If you are even a part-time fan of the Game of Thrones series, there’s a pretty good chance that you’ve heard of Greyscale. Greyscale is a devastating (but luckily fictional) infectious disease that is universally feared by every character in the popular Game of Thrones/A Song of Ice and Fire universe. But what is Greyscale? Is it based on a real life disease (Spoiler alert: YES!)? What is happening to people who are infected? This week on TV Medicine If you are interested in other posts about the Game of Thrones, and (soon) other TV Medicine posts, check out the rest of our TV Medicine series! WHAT IS GREYSCALE? Good luck stopping the spread of Greyscale with prayer. You'd have better luck dancing away the plague." ―Tyrion Lannister Greyscale is an infectious disease that is considered almost always fatal in adults. The disease is believed to be spread through physical contact, which is why sufferers are often exiled or quarantined. Although it isn’t explicitly stated how contagious Greyscale actually is, the collective fear of any physical contact with an infected individual implies that the rate must be sufficiently high. SYMPTOMS: Although the skin and the central nervous system manifestations of the disease are the most striking, most infected individuals initially present with peripheral neuropathy (by way of numbness in the fingertips and toes). In the books, when Tyrion comes into contact with someone in the advanced stages of Greyscale, he periodically pokes his fingers with a knife to make sure that they are not going numb. The numbness is usually progressive, and eventually envelops the entire extremity. As the numbness advances, the skin begins to turn gray and will eventually develop the cracked and scaly appearance we first see in Shareen Baratheon, and later Jorah Mormont. Just as with the numbness, the skin changes continue to spread until it covers most of the total body surface area. Blindness usually results when the disease progresses to the face and reaches the eye. Shareen with signs of cured Greyscale disease Once Greyscale reaches the brain, a “feral madness” ensues, causing the infected to act erratically and aggressively. In fact, the Stone Men (who are individuals with advanced Greyscale) are known to attack travellers in Essos, and are responsible for infecting Jorah Mormont. The progression of the disease is slow. From the onset of initial symptoms to full fledged insanity can take from months to years, and death invariably following many years later as the disease attacks the internal organs. The only positive thing about Greyscale (if you can be positive about the disease), is the lack of pain throughout the entire process. It is likely that the preceding numbing neuropathy during the initial presentation destroys any remaining pain receptors. Thus, there is no pain when the devastating skin lesions appear. ARE THERE ANY DISEASES SIMILAR TO GREYSCALE? Like most authors, George R.R. Martin has taken some literary inspiration from many real-life examples. Greyscale combines aspects of several human diseases, creating a scary and destructive plague. Here are the most similar human diseases: LEPROSY If we had to pick one disease that bears the most resemblance to Greyscale, it would be Leprosy. Leprosy is caused by Mycobacterium leprae, which was actually the first bacterium identified to cause disease in humans. The predominance of skin symptoms and the social stigma associated with Greyscale is likely inspired by historical accounts of Leprosy. Just like Greyscale, Leprosy causes a progressive skin numbing due to peripheral nerve damage. However, unlike it’s fictional disease counterpart, the numbness caused by leprosy usually comes after the first skin signs. The bacterium itself replicates to create an extremely large number of organisms, and infiltrates the sensory nerves wherever lesions occur. White blood cells from the host’s body (mostly macrophages, if you’re interested) attack the pathogen, causing significant inflammation and damage to the nerve tissue. Patients who are eventually cured of the disease will usually regain sensation over the course of several years after elimination of the infection. As you probably know, Leprosy is mostly known for the multiple skin symptoms. Though there are multiple forms of the disease, the hallmark is granulomatous (a fancy word that sorta means bulbous growths caused by immune reactions) skin lesions that leave the infected disfigured. These unsightly growths were one of the main reasons why lepers were shunned. The striking facial features of advanced leprosy. Photo: Public domain Unlike Greyscale, leprosy isn’t spread by physical contact. Instead, small droplets from the respiratory system enter the air and spread. Interestingly, it is similar to tuberculosis. Neither TB nor Leprosy are particularly easy to catch, but those who spend significant time in close quarters with lepers are at risk. In this fact, Leprosy shares another aspect with Greyscale: Many of the people who try to help the victims become infected and die as well. The arch maester at the Citadel speaks of a procedure to cure Greyscale, but says that it is forbidden as the maester who developed it contracted the disease in the process. Similarly, many of those who treated lepers have succumbed to it in the process. Perhaps the most famous being Father Damian who died of leprosy in 1889, and was made a Saint in 2009. Contrary to popular belief, “Lepers” (people who showed symptoms of leprosy) were less shunned than most people believe. However, leper colonies did exist, and most non-infected individuals put significant effort was put into avoiding contact with anyone showing skin symptoms. This stigma is very similar to those infected with Greyscale who are often exiled or isolated. Similarities: Disfiguring skin lesions, peripheral nerve damage, infectious spread, social stigma Differences: Skin lesions before numbness, lack of change in mental status, spread by aerosol secretions SYPHILIS Believe it or not, syphilis is more than just a simple sexually transmitted bacterial infection. If left untreated, it can cause many of same problems seen in Greyscale. One to three months after the initial infection, individuals begin to show a variety of symptoms. Most notably, a large rash can form and cover most of the body. This rash does differ from Leprosy, as it will usually resolve after several weeks and is less disfiguring. During this stage of the disease, there can also be joint pain, fever, and many other symptoms. Secondary syphilis in an HIV positive male. Photo from Herbert L. Fred, MD, and Hendrik A. van Dijk [CC BY 2.0 (http://creativecommons.org/licenses/by/2.0)], via Wikimedia Commons Many years (3-15) after being initially infected, syphilis enters the third and final stage. Victims begin to show severe mental deterioration, and large destructive skin lesions. Sounds familiar? It shows some of the same symptoms as the final stages of Greyscale. Similarities: Mental deterioration, long disease course, skin lesions Differences: Skin lesions do not persist until late in the disease, lack of peripheral neuropathy, many others HARLEQUIN-TYPE ICHTHYOSIS Drawing of infant with HTI. Public domain image Warning: Do not google for more images of this disease if you are at all squeamish. Harlequin-Type Ichthyosis is a genetic disorder that causes thickened, non-flexible skin to form over the entire body. Imagine if your skin could not stretch, bend, or compress. Instead, infants born with this disease suffer with large plates of thick skin, which crack and prevent movement. Constriction of the chest can make breathing difficult, and many infants die of infection or dehydration due to cracks in the skin. Modern treatments, including extremely potent forms of Vitamin A, have improved survival rates significantly. Similarities: Scale-like skin Differences: Non-infectious, and pretty much everything else FIBRODYSPLASIA OSSIFICANS PROGRESSIVA Skeleton of a FOP sufferer. Photo:By Joh-co (talk · contribs) (Own work) [CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons FOP is another extremely rare genetic disorder, with less than 1,000 people worldwide suffering from the disease. If you know a little bit of Latin, you may be able to surmise from the name that FOP involves progressive displacement of tissue with bone. Overtime, all of an individual’s muscle and connective tissue becomes calcified and hardens into a bone-like structure. Predictably, FOP sufferers slowly lose the ability to move. The most common causes of death include respiratory failure from lack of chest mobility, infections of lung, and heart conduction issues. Any injury, no matter how small, causes additional bone formation. Can you imagine? Every stubbed toe, every fall, and every paper cut causes you to slowly lose the ability to move. Greyscale is similar only in that the gray stone-like qualities progress over time like those in FOP. Unfortunately, there is still no effective treatments for FOP, and the disease is fatal. Similarities: Statue-like calcification of tissue Differences: Almost everything else WHAT IS HAPPENING (PHYSIOLOGICALLY)? In order to really try and parse this down, there are a few big assumptions that we will. have to make. We will try and point out these assumptions as they come up, but as a small disclaimer: this is all speculation about a fictional disease. Some of the information is based on the (limited) expertise that we have gained throughout our training. GREYSCALE IS A BACTERIAL INFECTION… PROBABLY Almost all infectious human diseases are caused by one of four categories: viruses, fungi, parasites or bacteria. Each class of disease causing agent shares some characteristics which allow us to semi-accurately predict what exactly causes Grayscale. (There are some rare diseases caused by lone proteins, and even some infectious cancers in the animal world, but these account for a very small proportion of infections.) The long disease course, broad range of symptoms, and the eventual involvement of the central nervous system leads us to believe that the infection is caused by a bacterium. (We are making the assumption that there are similarities between the causes of real-world diseases and the Westerosi ones. It could all be magic instead) Specifically, we feel that Greyscale’s symptom course is most similar to diseases caused by a subset of bacteria called Spirochetes. Spiral shaped spirochetes that cause syphilis. Photo: Public domain Spirochetes are very small single-celled organisms that have a spiral shape when viewed under a microscope (when you can actually see them). The most commonly known spirochete diseases are Syphilis and lyme disease, although they cause a variety of other diseases. If Jorah were in the real world, he’d probably be cured with a simple course of antibiotics. Many of the spirochete diseases are unable to mount meaningful resistance to certain antibiotics and are easily treated. THE PATHOGEN RESIDES IN THE NERVE TISSUE By infecting nerve tissue, the organism has a few primary advantages. First, nerve cells (neurons) are highly specialized and do not divide as frequently as other cell types. The lack of division creates a stable environment that will allow the Greyscale bug to thrive so long as it does not completely push out the native cells. The organism that causes leprosy uses this to its advantage and is able to invade the cells that wrap around nurons and remain there for long periods of time. Additionally, if the organism can invade the neuron directly, it will have increased access to the central nervous system (i.e. the brain). As you may know, it is usually difficult for infections to reach the brain due to the blood-brain-barrier. However, by travelling up the nerve and into the spinal cord it could penetrate through this barrier and enter the brain. The rabies virus works in this way: after the victim is bit by an infected animal, the virus travels up the nervous tissue through the spinal cord and into the brain. Greyscale seems to work in a similar fashion, as we see a progressive numbness up the limbs that eventually results in some form of dementia/brain damage. SKIN CELLS UNDERGO A CANCEROUS TRANSFORMATION Large, debilitating, discolored and scaly lesions are not very common in medicine. Other than the genetic disease listed above, there are only a few things that cause something that catastrophic. The first thing that comes to mind is the “tree-man” that pops up every once in awhile on medical documentaries or top-10 weirdest disease lists. The large growths are caused by a combination of a genetic disorder and a viral HPV infection. Yes- the same HPV that causes all kinds of warts. (Although don’t worry; if you do not have the mutation these particular HPV strains are usually benign) Large growths in man with HPV and Genetic condition. Photo: By Monirul Alam (Authors e-mail) [CC BY-SA 4.0 (http://creativecommons.org/licenses/by-sa/4.0) or GFDL (http://www.gnu.org/copyleft/fdl.html)], via Wikimedia Commons HPV causes abnormal skin growth when the viral DNA is accidentally incorporated into host’s genetic material. Once this happens, the skin cells begin to divide rapidly and uncontrollably. The uncontrolled division usually leads to warty growths, but can occasionally lead to cancer. Greyscale may cause some kind of transformation in the victim’s skin cells, causing them to grow and lose some of their elasticity. As the cells divide, they would form a thick and stiff layer of skin which would go on to crack and form scales. Gray color changes could result if there was not enough blood flow to the new skin layer. For example, some diabetic changes or venous stasis in the lower limbs cause a dark discoloration. CONCLUSION: We tend to get a little nerdy and speculate about physiology and medicine, and analyzing a fictional disease from one of our favorite shows is one of our favorite ways to do this.Greyscale is a pretty terrible disease, and regardless of whether he’s ultimately cured or not, Jorah is in for a world of pain under Sam’s untrained knife. Thanks for reading! Settle a bet for us: can the American spelling of the color be used in the disease name (as in Grayscale), or is it a proper noun? Let us know what you think in the comments!