Other Diseases of the Nervous System

Rabies

Rabies is a viral disease that causes acute encephalitis in warm-blooded animals.

Learning Objectives

Examine the causes and symptoms associated with infection by the rabies virus

Key Takeaways

Key Points

  • The rabies virus infects the central nervous system, travelling from the peripheral nerves to the brain.
  • Symptoms include hydrophobia, paranoia, terror, mania, hallucinations, and delirium.
  • Once symptoms have presented, survival is rare, but treatment administered before the onset of symptoms is highly successful.

Key Terms

  • hydrophobia: An aversion to water, as a symptom of rabies.
  • zoonotic: of or relating to zoonosis, the transmission of an infectious disease between species.

Rabies is a viral disease that causes acute encephalitis (inflammation of the brain) in warm-blooded animals. Rabies literally means “madness” in Latin. The disease is zoonotic and can be transmitted from one species to another, commonly by a bite from an infected animal. In humans, rabies is almost invariably fatal if postexposure prophylaxis is not administered prior to the onset of severe symptoms.

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Rabies Patient: Rabies symptoms include malaise, violent movements, terror, mania, and delirium.

The rabies virus infects the central nervous system, travelling from the peripheral nerves to the brain. In humans, the incubation period between infection and the first sign of symptoms is typically two to 12 weeks, although periods as short as four days and longer than six years have been documented. Incubation period depends on the quantity of virus introduced and the distance it must travel to reach the central nervous system. Once there, symptoms begin to show and the infection is virtually untreatable. Early-stage symptoms include malaise, headache and fever, violent movements, uncontrolled excitement, depression, confusion, agitation, anxiety, and hydrophobia. Late stage symptoms extend to paranoia, terror, mania, and hallucinations progressing into delirium. Once symptoms have presented, survival is rare. Death almost invariably occurs within two to 10 days. Treatment with human rabies immunoglobulin (HRIG) and rabies vaccine is highly successful if administered before the onset of symptoms.

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Rabid Dog: Close-up of a dog’s face during late-stage “dumb” paralytic rabies. Animals with “dumb” rabies appear depressed, lethargic, and uncoordinated. Gradually they become completely paralyzed. When their throat and jaw muscles are paralyzed, the animals will drool and have difficulty swallowing.

Rabies causes about 55,000 human deaths annually worldwide, with 95% of human deaths occurring in Asia and Africa. Roughly 97% of human rabies cases result from dog bites. In the U.S., animal control and vaccination programs have effectively eliminated domestic dogs as reservoirs of rabies. In several countries, including Australia and Japan, rabies carried by terrestrial animals has been eliminated entirely. While rabies was once eradicated in the United Kingdom, infected bats have recently been found in Scotland. In the U.S., the widespread vaccination of domestic dogs and cats and the development of effective human vaccines and immunoglobulin treatments has dropped the number of recorded human deaths from 100 or more annually in the early 20th century, to one to two per year (mostly caused by bat bites). Modern cell-based vaccines are similar to flu shots in terms of pain and side effects. The old nerve-tissue-based vaccinations that require multiple painful injections into the abdomen with a large needle are cheap, but are being phased out and replaced by affordable World Health Organization intradermal vaccination regimens.

Rabies may be diagnosed by PCR or viral culture of brain samples after death, or from skin samples taken before. Diagnosis can be made from saliva, urine, and cerebrospinal fluid samples with less accuracy. Cheaper rabies diagnosis will become possible for low-income settings using basic light microscopy techniques.

Poliomyelitis

Poliomyelitis is an infection by the polio virus that affects the motor neurons of the central nervous system.

Learning Objectives

Describe poliomyelitis and its effect on motor neurons

Key Takeaways

Key Points

  • Spinal polio is the most common type of polio and results in asymmetric paralysis, usually involving the legs.
  • Bulbar polio is infection of the cranial nerves and causes weakness and paralysis in muscles innervated by the cranial nerves, while bulbospinal polio occurs when both the cranial nerves and spinal nerves are affected.
  • Although approximately 90% of polio infections cause no symptoms at all, affected individuals can exhibit a range of symptoms if the virus enters the blood stream.

Key Terms

  • motor neuron: A neuron located in the central nervous system that projects its axon outside the CNS and directly or indirectly control muscles.
  • spinal polio: Spinal polio is characterized by asymmetric paralysis that most often involves the legs.
  • poliomyelitis: acute infection by the poliovirus, especially of the motor neurons in the spinal cord and brainstem, leading to muscle weakness, paralysis and sometimes deformity
  • paralysis: The complete loss of voluntary control of part of person’s body, such as one or more limbs.

OVERVIEW

Poliomyelitis, often called polio or infantile paralysis, is an acute, viral, infectious disease spread from person to person, primarily via the fecal-oral route.

Although approximately 90% of polio infections cause no symptoms at all, affected individuals can exhibit a range of symptoms if the virus enters the blood stream. In about 1% of cases, the virus enters the central nervous system, preferentially infecting and destroying motor neurons, leading to muscle weakness and acute flaccid paralysis.

Different types of paralysis may occur, depending on the nerves involved. Spinal polio is the most common form, characterized by asymmetric paralysis that most often involves the legs. Bulbar polio leads to weakness of muscles innervated by cranial nerves. Bulbospinal polio is a combination of bulbar and spinal paralysis.

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Polio: Man on street with atrophy and paralysis of the right leg and foot due to polio.

BACKGROUND

Poliomyelitis was first recognized as a distinct condition by Jakob Heine in 1840. Its causative agent, poliovirus, was identified in 1908 by Karl Landsteiner. Although major polio epidemics were unknown before the late 19th century, polio was one of the most dreaded childhood diseases of the 20th century. Polio epidemics have crippled thousands of people, mostly young children; the disease has caused paralysis and death for much of human history.

Polio had existed for thousands of years quietly as an endemic pathogen until the 1880s, when major epidemics began to occur in Europe; soon after, widespread epidemics appeared in the United States. By 1910, much of the world experienced a dramatic increase in polio cases and epidemics became regular events, primarily in cities during the summer months. These epidemics—which left thousands of children and adults paralyzed—provided the impetus for a “Great Race” towards the development of a vaccine.

DEVELOPMENT OF A VACCINE

Developed in the 1950s, polio vaccines are credited with reducing the global number of polio cases per year from many hundreds of thousands to today under a thousand. Enhanced vaccination efforts led by the World Health Organization, UNICEF, and Rotary International could result in global eradication of the disease.

Hantavirus

Hantaviruses are negative-sense RNA viruses that sometimes lead to hemorrhagic fever with renal syndrome in humans.

Learning Objectives

Paraphrase the causes of hantavirus and the phases of symptoms: febrile, hypotensive, oliguric, diuretic and convalescent

Key Takeaways

Key Points

  • The name hantavirus comes from the Hantaan River area in South Korea, where the first known strain – Hantaan virus (HTNV) – was isolated in 1978.
  • Human infections of hantaviruses have almost entirely been linked to human contact with rodent excrement, thus, rodent control is the primary strategy for preventing hantavirus infection.
  • There is no known antiviral treatment, but natural recovery from the virus is possible.

Key Terms

  • hypoxemia: an abnormal deficiency in the concentration of oxygen in the blood, be it the partial pressure of oxygen (mm Hg), the content of oxygen (ml oxygen per dl of blood) or the percent saturation of the blood’s hemoglobin, singly or in combination.
  • tachycardia: a rapid resting heart rate, especially one above 100 beats per minute.
  • proteinuria: excessive protein in the urine.

Hantaviruses are negative sense RNA viruses and are a relatively newly discovered genus in the Bunyaviridae family. The name hantavirus comes from the Hantaan River area in South Korea, where the first known strain – Hantaan virus (HTNV) – was isolated in 1978. Although some hantaviruses lead to potentially fatal diseases, such as hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), not all are associated with human disease.

Human infections of hantaviruses have almost entirely been linked to human contact with rodent excrement, thus, rodent control is the primary strategy for preventing hantavirus infection. Human-to-human transmission (via urine, saliva, etc. ) may also occur, and has been recently reported with the Andes virus in South America.

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Hantavirus pulmonary syndrome: Hantaviruses that cause Hantavirus pulmonary syndrome (HPS) are carried in rodent droppings, especially the deer mouse. Incubation lasts for 1–5wks. Sickness begins with fever and muscle aches, followed by shortness of breath and coughing.

HTNV is one of several hantaviruses that cause hemorrhagic fever with renal syndrome (HFRS), formerly known as Korean hemorrhagic fever. HFRS has an incubation time of two to four weeks in humans before symptoms of infection occur. The symptoms of HFRS can be split into five phases: febrile, hypotensive, oliguric, diuretic, and convalescent. The febrile phase begins two to three weeks after exposure, and normally lasts from three to seven days. Symptoms include fever, chills, diarrhea, malaise, headaches, nausea, abdominal and back pain, and respiratory and gastro-intestinal problems. These symptoms can resemble that of the flu. The hypotensive phase occurs when the blood platelet levels drop, and can lead to tachycardia and hypoxemia. This phase can last for 2 days. The oliguric phase begins with renal failure and proteinuria, and lasts from three to seven days. The diuretic phase is characterized by excessive urination (diuresis) of up to six liters per day, and can last for a couple of days up to a week. Although there is no known antiviral treatment for hantavirus, natural recovery is possible. The phase where symptoms begin to improve is the convalescent phase.

Hantavirus pulmonary syndrome (HPS) is another potentially fatal disease caused by hantavirus infection. Although rare, HPS is fatal in up to 60% of cases. HPS has been identified throughout the United States, and was first recognized in 1993 in the southwest where it was originally referred to as the “Four Corners disease. ” The symptoms are very similar to those of HFRS. Additionally, patients will develop difficulty breathing, coughing and shortness of breath, and may lead to cardiovascular shock.

Arboviral Encephalitis

Arboviral encephalitis (acute swelling in the brain) is caused by a group of arthropod-transmitted viruses.

Learning Objectives

Examine the mode of transmission and causes of arboviral encephalitis

Key Takeaways

Key Points

  • Arthropod vectors transmit the virus upon biting, allowing the virus to enter the circulatory system and replicate.
  • Arboviral encephalitis are found in many places throughout the world, and include California encephalitis, Japanese encephalitis, St. Louis encephalitis, Tick-borne encephalitis, and West Nile fever.
  • TBE Infection can be reliably prevented by vaccination, but is incurable once manifested.

Key Terms

  • sequelae: A pathological condition resulting from a disease, injury, or other trauma.
  • encephalitis: an inflammation of the brain
  • viremia: A medical condition where viruses enter the bloodstream and hence have access to the rest of the body.
  • zoonotic: of or relating to zoonosis, the transmission of an infectious disease between species.

Arboviral encephalitis are a group of arthropod-transmitted viruses that cause encephalitis (acute swelling in the brain). The word “arbovirus” directly refers to an ARthropod-BOrne virus. Arthropod vectors transmit the virus upon biting, allowing the virus to enter the circulatory system and replicate and shed additional infection into the bloodstream ( viremia ).

The majority of the arboviruses are spherical in shape although a few are rod-shaped. They are 17-150 nm in diameter and most have an RNA genome (the single exception is African swine fever virus, which has a DNA genome). Many arboviruses (such as African Swine Fever virus) do not infect humans or cause only mild and transient infections characterized by fever, headache, and rash. Those of the arboviral encephalitis group, however, can cause epidemic disease and severe infections that can be fatal. Arboviral encephalitis are found in many places throughout the world, and include California encephalitis, Japanese encephalitis, St. Louis encephalitis, Tick-borne encephalitis, and West Nile fever.

Tick-borne encephalitis (TBE) is an infectious disease of the central nervous system. It can infect a range of hosts including ruminants, birds, rodents, carnivores, horses, and humans. The disease can be zoonotic, with ruminants and dogs providing the principal source of infection for humans. TBE is transmitted through the bite of several species of infected ticks, including Ixodes scapularis, Ixodes ricinus and Ixodes persulcatus, and manifests most often as meningitis, encephalitis, or meningoencephalitis.

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Chelicera of the sheep tick: Sheep ticks (Ixodes ricinus) such as this engorged female transmit encephalitis.

TBE Infection can be reliably prevented by vaccination, but is incurable once manifested. Long-lasting or permanent neuropsychiatric sequelae are observed in 10-20% of infected patients; morality occurs in only 1-2% of the infected, with deaths occurring 5 to 7 days after the onset of neurologic symptoms.

TBE and other arboviral encephalitis can be diagnosed through a combination of blood tests, particularly immunologic, serologic, and/or virologic techniques such as ELISA, complement fixation, polymerase chain reaction, Neutralization test, and Hemoagglutination Inhibition test.

Because the arboviral encephalitides are viral diseases, antibiotics are not effective for treatment and no effective antiviral drugs have been discovered yet. Treatment is therefore only supportive, attempting to deal with problems such as swelling of the brain, loss of the automatic breathing, activity of the brain, and other treatable complications like bacterial pneumonia.

Therefore, the immune system plays an important role in defense against arbovirus infections. Arboviruses usually stimulate the production of interferons and antibodies, which help to diminish the extent of viremia. Cell-mediated immunity is also important. Increased immunity is observed with age progression.

Vector control measures, such as habitat control (including the elimination of stagnant water and the spraying of insecticides), are essential to reducing the transmission of disease by arboviruses. People can also reduce the risk of getting bitten by arthropods by employing personal protective measures such as sleeping under mosquito nets, wearing protective clothing, applying insect repellents, tick-checks, and avoiding areas known to harbor high arthropod populations.

Rickettsial Diseases

Rickettsia is a genus of bacteria that can be transmitted by arthropod vectors to humans, causing diseases.

Learning Objectives

List the characteristics of Rickettsia species

Key Takeaways

Key Points

  • Rickettsia are obligate intracellular parasites, and must replicate within the cytoplasm of eukaryotic host cells.
  • Rickettsia species are carried by many ticks, fleas, and lice, and cause diseases in humans such as typhus, rickettsialpox, Boutonneuse fever, African tick bite fever, Rocky Mountain spotted fever, Flinders Island spotted fever, and Queensland tick typhus (Australian Tick Typhus).
  • Rickettsia are one of closest living relatives to bacteria that were the origin of the mitochondria organelle that exists inside most eukaryotic cells. Indeed, certain segments of Rickettsia genomes resemble that of mitochondria, and ATP production is the same as that in mitochondria.

Key Terms

  • parthenogenesis: a form of asexual reproduction in which growth and development of embryos occurs without fertilization.
  • pleomorphic: the ability to alter shape or size in response to environmental conditions.

Rickettsia is a genus of bacteria that can be transmitted by arthropod vectors to humans, causing disease. Rickettsia species are non-motile, Gram-negative, non-sporeforming, highly pleomorphic bacteria that can present as cocci (0.1 μm in diameter), rods (1–4 μm long), or thread-like (10 μm long). They are obligate intracellular parasites, and must replicate within the cytoplasm of eukaryotic host cells. Rickettsia are one of closest living relatives to bacteria that were the origin of the mitochondria organelle that exists inside most eukaryotic cells. Unlike viruses, Rickettsia possess true cell walls and are similar to other gram-negative bacteria. Despite a similar name, Rickettsia bacteria do not cause rickets, which is a result of vitamin D deficiency.

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A Microbe versus Animal Cell: The large spheres are tick cells. The purple bars and dots are the bacterium Rickettsia rickettsii, which is the causative agent of Rocky Mountain spotted fever. Rickettsia rickettsii is a small bacterium that grows inside the cells of its hosts. These bacteria range in size from 0.2 x 0.5 micrometers to 0.3 x 2.0 micrometers.

Rickettsia species are carried by many ticks, fleas, and lice, and cause diseases in humans such as typhus, rickettsialpox, Boutonneuse fever, African tick bite fever, Rocky Mountain spotted fever, Flinders Island spotted fever, and Queensland tick typhus (Australian Tick Typhus). They have also been associated with a range of plant diseases.

Rickettsia can be classified into three groups based on serology and DNA sequencing: spotted fever, typhus, and scrub typhus. All three of these groups contain human pathogens. Recent studies reclassify the scrub typhus group as a new genus – Orienta, and suggest that the spotted fever group should be divided into two clades. Rickettsia are widespread, and can be associated with arthropods, leeches, and protists. Rickettsia found in Arthropods are generally associated with reproductive manipulation (such as parthenogenesis) to persist in host lineage.

Unlike free-living bacteria, Rickettsia species contain no genes for anaerobic glycolysis or those involved in the biosynthesis and regulation of amino acids and nucleosides. In this regard, certain segments of Rickettsia genomes resemble that of mitochondria, and ATP production is the same as that in mitochondria. (With the exception of R. prowazekii, whose genome contains a complete set of genes encoding for the tricarboxylic acid cycle and the respiratory chain complex). The genomes of both Rickettsia and mitochondria are frequently said to be “small, highly derived products of several types of reductive evolution. ”

Lyme Disease

Lyme disease is caused by bacteria from the Borrelia genus.

Learning Objectives

Discuss the mode of transmission and symptoms for lyme disease

Key Takeaways

Key Points

  • Borrelia is transmitted to humans through the bite of infected ticks belonging to a few species of the genus Ixodes (“hard ticks”).
  • Lyme disease can affect multiple body systems and produce a range of symptoms.
  • Lyme disease begins with a characterized bullseye rash called erythema chronicum migrans.

Key Terms

  • nymphal: In some invertebrates, of or pertaining to the immature form.
  • asymptomatic: not exhibiting any symptoms of disease.
  • paraplegia: A condition where the lower half of a patient’s body is paralyzed and cannot move.

Lyme disease (aka Lyme borreliosis) is caused by bacteria from the Borrelia genus, and is the most common tick-borne disease in the Northern Hemisphere. Borrelia burgdorferi sensu stricto is the main cause of Lyme disease in North America, whereas Borrelia afzelii and Borrelia garinii cause most European cases. Borrelia is transmitted to humans through the bite of infected ticks belonging to a few species of the genus Ixodes (“hard ticks” ). The disease is named after the towns of Lyme and Old Lyme, Connecticut, where a number of cases were identified in 1975. Although it was realized that Lyme disease was a tick-borne disease in 1978, the cause of the disease remained a mystery until 1981, when B. burgdorferi was identified.

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Deer Tick: Nymphal and adult deer ticks can be carriers of Lyme disease. Nymphs are about the size of a poppy seed.

Lyme disease can affect multiple body systems and produce a range of symptoms, though not all patients with Lyme disease will have all symptoms, and many of the symptoms are not specific to Lyme disease. The incubation period from infection to the onset of symptoms is usually one to two weeks, but can be much shorter (days), or much longer (months to years). Most infections are caused by ticks in the nymphal stage, as they are very small and may feed undetected for long periods of time, with symptoms occurring most often from May through September because of this life cycle. An infected tick must be attached for at least a day for transmission to occur, and only about 1% of recognized tick bites result in Lyme disease.

Lyme disease begins with a localized infection, affecting the area at the site of the tick bite with a circular, outwardly expanding rash called erythema chronicum migrans (EM), which gives the appearance of a bullseye. Patients may also experience flu-like symptoms, such as headache, muscle soreness, fever, malaise, fatigue, and depression. In most cases, the infection and its symptoms are eliminated by antibiotics, especially if the illness is treated early. Delayed or inadequate treatment can lead to more serious symptoms, which can be disabling and difficult to treat. Asymptomatic infections may occur, though this is the case in less than 7% of infected individuals in the United States. Asymptomatic infection may be more common in Europe.

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Lyme Disease: Erythematous rash in the pattern of a “bull’s-eye” from Lyme disease.

Left untreated, Borrelia bacteria begins to spread through the bloodstream within days to weeks after the onset of local infection, progressing symptoms to the joints, heart, and central nervous system. These symptoms include migrating pain in muscles, joints, and tendons; neck stiffness; sensitivity to light; and heart palpitations and dizziness caused by changes in heartbeat. Acute neurological problems, termed “neuroborreliosis”, appear in 10–15% of untreated patients. EM may even develop at sites across the body that bear no relation to the original tick bite. Radiculoneuritis causes shooting pains that may interfere with sleep, as well as abnormal skin sensations. Mild encephalitis may lead to memory loss, sleep disturbances, or mood changes.

After several months, untreated or inadequately treated patients may go on to develop severe and chronic symptoms, including permanent paraplegia in the most extreme cases. Patients may develop Lyme arthritis, usually affecting the knees; nerve pain radiating out of the spine (Bannwarth syndrome); and shooting pains, numbness, and tingling in the hands or feet. A neurologic syndrome called Lyme encephalopathy is associated with subtle cognitive problems, such as difficulties with concentration and short-term memory. These patients may experience profound fatigue. Chronic encephalomyelitis can involve cognitive impairment, weakness in the legs, awkward gait, facial palsy, bladder problems, vertigo, and back pain. In rare cases, untreated Lyme disease may cause frank psychosis, which has been mis-diagnosed as schizophrenia or bipolar disorder. Panic attacks and anxiety can occur; as well as delusional behavior and detachment from themselves and reality.

West Nile Virus

West Nile virus is a mosquito-borne arbovirus found in temperate and tropical regions of the world.

Learning Objectives

Discuss the causes, symptoms and diseases (West Nile encephalitis, meningitis, meningoencephalitis and poliomyelitis) caused by the West Nile virus (WNV)

Key Takeaways

Key Points

  • WNV is considered to be an endemic pathogen in Africa, Asia, Australia, the Middle East, Europe and in the United States, with one of the worst epidemics occurring in 2012.
  • Birds are the most commonly infected animal, and serve as the prime reservoir host.
  • The specific neurological diseases which may occur are encephalitis, meningitis, meningoencephalitis, and poliomyelitis.

Key Terms

  • zoonotic: of or relating to zoonosis, the transmission of an infectious disease between species.

West Nile virus (WNV) is a mosquito-borne zoonotic arbovirus belonging to the genus Flavivirus, and is found in temperate and tropical regions of the world.

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Global distribution of West Nile virus: Global distribution of West Nile virus.

WNV was first identified in the West Nile subregion in the East African nation of Uganda in 1937. Prior to the mid 1990s, WNV disease occurred only sporadically and was considered a minor risk for humans. This was until an outbreak in Algeria in 1994, with cases of WNV-caused encephalitis, and the first large outbreak in Romania in 1996, with a high number of cases with neuroinvasive disease. WNV has now spread globally, with the first case in the Western Hemisphere being identified in New York City in 1999. The virus has now spread across the continental United States, north into Canada, and southward into the Caribbean Islands and Latin America. The US experienced one of its worst epidemics to date in 2012. WNV also spread to Europe, beyond the Mediterranean Basin, with a new strain of the virus recently identified in Italy (2012). WNV is now considered to be an endemic pathogen in Africa, Asia, Australia, the Middle East, Europe and in the United States.

The main mode of WNV transmission is by mosquitoes, the prime vector. WNV has been found in various species of ticks. However, current research suggests they are not important vectors of the virus. WNV infects various mammal species, including humans. It has also been identified in reptilians (including alligators and crocodiles) and amphibians. Birds, especially passerines, are the most commonly infected animal, and serve as the prime reservoir host. Many species – including humans – do not develop viral levels sufficient to transmit the disease to uninfected mosquitoes, and are thus not considered major factors in WNV transmission.

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Transmission of the West Nile virus: The proboscis of a female mosquito pierces the epidermis and dermis to allow it to feed on humanblood from a capillary: this one is almost fully engorged. The mosquito injects saliva which contains an anesthetic, and an anticoagulant into the puncture wound; and in infected mosquitoes, the West Nile virus.

Approximately 80% of West Nile virus infections in humans cause no symptoms. West Nile fever is the manifestation of symptoms, with an incubation period typically between 2 and 15 days. Symptoms may include fever, headaches, fatigue, muscle pain or aches, malaise, nausea, anorexia, vomiting, myalgias and rash. Less than 1% of the cases are severe and result in neurological disease when the central nervous system is affected. People of advanced age, the very young, or those with immunosuppression are most susceptible.

The specific neurological diseases which may occur are:

  • West Nile encephalitis, which causes inflammation of the brain
  • West Nile meningitis, which causes inflammation of the meninges (the protective membranes that cover the brain and spinal cord)
  • West Nile meningoencephalitis, which causes inflammation of the brain and surrounding meninges
  • West Nile poliomyelitis (spinal cord inflammation, which results in a syndrome similar to polio that may cause acute flaccid paralysis).

Currently, no vaccine against WNV infection is available. The best method to reduce the rates of WNV infection is by public mosquito control (particularly the elimination of standing water) and by personal protection (mosquito nets and repellent).

Plague

The plague is an infectious disease caused by the Gram-negative rod-shaped bacteria Yersinia pestis.

Learning Objectives

Outline the route of pathogenesis for Yersinia pestis

Key Takeaways

Key Points

  • Although bubonic plague is often used synonymously with plague, it refers specifically to an infection that enters through the skin and travels through the lymph nodes (buboes).
  • Septicemic plague is a deadly blood infection; symptoms include hypotension, hepatosplenomegaly, delirium, seizures in children, shock, lethargy, and fever. Pneumonic plague manifests as a severe lung infection.
  • Y. pestis is spread most commonly between rodents (both urban and wild) and fleas.

Key Terms

  • pneumonic plague: a severe type of lung infection, one of three main forms of plague, all of which are caused by the bacterium Yersinia pestis
  • bubonic plague: a contagious, often fatal, epidemic disease caused by the bacterium Yersinia pestis, transmitted by the bite of fleas from an infected person or rodent, especially a rat, and characterized by delirium, chills, fever, vomiting, diarrhea, and the formation of buboes
  • hepatosplenomegaly: enlargement of both the liver and spleen.
  • plague: an epidemic or pandemic caused by any pestilence, but specifically by the above disease

The plague is an infectious disease caused by the Gram-negative rod-shaped bacteria Yersinia pestis . Human Y. pestis infection is manifested in three main forms: pneumonic, septicemic, and the notorious bubonic plagues. All three forms are widely believed to have been responsible for a number of high-mortality epidemics throughout human history, including the Plague of Justinian in 542, and the Black Death that accounted for the death of at least one-third of the European population between 1347 and 1353. It has now been conclusively shown that these plagues originated in rodent populations in China. Thousands of cases of the plague are still reported every year; with proper treatment, the prognosis for victims is now much improved. The plague also has a detrimental effect on non-human mammals. In the United States, animals such as the black-tailed prairie dog and the endangered black-footed ferret are under threat from the disease.

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Yersinia pestis: Scanning electron micrograph depicting a mass of Yersinia pestis bacteria (the cause of bubonic plague) in the foregut of the flea vector.

Although bubonic plague is often used synonymously with plague, it refers specifically to an infection that enters through the skin and travels through the lymph nodes (buboes). The incubation period of bubonic plague is from 2-6 days, while the bacteria actively replicate. Symptoms include a lack of energy, fever, headache and chills, and swelling of lymph nodes resulting in buboes, the classic sign of bubonic plague. Septicemic plague is a deadly blood infection; symptoms include hypotension, hepatosplenomegaly, delirium, seizures in children, shock, lethargy, and fever. Pneumonic plague manifests as a severe lung infection, and is more virulent and rare than bubonic plague. Symptoms include fever, chills, coughing, chest pain, dyspnea, hemoptysis, lethargy, hypotension, and shock. Symptoms of the plague are not always present, or the patient may die before any symptoms appear.

Y. pestis is spread most commonly between rodents (both urban and wild) and fleas. Any infected animal can transmit the infection to humans through contact with skin tissue. Humans can also spread the bacteria to other humans through sneezing, coughing, or with direct contact with infected tissue. The reservoir commonly associated with Y. pestis is several species of rodents. In the steppes, the reservoir species is believed to be principally the marmot. In the United States, several species of rodents are thought to maintain Y. pestis. However, the expected disease dynamics have not been found in any rodent species. It is known that rodent populations will have a variable resistance, which could lead to a carrier status in some individuals. In some regions of the world, the reservoir of infection is not clearly identified, which complicates prevention and early warning programs.

The transmission of Y. pestis by fleas is well characterized. Initial acquisition of Y. pestis by the vector occurs during feeding on an infected animal. Several proteins then contribute to the maintenance of the bacteria in the flea digestive tract, among them the hemin storage (Hms) system and Yersinia murine toxin (Ymt). Although Yersinia murine toxin is highly toxic to rodents and was once thought to be produced to ensure reinfection of new hosts, it has been demonstrated that Ymt is important for the survival of Y. pestis in fleas. The Hms system plays an important role in the transmission of Y. pestis back to a mammalian host. While in the insect vector, proteins encoded by Hms genetic loci induce biofilm formation in the proventriculus, a valve connecting the midgut to the esophagus. Aggregation in the biofilm inhibits feeding, as a mass of clotted blood and bacteria forms (referred to as “Bacot’s block”). Transmission of Y. pestis occurs during the futile attempts of the flea to feed. Ingested blood is pumped into the esophagus, where it dislodges bacteria lodged in the proventriculus and is regurgitated back into the host circulatory system.

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A flea infected with yersinia pestis: A flea infected with yersinia pestis, shown as a dark mass. The foregut of this flea is blocked by a Y. pestis biofilm, which is a prerequisite for efficient transmission.

The pathogenesis of Y. pestis infection in mammalian hosts is due to several factors. The bacteria proliferates inside lymph nodes where it is able to avoid destruction by cells of the immune system such as macrophages. Y. pestis is able to suppress the immune system, avoiding normal immune system responses such as phagocytosis and antibody production. Flea bites allow for the bacteria to pass the skin barrier. Y. pestis expresses the yadBC gene, which is similar to adhesins in other Yersinia species, allowing for adherence and invasion of epithelial cells. Finally, Y. pestis expresses a plasminogen activator that is an important virulence factor for pneumonic plague, which may also degrade on blood clots in order to facilitate systematic invasion. Two important anti-phagocytic antigens, Fraction 1 (F1) and LcrV (V), are both important for virulence. Natural or induced immunity is achieved, therefore, by the production of specific opsonic antibodies against F1 and V antigens.

The traditional first line treatment for Y. pestis has been the antibiotics streptomycin, chloramphenicol, tetracycline, and fluoroquinolones. Antibiotic treatment alone is insufficient for some patients, who may also require circulatory, ventilator, or renal support.