<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 Orgasm and can you explain it in depth? [/INST] Orgasm (from Greek ὀργασμός, orgasmos; "excitement, swelling") or sexual climax is the sudden discharge of accumulated sexual excitement during the sexual response cycle, resulting in rhythmic, involuntary muscular contractions in the pelvic region characterized by sexual pleasure. Experienced by males and females, orgasms are controlled by the involuntary or autonomic nervous system. They are usually associated with involuntary actions, including muscular spasms in multiple areas of the body, a general euphoric sensation and, frequently, body movements and vocalizations. The period after orgasm (known as the refractory period) is typically a relaxing experience, attributed to the release of the neurohormones oxytocin and prolactin as well as endorphins (or "endogenous morphine").Human orgasms usually result from physical sexual stimulation of the penis in males (typically accompanying ejaculation) and of the clitoris in females. Sexual stimulation can be by self-practice (masturbation) or with a sex partner (penetrative sex, non-penetrative sex, or other sexual activity).
The health effects surrounding the human orgasm are diverse. There are many physiological responses during sexual activity, including a relaxed state created by prolactin, as well as changes in the central nervous system such as a temporary decrease in the metabolic activity of large parts of the cerebral cortex while there is no change or increased metabolic activity in the limbic (i.e., "bordering") areas of the brain. There is also a wide range of sexual dysfunctions, such as anorgasmia. These effects affect cultural views of orgasm, such as the beliefs that orgasm and the frequency or consistency of it are either important or irrelevant for satisfaction in a sexual relationship, and theories about the biological and evolutionary functions of orgasm.

Definitions
In a clinical context, orgasm is usually defined strictly by the muscular contractions involved during sexual activity, along with the characteristic patterns of change in heart rate, blood pressure, and often respiration rate and depth. This is categorized as the sudden discharge of accumulated sexual tension during the sexual response cycle, resulting in rhythmic muscular contractions in the pelvic region. However, definitions of orgasm vary and there is sentiment that consensus on how to consistently classify it is absent. At least twenty-six definitions of orgasm were listed in the journal Clinical Psychology Review.There is some debate whether certain types of sexual sensations should be accurately classified as orgasms, including female orgasms caused by G-spot stimulation alone, and the demonstration of extended or continuous orgasms lasting several minutes or even an hour. The question centers around the clinical definition of orgasm, but this way of viewing orgasm is merely physiological, while there are also psychological, endocrinological, and neurological definitions of orgasm. In these and similar cases, the sensations experienced are subjective and do not necessarily involve the involuntary contractions characteristic of orgasm. However, the sensations in both sexes are extremely pleasurable and are often felt throughout the body, causing a mental state that is often described as transcendental, and with vasocongestion and associated pleasure comparable to that of a full-contractionary orgasm. For example, modern findings support distinction between ejaculation and male orgasm. For this reason, there are views on both sides as to whether these can be accurately defined as orgasms.

Achieving orgasm
Orgasms can be achieved during a variety of activities, including vaginal, anal or oral sex, non-penetrative sex or masturbation. They may also be achieved by the use of a sex toy, such as a sensual vibrator or an erotic electrostimulation. Achieving orgasm by stimulation of the nipples or other erogenous zones is rarer. Multiple orgasms are also possible, especially in women, but they are also uncommon. Multiple orgasms are orgasms that occur within a short period of one another.In addition to physical stimulation, orgasm can be achieved from psychological arousal alone, such as during dreaming (nocturnal emission for males or females) or by forced orgasm. Orgasm by psychological stimulation alone was first reported among people who had spinal cord injury. Although sexual function and sexuality after spinal cord injury is very often impacted, this injury does not deprive one of sexual feelings such as sexual arousal and erotic desires.Scientific literature focuses on the psychology of female orgasm significantly more than it does on the psychology of male orgasm, which "appears to reflect the assumption that female orgasm is psychologically more complex than male orgasm," but "the limited empirical evidence available suggests that male and female orgasm may bear more similarities than differences. In one controlled study by Vance and Wagner (1976), independent raters could not differentiate written descriptions of male versus female orgasm experiences".

Males
Variabilities
In men, the most common way of achieving orgasm is by physical sexual stimulation of the penis. This is usually accompanied by ejaculation, but it is possible, though also rare, for men to orgasm without ejaculation (known as a "dry orgasm"). Prepubescent boys have dry orgasms. Dry orgasms can also occur as a result of retrograde ejaculation, or hypogonadism. Men may also ejaculate without reaching orgasm, which is known as anorgasmic ejaculation. They may also achieve orgasm by stimulation of the prostate (see below).

Two-stage model
The traditional view of male orgasm is that there are two stages: emission accompanying orgasm, almost instantly followed by a refractory period. The refractory period is the recovery phase after orgasm during which it is physiologically impossible for a man to have additional orgasms. In 1966, Masters and Johnson published pivotal research about the phases of sexual stimulation. Their work included women and men, and, unlike Alfred Kinsey in 1948 and 1953, tried to determine the physiological stages before and after orgasm.
Masters and Johnson argued that, in the first stage, "accessory organs contract and the male can feel the ejaculation coming; two to three seconds later the ejaculation occurs, which the man cannot constrain, delay, or in any way control" and that, in the second stage, "the male feels pleasurable contractions during ejaculation, reporting greater pleasure tied to a greater volume of ejaculate". They reported that, unlike females, "for the man the resolution phase includes a superimposed refractory period" and added that "many males below the age of 30, but relatively few thereafter, have the ability to ejaculate frequently and are subject to only very short refractory periods during the resolution phase". Masters and Johnson equated male orgasm and ejaculation and maintained the necessity for a refractory period between orgasms.

Subsequent and multiple orgasms
There has been little scientific study of multiple orgasm in men. Dunn and Trost defined male multiple orgasm as "two or more orgasms with or without ejaculation and without, or with only very limited, de-tumescence (loss of erection) during one and the same sexual encounter". Although, due to the refractory period, it is rare for men to achieve multiple orgasms, some men have reported having multiple, consecutive orgasms, particularly without ejaculation. There may not be an obvious refractory period, and the final orgasm may cause a refractory period.  Multiple orgasms are more commonly reported in very young men than in older men. In younger men, the refractory period may only last a few minutes, but last more than an hour in older men.An increased infusion of the hormone oxytocin during ejaculation is believed to be chiefly responsible for the refractory period, and the amount by which oxytocin is increased may affect the length of each refractory period. A scientific study to successfully document natural, fully ejaculatory, multiple orgasms in an adult man was conducted at Rutgers University in 1995. During the study, six fully ejaculatory orgasms were experienced in 36 minutes, with no apparent refractory period.

Females
Orgasmic factors and variabilities
In women, the most common way to achieve orgasm is by direct sexual stimulation of the clitoris (meaning consistent manual, oral, or other concentrated friction against the external parts of the clitoris). General statistics indicate that 70–80% of women require direct clitoral stimulation to achieve orgasm, although indirect clitoral stimulation (for example, via vaginal penetration) may also be sufficient. The Mayo Clinic stated, "Orgasms vary in intensity, and women vary in the frequency of their orgasms and the amount of stimulation necessary to trigger an orgasm." Clitoral orgasms are easier to achieve because the glans of the clitoris, or clitoris as a whole, has more than 8,000 sensory nerve endings, which is as many (or more in some cases) nerve endings as are present in the human penis or glans penis. As the clitoris is homologous to the penis, it is the equivalent in its capacity to receive sexual stimulation.

One misconception, particularly in older research publications, is that the vagina is completely insensitive. However, there are areas in the anterior vaginal wall and between the top junction of the labia minora and the urethra that are especially sensitive. With regard to specific density of nerve endings, while the area commonly described as the G-spot may produce an orgasm, and the urethral sponge, an area in which the G-spot may be found, runs along the "roof" of the vagina and can create pleasurable sensations when stimulated, intense sexual pleasure (including orgasm) from vaginal stimulation is occasional or otherwise absent because the vagina has significantly fewer nerve endings than the clitoris. The greatest concentration of vaginal nerve endings are at the lower third (near the entrance) of the vagina.Sex educator Rebecca Chalker states that only one part of the clitoris, the urethral sponge, is in contact with the penis, fingers, or a dildo in the vagina. Hite and Chalker state that the tip of the clitoris and the inner lips, which are also very sensitive, are not receiving direct stimulation during penetrative intercourse. Because of this, some couples may engage in the woman on top position or the coital alignment technique to maximize clitoral stimulation. For some women, the clitoris is very sensitive after climax, making additional stimulation initially painful.Masters and Johnson argued that all women are potentially multiply orgasmic, but that multiply orgasmic men are rare, and stated that "the female is capable of rapid return to orgasm immediately following an orgasmic experience, if re-stimulated before tensions have dropped below plateau phase response levels". Though generally reported that women do not experience a refractory period and thus can experience an additional orgasm, or multiple orgasms, soon after the first one, some sources state that both men and women experience a refractory period because women may also experience a period after orgasm in which further sexual stimulation does not produce excitement. After the initial orgasm, subsequent orgasms for women may be stronger or more pleasurable as the stimulation accumulates.

Clitoral and vaginal categories
Discussions of female orgasm are complicated by orgasms in women typically being divided into two categories: clitoral orgasm and vaginal (or G-spot) orgasm. In 1973, Irving Singer theorized that there are three types of female orgasms; he categorized these as vulval, uterine, and blended, but because he was a philosopher, "these categories were generated from descriptions of orgasm in literature rather than laboratory studies". In 1982, Ladas, Whipple and Perry also proposed three categories: the tenting type (derived from clitoral stimulation), the A-frame type (derived from G-spot stimulation), and the blended type (derived from clitoral and G-spot stimulation). In 1999, Whipple and Komisaruk proposed cervix stimulation as being able to cause a fourth type of female orgasm.Female orgasms by means other than clitoral or vaginal/G-spot stimulation are less prevalent in scientific literature and most scientists contend that no distinction should be made between "types" of female orgasm. This distinction began with Sigmund Freud, who postulated the concept of "vaginal orgasm" as separate from clitoral orgasm. In 1905, Freud stated that clitoral orgasms are purely an adolescent phenomenon and that upon reaching puberty, the proper response of mature women is a change-over to vaginal orgasms, meaning orgasms without any clitoral stimulation. While Freud provided no evidence for this basic assumption, the consequences of this theory were considerable. Many women felt inadequate when they could not achieve orgasm via vaginal intercourse alone, involving little or no clitoral stimulation, as Freuds theory made penile-vaginal intercourse the central component to womens sexual satisfaction.The first major national surveys of sexual behavior were the Kinsey Reports. Alfred Kinsey was the first researcher to harshly criticize Freuds ideas about female sexuality and orgasm when, through his interviews with thousands of women, Kinsey found that most of the women he surveyed could not have vaginal orgasms. He "criticized Freud and other theorists for projecting male constructs of sexuality onto women" and "viewed the clitoris as the main center of sexual response" and the vagina as "relatively unimportant" for sexual satisfaction, relaying that "few women inserted fingers or objects into their vaginas when they masturbated". He "concluded that satisfaction from penile penetration [is] mainly psychological or perhaps the result of referred sensation".Masters and Johnsons research into the female sexual response cycle, as well as Shere Hites, generally supported Kinseys findings about female orgasm. Masters and Johnsons research on the topic came at the time of the second-wave feminist movement, and inspired feminists such as Anne Koedt, author of The Myth of the Vaginal Orgasm, to speak about the "false distinction" made between clitoral and vaginal orgasms and womens biology not being properly analyzed.

Clitoral and vaginal relationships
Accounts that the vagina is capable of producing orgasms continue to be subject to debate because, in addition to the vaginas low concentration of nerve endings, reports of the G-spots location are inconsistent—it appears to be nonexistent in some women and may be an extension of another structure, such as the Skenes gland or the clitoris, which is a part of the Skenes gland. In a January 2012 The Journal of Sexual Medicine review examining years of research into the existence of the G-spot, scholars stated that "[r]eports in the public media would lead one to believe the G-spot is a well-characterized entity capable of providing extreme sexual stimulation, yet this is far from the truth".Possible explanations for the G-spot were examined by Masters and Johnson, who were the first researchers to determine that the clitoral structures surround and extend along and within the labia. In addition to observing that the majority of their female subjects could only have clitoral orgasms, they found that both clitoral and vaginal orgasms had the same stages of physical response. On this basis, they argued that clitoral stimulation is the source of both kinds of orgasms, reasoning that the clitoris is stimulated during penetration by friction against its hood; their notion that this provides the clitoris with sufficient sexual stimulation has been criticized by researchers such as Elisabeth Lloyd.Australian urologist Helen OConnells 2005 research additionally indicates a connection between orgasms experienced vaginally and the clitoris, suggesting that clitoral tissue extends into the anterior wall of the vagina and that therefore clitoral and vaginal orgasms are of the same origin. Some studies, using ultrasound, have found physiological evidence of the G-spot in women who report having orgasms during vaginal intercourse, but OConnell suggests that the clitoriss interconnected relationship with the vagina is the physiological explanation for the conjectured G-spot. Having used MRI technology which enabled her to note a direct relationship between the legs or roots of the clitoris and the erectile tissue of the "clitoral bulbs" and corpora, and the distal urethra and vagina, she stated that the vaginal wall is the clitoris; that lifting the skin off the vagina on the side walls reveals the bulbs of the clitoris—triangular, crescental masses of erectile tissue. OConnell et al., who performed dissections on the female genitals of cadavers and used photography to map the structure of nerves in the clitoris, were already aware that the clitoris is more than just its glans and asserted in 1998 that there is more erectile tissue associated with the clitoris than is generally described in anatomical textbooks. They concluded that some females have more extensive clitoral tissues and nerves than others, especially having observed this in young cadavers as compared to elderly ones, and therefore whereas the majority of females can only achieve orgasm by direct stimulation of the external parts of the clitoris, the stimulation of the more generalized tissues of the clitoris via intercourse may be sufficient for others.French researchers Odile Buisson and Pierre Foldès reported similar findings to that of OConnells. In 2008, they published the first complete 3D sonography of the stimulated clitoris, and republished it in 2009 with new research, demonstrating the ways in which erectile tissue of the clitoris engorges and surrounds the vagina, arguing that women may be able to achieve vaginal orgasm via stimulation of the G-spot because the highly innervated clitoris is pulled closely to the anterior wall of the vagina when the woman is sexually aroused and during vaginal penetration. They assert that since the front wall of the vagina is inextricably linked with the internal parts of the clitoris, stimulating the vagina without activating the clitoris may be next to impossible. In their 2009 published study, the "coronal planes during perineal contraction and finger penetration demonstrated a close relationship between the root of the clitoris and the anterior vaginal wall". Buisson and Foldès suggested "that the special sensitivity of the lower anterior vaginal wall could be explained by pressure and movement of clitoriss root during a vaginal penetration and subsequent perineal contraction".Supporting a distinct G-spot is a study by Rutgers University, published 2011, which was the first to map the female genitals onto the sensory portion of the brain; brain scans showed that the brain registered distinct feelings between stimulating the clitoris, the cervix and the vaginal wall – where the G-spot is reported to be – when several women stimulated themselves in a functional magnetic resonance (fMRI) machine. "I think that the bulk of the evidence shows that the G-spot is not a particular thing," stated Barry Komisaruk, head of the research findings. "Its not like saying, What is the thyroid gland? The G-spot is more of a thing like New York City is a thing. Its a region, its a convergence of many different structures." Commenting on Komisaruks research and other findings, Emmanuele Jannini, a professor of endocrinology at the University of Aquila in Italy, acknowledged a series of essays published in March 2012 in The Journal of Sexual Medicine, which document evidence that vaginal and clitoral orgasms are separate phenomena that activate different areas of the brain and possibly suggest key psychological differences between women.

Other factors and research
Regular difficulty reaching orgasm after ample sexual stimulation, known as anorgasmia, is significantly more common in women than in men (see below). In addition to sexual dysfunction being a cause for womens inability to reach orgasm, or the amount of time for sexual arousal needed to reach orgasm being variable and longer in women than in men, other factors include a lack of communication between sexual partners about what is needed for the woman to reach orgasm, feelings of sexual inadequacy in either partner, a focus on only penetration (vaginal or otherwise), and men generalizing womens trigger for orgasm based on their own sexual experiences with other women.Scholars state "many couples are locked into the idea that orgasms should be achieved only through intercourse [vaginal sex]" and that "[e]ven the word foreplay suggests that any other form of sexual stimulation is merely preparation for the main event.... ...Because women reach orgasm through intercourse less consistently than men, they are more likely than men to have faked an orgasm". Sex counselor Ian Kerner stated, "Its a myth that using the penis is the main way to pleasure a woman." He cites research concluding that women reach orgasm about 25% of the time with intercourse, compared with 81% of the time during oral sex (cunnilingus).In the first large-scale empirical study worldwide to link specific practices with orgasm, reported in the Journal of Sex Research in 2006, demographic and sexual history variables were comparatively weakly associated with orgasm. Data was analyzed from the Australian Study of Health and Relationships, a national telephone survey of sexual behavior and attitudes and sexual health knowledge carried out in 2001–2002, with a representative sample of 19,307 Australians aged 16 to 59. Practices included "vaginal intercourse alone (12%), vaginal + manual stimulation of the mans and/or womans genitals (49%), and vaginal intercourse + manual + oral (32%)" and the "[e]ncounters may also have included other practices. Men had an orgasm in 95% of encounters and women in 69%. Generally, the more practices engaged in, the higher a womans chance of having an orgasm. Women were more likely to reach orgasm in encounters including cunnilingus".Other studies suggest that women exposed to lower levels of prenatal androgens are more likely to experience orgasm during vaginal intercourse than other women.

Exercise-induced
Kinsey, in his 1953 book Sexual Behavior in the Human Female, stated that exercise could bring about sexual pleasure, including orgasm. A review in 1990 on the sexual response itself as exercise, reviewed the literature and stated that the field was poorly researched; it also said that studies had found that aerobic or isotonic exercise that resembles sexual activity or sexual positions can induce sexual pleasure, including orgasm. A 2007 review of the relationship between pelvic floor dysfunction and sexual problems in men and women found that they are commonly linked and suggested that physical therapy strengthening the pelvic floor could help address the sexual problems but that it was not well studied enough to recommend. Starting in at least 2007, the term, "coregasm" was used in popular media to refer to exercise-induced orgasm or in academic parlance termed exercise-induced sexual pleasure or EISP, and an extensive discussion of the "yogasm" occurred in a 2011 Daily Beast posting. A paper published in 2012 presented results of an online survey of women who had experienced an orgasm or other sexual pleasure during exercise. The paper was widely discussed in popular media when it was published. The authors of the paper said that research on the relationship between exercise and sexual response was still lacking.

Anal and prostate stimulation
In both sexes, pleasure can be derived from the nerve endings around the anus and the anus itself, such as during anal sex. It is possible for men to achieve orgasms through prostate stimulation alone. The prostate is the male homologue (variation) to the Skenes glands (which are believed to be connected to the female G-spot), and can be sexually stimulated through anal sex, perineum massage or via a vibrator. Much of the available information about prostate-induced orgasms comes from anecdotal reports by individuals, and the exact mechanisms by which such orgasms are produced are unclear; some sources suggest this occurs via stimulation of nerves in the prostatic plexus surrounding the organ, others suggest it is via nerves within the prostate itself, and others say changes in the brain (neuroplasticity) are required to derive pleasure from prostate stimulation. Regardless, prostate-induced orgasms are often reported to be intensely pleasurable. Prostate stimulation can produce a deeper orgasm, described by some men as more widespread and intense, longer-lasting, and allowing for greater feelings of ecstasy than orgasm elicited by penile stimulation only. The practice of pegging (consisting of a woman penetrating a mans anus with a strap-on dildo) stimulates the prostate. It is typical for a man to not reach orgasm as a receptive partner solely from anal sex.For women, penile-anal penetration may also indirectly stimulate the clitoris by the shared sensory nerves, especially the pudendal nerve, which gives off the inferior anal nerves and divides into the perineal nerve and the dorsal nerve of the clitoris. The G-spot area, which is considered to be interconnected with the clitoris, may also be indirectly stimulated during anal sex. Although the anus has many nerve endings, their purpose is not specifically for inducing orgasm, and so a woman achieving orgasm solely by anal stimulation is rare. Direct stimulation of the clitoris, a G-spot area, or both, while engaging in anal sex can help some women enjoy the activity and reach orgasm during it.The aforementioned orgasms are sometimes referred to as anal orgasms, but sexologists and sex educators generally believe that orgasms derived from anal penetration are the result of the relationship between the nerves of the anus, rectum, clitoris or G-spot area in women, and the anuss proximity to the prostate and relationship between the anal and rectal nerves in men, rather than orgasms originating from the anus itself.

Nipple stimulation
For women, stimulation of the breast area during sexual intercourse or foreplay, or solely having the breasts fondled, can create mild to intense orgasms, sometimes referred to as a breast orgasm or nipple orgasm. Few women report experiencing orgasm from nipple stimulation. Before Komisaruk et al.s functional magnetic resonance (fMRI) research on nipple stimulation in 2011, reports of women achieving orgasm from nipple stimulation relied solely on anecdotal evidence. Komisaruks study was the first to map the female genitals onto the sensory portion of the brain; it indicates that sensation from the nipples travels to the same part of the brain as sensations from the vagina, clitoris and cervix, and that these reported orgasms are genital orgasms caused by nipple stimulation, and may be directly linked to the genital sensory cortex ("the genital area of the brain").An orgasm is believed to occur in part because of the hormone oxytocin, which is produced in the body during sexual excitement and arousal and labor. It has also been shown that oxytocin is produced when a man or womans nipples are stimulated and become erect. Komisaruk also relayed, however, that preliminary data suggests that nipple nerves may directly link up with the relevant parts of the brain without uterine mediation, acknowledging the men in his study who showed the same pattern of nipple stimulation activating genital brain regions.

Medical aspects
Physiological responses
Masters and Johnson were some of the first researchers to study the sexual response cycle in the early 1960s, based on the observation of 382 women and 312 men. They described a cycle that begins with excitement as blood rushes into the genitals, then reaches a plateau during which they are fully aroused, which leads to orgasm, and finally resolution, in which the blood leaves the genitals.In the 1970s, Helen Singer Kaplan added the category of desire to the cycle, which she argued precedes sexual excitation. She stated that emotions of anxiety, defensiveness and the failure of communication can interfere with desire and orgasm. In the late 1980s and after, Rosemary Basson proposed a more cyclical alternative to what had largely been viewed as linear progression. In her model, desire feeds arousal and orgasm, and is in turn fueled by the rest of the orgasmic cycle. Rather than orgasm being the peak of the sexual experience, she suggested that it is just one point in the circle and that people could feel sexually satisfied at any stage, reducing the focus on climax as an end-goal of all sexual activity.

Males
As a man nears orgasm during stimulation of the penis, he feels an intense and highly pleasurable pulsating sensation of neuromuscular euphoria. These pulsating sensations originates from the contractions of pelvic floor muscles that begin in the anal sphincter and travels to the tip of the penis, commonly described as a "throbbing" or "tingling" sensation. They eventually increase in speed and intensity as the orgasm approaches, until a final "plateau" (the orgasmic) pleasure sustained for several seconds.During orgasm, a human male experiences rapid, rhythmic contractions of the anal sphincter, the prostate, and the bulbospongiosus muscles of the penis. The sperm are transmitted up the vas deferens from the testicles, into the prostate gland as well as through the seminal vesicles to produce what is known as semen. The prostate produces a secretion that forms one of the components of ejaculate. Except for in cases of a dry orgasm, contraction of the sphincter and prostate force stored semen to be expelled through the peniss urethral opening. The process takes from three to ten seconds, and produces a pleasurable feeling. Ejaculation may continue for a few seconds after the euphoric sensation gradually tapers off. It is believed that the exact feeling of "orgasm" varies from one man to another.  After ejaculation, a refractory period usually occurs, during which a man cannot achieve another orgasm. This can last anywhere from less than a minute to several hours or days, depending on age and other individual factors.

Females
A womans orgasm may, in some cases, last a little longer than a mans. Womens orgasms have been estimated to last, on average, approximately 20 seconds, and to consist of a series of muscular contractions in the pelvic area that includes the vagina, the uterus, and the anus. For some women, on some occasions, these contractions begin soon after the woman reports that the orgasm has started and continue at intervals of about one second with initially increasing, and then reducing, intensity. In some instances, the series of regular contractions is followed by a few additional contractions or shudders at irregular intervals. In other cases, the woman reports having an orgasm, but no pelvic contractions are measured at all.Womens orgasms are preceded by erection of the clitoris and moistening of the opening of the vagina. Some women exhibit a sex flush, a reddening of the skin over much of the body due to increased blood flow to the skin. As a woman nears orgasm, the clitoral glans retracts under the clitoral hood, and the labia minora (inner lips) become darker. As orgasm becomes imminent, the outer third of the vagina tightens and narrows, while overall the vagina lengthens and dilates and also becomes congested from engorged soft tissue.Elsewhere in the body, myofibroblasts of the nipple-areolar complex contract, causing erection of the nipples and contraction of the areolar diameter, reaching their maximum at the start of orgasm. A woman experiences full orgasm when her uterus, vagina, anus, and pelvic muscles undergo a series of rhythmic contractions. Most women find these contractions very pleasurable.
Researchers from the University Medical Center of Groningen in the Netherlands correlated the sensation of orgasm with muscular contractions occurring at a frequency of 8–13 Hz centered in the pelvis and measured in the anus. They argue that the presence of this particular frequency of contractions can distinguish between voluntary contraction of these muscles and spontaneous involuntary contractions, and appears to more accurately correlate with orgasm as opposed to other metrics like heart rate that only measure excitation. They assert that they have identified "[t]he first objective and quantitative measure that has a strong correspondence with the subjective experience that orgasm ultimately is" and state that the measure of contractions that occur at a frequency of 8–13 Hz is specific to orgasm. They found that using this metric they could distinguish from rest, voluntary muscular contractions, and even unsuccessful orgasm attempts.Since ancient times in Western Europe, women could be medically diagnosed with a disorder called female hysteria, the symptoms of which included faintness, nervousness, insomnia, fluid retention, heaviness in abdomen, muscle spasm, shortness of breath, irritability, loss of appetite for food or sex, and "a tendency to cause trouble". Women considered suffering from the condition would sometimes undergo "pelvic massage" — stimulation of the genitals by the doctor until the woman experienced "hysterical paroxysm" (i.e., orgasm). Paroxysm was regarded as a medical treatment, and not a sexual release. The disorder has ceased to be recognized as a medical condition since the 1920s.

Brain
There have been very few studies correlating orgasm and brain activity in real time. One study examined 12 healthy women using a positron emission tomography (PET) scanner while they were being stimulated by their partners. Brain changes were observed and compared between states of rest, sexual stimulation, faked orgasm, and actual orgasm. Differences were reported in the brains of men and women during stimulation. However, changes in brain activity were observed in both sexes in which the brain regions associated with behavioral control, fear and anxiety shut down. Regarding these changes, Gert Holstege said in an interview with The Times, "What this means is that deactivation, letting go of all fear and anxiety, might be the most important thing, even necessary, to have an orgasm."While stroking the clitoris, the parts of the female brain responsible for processing fear, anxiety and behavioral control start to diminish in activity. This reaches a peak at orgasm when the female brains emotion centers are effectively closed down to produce an almost trance-like state. Holstege is quoted as saying, at the 2005 meeting of the European Society for Human Reproduction and Development: "At the moment of orgasm, women do not have any emotional feelings."However, a subsequent report by Rudie Kortekaas, et al. stated, "Gender commonalities were most evident during orgasm... From these results, we conclude that during the sexual act, differential brain responses across genders are principally related to the stimulatory (plateau) phase and not to the orgasmic phase itself."Research has shown that as in women, the emotional centers of a mans brain also become deactivated during orgasm but to a lesser extent than in women. Brain scans of both sexes have shown that the pleasure centers of a mans brain show more intense activity than in women during orgasm.Male and female brains demonstrate similar changes during orgasm, with brain activity scans showing a temporary decrease in the metabolic activity of large parts of the cerebral cortex with normal or increased metabolic activity in the limbic areas of the brain.EEG tracings from volunteers during orgasm were first obtained by Mosovich and Tallaferro in 1954. These research workers recorded EEG changes resembling petit mal or the clonic phase of a grand mal seizure. Further studies in this direction were carried out by Sem-Jacobsen (1968), Heath (1972), Cohen et al. (1976), and others. Sarrel et al. reported a similar observation in 1977. These reports continue to be cited. Unlike them, Craber et al. (1985) failed to find any distinctive EEG changes in four men during masturbation and ejaculation; the authors concluded that the case for the existence of EEG changes specifically related to sexual arousal and orgasm remained unproven. So disagreement arises as to whether the experiment conducted by Mosovich & Tallaferro casts a new light on the nature of orgasm. In some recent studies, authors tend to adopt the opposite point of view that there are no remarkable EEG changes during ejaculation in humans.

Health
General
Orgasm, and sexual activity as a whole, are physical activities that can require exertion of many major bodily systems. A 1997 study in the BMJ based upon 918 men age 45–59 found that after a ten-year follow-up, men who had fewer orgasms were twice as likely to die of any cause as those having two or more orgasms a week. A follow-up in 2001 which focused more specifically on cardiovascular health found that having sex three or more times a week was associated with a 50% reduction in the risk of heart attack or stroke.
There is some research suggesting that greater resting heart rate variability is associated with orgasms through penile-vaginal intercourse without additional simultaneous clitoral stimulation.A small percentage of men have a disease called postorgasmic illness syndrome (POIS), which causes severe muscle pain throughout the body and other symptoms immediately following ejaculation. The symptoms last for up to a week. Some doctors speculate that the frequency of POIS "in the population may be greater than has been reported in the academic literature", and that many POIS sufferers are undiagnosed.

Dysfunction and satisfaction
The inability to have orgasm, or regular difficulty reaching orgasm after ample sexual stimulation, is called anorgasmia or inorgasmia. If a male experiences erection and ejaculation but no orgasm, he is said to have sexual anhedonia (a condition in which an individual cannot feel pleasure from an orgasm) or ejaculatory anhedonia. Anorgasmia is significantly more common in women than in men, which has been attributed to the lack of sex education with regard to womens bodies, especially in sex-negative cultures, such as clitoral stimulation usually being key for women to orgasm.Approximately 25% of women report difficulties with orgasm, 10% of women have never had an orgasm, and 40% or 40–50% have either complained about sexual dissatisfaction or experienced difficulty becoming sexually aroused at some point in their lives. A 1994 study by Laumann et al. found that 75.0% of men and 28.6% of women always had orgasms with their spouse, while 40.2% of men and 79.7% of women thought their spouse always orgasmed during sex. These rates were different in non-marital straight relationships (cohabitational, long-term and short-term heterosexual relationships), with rates increasing to 80.5% for men and 43.0% for women orgasming during sex with their short-term partners, and 69.3% for men and 82.6% for women thinking their short-term partners always orgasmed. Women are much more likely to be nearly always or always orgasmic when alone than with a partner. However, in a 1996 study by Davis et al., 62% of women in a partnered relationship said they were satisfied with the frequency/consistency of their orgasms. Additionally, some women express that their most satisfying sexual experiences entail being connected to someone, rather than solely basing satisfaction on orgasm.Kinseys 1953 Sexual Behavior in the Human Female showed that, over the previous five years of sexual activity, 78% of women had orgasms in 60% to 100% of sexual encounters with other women, compared with 55% for heterosexual sex. Kinsey attributed this difference to female partners knowing more about womens sexuality and how to optimize womens sexual satisfaction than male partners do. Like Kinsey, scholars such as Peplau, Fingerhut and Beals (2004) and Diamond (2006) found that lesbians have orgasms more often and more easily in sexual interactions than heterosexual women do, and that female partners are more likely to emphasize the emotional aspects of lovemaking. In contrast, research by Diane Holmberg and Karen L. Blair (2009), published in the Journal of Sex Research, found that women in same-sex relationships enjoyed identical sexual desire, sexual communication, sexual satisfaction, and satisfaction with orgasm as their heterosexual counterparts.Specifically in relation to simultaneous orgasm and similar practices, many sexologists claim that the problem of premature ejaculation is closely related to the idea encouraged by a scientific approach in the early 20th century when mutual orgasm was overly emphasized as an objective and a sign of true sexual satisfaction in intimate relationships.
If orgasm is desired, anorgasmia may be attributed to an inability to relax. It may be associated with performance pressure and an unwillingness to pursue pleasure, as separate from the other persons satisfaction; often, women worry so much about the pleasure of their partner that they become anxious, which manifests as impatience with the delay of orgasm for them. This delay can lead to frustration of not reaching orgasmic sexual satisfaction. Psychoanalyst Wilhelm Reich, in his 1927 book Die Funktion des Orgasmus (published in English in 1980 as Genitality in the Theory and Therapy of Neurosis) was the first to make orgasm central to the concept of mental health, and defined neurosis in terms of blocks to having orgastic potency. Although orgasm dysfunction can have psychological components, physiological factors often play a role. For instance, delayed orgasm or the inability to achieve orgasm is a common side effect of many medications.
Menopause may involve loss of hormones supporting sexuality and genital functionality. Vaginal and clitoral atrophy and dryness affects up to 50%–60% of postmenopausal women. Testosterone levels in men fall as they age. Sexual dysfunction overall becomes more likely with poor physical and emotional health. "Negative experiences in sexual relationships and overall well-being" are associated with sexual dysfunction.

Theoretical biological and evolutionary functions of female orgasm
Shifts in research
The function or functions of the human female orgasm have been debated among researchers. Researchers have several hypotheses about the role, if any, of the female orgasm in the reproductive and therefore evolutionary process. The literature started with the argument that female orgasm is a byproduct of shared early male ontogeny, where male orgasm is an adaptation. Research has shifted to investigate and also support the sire-choice hypothesis, which proposes that female orgasm has been shaped by natural selection to function in the selection of high quality sires (male parents) for offspring. Therefore, orgasm increases the chances of conceiving with males of a high genetic quality. Research by Randy Thornhill et al. (1995) suggested that female orgasm is more frequent during intercourse with a male partner with low fluctuating asymmetry.

Selective pressure and mating
Wallen K and Lloyd EA stated, "In men, orgasms are under strong selective pressure as orgasms are coupled with ejaculation and thus contribute to male reproductive success. By contrast, womens orgasms in intercourse are highly variable and are under little selective pressure as they are not a reproductive necessity."Desmond Morris suggested in his 1967 popular-science book The Naked Ape that the female orgasm evolved to encourage physical intimacy with a male partner and help reinforce the pair bond. Morris suggested that the relative difficulty in achieving female orgasm, in comparison to the males, might be favorable in Darwinian evolution by leading the female to select mates who bear qualities like patience, care, imagination, and intelligence, as opposed to qualities like size and aggression, which pertain to mate selection in other primates. Such advantageous qualities thereby become accentuated within the species, driven by the differences between male and female orgasm. If males were motivated by, and taken to the point of, orgasm in the same way as females, those advantageous qualities would not be needed, since self-interest would be enough.

Fertility
There are theories that the female orgasm might increase fertility. For example, it has been suggested that the 30% reduction in size of the vagina could help clench onto the penis (much like, or perhaps caused by, the pubococcygeus muscles), which would make it more stimulating for the male (thus ensuring faster or more voluminous ejaculation). The British biologists Baker and Bellis have suggested that the female orgasm may have a peristalsis or "upsuck" action (similar to the esophagus ability to swallow when upside down), resulting in the retaining of favorable sperm and making conception more likely. They posited a role of female orgasm in sperm competition.
The observation that women tend to reach orgasm more easily when they are ovulating also has led to the suggestion that it is tied to increasing fertility. Evolutionary biologist Robin Baker argues in Sperm Wars that occurrence and timing of orgasms are all a part of the female bodys unconscious strategy to collect and retain sperm from more evolutionary fit men. This theory suggests that an orgasm during intercourse functions as a bypass button to a womans natural cervical filter against sperm and pathogens, and that an orgasm before functions to strengthen the filter.
Desmond Morris proposed that orgasm might facilitate conception by exhausting the female and keeping her horizontal, thus preventing the sperm from leaking out. This possibility, sometimes called the "Poleaxe Hypothesis" or the "Knockout Hypothesis",  is now considered unlikely. A 1994 Learning Channel documentary on sex had fiber optic cameras inside the vagina of a woman while she had sexual intercourse. During her orgasm, her pelvic muscles contracted and her cervix repeatedly dipped into a pool of semen in the vaginal fornix, which might ensure that sperm would proceed by the external orifice of the uterus, making conception more likely.Evolutionary psychologists Christopher Ryan and Cacilda Jethá, in their discussion of the female orgasm, address how long it takes for females to achieve orgasm compared to males, and females ability to have multiple orgasms, hypothesizing how especially well suited to multiple partners and insemination this is. They quote primate sexuality specialist Alan Dixson in saying that the monogamy-maintenance explanation for female orgasm "seems far-fetched" because "females of other primate species, and particularly those with multimale-multifemale [promiscuous] mating systems such as macaques and chimpanzees, exhibit orgasmic responses in the absence of such bonding or the formation of stable family units." On the other hand, Dixson states that "Gibbons, which are primarily monogamous, do not exhibit obvious signs of female orgasm."The female promiscuity explanation of female sexuality was echoed at least 12 years earlier by other evolutionary biologists, and there is increasing scientific awareness of the female proceptive phase. Though Dixson classifies humans as mildly polygynous in his survey of primate sexuality, he appears to have doubts, when he writes, "One might argue that ... the females orgasm is rewarding, increases her willingness to copulate with a variety of males rather than one partner, and thus promotes sperm competition." Ryan and Jethá use this as evidence for their theory that partible paternity and promiscuity were common for early modern humans.

Adaptive or vestigial
The clitoris is homologous to the penis; that is, they both develop from the same embryonic structure. While researchers such as Geoffrey Miller, Helen Fisher, Meredith Small and Sarah Blaffer Hrdy "have viewed the clitoral orgasm as a legitimate adaptation in its own right, with major implications for female sexual behavior and sexual evolution," others, such as Donald Symons and Stephen Jay Gould, have asserted that the clitoris is vestigial or nonadaptive, and that the female orgasm serves no particular evolutionary function. However, Gould acknowledged that "most female orgasms emanate from a clitoral, rather than vaginal (or some other), site" and stated that his nonadaptive belief "has been widely misunderstood as a denial of either the adaptive value of female orgasm in general, or even as a claim that female orgasms lack significance in some broader sense". He explained that although he accepts that "clitoral orgasm plays a pleasurable and central role in female sexuality and its joys," "[a]ll these favorable attributes, however, emerge just as clearly and just as easily, whether the clitoral site of orgasm arose as a spandrel or an adaptation". He said that the "male biologists who fretted over [the adaptionist questions] simply assumed that a deeply vaginal site, nearer the region of fertilization, would offer greater selective benefit" due to their Darwinian, summum bonum beliefs about enhanced reproductive success.Proponents of the nonadaptive hypothesis, such as Elisabeth Lloyd, refer to the relative difficulty of achieving female orgasm through vaginal sex, the limited evidence for increased fertility after orgasm and the lack of statistical correlation between the capacity of a woman to orgasm and the likelihood that she will engage in intercourse. "Lloyd is by no means against evolutionary psychology. Quite the opposite; in her methods and in her writing, she advocates and demonstrates a commitment to the careful application of evolutionary theory to the study of human behavior," stated Meredith L. Chivers. She added that Lloyd "meticulously considers the theoretical and empirical bases for each account and ultimately concludes that there is little evidence to support an adaptionist account of female orgasm" and that Lloyd instead "views female orgasm as an ontogenetic leftover; women have orgasms because the urogenital neurophysiology for orgasm is so strongly selected for in males that this developmental blueprint gets expressed in females without affecting fitness, just as males have nipples that serve no fitness-related function".A 2005 twin study found that one in three women reported never or seldom achieving orgasm during sexual intercourse, and only one in ten always orgasmed. This variation in ability to orgasm, generally thought to be psychosocial, was found to be 34% to 45% genetic. The study, examining 4000 women, was published in Biology Letters, a Royal Society journal. Elisabeth Lloyd has cited this as evidence for the notion that female orgasm is not adaptive.Miller, Hrdy, Helen OConnell and Natalie Angier have criticized the "female orgasm is vestigial" hypothesis as understating and devaluing the psychosocial value of the female orgasm. Hrdy stated that the hypothesis smacks of sexism. OConnell said, "It boils down to rivalry between the sexes: the idea that one sex is sexual and the other reproductive. The truth is that both are sexual and both are reproductive." OConnell used MRI technology to define the true size and shape of the clitoris, suggesting that it extends into the anterior wall of the vagina (see above).
OConnell describes typical textbook descriptions of the clitoris as lacking detail and including inaccuracies, saying that the work of Georg Ludwig Kobelt in the early 19th century provides a most comprehensive and accurate description of clitoral anatomy. She argues that the bulbs appear to be part of the clitoris and that the distal urethra and vagina are intimately related structures, although they are not erectile in character, forming a tissue cluster with the clitoris that appears to be the center of female sexual function and orgasm. By contrast, Nancy Tuana, at the 2002 conference for Canadian Society of Women in Philosophy, argues that the clitoris is unnecessary in reproduction, but that this is why it has been "historically ignored", mainly because of "a fear of pleasure. It is pleasure separated from reproduction. Thats the fear". She reasoned that this fear is the cause of the ignorance that veils female sexuality.

Fringe theories
Brody Costa et al. suggest that womens vaginal orgasm consistency is associated with being told in childhood or adolescence that the vagina is the important zone for inducing female orgasm. Other proposed factors include how well women focus mentally on vaginal sensations during penile-vaginal intercourse, the greater duration of intercourse, and preference for above-average penis length. Costa theorizes that vaginal orgasm is more prevalent among women with a prominent tubercle of the upper lip. His research indicates that "[a] prominent and sharply raised lip tubercle has been associated with greater odds (odds ratio = 12.3) of ever having a vaginal orgasm, and also with greater past month vaginal orgasm consistency (an effect driven by the women who never had a vaginal orgasm), than less prominent lip tubercle categories." However, lip tubercle was not associated with social desirability responding, or with orgasm triggered by masturbation during penile-vaginal sex, solitary or partner clitoral or vaginal masturbation, vibrator, or cunnilingus.An empirical study carried out in 2008 provides evidence for Freuds implied link between inability to have a vaginal orgasm and psychosexual immaturity. In the study, women reported their past month frequency of different sexual behaviors and corresponding orgasm rates and completed the Defense Style Questionnaire (DSQ-40), which is associated with various psychopathologies. The study concluded that a "vaginal orgasm was associated with less somatization, dissociation, displacement, autistic fantasy, devaluation, and isolation of affect." Moreover, "vaginally anorgasmic women had immature defenses scores comparable to those of established (depression, social anxiety disorder, panic disorder, and obsessive–compulsive disorder) outpatient psychiatric groups." In the study, a vaginal orgasm (as opposed to a clitoral orgasm) was defined as being triggered solely by penile–vaginal intercourse. According to Wilhelm Reich, the lack of womens capacity to have a vaginal orgasm is due to a lack of orgastic potency, which he believed to be the result of cultures suppression of genital sexuality.

Involuntary orgasm
Medical research shows that the genital reflex is also regulated by the spinal cord, and not necessarily under conscious control.An involuntary orgasm may occur as the result of sexual assault or rape, which may result in feelings of shame caused by internalization of victim-blaming attitudes. The incidence of those who experience unsolicited sexual contact and experience orgasm is very low, though possibly under-reported due to shame or embarrassment of the victim. Such orgasms may happen to either gender.An unwanted orgasm may arise from a persistent genital arousal disorder.
In consensual BDSM play, forced orgasm may be practised to exercise orgasm control.

Tantric sex
Tantric sex, which is not the same as Buddhist tantra (Vajrayana), is the ancient Indian spiritual tradition of sexual practices. It attributes a different value to orgasm than traditional cultural approaches to sexuality. Some practitioners of tantric sex aim to eliminate orgasm from sexual intercourse by remaining for a long time in the pre-orgasmic and non-emission state. Advocates of this, such as Rajneesh, claim that it eventually causes orgasmic feelings to spread out to all of ones conscious experience.Advocates of tantric and neotantric sex who claim that Western culture focuses too much on the goal of climactic orgasm, which reduces the ability to have intense pleasure during other moments of the sexual experience, suggest that eliminating this enables a richer, fuller and more intense connection.

Literature
Orgasm has been widely described in literature over the centuries. In antiquity, Latin literature addressed the subject as much as Greek literature: Book III of Ovids Metamorphoses retells a discussion between Jove and Juno, in which the former states: "The sense of pleasure in the male is far / More dull and dead, than what you females share." Juno rejects this thought; they agree to ask the opinion of Tiresias ("who had known Venus/Love in both ways," having lived seven years as a female). Tiresias offends Juno by agreeing with Jove, and she strikes him blind on the spot (Jove lessens the blow by giving Tiresias the gift of foresight, and a long life). Earlier, in the Ars Amatoria, Ovid states that he abhors sexual intercourse that fails to complete both partners.The theme of orgasm survived during Romanticism and is incorporated in many homoerotic works. In FRAGMENT: Supposed to be an Epithalamium of Francis Ravaillac and Charlotte Cordé, Percy Bysshe Shelley (1792–1822), "a translator of extraordinary range and versatility", wrote the phrase "No life can equal such a death." That phrase has been seen as a metaphor for orgasm, and it was preceded by the rhythmic urgency of the previous lines "Suck on, suck on, I glow, I glow!", which has been seen as alluding to fellatio. For Shelley, orgasm was "the almost involuntary consequences of a state of abandonment in the society of a person of surpassing attractions". Edward Ellerker Williams, the last love of Shelleys life, was remembered by the poet in "The Boat on the Serchio", which has been considered as possibly "the grandest portrayal of orgasm in literature":Shelley, in this poem, associates orgasm with death when he writes "the death which lovers love". In French literature, the term la petite mort (the little death) is a famous euphemism for orgasm; it is the representation of man who forgets himself and the world during orgasm. Jorge Luis Borges, in the same vision, wrote in one of the several footnotes of "Tlön, Uqbar, Orbis Tertius" that one of the churches of Tlön claims Platonically that "All men, in the vertiginous moment of coitus, are the same man. All men who repeat a line from Shakespeare are William Shakespeare." Shakespeare himself was knowledgeable of this idea: lines "I will live in thy heart, die in thy lap, and be buried in thy eyes" and "I will die bravely, like a smug bridegroom", said respectively by Benedick in Much Ado About Nothing and by King Lear in the play of that ilk, are interpreted as "to die in a womans lap" = "to experience a sexual orgasm". Sigmund Freud with his psychoanalytic projects, in The Ego and the Id (1923), speculates that sexual satisfaction by orgasm make Eros ("life instinct") exhausted and leaves the field open to Thanatos ("death instinct"), in other words, with orgasm Eros fulfills its mission and gives way to Thanatos. Other modern authors have chosen to represent the orgasm without metaphors. In the novel Lady Chatterleys Lover (1928), by D. H. Lawrence, we can find an explicit narrative of a sexual act between a couple: "As he began to move, in the sudden helpless orgasm there awoke in her strange thrills rippling inside her..."

Other animals
The mechanics of male orgasm are similar in most male mammals. Females of some mammal and some non-mammal species, such as alligators, have clitorises. There has been ongoing research about the sexuality of dolphins, one of many species which engage in sexual intercourse for reasons other than reproduction. The duration of orgasm varies considerably among different mammal species.

See also
References
Further reading
Banker-Riskin, Anita; Grandinetti, Deborah (1997). Simultaneous Orgasm: And Other Joys of Sexual Intimacy. Hunter House. ISBN 0-89793-221-8, ISBN 978-0-89793-221-9.
Gabriele Froböse, Rolf Froböse, Michael Gross (Translator): Lust and Love: Is it More than Chemistry? Publisher: Royal Society of Chemistry, ISBN 0-85404-867-7, (2006).
Komisaruk, Barry R.; Beyer-Flores, Carlos; Whipple, Beverly (2006). The Science of Orgasm. Baltimore, MD: The Johns Hopkins University Press. ISBN 9780801888953. OCLC 614506284.
PARTRIDGE, Eric (2001) </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 Marjolins ulcer 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 Spastic diplegia and can you explain it in depth? [/INST] Spastic diplegia is a form of cerebral palsy (CP) that is a chronic neuromuscular condition of hypertonia and spasticity—manifested as an especially high and constant "tightness" or "stiffness"—in the muscles of the lower extremities of the human body, usually those of the legs, hips and pelvis. Doctor William John Littles first recorded encounter with cerebral palsy is reported to have been among children who displayed signs of spastic diplegia.
Spastic diplegia accounts for about 22% of all diagnoses of cerebral palsy, and together with spastic quadriplegia and spastic triplegia make up the broad classification spastic cerebral palsy, which accounts for 70% of all cerebral palsy diagnoses.

Presentation
Individuals with spastic diplegia are very tight and stiff and must work very hard to successfully resist and "push through" the extra tightness they perpetually experience. Other than this, however, these individuals are almost always normal in every significant clinical sense. When they are younger, spastic diplegic individuals typically undergo gait analysis so that their clinicians can determine the best assistive devices for them, if any are necessary, such as a walker or crutches. The main difference between spastic diplegia and a normal gait pattern is its signature "scissor gait"—a style that some non-disabled people might tend to confuse with the effects of drunkenness, multiple sclerosis, or another nerve disease. The degree of spasticity in spastic diplegia (and, for that matter, other types of spastic CP) varies widely from person to person. No two people with spastic diplegia are exactly alike. Balance problems and/or stiffness in gait can range from barely noticeable all the way to misalignments so pronounced that the person needs crutches (typically forearm crutches/lofstrand crutches) or a cane / walking stick to assist in ambulation. Less often, spasticity is severe enough to compel the person to use a wheelchair. In general, however, lower-extremity spasticity in spastic diplegia is rarely so great as to totally prevent ambulation—most people with the condition can walk, and can do so with at least a basic amount of overall stability. Regardless, from case to case, steeply varying degrees of imbalance, potential tripping over uneven terrain while walking, or needing to hold on to various surfaces or walls in certain circumstances to keep upright, are typically ever-present potential issues and are much more common occurrences amongst those with spastic diplegia than among those with a normal or near-normal gait pattern. Among some of the people with spastic diplegia who choose to be ambulatory on either an exclusive or predominant basis, one of the seemingly common lifestyle choices is for the person to ambulate within his or her home without an assistive device, and then to use the assistive device, if any, once outdoors. Others may use no assistive device in any indoor situation at all, while always using one when outdoors. Above the hips, persons with spastic diplegia typically retain normal or near-normal muscle tone and range of motion, though some lesser spasticity may also affect the upper body, such as the trunk and arms, depending on the severity of the condition in the individual (the spasticity condition affecting the whole body equally, rather than just the legs, is spastic quadriplegia, a slightly different classification). In addition, because leg tightness often leads to instability in ambulation, extra muscle tension usually develops in the shoulders, chest, and arms due to compensatory stabilisation movements, regardless of the fact that the upper body itself is not directly affected by the condition.

Social implications
Although the term "spastic" technically describes the attribute of spasticity in spastic cerebral palsy and was originally an acceptable and common term to use in both self-description and in description by others, it has since gained more notoriety as a pejorative, in particular when used in pop culture to insult non-disabled people when they seem overly anxious or unskilled in sports (see also the article Spastic (word)).
In 1952, a UK charitable organization with a membership mainly of those with spastic CP was formed; this organization called itself The Spastics Society. However, the charity changed its name to Scope in 1994 due to the term spastics having become enough of a pejorative to warrant the name change.Spastic diplegias social implications tend to vary with the intensity of the condition in the individual. If its effects are severely disabling, resulting in very little physical activity for the person, social elements can also suffer. Workplace environments can also be limited, since most labor-intensive work requires basic physical agility that spastic diplegics may not possess. However, the degree of variability among individuals with spastic diplegia means that no greater or lesser degree of stigma or real-world limitation is standard. Lesser effects usually mean fewer physical limitations, better-quality exercise, and more real-world flexibility, but the person is still in general seen as different from the norm. How such a person chooses to react to outside opinion is of paramount importance when social factors are considered.

Mechanism
Spastic diplegias particular type of brain damage inhibits the proper development of upper motor neuron function, impacting the motor cortex, the basal ganglia and the corticospinal tract. Nerve receptors in the spine leading to affected muscles become unable to properly absorb gamma amino butyric acid (GABA), the amino acid that regulates muscle tone in humans. Without GABA absorption to those particular nerve rootlets (usually centred, in this case, around the sectors L1-S1 and L2-S2), affected nerves (here, the ones controlling the legs) perpetually fire the message for their corresponding muscles to permanently, rigidly contract, and the muscles become permanently hypertonic (spastic).The abnormally high muscle tone that results creates lifelong difficulty with all voluntary and passive movement in the legs, and in general creates stress over time—depending on the severity of the condition in the individual, the constant spasticity ultimately produces pain, muscle/joint breakdown including tendinitis and arthritis, premature physical exhaustion (i.e., becoming physically exhausted even when you internally know that you have more energy than you are able to use), contractures, spasms, and progressively worse deformities/mis-alignments of bone structure around areas of the tightened musculature as the persons years progress. Severe arthritis, tendinitis, and similar breakdown can start as early as the spastic diplegic persons mid-20s (as a comparison, typical people with normal muscle tone are not at risk of arthritis, tendinitis, and similar breakdown until well into their 50s or 60s, if even then).No type of CP is officially a progressive condition, and indeed spastic diplegia does not clinically "get worse" given the nerves, damaged permanently at birth, neither recover nor degrade. This aspect is clinically significant because other neuromuscular conditions with similar surface characteristics in their presentations, like most forms of multiple sclerosis, indeed do degrade the body over time and do involve actual progressive worsening of the condition, including the spasticity often seen in MS. However, spastic diplegia is indeed a chronic condition; the symptoms themselves cause compounded effects on the body that are typically just as stressful on the human body as a progressive condition is. Despite this reality and the fact that muscle tightness is the symptom of spastic diplegia and not the cause, symptoms rather than cause are typically seen as the primary area of focus for treatment, especially surgical treatment, except when a selective dorsal rhizotomy is brought into consideration, or when an oral baclofen regimen is attempted.Unlike any other condition that may present with similar effects, spastic diplegia is entirely congenital in origin—that is, it is almost always acquired shortly before or during a babys birth process. Things like exposure to toxins, traumatic brain injury, encephalitis, meningitis, drowning, or suffocation do not tend to lead to spastic diplegia in particular or even cerebral palsy generally. Overall, the most common cause of spastic diplegia is Periventricular leukomalacia, more commonly known as neonatal asphyxia or infant hypoxia—a sudden in-womb shortage of oxygen-delivery through the umbilical cord. This sudden lack of oxygen is also almost always combined with premature birth, a phenomenon that, even by itself, would inherently risk the infant developing some type of CP. On the other hand, the presence of certain maternal infections during pregnancy such as congenital rubella syndrome can also lead to spastic diplegia, since such infections can have similar end results to infant hypoxia.

Treatment
As a matter of everyday maintenance, muscle stretching, range of motion exercises, yoga, contact improvisation, modern dance, resistance training, and other physical activity regimens are often utilized by those with spastic CP to help prevent contractures and reduce the severity of symptoms.

Major clinical treatments for spastic diplegia are:
Baclofen (and its derivatives), a gamma amino butyric acid (GABA) substitute in oral (pill-based) or intrathecal form. Baclofen is essentially chemically identical to the GABA that the damaged, over-firing nerves cannot absorb, except that it has an extra chemical marker on it that makes the damaged nerves think it is a different compound, and thus those nerves will absorb it. Baclofen is noted for being the sole medication available for GABA-deficiency-based spasticity which acts on the actual cause of the spasticity rather than simply reducing symptomatology as muscle relaxants and painkillers do. The intrathecal solution is a liquid injected into the spinal fluid for trial, and if successful in reducing spasticity, thereafter administered via an intrathecal pump, which has variously been proven potentially very dangerous on one or another level with long-term use (see article), including sudden and potentially lethal baclofen overdose, whereas the oral route, which comes in 10- or 20-milligram tablets and the dosage of which can be gently titrated either upward or downward, as well as safely ceased entirely, has not.
Antispasmodic muscle relaxant chemicals such as tizanidine and botulinum toxin (Botox), injected directly into the spastic muscles; Botox wears off every three months.
Phenol and similar chemical nerve deadeners, injected selectively into the over-firing nerves in the legs on the muscle end to reduce spasticity in their corresponding muscles by preventing the spasticity signals from reaching the legs; Phenol wears off every six months.
Orthopedic surgery to release the spastic muscles from their hypertonic state, a usually temporary result because the spasticity source is the nerves, not the muscles; spasticity can fully reassert itself as little as one year post-surgery.
Selective dorsal rhizotomy, a neurosurgery directly targeting and eliminating ("cutting" or "lesioning") the over-firing nerve rootlets and leaving the properly firing ones intact, thereby permanently eliminating the spasticity but compelling the person to spend months re-strengthening muscles that will have been severely weakened by the loss of the spasticity, due to the fact of those muscles not really having had actual strength to begin with.

Prognosis
Unusually, cerebral palsy, including spastic cerebral palsy, is notable for a glaring overall research deficiency—the fact that it is one of the very few major groups of conditions on the planet in human beings for which medical science has not yet (as of 2011) collected wide-ranging empirical data on the development and experiences of young adults, the middle aged and older adults. An especially puzzling aspect of this lies in the fact that cerebral palsy as defined by modern science was first discovered and specifically addressed well over 100 years ago and that it would therefore be reasonable to expect by now that at least some empirical data on the adult populations with these conditions would have long since been collected, especially over the second half of the 20th century when existing treatment technologies rapidly improved and new ones came into being. The vast majority of empirical data on the various forms of cerebral palsy is concerned near-exclusively with children (birth to about 10 years of age) and sometimes pre-teens and early teens (11-13). Some doctors attempt to provide their own personal justifications for keeping their CP specialities purely paediatric, but there is no objectively apparent set of reasons backed by any scientific consensus as to why medical science has made a point of researching adult cases of multiple sclerosis, muscular dystrophy and the various forms of cancer in young and older adults, but has failed to do so with CP. There are a few orthopaedic surgeons and neurosurgeons who claim to be gathering pace with various studies as of the past few years, but these claims do not yet seem to have been matched by real-world actualisation in terms of easily accessible and objectively verifiable resources available to the general public on the internet and in-person, where many, including medical-science researchers and doctors themselves, would more than likely agree such resources would ideally belong.

Prevalence
In the industrialized world, the incidence of overall cerebral palsy, which includes but is not limited to spastic diplegia, is about 2 per 1000 live births. Thus far, there is no known study recording the incidence of CP in the overall nonindustrialized world. Therefore, it is safe to assume that not all spastic CP individuals are known to science and medicine, especially in areas of the world where healthcare systems are less advanced. Many such individuals may simply live out their lives in their local communities without any medical or orthopedic oversight at all, or with extremely minimal such treatment, so that they are never able to be incorporated into any empirical data that orthopedic surgeons or neurosurgeons might seek to collect. It is shocking to note that—as with people with physical disability overall—some may even find themselves in situations of institutionalization, and thus barely see the outside world at all.
From what is known, the incidence of spastic diplegia is higher in males than in females; the Surveillance of Cerebral Palsy in Europe (SCPE), for example, reports a M:F ratio of 1.33:1. Variances in reported rates of incidence across different geographical areas in industrialized countries are thought to be caused primarily by discrepancies in the criteria used for inclusion and exclusion.
When such discrepancies are taken into account in comparing two or more registers of patients with cerebral palsy and also the extent to which children with mild cerebral palsy are included, the incidence rates still converge toward the average rate of 2:1000.
In the United States, approximately 10,000 infants and babies are born with CP each year, and 1200–1500 are diagnosed at preschool age when symptoms become more obvious. Those with extremely mild spastic CP may not even be aware of their condition until much later in life: Internet chat forums have recorded men and women as old as 30 who were diagnosed only recently with their spastic CP.
Overall, advances in care of pregnant mothers and their babies have not resulted in a noticeable decrease in CP; in fact, because medical advances in areas related to the care of premature babies have resulted in a greater survival rate in recent years, it is actually more likely for infants with cerebral palsy to be born into the world now than it would have been in the past. Only the introduction of quality medical care to locations with less-than-adequate medical care has shown any decreases in the incidences of CP; the rest either have shown no change or have actually shown an increase. The incidence of CP increases with premature or very low-weight babies regardless of the quality of care.

See also
Inclusion (disability rights)
Cerebral palsy
Spasticity
Gamma amino butyric acid
Rhizotomy
Tizanidine

References
Further reading
Miller, F.; Bachrach, S.J. (2006). Cerebral Palsy A Complete Guide for Caregiving (2nd ed.). Johns Hopkins University Press </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 Phosphene and can you explain it in depth? [/INST] A phosphene is the phenomenon of seeing light without light entering the eye. The word phosphene comes from the Greek words phos (light) and phainein (to show).  Phosphenes that are induced by movement or sound may be associated with optic neuritis.Phosphenes can be induced by mechanical, electrical, or magnetic stimulation of the retina or visual cortex, or by random firing of cells in the visual system. Phosphenes have also been reported by meditators (called nimitta), people who endure long periods without visual stimulation (the prisoners cinema), or those who ingest psychedelic drugs.

Causes
Mechanical stimulation
The most common phosphenes are pressure phosphenes, caused by rubbing or applying pressure on or near the closed eyes. They have been known since antiquity, and described by the Greeks. The pressure mechanically stimulates the cells of the retina. Experiences include a darkening of the visual field that moves against the rubbing, a diffuse colored patch that also moves against the rubbing, well defined shapes such as bright circles that exist near or opposite to where pressure is being applied, a scintillating and ever-changing and deforming light grid with occasional dark spots (like a crumpling fly-spotted flyscreen), and a sparse field of intense blue points of light. Pressure phosphenes can persist briefly after the rubbing stops and the eyes are opened, allowing the phosphenes to be seen on the visual scene. Hermann von Helmholtz and others have published drawings of their pressure phosphenes. One example of a pressure phosphene is demonstrated by gently pressing the side of ones eye and observing a colored ring of light on the opposite side, as detailed by Isaac Newton.Another common phosphene is "seeing stars" from a sneeze, laughter, a heavy and deep cough, blowing of the nose, a blow on the head or low blood pressure (such as on standing up too quickly or prior to fainting). It is possible these involve some mechanical stimulation of the retina, but they may also involve mechanical and metabolic (such as from low oxygenation or lack of glucose) stimulation of neurons of the visual cortex or of other parts of the visual system.Less commonly, phosphenes can also be caused by some diseases of the retina and nerves, such as multiple sclerosis. The British National Formulary lists phosphenes as an occasional side effect of at least one anti-anginal medication.
The name "phosphene" was coined by J. B. H. Savigny, better known as the ships surgeon of the wrecked French frigate Méduse. It was first employed by Serre dUzes to test retinal function prior to cataract surgery.

Electrical stimulation
Phosphenes have been created by electrical stimulation of the brain, reported by neurologist Otfrid Foerster as early as 1929. Brindley and Lewin (1968) inserted a matrix of stimulating electrodes directly into the visual cortex of a 52-year-old blind female, using small pulses of electricity to create phosphenes. These phosphenes were points, spots, and bars of colorless or colored light. Brindley and Rushton (1974) used the phosphenes to create a visual prosthesis, in this case by using the phosphenes to depict Braille spots.
In recent years, researchers have successfully developed experimental brain–computer interfaces or neuroprostheses that stimulate phosphenes to restore vision to people blinded through accidents. Notable successes include the human experiments by William H. Dobelle and Mark Humayun and animal research by Dick Normann.
A noninvasive technique that uses electrodes on the scalp, transcranial magnetic stimulation, has also been shown to produce phosphenes.Experiments with humans have shown that when the visual cortex is stimulated above the calcarine fissure, phosphenes are produced in the lower part of the visual field, and vice versa.

Others
Phosphenes have been produced by intense, changing magnetic fields, such as with transcranial magnetic stimulation (TMS). These fields can be positioned on different parts of the head to stimulate cells in different parts of the visual system. They also can be induced by alternating currents that entrain neural oscillation as with transcranial alternating current stimulation. In this case they appear in the peripheral visual field. This claim has been disputed. The alternative hypothesis is that current spread from the occipital electrode evokes phosphenes in the retina. Phosphenes created by magnetic fields are known as magnetophosphenes.
Astronauts exposed to radiation in space have reported seeing phosphenes. Patients undergoing radiotherapy have reported seeing blue flashes of light during treatment; the underlying phenomenon has been shown to resemble Cherenkov radiation.Phosphenes can be caused by some medications, such as Ivabradine.

Mechanism
Most vision researchers believe that phosphenes result from the normal activity of the visual system after stimulation of one of its parts from some stimulus other than light. For example, Grüsser et al. showed that pressure on the eye results in activation of retinal ganglion cells in a similar way to activation by light. An ancient, discredited theory is that light is generated in the eye. A version of this theory has been revived, except, according to its author, that "phosphene lights are [supposed to be] due to the intrinsic perception of induced or spontaneous increased biophoton emission of cells in various parts of the visual system (from retina to cortex)"

Anthropological research
In 1988, David Lewis-Williams and T. A. Dowson published an article about phosphenes and other entoptic phenomena. They argued that non-figurative art of the Upper Paleolithic depicts visions of phosphenes and neurological "form constants", probably enhanced by hallucinogenic drugs.

Research
Research has looked into visual prosthesis for the blind, which involves use of arrays of electrodes implanted in the skull over the occipital lobe to produce phosphenes. There have been long term implants of this type. Risks such as infections and seizures, have been an impediment to their development.
A possible use of phosphenes as part of a brain to brain communication system has been reported. The system called BrainNet, produces phosphenes using transcranial magnetic stimulation (TMS). The goal of the research is to connect thoughts brain to brain using a system where signals are detected using electroencephalography (EEG) and  delivered using transcranial magnetic stimulation (TMS). An experiment was conducted with 5 different groups, each contained three people. The subjects were split into two groups. Two subjects functioned as the senders, and were connected to EEG electrodes, and a third person functioned as the receiver, who wore the TMS helmet. Each person was stationed in front of a television screen with a Tetris-style game. The senders had to determine if there was a need to rotate the falling blocks, but without the ability to rotate them – only the receiver was able to perform this operation. At the edges of each screen, were two icons with two flashing lights in two different frequencies, (one at 15 Hz and the other at 17 Hz). The sender focused on one icon, or the other to signal that the block should be rotated to the right or the left </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 Craniofrontonasal dysplasia and can you explain it in depth? [/INST] Craniofrontonasal dysplasia (craniofrontonasal syndrome, craniofrontonasal dysostosis, CFND) is a very rare X-linked malformation syndrome caused by mutations in the ephrin-B1 gene (EFNB1). Phenotypic expression varies greatly amongst affected individuals, where females are more commonly and generally more severely affected than males. Common physical malformations are: craniosynostosis of the coronal suture(s), orbital hypertelorism, bifid nasal tip, dry frizzy curled hair, longitudinal ridging and/or splitting of the nails, and facial asymmetry.The diagnosis CFND is determined by the presence of a mutation in the EFNB1 gene. Physical characteristics may play a supportive role in establishing the diagnosis.
The treatment is always surgical and is based on each patients specific phenotypic presentation.

Presentation
Phenotypic expression varies greatly between individuals with CFND. Some of the more prominent characteristics are:
Craniosynostosis of the coronal suture(s) (fusion of the coronal sutures),
Orbital hypertelorism (increased interocular distance),
Bifid nasal tip,
Dry frizzy curled hair,
Longitudinal ridging and / or splitting of the nails,
Facial Asymmetry.Other characteristics that are less frequently seen are: broad nasal base, low anterior hair line, low set ears, crowding of the teeth, maxillary hypoplasia, rounded and sloping shoulders, pectus excavatum, scoliosis, high arched palate, orbital dystopia, low implant of the breasts with asymmetric nipples and volume, webbed neck, hand or foot abnormalities such as clinodactyly (most common is a curved 5th finger) and cutaneous syndactyly (webbed fingers / toes).Females are more commonly and usually more severely affected than males. Males can however have (some of) the same symptoms as females, but this is not frequently seen. Most males have mild symptoms such as hypertelorism and a broad nasal base with bifid nose, but can also be a carrier of the mutation yet stay clinically unaffected.

Genetics
CFND is a very rare X-linked malformation syndrome caused by mutations in the ephrin-B1 gene (EFNB1). The EFNB1 gene codes for a membrane-anchored ligand which can bind to an ephrin tyrosine-kinase receptor. This ephrin receptor is, amongst other things, responsible for the regulation of embryonic tissue-border formation, and is important for skeletal and craniofacial development. As the ephrin receptor and its EFNB1 ligand are both bound to the (trans)membrane of the cell its cascade is activated through cell-cell interactions. These cell-cell interactions are disturbed due to the presence of cells with the mutant EFNB1 gene, as a result causing incomplete tissue-border formation.Paradoxical to other X-linked conditions, with CFND the females are more severely affected than males. This is due to the process of X-inactivation in females, where at random either the maternal or paternal X-chromosome is inactivated in a cell. Due to this process, the body’s tissues contain either cells with normal EFNB1 or the mutated EFNB1. This is called a mosaic pattern.  This mosaic pattern of cells interferes with the functionality of the cell-cell interactions, as a result causing the severe physical malformations in females.As with all X-linked conditions CFND has a preset chance of being passed down from parents to their offspring. Females have two X-chromosomes and males have one X-chromosome. When a mother is a carrier of CFND, there is a 50% chance of her passing down the X-chromosome containing the mutated EFNB1 gene to her offspring, regardless if the child is a boy or girl. If the father is a carrier there is a 100% chance of him passing down his X-chromosome with the EFNB1 mutation to a daughter, and 0% chance of him passing it down to a son.

Diagnosis
The diagnosis CFND is established only after the presence of a mutation in the EFNB1 gene has been determined. Physical manifestations are not necessarily part of the diagnostic criteria, but can help guide in the right direction. This is due to the large heterogeneity between patients regarding phenotypic expression.20% of the patients that present with CFND-like characteristics do not display a mutation in the EFNB1 gene. The group of patients diagnosed with CFND is thus often overestimated. However, it is important to distinguish this population from CFND for research purposes. On the other hand, especially in males, it is possible that someone is a carrier of the EFNB1 gene mutation yet does not present with any physical manifestations. Screening for the presence of an EFNB1 mutation is thus the most reliable method to establish the diagnosis CFND.Genetic counseling or prenatal screening may be advised if there is a reason to suspect the presence of an EFNB1 gene mutation. Prenatal screening may be done by performing an ultrasound, where can be searched specifically for hypertelorism or a bifid nasal tip. However, this is quite difficult as facial involvement may not be obvious at such an early age, especially in cases with mild phenotypic presentation. The most definitive way to prove the presence of CFND is done by genetic testing, through amniocentesis and chorionic villus sampling. This however carries a greater risk of premature termination of the pregnancy.

Treatment
There is no ‘standard treatment’ for people with CFND due to the large variations in phenotypic expression </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 Amnion nodosum 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 Glossoptosis 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 Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy and can you explain it in depth? [/INST] Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is disease of the arteries in the brain, which causes tissue loss in the subcortical region of the brain and the destruction of myelin in the CNS. CARASIL is characterized by symptoms such as gait disturbances, hair loss, low back pain, dementia, and stroke. CARASIL is a rare disease, having only been diagnosed in about 50 patients, of which ten have been genetically confirmed. Most cases have been reported in Japan, but Chinese and caucasian individuals have also been diagnosed with the disease. CARASIL is inherited in an autosomal recessive pattern. There is currently no cure for CARASIL. Other names for CARASIL include familial young-adult-onset arteriosclerotic leukoencephalopathy with alopecia and lumbago without arterial hypertension, Nemoto disease  and Maeda syndrome.

Signs and symptoms
Symptoms of CARASIL may include spondylosis deformans, lumbago (lower back pain) due to herniated disks, alopecia, spasticity in the limbs leading to gait disturbances, dysarthria, urinary incontinence, pseudobulbular signs, arteriosclerosis of cerebral arteries, mood changes, stroke, and dementia.Individuals with CARASIL may experience spondylosis and alopecia beginning in their teens, although alopecia is not seen in all patients. Other signs of the disease, particularly neurological abnormalities, may present from ages 20-40 with symptoms worsening over time. About 50% of affected patients present with stroke, and most strokes experienced by patients are lacunar infarcts. Many patients experience some form of mood changes, personality disorders, and/or dementia over time.

Cause
CARASIL is caused by mutation of the HTRA1 gene which encodes the HtrA serine peptidase 1 protein (HTRA1).  HTRA1 is located on chromosome 10 and encodes an enzyme that regulates signaling by the TGF-β family of proteins. TGF-β protein family plays an important role in cellular functions, especially in angiogenesis. Individuals with CARASIL have mutations in HTRA1 which leads to a reduced amount of HTRA1 protein or no HTRA1 protein at all. The mutant proteins are unable to suppress TGF-β activity. Increase in TGF-β1 activity has been seen in the tunica media of affected small arteries.CARASIL is an autosomal recessive disease, meaning that both parents must be a carrier for the allele in order for the disease to be passed on to the child. As with other autosomal recessive diseases, the likelihood of receiving a recessive allele from both parents increases if the parents are closely related to each other (consanguineous). This trend has been observed for CARASIL.

Pathophysiology
A few different types of mutations to the HTRA1 gene have been observed in CARASIL patients. Nonsense mutations have been shown to cause no HTRA1 protein to be produced, while missense mutations have been shown to produce some HTRA1 protein, but with reduced activity. Regardless of whether or not HTRA1 protein is produced, or its activity is greatly reduced, the normal regulatory activity of the HTRA1 protein is lost. This means that TGF-β (transforming growth factor beta) signaling cannot be repressed as normal. When TGF-β activity goes unchecked, it alters the structure of the small blood vessels in the brain, increasing an individuals risk of stroke and other neurological abnormalities. Abnormally increased TGF-β activity is also suspected to be involved in the alopecia and lumbago seen in CARASIL patients, but that has not been confirmed and the mechanism is not yet known.CARASIL is a disease characterized by damage to the small blood vessels of the brain. When blood vessels in the brain are damaged, blood flow can be reduced or stopped leading to stroke. It can also lead to a variety of different symptoms depending on what area of the brain has lost its blood supply. This is what causes the spasticity in the limbs, slurred speech, urinary incontinence, and dysarthria seen in some patients.Progressive damage to and loss of the white matter, or myelinated areas, in the brain leads to some of the other neurological symptoms, such as forgetfulness progressing to dementia, mood changes, confusion, and apathy.

Diagnosis
CARASIL can be tentatively diagnosed by a thorough medical history, examination of symptoms, differential diagnoses, and MRI scans of the brain. Diffuse white matter changes (leukoencephalopathy) and multiple lacunar infarcts in the basal ganglia of the thalamus are usually determining factors seen on MRI scans of affected individuals. Further genetic testing must be used to confirm the diagnosis.It is suspected that there are many cases of CARASIL that have not been diagnosed because of the similarities with other neurological disorders. Several disease that are frequently used for differential diagnoses include Binswangers disease, CADASIL, Nasu-Hakula disease, and chronic progressive multiple sclerosis.

Treatment
There is currently no treatment or cure for CARASIL. Most frequently, a combination of supportive care and medications to prevent the occurrence of stroke are recommended </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 Ectopic testis and can you explain it in depth? [/INST]  </s>