria from RCTs showing benefit are in selecting patients for MT. The DAWN trial used clinical imaging mismatch (imaging from CTP or DW-MRI and NIHSS scoring) as criteria to select patients with anterior circulation LVO for MT between 6 and 24 hours from last known well. The trial demonstrated an overall functional benefit at 90 days in the treatment group (mRS score 0 to 2, 49% versus 13%, adjusted difference 33%, 95% CI, 21 to 44; a probability of superiority greater than 0.999). The DEFUSE 3 trial used perfusion core mismatch and maximum core size as criteria in selecting the patient for MT with LVO in anterior circulation 6 to 16 hours from last time seen normal. This trial also showed outcome benefit at 90 days in the treated group (mRS score 0 to 2, 44.6% vs. 16.7%, RR 2.67, 95% CI, 1.60 to 4.48, p greater than 0.0001). DAWN and DEFUSE 3 are the only trials showing a benefit of mechanical thrombectomy greater than 6 hours from symptoms onset. Only criteria from these trials should be viable for patient selection who might benefit from MT.[21] One should be aware that most of the patients involved in DAWN and DEFUSE 3 trials had middle cerebral artery occlusions.
Beyond the acute management of stroke, the use of antihypertensives, dual antiplatelet therapy, anticoagulants, carotid endarterectomy should be used to prevent recurrent events. Antiplatelet therapy or anticoagulants are not recommended within 24h after alteplase administration. Aspirin is not a recommendation as a substitute for other interventions for acute stroke. Administration of glycoprotein IIb/IIIa receptor inhibitor is not recommended, and a recent Cochrane review showed that these agents correlated with a high risk of intracranial hemorrhage. Dual antiplatelet therapy (aspirin and clopidogrel) are recommended to start within 24 hours for 21 days in patients with minor stroke for early secondary stroke prevention. The CHANCE trial showed that the primary outcome of recurrent stroke at 90 days favored dual antiplatelet therapy over Aspirin alone (HR 0.68; 95% CI, 0.57 to 0.81, p<0.0001). Ticagrelor over aspirin in acute stroke treatment is not recommended. According to SOCRATES trial with the primary outcome of time to the composite endpoint of stroke, MI or death up to 90 days, ticagrelor was not found to be superior to aspirin (HR 0.89, 95% CI, 0.78-1.01; p=0.07). However, ticagrelor is a reasonable alternative in patients with contraindication to aspirin. The efficacy of tirofiban and eptifibatide is currently unknown.[21] [20]
Optimization of risk factors is essential for secondary prevention of stroke in order to improve outcomes from the principal event.[21]

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