title: Mark Hamill

text: Hamill has portrayed the Joker in a few Batman-themed video games, beginning with 2001's "Batman Vengeance", the Sega CD version of "The Adventures of Batman & Robin" (which was later used to create a "lost" episode of the animated series) and in "". Hamill again reprised the role in the "Arkham" sequel, "". In May 2010, Hamill declared to IGN that his role in "Arkham City" would be his last as the Joker. Some months later, with the announcement of "Arkham City", he clarified his statements in the interview by saying, via his Twitter account, "Only said Arkham Asylum would be hard to top, not that I was quitting." On October 19, 2011, shortly after the release of the game, Hamill announced his retirement on his Twitter account, saying "Hello/Goodbye Joker! I've enjoyed every minute behind the wheel of the Clown Prince's crazy car – I'm going to miss him more than I can say!!". In June 2012, WB Games released the expansion pack titled "The Last Laugh" for the video game "DC Universe Online", featuring Hamill as the Joker. In 2015, Hamill yet again returned as the Joker in "" with the character recurring through the game as a hallucination.


title: Mark Hamill

text: During a 2011 Comic-Con, when asked about Heath Ledger's Oscar-winning portrayal of the character in Christopher Nolan's "The Dark Knight", Hamill claimed that it was the most original performance that he had ever seen since Anthony Hopkins' Oscar-winning portrayal of Hannibal Lecter in "The Silence of the Lambs".


title: Mark Hamill

text: Hamill has commented that if there would ever be an animated version of "", he would gladly voice the Joker again, encouraging fans to campaign for said adaptation. On July 17, 2015, Hamill tweeted that he had his fingers crossed in hopes that he would be contacted to reprise his role as the Joker in the . On July 27, Collider reported that Hamill would voice the Joker in the film. The film was released in theaters for a two-day limited time. It was released on Digital HD on July 27, 2016. It was released on DVD and Blu-ray on August 2. Positive reception was met for Hamill's performance as the Joker, with some citing it as his best performance of the character.


title: Mark Hamill

text: Hamill reprised the Joker for the animated series "Justice League Action". He also reprised the Trickster for the series, as well as voicing Swamp Thing. In the animated short "Missing the Mark", Hamill voices a fictionalized version of himself, who appears alongside all three of his other characters. Hamill once again voiced Joker in "Lego DC Super-Villains", replacing voice actor Christopher Corey Smith.


title: Mark Hamill

text: Hamill has been nominated for two Annie Awards for his portrayal of the character, for an Interactive Achievement Award, for a Spike Video Game Award, and has won a British Academy Video Game Award for Best Performer.


title: Mark Hamill

text: Hamill is the co-writer of "The Black Pearl", a comic book miniseries published by Dark Horse Comics. He wrote an introduction to the Trade Paperback "Batman: Riddler Two-Face" which reprints various stories involving the Riddler and Two-Face to tie in with "Batman Forever". He has also written several stories for "Simpsons Comics", including "Catastrophe in Substitute Springfields!", which parodies DC's "Crisis on Infinite Earths" and also references several other classic comics.


title: Mark Hamill

text: According to a 1981 profile in "People", Hamill's "first serious love" was actor Anne Wyndham, cast as his sister on "General Hospital", with whom he had an offscreen relationship. He would later describe experiencing seasons of on-set awkwardness while working with her after their relationship ended. In a 2017 interview, he attributed his long, happy marriage to a non-actor to learning, through his relationship with Wyndham, the dangers of being in a relationship with a fellow actor.


title: Mark Hamill

text: On December 17, 1978, Hamill married dental hygienist Marilou York in a private civil ceremony. They have three children: Nathan Elias (born June 1979), Griffin Tobias (born March 1983), and Chelsea Elizabeth (born July 1988). Nathan was born during the production of "The Empire Strikes Back" and had a cameo appearance as one of the Royal Guards of Naboo in "". Chelsea made a photographic appearance as an infant Axel Walker in the 1990 television series "The Flash"; the same photograph was used in the 2014 series. All three have cameos as Resistance soldiers in "The Last Jedi".


title: Mark Hamill

text: On January 11, 1977, before shooting one of his scenes in "Star Wars", Hamill was in a car accident in which he fractured his nose and left cheekbone. As a result, a double was used for the landspeeder pickup shots. According to a recorded interview, he was driving his BMW on a freeway, became distracted, and seeing that he was missing his offramp, attempted to negotiate four lanes of traffic. Hamill later said that the stories surrounding his injuries had become exaggerated. Confirming that he had only broken his nose, he observed that "over the years it's [been] built up into having my face reconstructed with plastic surgery."


title: Mark Hamill

text: Hamill is an outspoken advocate of the Democratic Party and has supported its candidates. Prior to the 2012 presidential election, he referred to Mitt Romney as a "snake oil salesman". He endorsed P.G. Sittenfeld in the 2016 Ohio Senate election. He has also criticized the tweets of Donald Trump by reading them out in his Joker voice.


title: Mark Hamill

text: Hamill is a lifelong fan of Laurel and Hardy. In June 2016, he called into "The Ross Owen Show" on Black Sky Radio to talk for over an hour about his passion for Stan and Ollie. He was also an early fan of David Letterman, having occasionally appeared on "Late Night with David Letterman", as well as taping every episode and keeping a journal documenting the show. After encountering writer Chris Elliott, Hamill was asked for assistance in helping determine the 1,000th Viewer Mail that Letterman had answered. His practice continued to Letterman's new show on CBS, but eventually stopped.


title: Mark Hamill

text: In December 2017, Hamill became an affiliate member of the Royal Society of Chemistry, having had an interest in the science since childhood.


title: Mark Hamill

text: During the 2022 Brazilian general election, he declared his support for former president and presidential candidate Luiz Inácio Lula da Silva.


title: Multiple sclerosis

text: Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This damage disrupts the ability of parts of the nervous system to transmit signals, resulting in a range of signs and symptoms, including physical, mental, and sometimes psychiatric problems. Specific symptoms can include double vision, blindness in one eye, muscle weakness, and trouble with sensation or coordination. MS takes several forms, with new symptoms either occurring in isolated attacks (relapsing forms) or building up over time (progressive forms). In the relapsing forms of MS, between attacks, symptoms may disappear completely, although some permanent neurological problems often remain, especially as the disease advances.


title: Multiple sclerosis

text: While the cause is unclear, the underlying mechanism is thought to be either destruction by the immune system or failure of the myelin-producing cells. Proposed causes for this include genetics and environmental factors, such as viral infections. MS is usually diagnosed based on the presenting signs and symptoms and the results of supporting medical tests.


title: Multiple sclerosis

text: There is no known cure for multiple sclerosis. Treatments attempt to improve function after an attack and prevent new attacks. Physical therapy and occupational therapy can help with people's ability to function. Many people pursue alternative treatments, despite a lack of evidence of benefit. The long-term outcome is difficult to predict; better outcomes are more often seen in women, those who develop the disease early in life, those with a relapsing course, and those who initially experienced few attacks.


title: Multiple sclerosis

text: Multiple sclerosis is the most common immune-mediated disorder affecting the central nervous system. There are nearly one million people with MS in the United States in 2022, and in 2020, about 2.8 million people were affected globally, with rates varying widely in different regions and among different populations. The disease usually begins between the ages of twenty and fifty and is twice as common in women as in men. MS was first described in 1868 by French neurologist Jean-Martin Charcot. The name "multiple sclerosis" refers to the numerous glial scars (or sclerae – essentially plaques or lesions) that develop on the white matter of the brain and spinal cord.


title: Multiple sclerosis

text: A person with MS can have almost any neurological symptom or sign, with autonomic, visual, motor, and sensory problems being the most common. The specific symptoms are determined by the locations of the lesions within the nervous system, and may include loss of sensitivity or changes in sensation such as tingling, pins and needles or numbness, muscle weakness, blurred vision, pronounced reflexes, muscle spasms, or difficulty in moving; difficulties with coordination and balance (ataxia); problems with speech or swallowing, visual problems (nystagmus, optic neuritis or double vision), feeling tired, acute or chronic pain, and bladder and bowel difficulties (such as neurogenic bladder), among others. When multiple sclerosis is more advanced, walking difficulties can occur and the risk of falling increases.


title: Multiple sclerosis

text: Difficulties thinking and emotional problems such as depression or unstable mood are also common. The primary deficit in cognitive function that people with MS experience is slowed information processing speed, with memory also commonly affected, and executive function less commonly. Intelligence, language, and semantic memory are usually preserved, and the level of cognitive impairment varies significantly between people with MS.


title: Multiple sclerosis

text: Uhthoff's phenomenon, a worsening of symptoms due to exposure to higher than usual temperatures, and Lhermitte's sign, an electrical sensation that runs down the back when bending the neck, are particularly characteristic of MS. The main measure of disability and severity is the expanded disability status scale (EDSS), with other measures such as the multiple sclerosis functional composite being increasingly used in research. EDSS is also correlated with falls in people with MS. While it is a popular measure, EDSS has been criticized for some of its limitations, such as relying too much on walking.


title: Multiple sclerosis

text: The condition begins in 85% of cases as a clinically isolated syndrome (CIS) over a number of days with 45% having motor or sensory problems, 20% having optic neuritis, and 10% having symptoms related to brainstem dysfunction, while the remaining 25% have more than one of the previous difficulties. The course of symptoms occurs in two main patterns initially: either as episodes of sudden worsening that last a few days to months (called relapses, exacerbations, bouts, attacks, or flare-ups) followed by improvement (85% of cases) or as a gradual worsening over time without periods of recovery (10–15% of cases). A combination of these two patterns may also occur or people may start in a relapsing and remitting course that then becomes progressive later on.


title: Multiple sclerosis

text: Relapses are usually not predictable, occurring without warning. Exacerbations rarely occur more frequently than twice per year. Some relapses, however, are preceded by common triggers and they occur more frequently during spring and summer. Similarly, viral infections such as the common cold, influenza, or gastroenteritis increase their risk. Stress may also trigger an attack. Women with MS who become pregnant experience fewer relapses; however, during the first months after delivery the risk increases. Overall, pregnancy does not seem to influence long-term disability. Many events have been found not to affect relapse rates including vaccination, breast feeding, physical trauma, and Uhthoff's phenomenon.


title: Multiple sclerosis

text: MS may have a prodromal phase in the years leading up to MS manifestation, characterized by psychiatric issues, cognitive impairment, and increased utilization of healthcare.


title: Multiple sclerosis

text: The cause of MS is unknown; however, it is believed to occur as a result of some combination of genetic and environmental factors such as infectious agents.


title: Multiple sclerosis

text: Many microbes have been proposed as triggers of MS. One hypothesis is that infection by a widespread microbe contributes to disease development, and the geographic distribution of this organism significantly influences the epidemiology of MS. Two opposing versions of this hypothesis include the hygiene hypothesis and the prevalence hypothesis, the former being more favored. The hygiene hypothesis proposes that exposure to certain infectious agents early in life is protective; the disease is a response to a late encounter with such agents. The prevalence hypothesis proposes that an early, persistent, and silent infection increases risk of disease, and thus the disease is more common where the infectious agent is more common. Only in a few cases and after many years does it cause demyelination.


title: Multiple sclerosis

text: Human herpes viruses are a candidate group of viruses. Epstein-Barr virus (EBV), a herpes virus that can cause infectious mononucleosis and infects approximately 95% of adults, has been increasingly suspected to be an initiating cause of MS, in combination with other genetic and environmental factors, even though only a small proportion of those infected with EBV will later develop MS. A study of individuals in the United States military between 1993 and 2013 (total population greater than 10 million) compared 801 people who developed MS on or after military service to 1,566 matched controls who did not develop MS during this observation period. The study found a 32-fold increased risk of developing MS after infection with EBV. It did not find an increased risk after infection with other viruses, including the similarly transmitted cytomegalovirus. The finding strongly suggests that EBV plays a role in the onset of MS, although EBV alone may be insufficent to cause MS. Although some consider that this goes against the hygiene hypothesis, since the non-infected have probably experienced a more hygienic upbringing, others believe that there is no contradiction, since it is a first encounter with the causative virus relatively late in life that is the trigger for the disease. Other diseases that may be related include measles, mumps and rubella. Evidence for a virus as a cause include the presence of oligoclonal bands in the brain and cerebrospinal fluid of most people with MS, the association of several viruses with human demyelinating encephalomyelitis, and the occurrence of demyelination in animals caused by some viral infections.


title: Multiple sclerosis

text: MS is not considered a hereditary disease; however, a number of genetic variations have been shown to increase the risk. Some of these genes appear to have higher levels of expression in microglial cells than expected by chance. The probability of developing the disease is higher in relatives of an affected person, with a greater risk among those more closely related. An identical twin of an affected individual has a 30% chance of developing MS, 5% for a non-identical twin, 2.5% for a sibling, and an even lower chance for a half-sibling. If both parents are affected the risk in their children is 10 times that of the general population. MS is also more common in some ethnic groups than others.


title: Multiple sclerosis

text: Specific genes that have been linked with MS include differences in the human leukocyte antigen (HLA) system—a group of genes on chromosome 6 that serves as the major histocompatibility complex (MHC). That differences in the HLA region are related to susceptibility has been known since the 1980s, and this same region has also been implicated in the development of other autoimmune diseases such as diabetes type I and systemic lupus erythematosus. The most consistent finding is the association between multiple sclerosis and alleles of the MHC defined as DR15 and DQ6. Other loci have shown a protective effect, such as HLA-C554 and HLA-DRB1*11. Overall, it has been estimated that HLA differences account for between 20% and 60% of the genetic predisposition. Modern genetic methods (genome-wide association studies) have revealed at least 200 variants outside the HLA locus that modestly increase the probability of MS.


title: Multiple sclerosis

text: MS is more common in people who live farther from the equator, although exceptions exist. These exceptions include ethnic groups that are at low risk and that live far from the equator such as the Sami, Amerindians, Canadian Hutterites, New Zealand Māori, and Canada's Inuit, as well as groups that have a relatively high risk and that live closer to the equator such as Sardinians, inland Sicilians, Palestinians, and Parsi. The cause of this geographical pattern is not clear. While the north–south gradient of incidence is decreasing, as of 2010 it is still present.


title: Multiple sclerosis

text: MS is more common in regions with northern European populations and the geographic variation may simply reflect the global distribution of these high-risk populations.


title: Multiple sclerosis

text: A relationship between season of birth and MS lends support to this idea, with fewer people born in the northern hemisphere in November compared to May being affected later in life.


title: Multiple sclerosis

text: Environmental factors may play a role during childhood, with several studies finding that people who move to a different region of the world before the age of 15 acquire the new region's risk of MS. If migration takes place after age 15, however, the person retains the risk of their home country. There is some evidence that the effect of moving may still apply to people older than 15.


title: Multiple sclerosis

text: Smoking may be an independent risk factor for MS. Stress may be a risk factor, although the evidence to support this is weak. Association with occupational exposures and toxins—mainly organic solvents—has been evaluated, but no clear conclusions have been reached. Vaccinations were studied as causal factors; however, most studies show no association. Several other possible risk factors, such as diet and hormone intake, have been looked at; however, evidence on their relation with the disease is "sparse and unpersuasive". Gout occurs less than would be expected and lower levels of uric acid have been found in people with MS. This has led to the theory that uric acid is protective, although its exact importance remains unknown. Obesity during adolescence and young adulthood is a risk factor for MS.


title: Multiple sclerosis

text: The three main characteristics of MS are the formation of lesions in the central nervous system (also called plaques), inflammation and the destruction of myelin sheaths of neurons. These features interact in a complex and not yet fully understood manner to produce the breakdown of nerve tissue and in turn the signs and symptoms of the disease.


title: Multiple sclerosis

text: Cholesterol crystals are believed both to impair myelin repair and to aggravate inflammation. MS is believed to be an immune-mediated disorder that develops from an interaction of the individual's genetics and as yet unidentified environmental causes. Damage is believed to be caused, at least in part, by attack on the nervous system by a person's own immune system.


title: Multiple sclerosis

text: The name "multiple sclerosis" refers to the scars (sclerae – better known as plaques or lesions) that form in the nervous system. These lesions most commonly affect the white matter in the optic nerve, brain stem, basal ganglia, and spinal cord, or white matter tracts close to the lateral ventricles. The function of white matter cells is to carry signals between grey matter areas, where the processing is done, and the rest of the body. The peripheral nervous system is rarely involved.


title: Multiple sclerosis

text: To be specific, MS involves the loss of oligodendrocytes, the cells responsible for creating and maintaining a fatty layer—known as the myelin sheath—which helps the neurons carry electrical signals (action potentials). This results in a thinning or complete loss of myelin and, as the disease advances, the breakdown of the axons of neurons. When the myelin is lost, a neuron can no longer effectively conduct electrical signals. A repair process, called remyelination, takes place in early phases of the disease, but the oligodendrocytes are unable to completely rebuild the cell's myelin sheath. Repeated attacks lead to successively less effective remyelinations, until a scar-like plaque is built up around the damaged axons. These scars are the origin of the symptoms and during an attack magnetic resonance imaging (MRI) often shows more than ten new plaques. This could indicate that there are a number of lesions below which the brain is capable of repairing itself without producing noticeable consequences. Another process involved in the creation of lesions is an abnormal increase in the number of astrocytes due to the destruction of nearby neurons. A number of lesion patterns have been described.


title: Multiple sclerosis

text: Apart from demyelination, the other sign of the disease is inflammation. Fitting with an immunological explanation, the inflammatory process is caused by T cells, a kind of lymphocyte that plays an important role in the body's defenses. T cells gain entry into the brain as a result of disruptions in the blood–brain barrier. The T cells recognize myelin as foreign and attack it, explaining why these cells are also called "autoreactive lymphocytes."


title: Multiple sclerosis

text: The attack on myelin starts inflammatory processes, which trigger other immune cells and the release of soluble factors like cytokines and antibodies. A further breakdown of the blood-brain barrier, in turn, causes a number of other damaging effects such as swelling, activation of macrophages, and more activation of cytokines and other destructive proteins. Inflammation can potentially reduce transmission of information between neurons in at least three ways. The soluble factors released might stop neurotransmission by intact neurons. These factors could lead to or enhance the loss of myelin, or they may cause the axon to break down completely.


title: Multiple sclerosis

text: The blood–brain barrier (BBB) is a part of the capillary system that prevents the entry of T cells into the central nervous system. It may become permeable to these types of cells secondary to an infection by a virus or bacteria. After it repairs itself, typically once the infection has cleared, T cells may remain trapped inside the brain. Gadolinium cannot cross a normal BBB and, therefore, gadolinium-enhanced MRI is used to show BBB breakdowns.


title: Multiple sclerosis

text: Multiple sclerosis is typically diagnosed based on the presenting signs and symptoms, in combination with supporting medical imaging and laboratory testing. It can be difficult to confirm, especially early on, since the signs and symptoms may be similar to those of other medical problems.


title: Multiple sclerosis

text: The McDonald criteria, which focus on clinical, laboratory, and radiologic evidence of lesions at different times and in different areas, is the most commonly used method of diagnosis with the Schumacher and Poser criteria being of mostly historical significance.


title: Multiple sclerosis

text: Magnetic resonance imaging (MRI) of the brain and spine may show areas of demyelination (lesions or plaques). Gadolinium can be administered intravenously as a contrast agent to highlight active plaques and, by elimination, demonstrate the existence of historical lesions not associated with symptoms at the moment of the evaluation.


title: Multiple sclerosis

text: Central vein signs (CVS) have been proposed as a good indicator of MS in comparison with other conditions causing white lesions. One small study found fewer CVS in older and hypertensive people. Further research on CVS as a biomarker for MS is ongoing.


title: Multiple sclerosis

text: Testing of cerebrospinal fluid obtained from a lumbar puncture can provide evidence of chronic inflammation in the central nervous system. The cerebrospinal fluid is tested for oligoclonal bands of IgG on electrophoresis, which are inflammation markers found in 75–85% of people with MS.


title: Multiple sclerosis

text: There are several diseases that present similarly to multiple sclerosis. Intractable vomiting, severe optic neuritis, or bilateral optic neuritis raises suspicion for neuromyelitis optica spectrum disorder (NMOSD). Involvement of multiple cranial nerves raises suspicion for neurosarcoidosis. Longitudinally extensive transverse myelitis (LETM), in which spinal cord damage spans three or more vertebral segments, raises suspicion for NMOSD, neurosarcoidosis, anti-MOG–associated myelitis, systemic rheumatologic disease, or a paraneoplastic disorder.


title: Multiple sclerosis

text: Several phenotypes (commonly termed "types"), or patterns of progression, have been described. Phenotypes use the past course of the disease in an attempt to predict the future course. They are important not only for prognosis but also for treatment decisions.


title: Multiple sclerosis

text: The International Advisory Committee on Clinical Trials of MS describes four types of MS (revised in 2013) in what is known as the Lublin classification:


title: Multiple sclerosis

text: Relapsing-remitting MS is characterized by unpredictable relapses followed by periods of months to years of relative quiet (remission) with no new signs of disease activity. Deficits that occur during attacks may either resolve or leave problems, the latter in about 40% of attacks and being more common the longer a person has had the disease. This describes the initial course of 80% of individuals with MS.


title: Multiple sclerosis

text: The relapsing-remitting subtype usually begins with a clinically isolated syndrome (CIS). In CIS, a person has an attack suggestive of demyelination, but does not fulfill the criteria for multiple sclerosis. 30 to 70% of persons who experience CIS, later develop MS.


title: Multiple sclerosis

text: Primary progressive MS occurs in approximately 10–20% of individuals with the disease, with no remission after the initial symptoms. It is characterized by progression of disability from onset, with no, or only occasional and minor, remissions and improvements. The usual age of onset for the primary progressive subtype is later than of the relapsing-remitting subtype. It is similar to the age that secondary progressive usually begins in relapsing-remitting MS, around 40 years of age.


title: Multiple sclerosis

text: Secondary progressive MS occurs in around 65% of those with initial relapsing-remitting MS, who eventually have progressive neurologic decline between acute attacks without any definite periods of remission. Occasional relapses and minor remissions may appear. The most common length of time between disease onset and conversion from relapsing-remitting to secondary progressive MS is 19 years.


title: Multiple sclerosis

text: Independently of the types published by the MS associations, regulatory agencies like the FDA often consider special courses, trying to reflect some clinical trials results on their approval documents. Some examples could be "Highly Active MS" (HAMS), "Active Secondary MS" (similar to the old Progressive-Relapsing) and "Rapidly progressing PPMS".


title: Multiple sclerosis

text: Also, when deficits always resolve between attacks, this is sometimes referred to as "benign MS", although people will still build up some degree of disability in the long term. On the other hand, the term "malignant multiple sclerosis" is used to describe people with MS having reached significant level of disability in a short period.


title: Multiple sclerosis

text: Atypical variants of MS have been described; these include tumefactive multiple sclerosis, Balo concentric sclerosis, Schilder's diffuse sclerosis, and Marburg multiple sclerosis. There is debate on whether they are MS variants or different diseases. Some diseases previously considered MS variants like Devic's disease are now considered outside the MS spectrum.


title: Multiple sclerosis

text: Although there is no known cure for multiple sclerosis, several therapies have proven helpful. Several effective treatments can significantly decrease the number of attacks and the rate of progression. The primary aims of therapy are returning function after an attack, preventing new attacks, and preventing disability. Starting medications is generally recommended in people after the first attack when more than two lesions are seen on MRI.


title: Multiple sclerosis

text: Older medications used to treat MS were modestly effective, could have side effects, and were poorly tolerated. However, several treatment options with better safety and tolerability profiles have been introduced, changing the prognosis of MS. In the treatment era, 16% of people with relapsing MS went on to need a cane to walk after 20 years.


title: Multiple sclerosis

text: As with any medical treatment, medications used in the management of MS have several adverse effects. Alternative treatments are pursued by some people, despite the shortage of supporting evidence of efficacy.


title: Multiple sclerosis

text: During symptomatic attacks, administration of high doses of intravenous corticosteroids, such as methylprednisolone, is the usual therapy, with oral corticosteroids seeming to have a similar efficacy and safety profile. Although effective in the short term for relieving symptoms, corticosteroid treatments do not appear to have a significant impact on long-term recovery. The long-term benefit is unclear in optic neuritis as of 2020. The consequences of severe attacks that do not respond to corticosteroids might be treatable by plasmapheresis.


title: Multiple sclerosis

text: As of 2021, multiple disease-modifying medications were approved by regulatory agencies for relapsing-remitting multiple sclerosis (RRMS). In RRMS they are modestly effective at decreasing the number of attacks. The interferons and glatiramer acetate are first-line treatments and are roughly equivalent, reducing relapses by approximately 30%. Early-initiated long-term therapy is safe and improves outcomes.


title: Multiple sclerosis

text: Treatment of clinically isolated syndrome (CIS) with interferons decreases the chance of progressing to clinical MS. Efficacy of interferons and glatiramer acetate in children has been estimated to be roughly equivalent to that of adults. The role of some newer agents such as fingolimod, teriflunomide, and dimethyl fumarate, is not yet entirely clear. It is difficult to make firm conclusions about the best treatment, especially regarding the long‐term benefit and safety of early treatment, given the lack of studies directly comparing disease modifying therapies or long-term monitoring of patient outcomes.


title: Multiple sclerosis

text: The relative effectiveness of different treatments is unclear, as most have only been compared to placebo or a small number of other therapies. Direct comparisons of interferons and glatiramer acetate indicate similar effects or only small differences in effects on relapse rate, disease progression and magnetic resonance imaging measures. Alemtuzumab, natalizumab, and fingolimod may be more effective than other drugs in reducing relapses over the short term in people with RRMS. Natalizumab and interferon beta-1a (Rebif) may reduce relapses compared to both placebo and interferon beta-1a (Avonex) while Interferon beta-1b (Betaseron), glatiramer acetate, and mitoxantrone may also prevent relapses. Evidence on relative effectiveness in reducing disability progression is unclear. All medications are associated with adverse effects that may influence their risk to benefit profiles.


title: Multiple sclerosis

text: , only one medication, mitoxantrone, had been approved for secondary progressive MS. In this population tentative evidence supports mitoxantrone moderately slowing the progression of the disease and decreasing rates of relapses over two years.


title: Multiple sclerosis

text: As of 2013, review of 9 immunomodulators and immunosuppressants found no evidence of any being effective in preventing disability progression in people with progressive MS.


title: Multiple sclerosis

text: In March 2017 the FDA approved ocrelizumab as a treatment for primary progressive MS in adults, the first drug to gain that approval, with requirements for several Phase IV clinical trials. It is also used for the treatment of relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease in adults.


title: Multiple sclerosis

text: In 2019, siponimod and cladribine were approved in the United States for the treatment of secondary progressive multiple sclerosis.


title: Multiple sclerosis

text: The disease-modifying treatments have several adverse effects. One of the most common is irritation at the injection site for glatiramer acetate and the interferons (up to 90% with subcutaneous injections and 33% with intramuscular injections). Over time, a visible dent at the injection site, due to the local destruction of fat tissue, known as lipoatrophy, may develop. Interferons may produce flu-like symptoms; some people taking glatiramer experience a post-injection reaction with flushing, chest tightness, heart palpitations, and anxiety, which usually lasts less than thirty minutes. More dangerous but much less common are liver damage from interferons, systolic dysfunction (12%), infertility, and acute myeloid leukemia (0.8%) from mitoxantrone, and progressive multifocal leukoencephalopathy occurring with natalizumab (occurring in 1 in 600 people treated).


title: Multiple sclerosis

text: Fingolimod may give rise to hypertension and slowed heart rate, macular edema, elevated liver enzymes, or a reduction in lymphocyte levels. Tentative evidence supports the short-term safety of teriflunomide, with common side effects including: headaches, fatigue, nausea, hair loss, and limb pain. There have also been reports of liver failure and PML with its use and it is dangerous for fetal development. Most common side effects of dimethyl fumarate are flushing and gastrointestinal problems. While dimethyl fumarate may lead to a reduction in the white blood cell count there were no reported cases of opportunistic infections during trials.


title: Multiple sclerosis

text: Both medications and neurorehabilitation have been shown to improve some symptoms, though neither changes the course of the disease. Some symptoms have a good response to medication, such as bladder spasticity, while others are little changed. Equipment such as catheters for neurogenic bladder or mobility aids can be helpful in improving functional status.


title: Multiple sclerosis

text: A multidisciplinary approach is important for improving quality of life; however, it is difficult to specify a 'core team' as many health services may be needed at different points in time. Multidisciplinary rehabilitation programs increase activity and participation of people with MS but do not influence impairment level. Studies investigating information provision in support of patient understanding and participation suggest that while interventions (written information, decision aids, coaching, educational programmes) may increase knowledge, the evidence of an effect on decision making and quality of life is mixed and low certainty. There is limited evidence for the overall efficacy of individual therapeutic disciplines, though there is good evidence that specific approaches, such as exercise, and psychological therapies are effective. Cognitive training, alone or combined with other neuropsychological interventions, may show positive effects for memory and attention though firm conclusions are not possible given small sample numbers, variable methodology, interventions and outcome measures. The effectiveness of palliative approaches in addition to standard care is uncertain, due to lack of evidence. The effectiveness of interventions, including exercise, specifically for the prevention of falls in people with MS is uncertain, while there is some evidence of an effect on balance function and mobility. Cognitive behavioral therapy has shown to be moderately effective for reducing MS fatigue. The evidence for the effectiveness of non-pharmacological interventions for chronic pain is insufficient to recommend such interventions alone, however their use in combination with medications may be reasonable.


title: Multiple sclerosis

text: The spasticity associated with MS can be difficult to manage because of the progressive and fluctuating course of the disease. Although there is no firm conclusion on the efficacy in reducing spasticity, PT interventions can be a safe and beneficial option for patients with multiple sclerosis. Physical therapy including vibration interventions, electrical stimulation, exercise therapy, standing therapy, and radial shock wave therapy (RSWT), were beneficial for limiting spasticity, helping limit excitability, or increasing range of motion.


title: Multiple sclerosis

text: Over 50% of people with MS may use complementary and alternative medicine, although percentages vary depending on how alternative medicine is defined. Regarding the characteristics of users, they are more frequently women, have had MS for a longer time, tend to be more disabled and have lower levels of satisfaction with conventional healthcare. The evidence for the effectiveness for such treatments in most cases is weak or absent. Treatments of unproven benefit used by people with MS include dietary supplementation and regimens, vitamin D, relaxation techniques such as yoga, herbal medicine (including medical cannabis), hyperbaric oxygen therapy, self-infection with hookworms, reflexology, acupuncture, and mindfulness. Evidence suggests vitamin D supplementation, irrespective of the form and dose, provides no benefit for people with MS; this includes for measures such as relapse recurrence, disability, and MRI lesions while effects on health‐related quality of life and fatigue are unclear. There is insufficient evidence supporting high-dose biotin and some evidence for increased disease activity and higher risk of relapse with its use.


title: Multiple sclerosis

text: The availability of treatments that modify the course of multiple sclerosis beginning in the 1990s, known as disease-modifying therapies (DMTs), has improved prognosis. These treatments can reduce relapses and slow progression, but as of 2022 there is no cure.


title: Multiple sclerosis

text: The prognosis of MS depends on the subtype of the disease, and there is also great individual variation in the progression of the disease. For relapsing MS, which is the most common subtype, approximately one of every five people later transition to secondary progressive MS, a form characterized by more progressive decline. A 2016 cohort study found that after a median of 16.8 years from onset, one in ten of those with relapsing MS needed a walking aid, and almost two in ten transitioned to secondary progressive MS. With treatments available in the 2020s, relapses can be eliminated or substantially reduced. However, "silent progression" of the disease still occurs.


title: Multiple sclerosis

text: In addition to secondary progressive MS (SPMS), a small proportion of people with MS (10-15%) experience progressive decline from the onset, known as primary progressive MS (PPMS). Most treatments have been approved for use in relapsing MS; there are limited effective treatments for progressive forms of MS, and treatments aren't as effective. The prognosis for progressive MS is worse, with faster accumulation of disability, though the rate of decline varies considerably between people. In untreated PPMS, the median time from onset to requiring a walking aid is estimated as seven years. In SPMS, a 2014 cohort study reported that people required a walking aid after an average of five years from onset of SPMS, and were chair or bedbound after average fifteen years.


title: Multiple sclerosis

text: After diagnosis of MS, characteristics that predict a worse course are male sex, older age, and greater disability at the time of diagnosis. Female sex, though, is associated with a higher relapse rate. As of 2018, no biomarker can accurately predict disease progression in every patient. Spinal cord lesions, abnormalities on MRI, and more brain atrophy are predictive of a worse course, though brain atrophy as a predictor of disease course is experimental and not used in clinical practice as of 2018. Early treatment leads to a better prognosis, but a higher relapse frequency when treated with DMTs is associated with a poorer prognosis.


title: Multiple sclerosis

text: MS is the most common autoimmune disorder of the central nervous system. As of 2022, there are nearly one million known cases of multiple sclerosis in the United States. In 2020, the number of people with MS was 2.8 million globally, with rates varying widely in different regions. In Africa rates are less than 0.5 per 100,000, while they are 2.8 per 100,000 in South East Asia, 8.3 per 100,000 in the Americas, and 80 per 100,000 in Europe. Rates surpass 200 per 100,000 in certain populations of Northern European descent. The number of new cases that develop per year is about 2.5 per 100,000.


title: Multiple sclerosis

text: Increasing rates of MS may be explained simply by better diagnosis. Studies on populational and geographical patterns have been common and have led to a number of theories about the cause.


title: Multiple sclerosis

text: MS usually appears in adults in their late twenties or early thirties but it can rarely start in childhood and after 50 years of age. The primary progressive subtype is more common in people in their fifties. Similarly to many autoimmune disorders, the disease is more common in women, and the trend may be increasing. As of 2008, globally it is about two times more common in women than in men. In children, it is even more common in females than males, while in people over fifty, it affects males and females almost equally.


title: Multiple sclerosis

text: Robert Carswell (1793–1857), a British professor of pathology, and Jean Cruveilhier (1791–1873), a French professor of pathologic anatomy, described and illustrated many of the disease's clinical details, but did not identify it as a separate disease. Specifically, Carswell described the injuries he found as "a remarkable lesion of the spinal cord accompanied with atrophy". Under the microscope, Swiss pathologist Georg Eduard Rindfleisch (1836–1908) noted in 1863 that the inflammation-associated lesions were distributed around blood vessels.


title: Multiple sclerosis

text: The French neurologist Jean-Martin Charcot (1825–1893) was the first person to recognize multiple sclerosis as a distinct disease in 1868. Summarizing previous reports and adding his own clinical and pathological observations, Charcot called the disease "sclerose en plaques".


title: Multiple sclerosis

text: The first attempt to establish a set of diagnostic criteria was also due to Charcot in 1868. He published what now is known as the "Charcot Triad", consisting in nystagmus, intention tremor, and telegraphic speech (scanning speech). Charcot also observed cognition changes, describing his patients as having a "marked enfeeblement of the memory" and "conceptions that formed slowly".


title: Multiple sclerosis

text: Diagnosis was based on Charcot triad and clinical observation until Schumacher made the first attempt to standardize criteria in 1965 by introducing some fundamental requirements: Dissemination of the lesions in time (DIT) and space (DIS), and that "signs and symptoms cannot be explained better by another disease process". The DIT and DIS requirement was later inherited by Poser criteria and McDonald criteria, whose 2017 revision is in use.


title: Multiple sclerosis

text: During the 20th century, theories about the cause and pathogenesis were developed and effective treatments began to appear in the 1990s. Since the beginning of the 21st century, refinements of the concepts have taken place. The 2010 revision of the McDonald criteria allowed for the diagnosis of MS with only one proved lesion (CIS).


title: Multiple sclerosis

text: In 1996, the US National Multiple Sclerosis Society (NMSS) (Advisory Committee on Clinical Trials) defined the first version of the clinical phenotypes that is in use. In this first version they provided standardized definitions for four MS clinical courses: relapsing-remitting (RR), secondary progressive (SP), primary progressive (PP), and progressive relapsing (PR). In 2010, PR was dropped and CIS was incorporated. Three years later, the 2013 revision of the "phenotypes for the disease course" were forced to consider CIS as one of the phenotypes of MS, making obsolete some expressions like "conversion from CIS to MS". Other organizations have proposed later new clinical phenotypes, like HAMS (Highly Active MS).


title: Multiple sclerosis

text: There are several historical accounts of people who probably had MS and lived before or shortly after the disease was described by Charcot.


title: Multiple sclerosis

text: A young woman called Halldora who lived in Iceland around 1200 suddenly lost her vision and mobility but recovered them seven days after. Saint Lidwina of Schiedam (1380–1433), a Dutch nun, may be one of the first clearly identifiable people with MS. From the age of 16 until her death at 53, she had intermittent pain, weakness of the legs and vision loss: symptoms typical of MS. Both cases have led to the proposal of a "Viking gene" hypothesis for the dissemination of the disease.


title: Multiple sclerosis

text: Augustus Frederick d'Este (1794–1848), son of Prince Augustus Frederick, Duke of Sussex and Lady Augusta Murray and a grandson of George III of the United Kingdom, almost certainly had MS. D'Este left a detailed diary describing his 22 years living with the disease. His diary began in 1822 and ended in 1846, although it remained unknown until 1948. His symptoms began at age 28 with a sudden transient visual loss (amaurosis fugax) after the funeral of a friend. During his disease, he developed weakness of the legs, clumsiness of the hands, numbness, dizziness, bladder disturbance and erectile dysfunction. In 1844, he began to use a wheelchair. Despite his illness, he kept an optimistic view of life. Another early account of MS was kept by the British diarist W. N. P. Barbellion, pen name of Bruce Frederick Cummings (1889–1919), who maintained a detailed log of his diagnosis and struggle. His diary was published in 1919 as "The Journal of a Disappointed Man".


title: Multiple sclerosis

text: As of 2022, the pathogenesis of MS as it relates to EBV is actively investigated, as are disease-modifying therapies; understanding of how risk factors combine with EBV to initiate MS is sought. Whether EBV is the only cause of MS might be better understood if an EBV vaccine is developed and shown to prevent MS as well.


title: Multiple sclerosis

text: Medications that influence voltage-gated sodium ion channels are under investigation as a potential neuroprotective strategy because of hypothesized role of sodium in the pathological process leading to axonal injury and accumulating disability. There is insufficient evidence of an effect of sodium channel blockers for people with MS.


title: Multiple sclerosis

text: MS is a clinically defined entity with several atypical presentations. Some auto-antibodies have been found in atypical MS cases, giving birth to separate disease families and restricting the previously wider concept of MS.


title: Multiple sclerosis

text: Anti-AQP4 autoantibodies were found in neuromyelitis optica (NMO), which was previously considered a MS variant. A spectrum of diseases named NMOSD (NMO spectrum diseases) or anti-AQP4 diseases has been accepted. Some cases of MS were presenting anti-MOG autoantibodies, mainly overlapping with the Marburg variant. Anti-MOG autoantibodies were found to be also present in ADEM, and a second spectrum of separated diseases is being considered. This spectrum is named inconsistently across different authors, but it is normally something similar to anti-MOG demyelinating diseases.


title: Multiple sclerosis

text: A third kind of auto-antibodies is accepted. They are several anti-neurofascin auto-antibodies which damage the Ranvier nodes of the neurons. These antibodies are more related to the peripheral nervous demyelination, but they were also found in chronic progressive PPMS and combined central and peripheral demyelination (CCPD, which is considered another atypical MS presentation).


title: Multiple sclerosis

text: In addition to the significance of auto-antibodies in MS, four different patterns of demyelination have been reported, opening the door to consider MS as a heterogeneous disease.


title: Multiple sclerosis

text: Since disease progression is the result of degeneration of neurons, the roles of proteins showing loss of nerve tissue such as neurofilaments, tau, and N-acetylaspartate are under investigation.


title: Multiple sclerosis

text: Improvement in neuroimaging techniques such as positron emission tomography (PET) or magnetic resonance imaging (MRI) carry a promise for better diagnosis and prognosis predictions. Regarding MRI, there are several techniques that have already shown some usefulness in research settings and could be introduced into clinical practice, such as double-inversion recovery sequences, magnetization transfer, diffusion tensor, and functional magnetic resonance imaging. These techniques are more specific for the disease than existing ones, but still lack some standardization of acquisition protocols and the creation of normative values. This is particularly the case for proton magnetic resonance spectroscopy, for which a number of methodological variations observed in the literature may underlie continued inconsistencies in central nervous system metabolic abnormalities, particularly in N-acetyl aspartate, myoinositol, choline, glutamate, GABA, and GSH, observed for multiple sclerosis and its subtypes. There are other techniques under development that include contrast agents capable of measuring levels of peripheral macrophages, inflammation, or neuronal dysfunction, and techniques that measure iron deposition that could serve to determine the role of this feature in MS, or that of cerebral perfusion.


title: Multiple sclerosis

text: The hospitalization rate was found to be higher among individuals with MS and COVID-19 infection, at 10%, while the pooled infection rate is estimated at 4%. The pooled prevalence of death in hospitalized individuals with MS is estimated as 4%.


title: Multiple sclerosis

text: One emerging hypothesis, referred to as the hygiene hypothesis, suggests that early-life exposure to infectious agents helps to develop the immune system and reduces susceptibility to allergies and autoimmune disorders, including MS. Germ-free mice infected with transplanted fecal matter from MS patients exhibit an increased risk of developing EAE, an animal model of MS. It has also been proposed that certain bacteria found in the gut use molecular mimicry to infiltrate the brain via the gut-brain axis, initiating an inflammatory response and increasing blood-brain barrier permeability. Vitamin D levels have also been correlated with MS; lower levels of vitamin D correspond to an increased risk of MS, suggesting a reduced prevalence in the tropics - an area with more Vitamin D-rich sunlight - strengthening the impact of geographical location on MS development. MS mechanisms begin when peripheral autoreactive effector CD4+ T cells get activated and move into the CNS. Antigen-presenting cells localize the reactivation of autoreactive effector CD4-T cells once they have entered the CNS, attracting more T cells and macrophages to form the inflammatory lesion. In MS patients, macrophages and microglia assemble at locations where demyelination and neurodegeneration are actively occurring, and microglial activation is more apparent in the normal-appearing white matter of MS patients. Astrocytes generate neurotoxic chemicals like nitric oxide and TNFα, attract neurotoxic inflammatory monocytes to the CNS, and are responsible for astrogliosis, the scarring that prevents the spread of neuroinflammation and kills neurons inside the scarred area.


title: Supernatural (American TV series)

text: Supernatural is an American dark fantasy drama television series created by Eric Kripke. It was first broadcast on September 13, 2005, on The WB, and subsequently became part of successor The CW's lineup. Starring Jared Padalecki as Sam Winchester and Jensen Ackles as Dean Winchester, the series follows the two brothers as they hunt demons, ghosts, monsters, and other supernatural beings. The series was produced by Warner Bros. Television, in association with Wonderland Sound and Vision. Along with Kripke, executive producers have been McG, Robert Singer, Phil Sgriccia, Sera Gamble, Jeremy Carver, John Shiban, Ben Edlund and Adam Glass. Former executive producer and director Kim Manners died of lung cancer during production of the fourth season.


title: Supernatural (American TV series)

text: The series was filmed in Vancouver, British Columbia, and surrounding areas. It was in development for nearly ten years, as creator Kripke spent several years unsuccessfully pitching it. The pilot was viewed by an estimated 5.69 million viewers, and the ratings of the first four episodes prompted The WB to pick up the series for a full season. Originally, Kripke planned the series for three seasons but later expanded it to five. The fifth season concluded the series' main storyline, and Kripke departed the series as showrunner. The series continued on for 10 more seasons with new showrunners, including Sera Gamble, Jeremy Carver, Robert Singer and Andrew Dabb. With its eleventh season, "Supernatural" became the longest-running American live-action fantasy TV series. The series was renewed for a fifteenth and final season that consisted of 20 episodes, and premiered on October 10, 2019. The series concluded on November 19, 2020, with 327 episodes aired.


title: Supernatural (American TV series)

text: Before bringing "Supernatural" to television, creator Eric Kripke had been developing the series for nearly ten years, having been fascinated with urban legends since he was a child. He had originally envisioned "Supernatural" as a movie. He later developed it as a TV series and spent a few years pitching it before it was picked up by The WB. The concept went through several phases before becoming the eventual product, shifting from the original idea of an anthology series to one of tabloid reporters driving around the country in a van "fighting the demons in search of the truth". Kripke wanted it to be a road trip series, feeling that it was the "best vehicle to tell these stories because it's pure, stripped down and uniquely American... These stories exist in these small towns all across the country, and it just makes so much sense to drive in and out of these stories."


title: Supernatural (American TV series)

text: As he had previously written for The WB series "Tarzan", Kripke was offered the chance to pitch show ideas to the network and used the opportunity for "Supernatural". However, the network disliked his tabloid reporter idea, so Kripke successfully pitched his last-minute idea of the characters being brothers. He decided to have the brothers be from Lawrence, Kansas, because of its closeness to Stull Cemetery, a location famous for its urban legends.


title: Supernatural (American TV series)

text: When it came time to name the two lead characters, Kripke decided on "Sal" and "Dean" as an homage to Jack Kerouac's road-trip novel "On the Road". However, he felt that "Sal" was inappropriate for a main character and changed the name to "Sam". It was originally intended for the brothers' last name to be "Harrison" as a nod to actor Harrison Ford, as Kripke wanted Dean to have the "devil-may-care swagger of Han Solo". However, there was a Sam Harrison living in Kansas, so the name had to be changed for legal reasons. Combining his interest in the Winchester Mystery House and his desire to give the series the feel of "a modern-day Western", Kripke settled on the surname of "Winchester". However, this also presented a problem. The first name of Sam and Dean's father was originally Jack, but there was a Jack Winchester residing in Kansas, so Kripke was forced to change the character's name to John.


title: Supernatural (American TV series)

text: Growing up, Kripke connected to television shows that had signature cars, such as "The Dukes of Hazzard" and "Knight Rider". This prompted him to include one in "Supernatural". "We say it's a modern American Western – two gunslingers who ride into town, fight the bad guys, kiss the girl and ride out into the sunset again. And we were always talking from the very beginning that if you're going to have cowboys, they need a trusty horse." He originally intended for the car to be a '65 Mustang, but his neighbor convinced him to change it to a '67 Impala, since "you can put a body in the trunk" and because "you want a car that, when people stop next to it at the lights, they lock their doors." Kripke has commented, "It's a Rottweiler of a car, and I think it adds authenticity for fans of automobiles because of that, because it's not a pretty ride. It's an aggressive, muscular car, and I think that's what people respond to, and why it fits so well into the tone of our show."


title: Supernatural (American TV series)

text: Kripke had previously pitched the series to Fox executive Peter Johnson, and when Johnson moved to Wonderland Sound and Vision as president of TV, he contacted Kripke. Johnson soon signed on as co-executive producer, as did Wonderland owner McG as executive producer, with the production company set to make the pilot episode. Before it could be filmed, however, script issues needed to be dealt with. Originally, the brothers were not raised by their father, but rather by their aunt and uncle. Thus, when Dean comes to Sam for assistance in the pilot episode, he has to convince him that the supernatural exists. However, Kripke realized that this made the backstory too complicated and reworked it with Peter Johnson so that their father raised them to be hunters.


title: Supernatural (American TV series)

text: The script went through many additional revisions. One of the original ideas was for Sam's girlfriend Jessica to be revealed as a demon, which prompts him to join Dean on the road; however, Kripke felt it was more appropriate for Sam's motivation to be Jessica's death, so he had her killed in the same manner as Sam's mother, making them the "right bookends". Other revised concepts include Sam believing Dean to be a serial killer who murders their father and their father dying in Jessica's place. Filming for the pilot episode was greenlit after director David Nutter, who previously had worked with Kripke on "Tarzan", signed on. When the series was eventually picked up, the studio brought in Robert Singer as executive producer, as it wanted Kripke to work with someone with production experience. Due to his previous work on "The X-Files, "co-executive producer John Shiban was also hired to help design the series mythology. Kripke had the series planned out for three seasons but later expanded it to five and hoped to end it there on a high note.


title: Supernatural (American TV series)

text: The staff for the first season consisted of Kripke and five other writers, with assistants to help with researching urban legends. Most of the work done in writing the series is very collaborative, with the writers often breaking up into groups. At the beginning of each season, the writers are brought together and pitch their ideas, which are then assigned to a specific writer to be developed. Each story idea is outlined on a dry-erase board, with Kripke and Bob Singer making necessary changes. Afterward, the script is written, and Kripke goes through it to make sure it has the same tone as other episodes. Kripke found this task very difficult to do in the first season, but he felt it became easier by the third season, as the staff came to "really understand the show's style". Following the fifth season, Kripke stepped down as showrunner but maintained his connection with the series as an executive consultant. In a 2016 interview with "Collider", he responded to the question as to how involved he still is with the show with the answer, "I would define myself as a proud parent who has sent their child off to college." He elaborated on this analogy, explaining, "I'm there if they need me, I'm happy to help, but I also stay out of their way if they don't need me."


title: Supernatural (American TV series)

text: The tone of "Supernatural" was heavily influenced by films such as "Poltergeist"—having the horror happen in a family setting rather than remote location—and "Evil Dead II" and "An American Werewolf in London"—having bits of comedy mixed in. Commenting on the former, Kripke said, "It's the idea that horror can happen in your own backyard. How many viewers have to worry about the vampire in the gothic castle?" "It's always been a show about "family"." Other influences include "The Two Sisters" and Asian horror films "The Eye", "Ju-on", and "Ring".


title: Supernatural (American TV series)

text: According to creator Eric Kripke, the show originally was intended to focus on the weekly monsters, with Sam and Dean Winchester merely being "an engine to get us in and out of different horror movies every week". His sole desire was to merely "scare the crap out of people". However, a few episodes in, Kripke and executive producer Bob Singer noticed the onscreen chemistry between Jared Padalecki and Jensen Ackles. This revelation caused them to change the series to focus more on the brothers than the monsters, basing the weekly monster around the storyline they wanted for the Winchesters. According to Kripke, "... sometimes we don't even have the monster until way late in the break, once we get all the angst and the drama done first."


title: Supernatural (American TV series)

text: Though companies were hired for work on the pilot episode—such as Entity FX for the visual effects—effects departments now work exclusively for the series. Ivan Hayden is the visual effects supervisor, and works with many levels of the production staff. During pre-production, Hayden must go through the scripts, looking for possible visual effects. He then has a concept meeting with the writers, and after settling on the effect designs to use, coordinates with the special effects and stunt departments. Hayden is also present during filming to help the director make sure that the scenes are being filmed in the best way for the visual effects, such as by ensuring that the actors are looking at the correct location where an effect will later be added. Afterward, he then meets with the editors. Another aspect of the visual effects department is coming up with rules and physics for each supernatural creature, though the rules are often bent if it benefits the story. In 2012, it was announced that Hayden would be working at the new Vancouver location of Encore for its VFX division.


title: Supernatural (American TV series)

text: "Supernatural" features a synthesized orchestral score, although traditional acoustic instruments such as guitars and cellos are used at times. Special instruments have also been used in specific episodes, such as "bluesy gospel music" played on a broken-down piano in the faith-healing episode "Faith". Unlike other television shows, the series features two composers: Christopher Lennertz and Jay Gruska. Each composer scores every other episode, giving them extra time to write the scores, which usually end up being around 30 minutes per episode. They write themes for their own episodes and characters and work with one another if there is overlap between episodes. They try to base the music on the visuals of the episode, such as in the episode "Dead in the Water", in which off-angle shots are accompanied by repetitive and discordant notes, and spoken words such as "water" and "die" are followed by a lower pitch to create a "gurgly" sound. While there are similarities in the scores for situations such as the brothers and their father, about a third of each episode's score is newly written for the series.


title: Supernatural (American TV series)

text: While original scores are used throughout episodes, another important aspect of the series' music is the use of classic rock, over which creator Eric Kripke threatened to quit when the network would not allow its inclusion. Most of the songs are from Kripke's private collection, although one of his favorite bands—Led Zeppelin—is too expensive to use. Some episode titles are references to Led Zeppelin songs. The series has featured such bands as Blue Öyster Cult, Bad Company, Stevie Ray Vaughan, Rush, Boston, Triumph and AC/DC on more than one occasion. Multiple songs are usually used throughout each episode, and accompany "The Road So Far" sequences before select episodes that highlight a montage of past events. Although Kripke prefers to keep a fine line between the score and songs used, sometimes Lennertz and Gruska are required to write short sections of rock-like music to fill 15-to-20-second gaps, as it would be too costly to acquire song rights. On the last episode of every season except the first, the song "Carry On Wayward Son" by Kansas is played at the beginning.


title: Supernatural (American TV series)

text: Though the pilot was filmed in Los Angeles, principal filming takes place in Vancouver, British Columbia. Thus, on-location filming usually takes place in the area. "Dead in the Water" was filmed at Buntzen Lake, and the final scenes of "Simon Said" were filmed at Cleveland Dam. Other locations used on the show are often reused two or three times, with the art department making variations to conceal this. Heritage Park in Burnaby has been used as a cemetery in "Red Sky at Morning", and as the location of the gingerbread-house cottage in "Bedtime Stories". Also, Riverview Hospital in Coquitlam has served many functions for the series, including an asylum in "Asylum", a hospital in "In My Time of Dying", and a prison in "Folsom Prison Blues". The episode "Houses of the Holy" was filmed on location in Vancouver at St. Andrew's-Wesley United Church. Because episodes usually take place in the middle of nowhere, filming often takes place at an old military base. Having been shut down for years, the buildings have been removed, leaving just roads on which sets are erected, such as for crossroads scenes.


title: Supernatural (American TV series)

text: Rather than having the series debut on television, The WB instead made the pilot episode available for online streaming through Yahoo! a week before it was set to premiere on the network as part of a promotional scheme. Following the transition to The CW, "Supernatural" episodes were added to Apple's iTunes Store starting in December 2006, being one of the first CW series to be made available for sale online. The following month, the network began streaming episodes of the series on its website with limited commercial interruption, available for up to four weeks after the initial airings. Beginning January 11, 2007, Australia's Network Ten also began offering full episodes for download via their website, through a deal with Warner Bros. Television. To combat piracy, Ten debuted the second-season premiere five days before its initial broadcast in the country, making "Supernatural" the first major network show available for free download in Australia before being aired. Subsequent episodes became available online just hours after being televised. Around the same time, episodes were also made available for download on Microsoft's Xbox Live Marketplace. In September 2008, Amazon.com launched its new on-demand TV service, with "Supernatural" being one of the many television shows available for sale.


title: Supernatural (American TV series)

text: The series originally focuses primarily on the brothers Dean Winchester and Sam Winchester, played by Jensen Ackles and Jared Padalecki, as they travel throughout the country hunting down evil supernatural creatures. Padalecki became interested in the role because he liked horror series, including both "The X-Files" and "The Twilight Zone", which he found similar to the proposed plot of "Supernatural". He was also excited to play "the reluctant hero", comparing Sam to "The Matrix"s Neo and Luke Skywalker of "Star Wars". Padalecki had previous experience working with executive producers McG and David Nutter, the former convincing him to audition for the role. Ackles was originally asked by Nutter to audition for the role of Sam but preferred the character of Dean after reading the script. At the time of his audition, he was already a series regular on fellow WB series "Smallville". After landing the part of Dean, his "Smallville" role was cut short.


title: Supernatural (American TV series)

text: While the series does not have many lead characters, there are many recurring characters. Jeffrey Dean Morgan portrays John Winchester, father of Sam and Dean. Making an appearance in the pilot episode, John does not return until nearly halfway through the first season, after which he becomes a recurring character until his eventual death in the second season's premiere episode, though his spirit returns to help his sons in the season finale. Later in the series, it is announced that John Winchester fathered a third son with another woman; a half-brother to Sam and Dean. According to writer John Shiban, it was decided early on that John would die. The writers found that having the brothers being separated from their father "split the show". Shiban noted that "... the boys were looking for Dad, and they were looking for a monster of the week, whatever that is, whatever case crosses their path. It became difficult, because we thought it was like – 'what is Dad doing? Is he doing more interesting things than the boys are doing, or what?'" They believed Morgan was initially reluctant about returning to "Supernatural" for the second season because of his recurring role on the series "Grey's Anatomy". Future appearances of the character have been hindered by Morgan's busy schedule.


title: Supernatural (American TV series)

text: Also introduced in the first season are the demon Azazel and his unnamed daughter. While Azazel mainly appears merely as shadows or silhouettes in the first season, taking physical form only when he possesses John Winchester, Azazel's daughter uses a girl named Meg Masters—portrayed by Nicki Lynn Aycox—as a host. In the second-season premiere, Azazel's host is portrayed by Fredric Lehne; originally brought on for only one episode, Lehne impressed the showrunners so much that he was asked to return for the season's two-part finale. Even after the character's death, Azazel makes appearances in subsequent seasons, being portrayed by different actors. Lehne also reprises the role in the first episode of season six when Dean is poisoned and begins to see Azazel again. Likewise, after Azazel's daughter is exorcised from Meg towards the end of the first season, the demon and her host continued to appear in the series, although now as two separate characters. Aycox continued her role in the fourth season when the angry spirit of Meg tries to kill the Winchesters. The demon returns for an episode in the second season played by Padalecki, temporarily taking Sam as a host. She appears once again in the fifth season, her newest host being portrayed by Rachel Miner, in a recurring role.


title: Supernatural (American TV series)

text: The writers eventually wanted to flesh out the concept of hunters, resulting in the introduction of many new characters. Actor Jim Beaver makes his first appearance as Bobby Singer, an old family friend of the Winchesters, at the end of the first season. Becoming a sort of surrogate father to Sam and Dean after their father's death, the character acts as their mentor and foremost point of contact before his departure in the seventh season. Other hunters appear in the second season with the introduction of Harvelle's Roadhouse, a saloon frequented by hunters. It is owned by Ellen Harvelle (played by Samantha Ferris), whose late husband was a friend of John Winchester. Working alongside her mother is Jo Harvelle (played by Alona Tal). Also present is the computer guy Ash (played by Chad Lindberg), who uses his vast computer skills to track the paranormal. Tal was eventually written out of the series, and believes the reason to be that the producers felt she looked like Sam and Dean's "14-year-old sister". Kripke claims the character was incorrectly conceived, and also cites poor fan reaction for her removal. Also, the character of Ash is killed off in the second-season finale with the destruction of the Roadhouse. Ellen was meant to return in the third season, but the episode had to be scrapped due to the writer's strike. The writers intended for her to be featured in the third-season finale, but Ferris declined because the deal offered to her was not acceptable, as "It could cost [her] money and work". However, both actresses returned as Jo and Ellen in the fifth season.


title: Supernatural (American TV series)

text: For the third season, the writers decided to introduce Ruby, a demonic former witch who claims to be an ally to the Winchesters. However, The CW requested that another female be added, so the character Bela Talbot, a self-centered thief who sells occult objects to wealthy clients and who was already intended to appear in multiple episodes, was upgraded to a series regular. Katie Cassidy and Lauren Cohan were eventually cast as Ruby and Bela, respectively, though they originally auditioned for the others' role. Though making only six appearances each in the third season, both actresses were credited as co-stars for their episodes. At the end of the season, Bela was killed off, and Cassidy was let go for budgetary reasons. The role of Ruby was recast for the fourth season, auditions describing the character only as "a love interest". Genevieve Cortese (who later married Padalecki) took over the role until the character's death at the end of the season.


title: Supernatural (American TV series)

text: Wanting to bring in Christian mythology to the series, the writers created the angel Castiel. With Kripke wanting to keep the introduction of an angel a secret, the character was instead described as a demon during auditions. Misha Collins was cast as the character. Making his debut in the fourth-season premiere, Castiel resurrects Dean from Hell after his death in the third season, and comes to be an ally of the Winchesters. The character was originally intended for only a six-episode story arc, but the role was later expanded. Collins was promoted to a series regular for the fifth and sixth season, something Collins believes to be mainly due to fan support. Collins was downgraded to recurring status for the seventh and eighth seasons, but returned to series regular status for seasons nine and ten.


title: Supernatural (American TV series)

text: Along with Castiel came other angelic characters, with Robert Wisdom portraying the "militant" and "dogmatic" Uriel, who secretly supports Lucifer; Julie McNiven playing the fallen angel Anna Milton, who eventually regains her angelic form but remains an outcast of Heaven; and Kurt Fuller as Castiel's boss Zachariah, who wishes to start the Apocalypse in order to bring Paradise to Earth. Though Wisdom's character is eventually killed, McNiven and Fuller continue their roles into the fifth season and are joined by Mark Pellegrino as the recently released but fallen archangel Lucifer. Pellegrino also appears as Lucifer as a hallucination in Sam's head in season 7. Pellegrino had been the second choice for the role of Castiel and was offered the role of Lucifer without an audition. Further on, Fuller's and McNiven's characters were also killed along with both Harvelle characters.


title: Supernatural (American TV series)

text: Season 5 introduces the demon Crowley, played by Mark Sheppard, who would become the Winchester's longest-recurring antagonist and occasional anti-hero in the series. Crowley appears in three episodes of season 5 to help the Winchesters seal Lucifer back in the Cage, believing that once he destroys humanity he will target all demonkind next. In season 6, Crowley becomes the King of Hell and one of the main antagonists working with Castiel to stop Archangel Raphael, the other main antagonist of season 6, from restarting the Apocalypse by harnessing the souls of Purgatory and splitting the power with Castiel. In season 7, Crowley becomes an antihero who helps the Winchesters against the threat of Leviathans led by Dick Roman after they are released from Purgatory by Castiel. Crowley becomes the main antagonist of season 8, attempting to harness the Words of God and their powers and stop the Winchesters from sealing hell forever. In season 9, Crowley becomes an unwilling prisoner of the Winchesters but is forced to deal with Abaddon trying to steal his position as King of Hell. Sheppard was promoted to series regular status for season 10.


title: Supernatural (American TV series)

text: Season 7 introduces Kevin Tran the prophet (played by Osric Chau), who translates the word of God to help the Winchesters stop the Leviathans, which leads to their destruction. In season 8, Kevin works to translate another word of God to find the means of sealing hell forever. In season 9, Kevin instead tries to find the means of returning the fallen angels to Heaven but is killed by a Gadreel-possessed Sam.


title: Supernatural (American TV series)

text: Also introduced in Season 7 is Charlie Bradbury, a tech-savvy geek (played by Felicia Day) who works at Richard Roman Enterprises. After hacking into Frank's hard drive and learning about the existence of monsters, Charlie becomes an ally of the Winchesters and occasionally helps them out with technical problems and hunts.


title: Supernatural (American TV series)

text: Season 9 introduces the angel Gadreel, who originally poses as Ezekiel, played by Tahmoh Penikett and Padalecki. After Sam is seriously injured when he decides not to seal Hell, Gadreel comes to Dean in response to his prayer for help, possesses Sam to heal him, and becomes Dean's ally. However, Gadreel's true identity is later revealed by Metatron to be the guardian who had allowed Lucifer into the Garden of Eden and was imprisoned until the fall. Gadreel then allies with Metatron in an attempt to redeem himself and lead the angels back to Heaven. He kills Kevin Tran and is later expelled from Sam and possesses his original vessel again. However, after Metatron begins sacrificing angels for his plans, Gadreel becomes regretful and joins Sam, Dean and Castiel.


title: Supernatural (American TV series)

text: Season 4 introduces Chuck Shurley as one of God's prophets portrayed by Rob Benedict. Later in season 11, it is revealed that Chuck is God masquerading under the guise of a human to allow angels and mankind free will. In season 15, it is revealed that Chuck is manipulating events in the lives of the Winchesters and their allies for his own perverse amusement and entertainment.


title: Supernatural (American TV series)

text: Season 10 introduces the antagonistic witch Rowena MacLeod (portrayed by Ruth Connell), who is later revealed to be the mother of Crowley, who was previously named Fergus. Rowena returns as a sometime ally of the Winchesters throughout seasons 11 to 15, making her one of the long-standing female characters to exist on the show. Rowena's antagonistic and unpredictable nature is redeemable by her sacrifice in season 15 to close hell's portal opened by Chuck.


title: Supernatural (American TV series)

text: Season 11 introduces Amara / The Darkness, portrayed by Emily Swallow. The Darkness would later on go on to become an antagonist after being released from imprisonment once the Mark of Cain is broken. The Mark was a seal that kept the Darkness imprisoned in order for God's creation and humanity to survive. Later, it is revealed that the Darkness is a sibling of God.


title: Supernatural (American TV series)

text: Season 13 introduces a Nephilim, Jack Kline portrayed by Alexander Calvert as the son of Lucifer. Jack would later on become a member of the Winchester family and an important ally in rescuing the people of Apocalypse World (a world without Winchesters to prevent the endtimes) and defeating Apocalypse World, archangel Michael. Jack would go on to be killed by God as part of Chuck's plan only to be resurrected by Billie, a reaper who is a newly turned replacement for Death.


title: Supernatural (American TV series)

text: Because the show focuses mainly on the two Winchester brothers, the writers realized that viewers would know that the characters are not in danger of being permanently killed. To fix this, the staff often writes in guest characters to give tension to the episode, occasionally having them die.


title: Supernatural (American TV series)

text: The first season consists of 22 episodes. It premiered on The WB on September 13, 2005, and concluded on May 4, 2006. The first 16 episodes aired on Tuesdays at 9:00 pm, after which the series was rescheduled to Thursdays at 9:00 pm.


title: Supernatural (American TV series)

text: After their father goes missing during a "hunting trip," Dean Winchester tracks down his brother Sam at Stanford University and they begin to live a life on the road, in Dean's black 1967 Chevrolet Impala. However, their father is not a typical hunter: he hunts supernatural creatures like ghosts, vampires, and spirits, and has trained his sons to do the same. Along the way, Sam and Dean save innocent people, fight creatures and ghosts, and collect clues to their father's whereabouts.


title: Supernatural (American TV series)

text: The second season consists of 22 episodes, and it aired on Thursdays at 9:00 pm on The CW, beginning September 28, 2006, and ending May 17, 2007.


title: Supernatural (American TV series)

text: Sam and Dean continue to hunt the demon Azazel. Part of Azazel's master plan is revealed as he gathers Sam and others with similar psychic abilities to fight each other, leading to Sam's death. Dean makes a deal with a crossroads demon to bring Sam back in exchange for his soul, which will be collected in one year and taken to Hell. With the help of the spirit of John Winchester, Dean kills Azazel and the portal is closed.


title: Supernatural (American TV series)

text: The third season consists of 16 episodes that aired on Thursdays at 9:00 pm beginning October 4, 2007, and ending May 15, 2008. Originally 22 episodes were ordered for the third season, but production was halted on December 5, 2007, upon completion of the twelfth episode by the 2007–08 Writers Guild of America strike. The season number was shortened to sixteen episodes, with four new episodes airing in April and May 2008.


title: Supernatural (American TV series)

text: The season focuses on trying to save Dean from his deal and tracking down the demons that were released from hell. The brothers learn which demon holds Dean's contract: a powerful demon named Lilith. The brothers, along with Ruby, track Lilith down and attempt to kill her. Lilith is unable to stop Sam on account of his mysterious abilities; however, Dean's contract expires and his soul is taken to Hell.


title: Supernatural (American TV series)

text: The fourth season consists of 22 episodes that aired on Thursdays at 9:00 pm beginning September 18, 2008, and ending May 14, 2009.


title: Supernatural (American TV series)

text: Dean is rescued from Hell and brought back by an angel of the Lord named Castiel. The rest of the season follows the brothers as they work with Castiel to stop Lilith's plan of breaking the 66 seals, which would allow the fallen archangel Lucifer to walk the Earth free once again. Dean escapes and tries to stop Sam after learning that Lilith is, in fact, the last seal, but Sam kills her anyway, breaking open Lucifer's prison. Ruby reveals her true colors as a demon loyal to Lucifer, and Dean kills her. As the season ends, Lucifer's cage opens and he escapes from hell.


title: Supernatural (American TV series)

text: The fifth season consists of 22 episodes that aired on Thursdays at 9:00 pm beginning September 10, 2009, and ending May 13, 2010. This season was rumored to be the last season, but Padalecki and Ackles had contracts for a sixth season, and The CW renewed it on February 16, 2010.


title: Supernatural (American TV series)

text: The fifth season revolves around the fight to stop Lucifer and save the world from the Apocalypse. In the end, Sam throws himself and Adam into the Cage to trap Lucifer once more. Castiel is resurrected by God and returns to Heaven to restore order. Dean returns to his old girlfriend Lisa to live a normal life. Sam is mysteriously freed of the Cage.


title: Supernatural (American TV series)

text: The sixth season consists of 22 episodes that aired on Fridays at 9:00 pm beginning September 24, 2010, and ending May 20, 2011. Beginning with this season, Kripke left as showrunner, leaving executive producer Sera Gamble to take over the reins.


title: Supernatural (American TV series)

text: Sam and Dean are forced to work to capture Alpha monsters for Crowley. Dean discovers that Sam's soul is still in the Cage, so he implores the Horseman Death to retrieve it. The brothers discover Castiel has orchestrated all of these events from behind the scenes and was working with Crowley the entire time. Castiel proceeds with his plan, absorbing all the souls from Purgatory and pronouncing himself God.


title: Supernatural (American TV series)

text: The seventh season consists of 23 episodes that aired on Fridays at 9:00 pm beginning September 23, 2011, and ending May 18, 2012.


title: Supernatural (American TV series)

text: After declaring himself God, Castiel unwittingly releases the Leviathans, ravenous creatures who feed on human flesh. Sam and Dean must work to stop the Leviathans and their leader Dick Roman. The brothers learn that the only way to kill the Leviathans is with the "bone of a righteous mortal washed in the three bloods of the fallen". Dean and Castiel kill Dick but are dragged into Purgatory as a result, while Sam is left alone to deal with Crowley, who plans to rise to power.


title: Supernatural (American TV series)

text: The eighth season consists of 23 episodes that aired on Wednesdays at 9:00 pm beginning October 3, 2012, and ending May 15, 2013.


title: Supernatural (American TV series)

text: The two brothers begin a fight against Crowley to find the Demon Tablet and trap all demons in Hell. Kevin Tran translates three trials that must be completed in order to lock the Gates of Hell for good, but although Sam completed the first two, Dean ends the trials before the third can be finished as completing the trials would kill Sam. Castiel is tricked by the angel Metatron into banishing every angel apart from Metatron to Earth.


title: Supernatural (American TV series)

text: The ninth season consists of 23 episodes that aired on Tuesdays at 9:00 pm beginning October 8, 2013, and ending May 20, 2014.


title: Supernatural (American TV series)

text: The brothers search for a way to return the angels to Heaven. The angel Gadreel murders Kevin Tran and escapes to join Metatron. Sam expels Gadreel, but the experience causes Sam and Dean to split up. Castiel begins a search of his own for Metatron, believing him to be the key to reversing the expulsion of the angels. Metatron begins trying to unite all the angels under his rule while Castiel leads other angels against him to retake Heaven. Castiel defeats Metatron after a repentant Gadreel sacrifices himself. Metatron kills Dean, causing Dean to become a demon.


title: Supernatural (American TV series)

text: The tenth season consists of 23 episodes that aired beginning on October 7, 2014, and ended on May 20, 2015. The season began airing Tuesdays at 9:00 pm, and moved to Wednesdays at 9:00 pm beginning March 18, 2015.


title: Supernatural (American TV series)

text: Dean is now a demon, working alongside Crowley. Meanwhile, Sam continues to search for Dean. After Dean refuses to follow Crowley's order and embarrasses him in front of his demon followers, Crowley gives Sam his brother's location. Sam and Castiel cure Dean by using sanctified human blood. A mysterious new witch comes into play, revealed to be Crowley's mother, Rowena.


title: Supernatural (American TV series)

text: A large focus of the season is Dean's quest to overcome the Mark of Cain and have it removed if possible. New hope for ridding Dean of the Mark comes when Charlie unearths the "Book of the Damned".


title: Supernatural (American TV series)

text: In the eleventh season, Sam and Dean deal with the release of Amara / The Darkness. When nothing works to get rid of the Darkness, Amara claims that God must appear Himself to see her destroying everything He created and loves. Chuck returns and tells Metatron he is God. Amara and Chuck reconcile and leave the Earth, but not before Amara tells Dean she is going to give him what he wants most for helping her: a reunion with his mother.


title: Supernatural (American TV series)

text: The twelfth season premiered on October 13, 2016, and concluded on May 18, 2017, consisting of 23 episodes.


title: Supernatural (American TV series)

text: Lucifer makes the President of the United States his human vessel. The president gets his assistant Kelly Kline pregnant and Kelly gives birth to the Nephilim, while Crowley sacrifices himself to kill Lucifer. Crowley and Castiel die trying to kill Lucifer, while Mary and Lucifer are pulled into the rift created by the Nephilim's birth. Sam is shocked to see Jack the Nephilim grown into a teenager.


title: Supernatural (American TV series)

text: The thirteenth season premiered on October 12, 2017, and concluded on May 17, 2018, consisting of 23 episodes.


title: Supernatural (American TV series)

text: Dean and Sam are left to 'raise' Jack. Sam is willing to give the boy a chance, while Dean is concerned due to his heritage. As Jack sides with Mary and the humans against the angels, the Winchesters and Castiel gather the ingredients for a spell to open the portal to hell while Lucifer tries to reestablish himself as king of heaven. Dean kills Lucifer, but the season ends with Michael taking control of Dean's body.


title: Supernatural (American TV series)

text: The fourteenth season premiered on October 11, 2018, and concluded on April 25, 2019, consisting of 20 episodes.


title: Supernatural (American TV series)

text: Michael begins experimenting with monsters, making them immune to their former weaknesses. Dean, Sam, Castiel and Jack decide to take down Michael and his army of monsters once and for all, but Michael retakes control of Dean and unleashes his monsters on the city. God returns and tells the boys that they must use a gun that he built to kill Jack, but Sam and Dean refuse. Angered at their defiance, God smites Jack and unleashes every vengeful spirit from Hell back on Earth.


title: Supernatural (American TV series)

text: The fifteenth and final season premiered on October 10, 2019. The season consisted of 20 episodes and aired on Thursdays at 8:00 pm (ET) with the exception of two episodes in March 2020 which aired on Mondays at 8:00 pm. The series finale was scheduled to air on May 18, 2020. In March 2020, Warner Bros. Television shut down production on the series due to the COVID-19 pandemic. Later in March, showrunner Andrew Dabb revealed that the series would go on hiatus after the March 23 episode. The season resumed airing on October 8, and the series finale aired on November 19, 2020.


title: Supernatural (American TV series)

text: Throughout the series, Dean drives a black 1967 Chevrolet Impala which he refers to as "Baby". Having been passed down to him by his father (John), it is Dean's most prized possession, with actor Jensen Ackles feeling it is Dean's "life" and "sanctuary". The brothers travel in it throughout the country as they hunt the supernatural, and the trunk holds various weaponry and their fake IDs. In the first two seasons, it has a Kansas license plate with the number KAZ 2Y5, a reference to the Winchesters' home state of Kansas, and the series premiere date of 2005. Towards the end of the second season, the car sports a new Ohio license plate (CNK 80Q3) to aid the brothers in hiding from the FBI.


title: Supernatural (American TV series)

text: All of the cars used in the show are stock 1967 Chevrolet Impala four door hardtops. They feature Chevrolet small-block engines, recolored interiors, custom seats, and nonfunctioning radios. Other than the one used in the original, all of the Impalas had to be painted black for the series. One of the Impalas used features a detachable roof and doors for up-close shots, and is capable of being separated in half. After filming of the series concluded, Ackles was allowed by Warner Bros. and The CW to keep the main Impala.


title: Supernatural (American TV series)

text: The 1836 Colt Paterson revolver, usually referred to simply as "the Colt", was made by Samuel Colt, a paranormal hunter. According to legend, anything shot by this gun, using one of its thirteen original bullets, will die, including creatures normally immune to any and all weapons.


title: Supernatural (American TV series)

text: The gun used in the series is actually a replica Paterson modified to fire metallic cartridges. The gun was described as being built in 1835, before Colt made firearms, and fires metallic cartridges, which were never made to fire in a Colt revolver until 10 years after Samuel Colt's death. On the barrel of the gun is inscribed the Latin phrase "non-timebo mala", meaning "I will fear no evil". On the grip is a carving of a pentagram, with much of the finish removed to give it an aged appearance. The prop department also has a rubber version of the Colt to be used in fight scenes for pistol-whipping.


title: Supernatural (American TV series)

text: Ruby possesses a mysterious and presumably magical demon-killing knife, which Kripke refers to as "a hand-to-hand version of the Colt". Its handle is made of elk antlers, and the knife has engravings on both sides of the blade, although the symbols are all nonsensical. It has been seen and used many times following its introduction in the third season. Creator Eric Kripke doubted that how the knife functions would ever be revealed, stating, "I like to leave some things mysterious. And that's likely to remain mysterious." However, the eighth season reveals it to be "an ancient demon-killing knife of the Kurds".


title: Supernatural (American TV series)

text: The advertisements The WB chose for the show went beyond just commercials and billboards. Before the series debuted, the network placed signs for the show at gas station pumps, and gave out rubber glow-in-the-dark bracelets at New York and Los Angeles movie theaters. Also, coffee cup sleeves revealed the image of a "terrified woman seemingly pinned to a ceiling" when heated were distributed to 500 cafes throughout New York, Chicago, and Los Angeles. The same image was used in special mirrors the network installed in almost 200 nightclubs throughout three cities in order to reach "young, hip horror fans". Additional advertisements were also placed in bars, movie theaters, and video game stores, with hundreds of the bars also receiving "Supernatural" napkins and coasters.


title: Supernatural (American TV series)

text: The series also has many real-life tie-ins. The urban legend website "Hellhounds Lair" featured in the season one episode "Hell House" was a real website set up by the show's producers. As a tie-in to the sequel episode "Ghostfacers", in which the owners of "Hellhounds Lair" create their own "Ghost Hunters"-style reality show, The CW set up Ghostfacers.com. The Winchesters later visit this website in the fourth-season episode "It's a Terrible Life". Series tie-ins, however, extend beyond the internet. For a time, Dean's cell number—revealed in the first-season episode "Phantom Traveler" to be 1–866–907–3235—was a real number, with Jensen Ackles reading the message: "This is Dean Winchester. If this is an emergency, leave a message. If you are calling about 11–2–83, page me with your coordinates." The second-season episode "Tall Tales" featured a tie-in to that week's issue of the tabloid newspaper "Weekly World News". The February 19 and March 19, 2007, editions of the paper featured exclusive interviews with Sam and Dean, the articles being written by Paul Kupperberg.


title: Supernatural (American TV series)

text: "Supernatural" has a vast amount of merchandise available, including calendars, T-shirts, shot glasses, temporary tattoos and posters. Inkworks has released trading cards for the show, some cards featuring actors' autographs and swatches from actual costumes used on the series.


title: Supernatural (American TV series)

text: The "Supernatural Role Playing Game" (a pen-and-paper role-playing game) was developed by Margaret Weis Productions, Ltd. Originally scheduled for release in October 2007, it was delayed until August 2009. The game uses material from the series, novels, and comics. Additionally, on September 7, 2010, Watertower Music released Supernatural: Original Television Soundtrack – Seasons 1–5. It features 18 original tracks by Supernatural series composers Christopher Lennertz and Jay Gruska. Funko has also released three Pop! form figures of Dean, Sam, and Castiel as of November 21, 2013.