The history of multiple sclerosis (MS) is a detective story spanning more than a century. Many clues have been pieced together, but only now are answers emerging. To appreciate why the trail to a solution has been so long and hard, it is necessary to understand what we scientists now believe to be true about MS.
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Because of this geographical distribution, it is believed that MS involves a genetic susceptibility, although it is not directly inherited. It usually causes sudden neurologic symptoms including loss of vision, paralysis, numbness, and difficulty walking. The symptoms are diverse and confusing, often coming and going without any pattern, making it difficult to diagnose, even today. Symptoms appear because nerves in the brain and spinal-cord lose their ability to transmit signals. Myelin, a complex substance surrounding and insulates nerve-fibres, is essential for nerves to conduct electricity and carry out their function. Myelin is destroyed in MS. Cells and proteins of the body's immune-system – which normally defend the body against infections – leave the blood-vessels serving the central nervous system, leaking through the blood-brain barrier into the cerebral cortex and spinal-cord, destroying myelin. The specific triggering mechanism which causes an immune-system to attack its own myelin remains a mystery, although a viral infection in addition to an inherited genetic susceptibility is a leading suspect. Multiple sclerosis is one of the most common diseases of the nervous system, afflicting people of virtually all ages around the world, although it has a special preference for young people, especially women, and those from Nordic countries. These areas include many places where the incidence of MS is higher than average including Iceland, Norway, Sweden, Denmark, the Faeroe the Orkney islands, the Shetland Islands, Scotland and northern Ireland. Cases of MS in other regions such as the USA, Canada, Australia, and New Zealand may be attributed in a large part to the expanding British Empire and the Scottish emigrants moving to these areas during the 19th century. Scotland – in particular the mainland around Aberdeen, the Orkney and Shetland Islands has the highest incidence of MS in the world. |
Trust & McAlpine's multiple sclerosis 2005 |
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Until the early years of the 19th century, physicians relied on superstition, hearsay, and the wisdom of the ancients to care for the sick. Medical ideas were not scientifically tested. Even so, physicians were sometimes good observers and we can identify people who undoubtedly had MS from descriptions written as long ago as the Middle Ages. Once scientific method was adopted in medicine, MS was among the first diseases to be described scientifically. 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. These 19th-century doctors simply didn't understand what they saw and recorded, but drawings from autopsies done as early as 1838 clearly show what we today recognize as MS. Then, in 1868, Jean-Martin Charcot (1825–1893), a professor of neurology at the University of Paris, ("the father of neurology"), carefully examined a young woman with a tremor of a type he had never seen before. He noted her other neurological problems including three significant signs of MS now known as "Charcot's triad": slurred speech, abnormal eye movements though these are not unique to MS. Charcot also observed cognition changes, describing his patients as having a "marked enfeeblement of the memory" and "conceptions that formed slowly". He compared them with those of other patients he had seen. When she died, he examined her brain and found the characteristic scars or "plaques" of MS. Prof. Charcot wrote a complete description of the disease and the changes in the brain which accompany it. However, he was baffled by its cause and frustrated by its resistance to all of his treatments which included electrical stimulation and strychnine - because this poison is a nerve stimulant. He also tried injections of gold and silver, as they were somewhat helpful in the other major nerve disorder common at that time - syphilis. It was Dr. Jean Martin Charcot (1825 - 1893) who first scientifically described, documented, and named the disease process, we still call Multiple Sclerosis. So named from the many scars found widely dispersed throughout the central nervous system (CNS), but are usually found to be arrayed in a symetrical pattern near the Cerebrum's Lateral Ventricles from Greek sklerosis, from skleroun ‘harden’. |
Following Charcot's description, Eugène Devic (1858–1930), Jozsef Balo (1895–1979), Paul Ferdinand Schilder (1886–1940), and Otto Marburg (1874–1948) described special cases of multiple sclerosis.
During the final decades of the 19th century, leading physicians came to understand that MS was a specific disease. MS was recognized in England by Dr. Moxon in 1873, and in the United States by Dr. Edward Seguin in 1878. By the end of the century, much of what can be learned about MS from careful observation was known: that the disease is more common in women than men, that it is not directly inherited, and that it can produce many different neurological symptoms.
But observation can go only so far. Knowledge of MS could not advance without deeper understanding of biology and better research tools. The very existence of the immune-system was unknown. Doctors assumed the same disease rarely struck the same person twice because a disease "used up" the materials in the body it needed to live, much the way crops use up soil nutrients and die unless they are rotated. In the 19th century, scientists first learned that bacteria cause many diseases. As the new century began, they discovered even smaller organisms, viruses, and developed techniques for growing and studying bacteria and viruses in the laboratory.
In 1906, the Nobel Prize for medicine was awarded to Drs. Camillo Golgi and Santiago Ramony Cajal, who perfected new chemicals to enhance the visibility of nerve cells under the microscope. Equipped with this new technology, Dr. James Dawson at the University of Edinburgh in 1916 performed detailed microscopic examinations of the brains of patients who had died with MS. Dr. Dawson wrote a description of the inflammation surrounding blood-vessels and the damage to the myelin with a clarity and thoroughness which has never been improved. But so little was known about the brain's function that the meaning of these changes could only be guessed at.
In the decade after World War I (1918-28), MS research grew more complex. Abnormalities in spinal fluid were noted for the first time in 1919, though their significance was a puzzle. Myelin, which had been discovered in 1878 by Dr. Ranvier, was studied intensively under the microscope and the cell that makes myelin, the oligodendrocyte, was discovered in 1928.
The first electrical recording of nerve transmission, by Lord Edgar Douglas Adrian in 1925, established techniques needed to study the activity of nerves and launched a series of experiments to determine just how the nervous system works. Ultimately, six Nobel Prizes were awarded for these studies. The resulting knowledge included clarification of the rôle of myelin in nerve conduction and a realization that demyelinated nerves cannot sustain electrical impulses.
At this time, scientists suspected that some form of toxin or poison caused MS. Because most MS damage occurs around blood-vessels, it seemed reasonable that a toxin circulating in the bloodstream leaked out into the brain, even though researchers found no trace of it. Just before World War II, an important breakthrough occurred. An animal model of MS was developed out of research on vaccines. It had been known that people vaccinated against viral illnesses, especially rabies, sometimes developed a disease resembling MS. It had been assumed that this occurred because the virus in the vaccines was not completely inactivated. Rabies vaccines were prepared by growing the rabies virus in nerve tissue.
In 1935, Dr. Thomas Rivers at Rockefeller Institute in New York City demonstrated that nerve tissue, not viruses, produced the MS-like illness. By injecting myelin he knew to be virus-free into laboratory animals under the proper conditions, he could induce their immune- systems to attack their own myelin, producing a disease very similar to MS. This laboratory animal form of MS, experimental allergic encephalomyelitis (EAE), would later become an important model for studying the immunology and treatment of MS. In fact, it paved the way to modern theories of autoimmunity, for it demonstrated how the body can generate an immunologic attack against itself.
But most doctors in the 1930s were still analyzing toxins or checking blood circulation in MS. The importance of EAE to NIS was virtually ignored. Instead, a flurry of experiments in laboratory animals demonstrated that blocking the blood supply to the brain sometimes caused myelin to die. The damage looked a bit like MS. Doctors wondered if MS was caused by circulation problems and they tried therapies to stimulate blood flow including blood-thinners and drugs to dilate blood vessels. X-rays were also used to treat NIS, although more for their novelty than for any sound scientific reason. It would be many more years before the essential similarity of EAE and MS was fully understood and a link between the immune system and MS was forged.
In 2009, Dr Hugh Brady from the Department of Life Sciences at Imperial College London, together with the Medical Research Council's National Institute for Medical Research succeed in immobilising a stem-cell gene, E4bp4, in a mouse model, creating the world's first animal model entirely lacking NK cells, but with all other blood cells and immune cells intact. This breakthrough model may solve the mystery of the role which Natural Killer cells play in autoimmune diseases, such as diabetese and multiple sclerosis. Scientists believe that these diseases are caused by malfunctioning NK cells which turn on the body and attack healthy cells, causing disease instead of fighting it. Clarifying NK cells' role could lead to new ways of treating these conditions. The gene E4bp4 is the 'master gene' for NK-cell production, which means it is the primary driver that causes blood stem-cells to differentiate into NK cells. Clarifying NK cells' role could lead to new ways of treating these conditions.
(Based on an article published in 1996 in the USA
by the National Multiple Sclerosis Society)
Italy's Dr. Paolo Zamboni brought the concept to the forefront of the medical world, yet it has roots in decades of research. In fact, researchers have been investigating the link between MS and blood flow in the neck for close to a century. Austria's Dr. Franz Schelling was among those who studied the link. For 30 years, the now-retired doctor has been on a frustrating mission to get someone to study his findings. He theorized that poor blood flow from their brains of MS patients might be caused by damaged veins, which then triggers or contributes to the symptoms that mark MS. Dr. Schelling worked as a family doctor trained in radiology and neurology and spent much of his career treating patients with MS. He became convinced it was not just a disease of the immune system. He collected research that pointed to damage in the brains in those with MS. He also analyzed X-rays of MS patients and found odd anomalies in the neck and skulls of patients compared to healthy people. But Schelling's requests for more study were repeatedly rejected by MS specialists who insisted what has long been promoted: the disease is caused by immune problems, not the veins.
The first few years of the 21st century have seen a large number of studies on the relationships of human population groups throughout the world
