 So our next speaker is Soranthi Vaigunta. She's one of our PGY3 residents and she's going to be speaking about Cuban cigars, rum, and the communist regime. And if we're lucky, she'll tell us about her travel misadventures and her small amount of jet lag. Yes, I just got back from Micronesia. It was an amazing trip and so lucky to be part of it. But it took about two days for us to get back. We were in Guam for a day extra on the way back, but it was a fun trip regardless. It was really great. So we're going to switch topics completely, as you can see, going to history and rather than retina, we're going to go into neuro-automology. So what does this act of title actually mean? You'll find out. So have you heard about the largest epidemic of neurological disease in the 20th century? Okay, I'll tell you all about it. So that look at the presentation is that we'll talk about the geopolitics of the time. We'll talk about the relationships between the Soviet Union, Cuba, and the United States, the epidemic itself, and we'll talk about how they identified the cause at that time and pathophysiology briefly and a discussion of the situation. So this is a great picture of Fidel Castro the same year he took over power in Cuba, 1959. He's eating some ice cream at the Bronx Zoo. So he secretly, actually the background behind this picture is that he secretly had a child who was going to school in New York at that time, but he was trying to keep it on the DL. So Fidel Castro had been in power since 1959, and since his takeover of power, the U.S. declared an embargo on sanctions to isolate Cuba politically and diplomatically from the rest of Latin America and the world. So the U.S. declared this embargo on trade with socialist countries as well as Cuba, and it's still in place until present day, although not as severe. Cuba reported successful health indicators at this time. Overall, the infant mortality rate was very low, the same as it was in the United States, and life expectancy was also the same as it was in the U.S., which was 75 years. The health system, they think this was the success of this health system was built on its extensive infiltration into urban and rural areas and a high doctor-to-patient ratio of 1 to 170, which is pretty great. In Cuba, even to this day, has that high doctor-to-patient ratio. This is a picture of a family physician's office and home in the community in Havana, and it's known that the physicians there are well-integrated into the community and well-known by the citizens there. So the Soviet Union at this time was providing billions of dollars in aid to Cuba annually, but after the Soviet Union collapsed in about 1989 and 1991, those billions of dollars of aid just ended, and Cuba at that time suffered a significant drop in GDP from to about like 35 to 50 percent as a drop-to-drop. Cuba, because it was so closely associated with the Soviet Union and socialist bloc countries, was essentially economically isolated from the rest of the world and had to start expanding its trade partners. So at this time, due to the economic decline, in order to sort of sugarcoat it, I think, Fidel Castro called this period the special period in a time of peace. So during this time, as the Soviet Union was declining in the late 1980s, trade with U.S. subsidiaries increased from about $230 million in 1988 to over $700 million in 1990, but it still wasn't enough. There wasn't enough trade and enough food incoming to Cuba to keep up with their great need to import food. Over 80 percent of this food was imported. This was mostly because Cuba was ruled previously as a Spanish colony, and it was set up as a colony to produce sugar, rum, and honey and molasses, but not necessary to produce all these different types of vegetables and fruits that needed to sustain the population. So the Cuban people actually renamed this the special hardship rather than the special period because of all the food rationing and the lack of resources. So the daily average calorie intake of the population on average per person decreased from 2,900 calories to 1,860. And the physical demands of the population increased during this time because there was less fuel coming in. So people had to walk or walk more, bicycle more, pool carts to be able to transport goods. So 27 percent of adults lost greater than 10 percent of their body weight during this time. And also Cuba ended up importing over 700,000 bicycles, which they could subsidize and sell cheaply to the population. So more on the special period. The food was subsidized, but it wasn't nutritious enough to provide the needed vitamins that the population needed. So for example, there was a soy hamburger that was distributed because meat was very expensive and difficult to import. So the soy hamburger was rationed at one serving per person once or twice a month only, that was it. And bread rolls were given out about one roll per person per day. Corn and root vegetables used to be their main staples of their diet, but that changed when the Chinese introduced rice. So then beans and rice became their main staples, which wasn't enough to provide the nutrition they needed. Animal products, animal protein and fat and vegetables and fruits were also rationed even more strictly, and they were also expensive to buy in the black market itself. However, tobacco and bootleg alcohol was pretty cheap. So the Cuban Democracy Act of 1992. So this brings us a few years after this significant decline in GDP, President George H. W. Bush reluctantly passed this Cuban Democracy Act, which placed an even stricter embargo against Cuba. So the one loophole in the embargo that was already placed was that the U.S. could trade food, medical supplies and medicines with Cuba, but this embargo would kind of restrict that further. And President Clinton called this the most restrictive embargo ever placed by the U.S. against any country. Unfortunately, it was predicted during that time by the American Public Health Association, and they reported to the U.S. Senate that, you know, tightening this embargo is not going to be good for the population. It's going to lead to widespread famines in that area, and the U.N. also recognized this and vetoed passing of this embargo, but it still went through. After it was passed the American Public Health Association, American Academy of Neurology, and the Inter-American Commission on Human Rights all spoke against this and said, we are finding health indicators that the Cuban population is suffering, most of the public health indicators, including infant mortality and life expectancy and things like that, and the American Academy of Neurology asked for lifting of the embargo for humanitarian reasons so they could get the resources that they needed. But the opposite happened. Instead of lifting the embargo, the Helms-Burton Act was passed in 1996, and this further limited the trade of other countries outside of the U.S. to trade with Cuba as well. So this, of course, led to a lot of issues and protests from Canada, Mexico, and Europe, which felt that this act was a significant violation of their sovereignty, nationality, and property. So let's talk about the epidemics. That's a little background on what the situation was at the time. So the story of the epidemic starts in the region in Cuba called Pinar del Río. It's the western-most region in January 1992. So at this time, there were men about ages 25 to 64 who were presenting with a subacute bilateral vision loss. They had parasthesias and dysasthesias, weight loss, fatigue, and polyuria. By the end of the year, a thousand cases had been reported. So this is turning into an epidemic. Locally, the Cuban neurology and neurosurgery institutes started studying this as well as they could try to figure out what was the cause of this vision loss. Then many of these researchers I listed here are still publishing on this topic today. So the Cuban Ministry of Health evaluated the issue, and they found that there were two types of neuropathy that were showing up. There was an optic form, which men had more significantly, and peripheral form, which affected women slightly more significantly. In the optic form, they did include, if they had optic and some peripheral issues, they combined it with op. There were a few risk factors that were isolated, like smoking cigars and cigarettes, drinking alcohol, also deficiencies in vitamins, of course, folic acid and B vitamins. A lot of these patients ended up having lumbar punctures and CSF studies done, which actually ended up showing up positive for coxaki virus. But these cases were still poorly defined. By 1993, there was an alarming 40,000 cases, and the population of Cuba is just 11 million. So that's a significant number of the population, not 0.5%. So you can see here the exponential increase on the graph from 1992 to 1993 of both the optic and peripheral forms. And there was also a pattern to how this neuropathy was sort of spreading across the country. So it seemed to go from west to east, and so the highest incidence rate was it's still in Pinar del Río, on the western-most side of the island. And then the lowest was in Guantanamo, all the way here, 65,000-400,000. So given all these issues and the presentations, there was still a large differential diagnosis that needed to be narrowed. Was it nutritional? Was it toxic? Was it infectious or genetic? What was the actual cause of the optic neuropathy and peripheral neuropathy? So the Cuban Ministry of Health, once the incidence rate reached such a high level, and the prevalence was 40,000, almost 50,000, they asked for help from the World Health Organization, the Pan American Health Organization, NIH, CDC, and ORVIS. And so this was a collaboration between several different sub-specialties of physicians and epidemiologists, public health officials. So the Pan American Health Organization and WHO sent a delegation of experts that they recruited from the United States and other countries to Cuba to help figure out what's going on. So from the United States, Dr. Alfredo Sadoon, who was a neurophthalmologist at USC, he's still working there. He was recruited because he was a world expert in labor's heritatory optic neuropathy, and this was still in the differential. So he has helped establish a case definition. And as Dr. Warner pointed out, so he actually came to Moran to present, he printed out the U.S. Dinner, the Henry Bandai Dinner, and like the Translational Research Day as well. So he found that these patients presented with this weight loss, fatigue, they had a taxia and hearing loss, and the vision loss occurred usually over days to weeks with profound color vision loss. Usually they didn't have any affected family members with optic neuropathy as well, they did not. The visual acuity was less than 20 over 400. Contrast sensitivity was an issue. They had sluggish pupils that reacted briskly to near stimulation but not light. Psychotic pursuit eye movements was an issue as well, and they lost sensation in their hands and feet in sort of a stocking glove pattern. So this is one of the most striking features on physical exam of these patients, and this was used to help define the cases in this situation. So he found that there was a normal looking optic nerve head with a wedge-shaped defect in the wedge-shaped temporal defect right there with pallor, and that involved a papillomacular bundle. Whereas the surrounding nerve fiber layer was actually swollen as you can see here as pointed out with these arrows. Also another striking feature was the secocentral scotomas and central scotomas that patients had. So his case definition included a requirement of nerve fiber layer loss especially in the papillomacular bundle, plus any three of the following conditions that were listed previously. So subacute vision loss, color vision problems, irregular eye movements, visual field defects, and contrast sensitivity issues. That led to a nice succinct case definition help out with providing further treatment to patients and also doing further studies on these patients. But there were still some issues that needed to be answered. So this is actually a slide directly from his presentation when he was here. So he actually sent samples of bootleg rum back to the United States, the samples that he collected. And he found that the bootleg rum that was made at home had a much higher percentage of methanol compared to the aged rum. So 1% for the bootleg and less than 0.01% for the aged rum. So this was a significantly more amount of methanol, but in order to have true methanol toxicity, patients would have to consume between 10 to 20 milliliters of this over a 12 hour period because methanol is converted to formic acid and that's what leads to toxicity on the Krebs cycle. So 1% methanol was probably more than enough to produce a subacute problem but not enough to cause acute toxicity. He also had this slide's presentation which is pretty interesting. So one of the theories was that maybe the rate of travel of the disease from west to east, which was 26 kilometers a day, was close to the rate that a donkey would travel across the country. Maybe carrying bootleg rum. But there was still the question of whether or not there was a genetic component. So only one of his 20 cases that he initially evaluated was positive for labor's mutation. So to look even further, there was a retrospective case control study done on 123 cases and controls. And the conclusions from this were that there were certain risk factors that these patients had. Higher body mass index being male, being 25 to 65 years of age, cigar smoking, and cigar smoking or cigarette smoking even had a dose response relationship with how often opiate gravity was diagnosed. And cassava consumption cassava is also known as yucca, which is a root vegetable that was consumed there. Lower socioeconomic status and of course deficiencies and essential vitamins as well. And serum levels were also measured and these patients had lower levels of B12 fully in antioxidants. Some things that were also found during the study was that the CSF of these of the cases was actually normal. So Cocksackie was thought to be contaminated and had to muddled the whole differential initially. And none of these cases were positive for labor's mutations. There was also interestingly no association between the whole brute alcohol consumption between the cases and the controls. And there was no difference between the case and controls. And so no association with opiate neuropathy as well. So the conclusion was that this was likely a toxic optic neuropathy combined with nutritional optic neuropathy, sort of like a two hit hypothesis on the mitochondrial function. So how did this work together? So why did toxicity and nutritional neuropathy combine in this case to form such a severe optic neuropathy? So of course there was poor access to nutrition, but this led to poor vitamin B complex folate levels. And vitamin B again, B12 especially is absorbed even more poorly when patients are consuming high levels of alcohol. And then cyanide was thought to be accumulating in these patients due to smoking and yucca or the cost of consumption. So those were the theories. And so cyanide is consumed and that would lead to again lower levels of folate and B12 because cyanide can inhibit absorption of those as well. So the pathophysiology of this, again with the two hit hypothesis it was thought that the toxicity on top of methanol and cyanide due to smoking and possibly Kosova led to poor mitochondrial function which was kind of like an acquired labor's type picture. So folate and B12 in addition to being important parts of the prep cycle were really important for DNA synthesis. So B12 especially is involved in myelin synthesis. So deficiency in B12 can lead to demyelination, sensory loss, and dementia. And this is exclusively acquired from animal products. So vegans have to acquire it additionally. So this is a nice schematic of all the different effects that the vitamin deficiencies and formic acid accumulation from methanol toxicity had on potentially inhibiting the prep cycle and also decreasing production of ATP and consuming exo formic acid when it's trying to be, let me see if I can actually, there we go. So formic acid when it is neutralized by the body uses up folic acid as well. So it kind of shows you the schematic there. Cyanide can inhibit the prep cycle. The free radicals can inhibit as well. B12 vitamin can be inhibited by cyanide as well. All right. So how does this affect optic nerves? So the metabolic demand that our axons have is primarily from the axoplasmic transport and sodium potassium pumps in the membranes. So the greatest demand of ATP comes from fibers that are the smallest and the least myelinated. So these are the least efficient fibers in our bodies. So the least efficient fibers includes the most inefficient, I guess the same thing, small sensory fibers in our hands and our feet and also the macular bundles fibers which are small, they're poorly myelinated and they undergo a sharp turn as they're coming out of the optic nerve. So it requires a little bit more energy to transport up and down axons, transport energy up and down axons. So how does this eventually lead to resolution of the crisis? All these studies were very helpful in trying to come up with great case definition and also led to training of physicians to screen based on the case definition. So training of ophthalmologist, family physicians, internists to help with the screening and set up a system of referrals between the primary care physicians and the ophthalmologists in rural and urban areas actually. So eventually this also led to the studies led to a great understanding of how vitamins were actually were able to improve optic neuropathy. So three vitamin supplements were available to the population that was affected initially and then to the entire population. Patients who were the most severely affected were actually hospitalized and given intravenous B vitamins. The rest of the population was given oral vitamins including children who received half doses of those and then a public health campaign was started as well to discourage smoking and provide nutritional education. So this is a picture of these of two Cuban ladies in Havana who actually posed for tourists like this to get their pictures taken. But why did this happen in Cuba? There have been bambins all around the world, right? They're countries that have much fewer resources than maybe Cuba at that time. But is it likely because they were going unrecognized whereas Cuba had a very strong and robust infrastructure to their medical system? Or was there some other reason? But were Cubans more likely to be susceptible to this situation due to genetic misposition in their mitochondria? There weren't further studies that were done on any other mutations or functions of the Cuban population like mitochondria necessarily as slavers. But also did the abrupt decline in nutrition causes rather than a gradual decline? So to go on with that theory, the Pinar del Río region which was the most affected compared to the Guantanamo region, Pinar del Río had initially higher access to resources because it was a very rich region because of tobacco cultivation and consumption as well. So the abrupt decline may have had a greater impact on the optic neuropathy versus Guantanamo which had a different baseline. The Guantanamo population had historically adapted to these lower energy levels and the decline in the nutrition was an extreme for them. They also had different staples in their diet. They depended more on vegetable oil rather than animal fats. They ate more plantains and vegetables to start off with and less rice than the rest of Cuba as well. Those are just some theories that are out there that's kind of interesting. In 2005 follow-up study about over 4,000 patients were evaluated and 90% of them still had low vision but they were called functional. Only like a small percentage of them had visual acuity that was like better than 2040 so about 10% had better than 2040 visual acuity. But now trade with Cuba is slowly improving. Tourism is also possible as we see Brad was there recently. So that's the story and I'd like to thank Dr. Warner for welcoming me out with this presentation and I'll take any questions. One comment is you know I do medical missions to Central America and it's with a group so back in Kennedy's time all the different states in the US were paired with a Central and South American country called Partners with America and the idea was to exchange medical supplies and engineering and things like that but in reality it was to isolate Cuba because if you pair a state with one of the countries down there but not Cuba then we were able to kind of keep Cuba from getting a foothold in the other Latin American countries. Wisconsin was paired with Nicaragua initially and so sharing resources were a lot established for that reason and that's the group that I did medical missions into Nicaragua and Honduras now with but it's just interesting how a lot of the politics kind of play into the the missionary work as well as the trade. They had very few Latin American countries that had asked for help. Venezuela was one of the few countries that provided physicians and scientists to actually come and give their opinion and also is one of the few countries even provide oil to them. I don't think they embraced Partners with America. So those of you who know too many of us that's in the end in Kenya are you telling the residents who've been going whatever you do local customers to invite you for a drink down the road those of you who've been to Arusha you go down the high street there are those two bars outdoor bars I always tell your residents do not go and have a drink there because they're like a brew in Kenya and Tanzania and Uganda called Chang'a and it's very very cheap one cent and it makes you find the next morning the meaning of the word Chang'a in Swahili is kill me quick and it's made out of the two cheapest materials available in Africa battery acid for obvious reasons and surprisingly jet fuel for some reason jet fuel is cheap to buy on the street so they mix it with the billets of the maze brew and make Chang'a and so there are episodes of mass blindness just like you're describing in Cuba where if the concentration is a particular level methanol poisoning causes severe blindness so I always tell the residents there's a beer that will tusk up brew you can drink that safely but do not drink Chang'a I'm looking at you that's fascinating Cuba same sort of a problem same there's an illegal brewing that same sort of methanol in the room same we were in Micronesia one of the um partners there was talking about how young men they're getting easy access to um you know cheap alcohol this way too and they end up going blind because the methanol that they're consuming thank you thank you