Poliomyelitis

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Overview
Poliomyelitis (from the Greek polio (πολίός), meaning gray, myelon (µυЄλός), referring to the spinal cord, and -itis denotes inflammation ) often called polio or infantile paralysis, is an acute viral infectious disease spread from person-to-person, primarily via the fecal-oral route. While roughly 90% of polio infections are asymptomatic, affected individuals can exhibit a range of more severe symptoms if the virus enters the blood stream. In less than 1% of polio cases the virus enters the central nervous system (CNS), preferentially infecting and destroying motor neurons. The destruction of motor neurons causes muscle weakness and acute flaccid paralysis.

While polio-like symptoms have been identified in ancient cultures retrospectively, poliomyelitis was first recognized as a distinct condition by Jakob Heine in 1840. In the early 20th century much of the world experienced a dramatic increase in the number of polio cases, leading to a series of epidemics. These epidemics&mdash;which left thousands of children and adults paralyzed&mdash;provided the impetus for a "Great Race" towards the development of an effective vaccine. The development of polio vaccines by Jonas Salk (1952) and Albert Sabin (1962), are credited with reducing of the annual number of polio cases from many hundreds of thousands to around a thousand today. Recently, enhanced vaccination efforts led by the World Health Organization, UNICEF and Rotary International may soon result in global eradication of the disease.

Cause


Poliomyelitis is caused by infection with poliovirus, a human pathogen which cannot naturally infect other species. A small RNA enterovirus, poliovirus is structurally very simple; it is composed of an RNA genome enclosed in a non-enveloped capsid. There are three different serotypes of poliovirus, poliovirus type 1 (PV1), type 2 (PV2), and type 3 (PV3), each with a slightly different capsid protein. All three forms are extremely virulent and produce the same disease symptoms. PV1 is the most commonly encountered form.

Transmission
Poliomyelitis is a highly contagious disease which spreads easily via human-to-human contact. In endemic areas wild polioviruses can infect virtually the entire human population. In temperate climates poliomyelitis is a seasonal disease, with periods of peak transmission in the summer and autumn and reduced levels during winter. In tropical areas seasonal differences in transmission are far less pronounced.

The incubation period of polio, from the time of first exposure to first symptoms, is 2-20 days, with a range of 3 to 35 days. Following the initial poliovirus infection, virus particles are excreted in the feces for several weeks. The infection is transmitted via the fecal-oral route: poor hand washing allows the virus to remain on the hands after eating or using the bathroom. While the risk of transmission is highest seven to 10 days before and after the onset of symptoms, transmission is possible as long as the virus remains in the throat or feces.

Factors which increase the risk of polio infection or affect the severity of the disease include immune deficiency, malnutrition, tonsillectomy, physical activity immediately following the onset of paralysis, intramuscular injection, and pregnancy. During pregnancy, the virus can cross the placenta, however it does not appear that the fetus is affected by either maternal infection with wild poliovirus, or by polio vaccination. Maternal antibodies to poliovirus are able to cross the placenta, providing passive immunity that protects the infant from polio infection during the first few months of life.

Classification
The term "poliomyelitis" is used to identify all conditions caused by any of three poliovirus serotypes. During the acute polio epidemics in the early 20th century, several categories of poliomyelitis were defined to classify the extent and seriousness of the disease. Two basic patterns of polio infection are described: a minor illness which does not involve the central nervous system (CNS), sometimes called abortive polio, and a major illness involving the CNS, which may be paralytic or non-paralytic.

In the majority of immunocompetent individuals (those with a normal immune system), a poliovirus infection is abortive, producing either no– or minor symptoms such as upper respiratory tract infection (sore throat and fever), gastrointestinal tract disturbances (nausea, vomiting, abdominal pain, constipation or, rarely, diarrhea), and influenza-like illnesses.

In about 3% of poliovirus infections, the virus enters the central nervous system. In 1–2% of infections patients develop non-paralytic aseptic meningitis, with symptoms of headache, neck, back, abdominal and extremity pain, fever, vomiting, lethargy and irritability.

In approximately 1 in 200 to 1 in 1000 cases, poliovirus infection leads to the development of paralytic disease, in which the muscles become weak, floppy and poorly-controlled, and finally completely paralyzed; this condition is known as acute flaccid paralysis (AFP). Depending on the site of paralysis, paralytic poliomyelitis is classified as spinal, bulbar, or bulbospinal.

In rare cases, encephalitis (an infection of the brain tissue itself) can occur. This form is usually restricted to infants and is characterized by confusion, changes in mental status, headaches, and fever; seizures and spastic paralysis may also occur.

Mechanism


Poliovirus enters the body through the mouth, infecting the first cells it comes into contact with&mdash;follicular dendritic cells residing within the germinal centers of the tonsils and intestinal M cells&mdash;by binding to a immunoglobulin-like receptor known as the poliovirus receptor (CD155) on the cell surface. Once inside a human cell the virus hijacks the host cell's own machinery, and begins to replicate. Poliovirus divides within gastrointestinal cells for about one week before penetrating the intestinal lining. Following penetration, the virus is absorbed into the blood via the mesentery, and into the lymphatic system via the Peyer's patches.

Once the virus enters the bloodstream it becomes a viremia and is widely-distributed throughout the body. Poliovirus can survive and multiply within the blood and lymphatics for long periods of time, sometimes as long as 17 weeks. In a small percentage of cases the virus spreads and replicates in other sites such as brown fat, the reticuloendothelial tissues, and muscle. This sustained replication causes a secondary major viremia, and leads to the development of minor influenza-like symptoms.

Rarely, the major viremia progresses and the virus invades the central nervous system (CNS), causing a local inflammatory response. In most cases this causes a self limiting inflammation of the meninges, the layers of tissue surrounding the brain, causing non-paralytic aseptic meningitis. Penetration of the CNS provides no known benefit to the virus, and is quite possibly an "accidental" deviation of a normal gastrointestinal infection. The mechanisms by which poliovirus spreads to the CNS are poorly understood, but it appears to be primarily a chance event&mdash;largely independent of the age, gender, or socioeconomic position of the individual.

Paralytic polio


In approximately 1% of infections poliovirus spreads along certain nerve fiber pathways, preferentially replicating in and destroying motor neurons within the spinal cord, brain stem, or motor cortex, which leads to the development of paralytic poliomyelitis. The various forms of paralytic poliomyelitis (spinal, bulbar, and bulbospinal) vary only with the amount of neuronal damage and inflammation that occurs, and the region of the CNS that is affected.

The destruction of neuronal cells produces lesions within the spinal ganglia; lesions can also be found in the reticular formation, vestibular nuclei, cerebellar vermis, and deep cerebellar nuclei. Inflammation associated with nerve cell destruction often alters the color and appearance of the gray matter in the spinal column, causing it to appear reddish and swollen. Other changes associated with paralytic disease occur in the hypothalamus and thalamus. The molecular mechanisms by which poliovirus causes paralytic disease are poorly understood.

Early symptoms of paralytic polio include a high fever, headache, stiffness in the back and neck, asymmetrical weakness of various muscles, sensitivity to touch, difficulty swallowing, muscle pain, loss of superficial and deep reflexes, paresthesia, irritability, constipation, or difficulty urinating. Paralysis generally develops 1 to 10 days after early symptoms begin, and progresses for 2 to 3 days. Paralysis is usually complete when the fever breaks.

The likelihood of developing paralytic polio and the extent of paralysis increase with age. In children non-paralytic meningitis is the most likely consequence of CNS involvement, and paralysis occurs in only 1 in 1000 cases. In adults paralysis occurs in 1 in 75 cases. In children under 5 years of age paralysis of one leg is most common, while in adults extensive paralysis in the trunk and muscles of the chest and abdomen and affecting all four limbs—quadriplegia—is more likely. Paralysis rates also vary depending on the serotype of the infecting poliovirus. The highest rates of paralysis (1 in 200) are associated with poliovirus type 1, the lowest rates (1 in 2,000) are associated with type 2.

Spinal polio


Spinal polio is the most common form of paralytic poliomyelitis. This form of the disease results from viral invasion of the motor neurons of the anterior horn cells, or the ventral (front) gray matter section in the spinal column, which are responsible for movement of the muscles, including the trunk, limb and intercostal muscles.

Poliovirus invasion causes inflammation of the nerve cells, and results in damage or destruction of motor neuron ganglia. When spinal neurons die Wallerian degeneration takes place, resulting in weakness of those muscles formerly innervated by the now dead neurons. With the destruction of nerve cells, the muscles no longer receive signals from the brain or spinal cord; without nerve stimulation, the muscles begin to atrophy, becoming weak, floppy and poorly controlled, and finally completely paralyzed. Progression to maximum paralysis is rapid (two to four days), and is usually associated with fever and muscle pain. Deep tendon reflexes are also affected and are usually absent or diminished; sensation (the ability to feel) however, is not affected in the paralyzed limbs.

The extent of spinal paralysis depends on the part of the spinal cord affected, which may be cervical, thoracic, or lumbar. The virus may affect muscles on both sides of the body, but more often the paralysis is asymmetric and affects unbalanced parts of the body. Any limb or combination of limbs may be affected—one leg, one arm, or both legs and both arms. Paralysis is often more severe proximally (where the limb joins the body) than distally (i.e. the fingertips and toes).

Bulbar polio


Bulbar polio is a form of paralytic poliomyelitis which occurs when poliovirus invades and destroys nerves within the bulbar region of the brain stem. This form of the disease occurs in approximately 2% of cases of paralytic polio.

The bulbar region is a white matter pathway which connects the cerebral cortex to the brainstem. In bulbar polio the destruction of these nerves weakens the muscles supplied by the cranial nerves, producing symptoms of encephalitis, and causing breathing, speaking and swallowing to become difficult. Critical nerves affected are the glossopharyngeal nerve, which in part controls swallowing and functions in the throat, tongue movement and taste; the vagus nerve that sends signals to the heart, intestines, and lungs and the accessory nerve that controls upper neck movement. Due to the effect on swallowing, secretions of mucus may build up in the airway causing suffocation. Other signs and symptoms of bulbar polio include: facial weakness caused by destruction of the trigeminal nerve and facial nerve which innervate cheeks, tear ducts, gums, and muscles of the face, among others; double vision, difficulty in chewing, and abnormal respiratory rate, depth, and rhythm, which may lead to respiratory arrest. Pulmonary edema and shock are also possible, and may be fatal.

Nineteen percent of all paralytic polio cases appear as a combination of the symptoms of both bulbar and spinal polio, this form of the disease is called respiratory polio or bulbospinal polio. In bulbospinal cases, the virus affects the upper part of the cervical spinal cord (C3-4-5), and paralysis of the diaphragm occurs. The critical nerves affected are the phrenic nerve (the nerve driving the diaphragm to inflate the lungs) and the innervation of muscles needed for swallowing. By destroying these nerves this form of polio affects breathing, making it difficult or impossible for the patient to breathe without the support of a respirator. It can lead to paralysis of the arms and legs and may also affect swallowing and heart functions.

Prognosis
Patients with abortive polio infections recover completely. In those patients that develop aseptic meningitis, the symptoms can be expected to persist for two to ten days, followed by complete recovery. In cases of spinal polio, if the nerve cells affected by polio are completely destroyed, paralysis will be permanent; cells that are not destroyed but lose function temporarily may recover within 4–6 weeks after onset. Fifty percent of patients with spinal polio recover fully, 25% recover with mild disability and 25% are left with a severe disability. The degree of both acute paralysis and residual paralysis is likely to be proportional to the degree of viraemia, and inversely proportional to the degree of immunity. Spinal polio is rarely fatal.



Without respiratory support, poliomyelitis with respiratory involvement is likely to result in suffocation, or aspiration of secretions and resulting pneumonia. Overall 5–10% of patients with paralytic polio die due to the paralysis of muscles used for breathing. The mortality rate varies by age: 2%–5% of children, and up to 15%–30% of adults die. Without mechanical ventilation, the bulbar form of paralytic poliomyelitis often results in death. With respiratory support the mortality rate of bulbar polio ranges from 25% to 75%, depending on the age of the patient.

Recovery
Many cases of poliomyelitis result in only temporary paralysis. Within a month, nerve impulses begin to return to the apparently paralyzed muscle; recovery is usually complete within six to eight months. The neurophysiological processes involved in recovery following acute paralytic poliomyelitis are quite effective; muscles are able to retain normal strength even after 50 percent of the original motor neurons have been lost. Paralysis remaining after one year is likely to be permanent, but modest recoveries of muscle strength are possible 12 to 18 months after infection.

One mechanism involved in recovery is nerve terminal sprouting, in which remaining brainstem and spinal cord motor neurons develop new branches, or axonal sprouts. These sprouts can reinnervate orphaned muscle fibers that have been denervated by acute polio infection, restoring the capacity of muscle fibers to contract and improving strength. Terminal sprouting may result in a few significantly enlarged motor neurons doing work previously performed by as many as four or five units: a single motor neuron that once controlled 200 muscle cells might control 800 to 1000 cells. Other mechanisms that occur during the rehabilitation phase and contribute to muscle strength restoration include Myofiber hypertrophy&mdash;enlargement of muscle fibers through exercise and activity&mdash;and transformation of type II muscle fibers to  type I muscle fibers.

In addition to these physiological processes, the body possesses a number of compensatory mechanisms to maintain function in the presence of residual paralysis, including the use of weaker muscles at a higher than usual intensity relative to the muscle's maximal capacity, enhancing athletic development of previously little-used muscles, and using ligaments for stability, which results in greater mobility.

Complications
Residual complications of paralytic polio often result following the initial recovery process. Muscle paresis and paralysis can sometimes result in skeletal deformities, tightening of the joints and movement disability. Once the muscles in the limb become flaccid, they may interfere with the function of other muscles. A typical manifestation of this problem is equinus foot (similar to club foot). This deformity results when the muscles that pull the toes downward are working, but those that pull it upward are not, and foot naturally tends to drop toward the ground. If the problem is left untreated, the Achilles tendons at the back of the foot retract and the foot cannot take on a normal position. Polio victims that develop equinus foot cannot walk properly because they cannot put their heel on the ground. A similar situation can develop if the arms become paralyzed.

In some cases the growth of an affected leg is slowed by polio, while the other leg continues to grow normally. The result is that one leg is shorter than the other and the person limps, and leans to one side, in turn leading to deformities of the spine (such as scoliosis). Osteoporosis and increased likelihood of bone fractures may occur. Extended use of braces or wheelchairs may cause compression neuropathy, as well as a loss of proper function of the veins in the legs, due to pooling of blood in paralyzed lower limbs.

Complications resulting from prolonged immobility involving the lungs, kidneys and heart include pulmonary edema, aspiration pneumonia, urinary tract infections, kidney stones, paralytic ileus, myocarditis and cor pulmonale.

Post-polio syndrome
Approximately one quarter of individuals who survive paralytic polio in childhood have developed additional symptoms decades after recovering from the acute poliovirus infection, notably muscle weakness, extreme fatigue, or paralysis. This condition is known as post-polio syndrome (PPS). The symptoms of PPS are thought to involve a failure of the over-sized motor units created during recovery from paralytic disease. PPS is observed in 28.5% of patients who had recovered from an acute polio infection. Factors that increase the risk of PPS include the length of time since acute poliovirus infection, the presence of permanent residual impairment after recovery from the acute illness, and overuse and disuse of neurons. Post-polio syndrome is not an infectious process, and persons experiencing the syndrome do not shed poliovirus.

Diagnosis
A laboratory diagnosis of poliomyelitis is usually made based on recovery of poliovirus from the stool or pharynx. Neutralizing antibodies to poliovirus can be diagnostic and are generally detected in the blood of infected patients early in the course of infection. Analysis of the patient's cerebrospinal fluid (CSF), which is collected by a lumbar puncture ("spinal tap") reveals an increased number of white blood cells (primarily lymphocytes) and a mildly elevated protein level. Detection of virus from the CSF is diagnostic of paralytic polio, but rarely occurs.

If poliovirus is isolated from a patient experiencing acute flaccid paralysis it is further tested, using oligonucleotide mapping (genetic fingerprinting), or more recently by PCR amplification, to determine if the virus is “wild type” (that is, the virus encountered in nature) or vaccine type (is derived from a strain of poliovirus used to produce polio vaccine). For each reported case of paralytic polio caused by wild poliovirus, it is estimated that another 200 to 3,000 contagious asymptomatic carriers exist. Therefore, isolation of wild poliovirus constitutes a public health emergency, and appropriate efforts to control the spread of the disease must be initiated immediately.

Treatment


No cure for polio exists, and the focus of modern polio treatment has been on increasing comfort, speeding recovery and preventing complications. Supportive measures include: antibiotics to prevent infections in weakened muscles, analgesics for pain, moderate exercise and a nutritious diet. Treatment of polio also often requires long-term rehabilitation including physical therapy, braces, corrective shoes and, in some cases, orthopedic surgery.

Portable ventilators may be required to support breathing. Historically, a noninvasive negative-pressure ventilator (more commonly called an iron lung) was used to artificially maintain respiration during an acute polio infection until a person could breathe independently; generally about one to two weeks. Today many polio survivors with permanent respiratory paralysis use modern jacket-type negative-pressure ventilators that are worn over the chest and abdomen.

Other historical treatments for polio have included hydrotherapy, electrotherapy and surgical treatments such as tendon lengthening and nerve grafting. The use of devices such as rigid braces and body casts&mdash;which tended to cause muscle atrophy due to the limited movement of the user&mdash;were also touted as effective treatments. Massage, passive motion exercises, and vitamin C were also used to treat polio victims, with varying degrees of success.

Antibody serum
In 1950 William Hammon at the University of Pittsburgh isolated a serum from the blood of polio survivors. Hammon proposed that the serum, which contained antibodies to poliovirus, could be used to halt poliovirus infection, prevent disease, and reduce the severity of disease in other patients who had contracted polio. The results of a large clinical trial were promising; the serum was shown to be about 80% effective in preventing the development of paralytic poliomyelitis. The serum was also shown to reduce the severity of the disease in patients that developed polio. The antibody approach was later deemed impractical for widespread use, however, due in large part to the limited supply of blood plasma, and the medical community turned its focus to the development of a polio vaccine.

Vaccine
Two polio vaccines are used throughout the world to combat polio. Both vaccines induce immunity to polio, efficiently blocking person-to-person transmission of wild poliovirus, thereby protecting both individual vaccine recipients and the wider community (so-called herd immunity).

The first polio vaccine was developed in 1952 by Jonas Salk at the University of Pittsburgh, and announced to the world on April 12, 1955. The Salk vaccine, or inactivated poliovirus vaccine (IPV), is based on poliovirus grown in a type of monkey kidney tissue culture (Vero cell line), which is chemically-inactivated with formalin. After two doses of IPV, ninety percent or more of individuals develop protective antibody to all three serotypes of poliovirus, and at least 99% are immune to poliovirus following three doses. IPV is currently the vaccine of choice in most countries.

Eight years after Salk's success, Albert Sabin developed an oral polio vaccine (OPV) using live but weakened (attenuated) virus, produced by the repeated passage of the virus through non-human cells at sub-physiological temperatures. Human trials of Sabin's vaccine began in 1957 and it was licensed in 1962. The attenuated poliovirus in the Sabin vaccine replicates very efficiently in the gut, the primary site of wild poliovirus infection and replication, but the vaccine strain is unable to replicate efficiently within nervous system tissue. OPV produces excellent immunity in the intestine, which helps prevent infection with wild virus in areas where the virus is endemic. A single dose of oral polio vaccince produces immunity to all three poliovirus serotypes in approximately 50% of recipients. Three doses of live-attenuated OPV produce protective antibody to all three poliovirus types in more than 95% of recipients.

Eradication
Following the widespread use of poliovirus vaccine in the mid-1950s, the incidence of poliomyelitis declined rapidly in many industrialized countries. A global effort to eradicate polio began in 1988 and was led by the World Health Organization, UNICEF, and The Rotary Foundation. These efforts have reduced 99% of annual diagnosed cases from an estimated 350,000 cases in 1988 to fewer than 2,000 cases in 2006. Should eradication be successful it will represent only the second time mankind has ever completely eliminated a disease. The first such disease was smallpox, which was officially eradicated in 1979.

A number of eradication milestones have already been reached, and several regions of the world have been certified polio-free. The Americas were declared polio-free in 1994. In 2000 polio was officially eradicated in 36 Western Pacific countries, including China and Australia. Europe was declared polio-free in 2002. Today, polio remains endemic in just four countries: Nigeria, India, Pakistan, and Afghanistan.

History
The effects of a polio infection have been known since prehistory: Ancient Egypt paintings and carvings depict otherwise healthy people with withered limbs, and children walking with canes at a young age. The first clinical description of poliomyelitis was provided by the British physician Michael Underwood in 1789&mdash;he refers to polio as “a debility of the lower extremities". The work of physicians Jakob Heine in 1840 and Karl Oskar Medin in 1890 led to the disease being known as Heine-Medin disease. The disease was later called infantile paralysis, based on its propensity to affect children.

Prior to the 20th century, polio infections were rarely seen in infants before 6 months of age and most cases occurred in children 6 months to 4 years of age. Poorer sanitation of the time resulted in a constant exposure to the virus, which enhanced a natural immunity within the population. In developed countries during the late 19th and early 20th centuries, improvements were made in community sanitation, including improved sewage disposal and clean water supplies. These changes also drastically increased the proportion of children and adults at risk of paralytic polio infection, by reducing childhood exposure and immunity to the disease.

Around 1900, small, localized paralytic polio epidemics began to appear in Europe and the United States. Outbreaks reached pandemic proportions in Europe, North America, Australia, and New Zealand during the first half of the 20th century. By 1950 the peak age incidence of paralytic poliomyelitis in the United States had shifted from infants to children aged five to nine years, when the risk of paralysis is greater; about one-third of the cases were reported in persons over 15 years of age. Accordingly, the rate of paralysis and death due to polio infection also increased during this time. In the United States, the 1952 polio epidemic would be the worst outbreak in the nation's history. Of the nearly 58,000 cases reported that year 3,145 died and 21,269 were left with mild to disabling paralysis.

The polio epidemics changed not only the lives of those who survived them, but also affected profound cultural changes: the emergence of grassroots fund-raising campaigns that would revolutionize medical philanthropy, the rise of rehabilitation therapy and—through campaigns for the social and civil rights of the disabled—polio survivors helped to spur the modern disability rights movement. Today polio survivors are one of the largest disabled groups in the world. The World Health Organization estimates that there are 10 to 20 million polio survivors worldwide. In 1977 there were 254,000 persons living in the United States who had been paralyzed by polio. According to doctors and local polio support groups, some 40,000 polio survivors with varying degrees of paralysis live in Germany, 30,000 in Japan, 24,000 in France, 16,000 in Australia, 12,000 in Canada and 12,000 in the United Kingdom.