Fungal, Protozoan, Prion, and Other Diseases of the Nervous System

Cryptococcosis

Cryptococcosis is a disease caused by fungi that can be fatal.

Learning Objectives

Recognize the causes and symptoms associated with cryptococcosis

Key Takeaways

Key Points

  • Cryptococcal meningitis is caused when the disease-causing fungus gets in the membranes around the brain.
  • Cryptococcosis is an opportunistic infection, it often affects people who are immune -compromised, such as people who have AIDS.
  • As people who get cryptoccosis often have other health problems, even treatment with anti- fungal agents may not cure the infection.
  • Cryptococcosis can infect animals such as cats; it is not solely a human pathogen.

Key Terms

  • meninges: The three membranes that envelop the brain and spinal cord.
  • propagule: A reproductive particle released by an organism that may germinate into another.

Cryptococcosis, or cryptococcal disease, is a potentially fatal fungal disease. It is caused by one of two species: Cryptococcus neoformans and Cryptococcus gattii. These were all previously thought to be subspecies of C. neoformans, but have now been identified as distinct species. Cryptococcosis is believed to be acquired by inhalation of the infectious propagule from the environment. Although the exact nature of the infectious propagule is unknown, the leading hypothesis is the basidiospore created through sexual or asexual reproduction.

image

Cryptococcus: A micrograph of cryptococcus (purple), the fungus that can cause cryptococcosis.

Causes

Cryptococcal meningitis (infection of the meninges, the tissue covering the brain) is believed to result from dissemination of the fungus from either an observed or unappreciated pulmonary infection. Often there is also silent dissemination throughout the brain when meningitis is present. Cryptococcus gattii causes infections in immunocompetent people (those having a functioning immune system), but C. neoformans v. grubii, and v. neoformans usually only cause clinically evident infections in persons who have some form of defect in their immune systems ( immunocompromised persons). People who have defects in their cell-mediated immunity; for example, people with AIDS; are especially susceptible to disseminated cryptococcosis. Cryptococcosis is often fatal, even if treated. The ten-week survival averages near 70% with optimal therapy.

Although the most common presentation of cryptococcosis is of C. neoformans infection in an immunocompromised person (such as persons living with AIDS), the C. gattii is being increasingly recognised as a pathogen in presumptively immunocompetent hosts, especially in Canada and Australia. This may be due to rare exposure and high pathogenicity, or to unrecognised isolated defects in immunity, specific for this organism.

Cryptococcosis is a defining opportunistic infection for AIDS. Other conditions which pose an increased risk include certain lymphomas (e.g. Hodgkin’s lymphoma), sarcoidosis, liver cirrhosis, and patients on long-term corticosteroid therapy. Distribution is worldwide in soil. The prevalence of cryptococcosis has been increasing over the past 20 years for many reasons, including the increase in incidence of AIDS and the expanded use of immunosuppressive drugs.

Treatment

Treatment options in non-AIDS patients who have reduced immune-system function is not well studied. Intravenous Amphotericin B combined with oral flucytosine may be effective. Every attempt should be made to reduce the amount of immunosuppressive medication until the infection is resolved. Persons living with AIDS often have a greater chance of disease and higher mortality (30-70% at ten-weeks), but recommended therapy is with antifungal agents such as Amphotericin B and flucytosine.

Cryptococcosis in Animals

Cryptococcosis is also seen in cats and occasionally dogs. It is the most common deep fungal disease in cats, usually leading to chronic infection of the nose and sinuses, and skin ulcers. Cats may develop a bump over the bridge of the nose from local tissue inflammation. It can be associated with feline leukemia virus infection in cats. Cryptococcosis is most common in dogs and cats, but cattle, sheep, goats, horses, wild animals and birds can also be infected. Soil, fowl manure, and pigeon droppings are among the sources of infection.

African Trypanosomiasis

Sleeping sickness is caused by a protozoa transmitted by the tsetse fly.

Learning Objectives

Outline the life cycle of Trypanosoma brucei and its route of transmission that causes African trypanosomiasis

Key Takeaways

Key Points

  • The disease is caused by protozoa of the species Trypanosoma brucei, which in a mammalian blood system become a trypomastigote and travels throughout the host mammalian and infects spinal fluid and lymph nodes.
  • The protozoa Trypanosoma brucei infects the tsetse fly when it feeds on the blood of an infected mammal. Once infected a tsetse fly can transmit the disease to other mammals.
  • Initially, sleeping sickness has many symptoms of other viral infections, but if left untreated it will affect the nervous system, causing lethargy.

Key Terms

  • trypomastigote: A stage in unicellular life-cycle, typically trypanosomes, where the flagellum is posterior of the nucleus, and connected to the cell body by a long undulating membrane.
  • epimastigotes: A stage in unicellular life-cycle, typically trypanosomes, where the flagellum is anterior of the nucleus, and attached the cell body by a short membrane.

Human African trypanosomiasis, sleeping sickness, African lethargy, or Congo trypanosomiasis is a parasitic disease of people and animals, caused by protozoa of the species Trypanosoma brucei and transmitted by the tsetse fly. The disease is endemic in some regions of sub-Saharan Africa, covering areas in about 37 countries containing more than 60 million people. An estimated 50-70 thousand people are currently infected, the number having declined somewhat in recent years. The number of reported cases was below ten thousand in 2009, the first time in 50 years. Many cases are believed to go unreported. About 48 thousand people died of it in 2008. Four major epidemics have occurred in recent history: one from 1896-1906, primarily in Uganda and the Congo Basin, two epidemics in 1920 and 1970 in several African countries, and a recent 2008 epidemic in Uganda.

Transmission

The tsetse fly (genus Glossina) is a large, brown, biting fly that serves as both a host and vector for the trypanosome parasites. While taking blood from a mammalian host, an infected tsetse fly injects metacyclic trypomastigotes into skin tissue. From the bite, parasites first enter the lymphatic system and then pass into the bloodstream. Inside the mammalian host, they transform into bloodstream trypomastigotes, and are carried to other sites throughout the body, reach other body fluids (e.g., lymph, spinal fluid), and continue to replicate by binary fission. The entire life cycle of African trypanosomes is represented by extracellular stages. A tsetse fly becomes infected with bloodstream trypomastigotes when taking a blood meal on an infected mammalian host. In the fly’s midgut, the parasites transform into procyclic trypomastigotes, multiply by binary fission, leave the midgut, and transform into epimastigotes. The epimastigotes reach the fly’s salivary glands and continue multiplication by binary fission.The entire life cycle of the fly takes about three weeks.

image

Life Cycle of the Trypanosoma brucei parasite: Here is an outline of the life cycle of the protozoa Trypanosoma brucei, the parasite responsible for African trypanosomiasis (sleeping sickness).

In addition to the bite of the tsetse fly, the disease can be transmitted by, mother-to-child infection; the trypanosome can sometimes cross the placenta and infect the fetus. Transmission can also occur in laboratories by accidental infections; for example, through the handling of blood of an infected person and organ transplantation, though this is uncommon. Blood transfusions and possibly sexual contact, are two other causes.

Symptoms

African trypanosomiasis symptoms occur in two stages. The first stage, known as the haemolymphatic phase, is characterized by fever, headaches, joint pains, and itching. Invasion of the circulatory and lymphatic systems by the parasites is associated with severe swelling of lymph nodes, often to tremendous sizes. If left untreated, the disease overcomes the host’s defenses and can cause more extensive damage, broadening symptoms to include anemia, endocrine, cardiac, and kidney dysfunctions. The second phase, the neurological phase, begins when the parasite invades the central nervous system by passing through the blood–brain barrier. The term “sleeping sickness” comes from the symptoms of the neurological phase. The symptoms include confusion, reduced coordination, and disruption of the sleep cycle, with bouts of fatigue punctuated with manic periods, leading to daytime slumber and night-time insomnia. Without treatment, the disease is invariably fatal, with progressive mental deterioration leading to coma and death. Damage caused in the neurological phase is irreversible.

Amoebic Meningoencephalitis

Amoebic meningoencephalitis is an often-fatal central nervous system infection caused by Naegleria fowleri.

Learning Objectives

Summarize the route of transmission and effects of infection by Naegleria fowleri

Key Takeaways

Key Points

  • Amoebic meningoencephalitis is not actually caused by an ameoba but rather Naegleria fowleri a protist found in warm fresh water.
  • Once Naegleria fowleri enters deep into the nasal passage, digesting through the olfactory bulbs it then migrates into the forebrain, where the protists eat neuronal tissue in the brain, leading to death within 14 days from initial exposure.
  • The disease is largely asymptomatic until its final stages; often by the time it is diagnosed, it is too late to treat, causing a very high mortality rate.
  • Antimicrobial drugs can combat Naegleria fowleri infection if it is treated soon enough. Avoiding the infection by wearing nose plugs when swimming in warm water is a good preventative measure.

Key Terms

  • anosmia: Inability to smell; to perceive odors.
  • protist: Any of the eukaryotic unicellular organisms including protozoans, slime molds and some algae; historically grouped into the kingdom Protoctista.
  • parosmia: A distorted sense of smell, often resulting in phantom, non-existent, and mostly unpleasant, smells.
  • ageusia: Partial or complete loss of the sense of taste.

Primary amoebic meningoencephalitis (PAM, or PAME) is a disease of the central nervous system caused by infection from Naegleria fowleri.

Naegleria fowleri is commonly referred to as an amoeba but is actually a unicellular parasitic protist that is ubiquitous in soils and warm, stagnant bodies of freshwater, especially during the summer months. Patients typically have a history of exposure to a natural body of water.

image

Naegleria fowleri: Antibody detection (green) of Naegleria fowleri, the organism responsible for Primary amoebic meningoencephalitis (PAM).

The organism specifically prefers temperatures above 32 °C, as might be found in a tropical climate or in water heated by geothermal activity. The organism is extremely sensitive to chlorine (<0.5 ppm). Exposure to the organism is extremely common due to its wide distribution in nature.

However, thus far the only route for Naegleria fowleri to enter the central nervous system is via deep insufflation of infected water as it attaches itself to the olfactory nerve, which is exposed only at the extreme vertical terminus of the paranasal sinuses.

When this occurs, it then migrates through the cribiform plate and into the olfactory bulbs of the forebrain, where it multiplies itself greatly by feeding on nerve tissue. During this stage, occurring approximately 3–7 days post-infection, the typical symptoms are parosmia, rapidly progressing to anosmia (with resultant ageusia) as the nerve cells of the olfactory bulbs are consumed and replaced with necrotic lesions.

After the organisms have multiplied and largely consumed the olfactory bulbs, the infection rapidly spreads through the mitral cell axons to the rest of the cerebrum, resulting in onset of frank encephalitic symptoms, including cephalgia (headache), nausea, and rigidity of the neck muscles, progressing to vomiting, delirium, seizures, and eventually irreversible coma. Death usually occurs within 14 days of exposure as a result of respiratory failure when the infection spreads to the brain stem, destroying the autonomic nerve cells of the medulla oblongata.

The disease is both exceptionally rare and highly lethal: there have been fewer than 200 confirmed cases in recorded medical history as of 2004, and 300 cases as of 2008, with an in-hospital case fatality rate of ~97% (3% patient survival rate). Its high mortality rate is largely blamed on the unusually non-suggestive symptomology in its early stages, compounded by the necessity of microbial culture of the cerebrospinal fluid to effect a positive diagnosis. The parasite also demonstrates a particularly rapid late-stage propagation through the nerves of the olfactory system to many parts of the brain simultaneously (including the vulnerable medulla).

Michael Beach, a recreational waterborne-illness specialist for the Centers for Disease Control and Prevention, stated in remarks to the Associated Press that the wearing of nose-clips to prevent nasal uptake of contaminated water would be an effective protection against contracting PAM, noting that, “You’d have to have water going way up in your nose to begin with”.

PAM can be effectively treated with antimicrobiotics, if the patient is treated early enough.

Bovine Spongiform Encephalopathy

Bovine spongiform encephalopathy (BSE) is a fatal neurodegenerative disease in cows.

Learning Objectives

Recognize the route of transmission and causes of bovine spongiform encephalopathy (BSE)

Key Takeaways

Key Points

  • BSE is probably caused by a misfolded protein known as a prion; a prion can cause other correctly folded proteins to misfold thus propagating the disease.
  • Cooking of prions does not destroy them.
  • Evidence exists that when the prions in cows that cause BSE are consumed by humans this causes prion transmission to humans and the neurodegenerative Creutzfeldt-Jakob disease.

Key Terms

  • prion: A self-propagating misfolded conformer of a protein that is responsible for a number of diseases that affect the brain and other neural tissue.
  • beta sheet: A secondary structure in proteins consisting of multiple strands connected laterally.
  • alpha helix: A secondary structure found in many proteins, where the amino acids are arranged in a coil, or helix, with almost no free space on the inside and all side chains being pointed towards the outside.

Bovine spongiform encephalopathy (BSE), commonly known as mad cow disease, is a fatal neurodegenerative disease in cattle that causes a spongy degeneration in the brain and spinal cord. BSE has a long incubation period, about 30 months to eight years, usually affecting adult cattle at a peak age of four to five years, all breeds being equally susceptible.

image

Bovine spongiform encephalopathy (BSE): A cow suffering from BSE. The disease has progressed so far the animal cannot stand.

In the United Kingdom, the country worst affected, more than 180,000 cattle have been infected and 4.4 million slaughtered during the eradication program. The disease may be most easily transmitted to human beings by eating food contaminated with the brain, spinal cord or digestive tract of infected carcasses. However, it should also be noted that the infectious agent, although most highly concentrated in nervous tissue, can be found in virtually all tissues throughout the body, including blood. In humans, it is known as new variant Creutzfeldt–Jakob disease (vCJD or nvCJD), and by October 2009, had killed 166 people in the United Kingdom and 44 elsewhere. Between 460,000 and 482,000 BSE-infected animals had entered the human food chain before controls on high-risk offal were introduced in 1989.

The infectious agent in BSE is believed to be a specific type of misfolded protein called a prion. Prions will not disappear even if the beef containing them is cooked. Prion proteins carry the disease between individuals and cause deterioration of the brain.

BSE is a type of transmissible spongiform encephalopathy (TSE). TSEs can arise in animals that carry an allele which causes previously normal protein molecules to contort by themselves from an alpha helix arrangement to a beta sheet, which is the disease-causing shape for the particular protein. Transmission can occur when healthy animals come in contact with tainted tissues from others with the disease. In the brain, these proteins cause native cellular prion protein to deform into the infectious state, which then goes on to deform further prion protein in an exponential cascade. This results in protein aggregates, which then form dense plaque fibers, leading to the microscopic appearance of “holes” in the brain, degeneration of physical and mental abilities, and ultimately death.

image

BSE infected brain tissue: This micrograph of brain tissue reveals the cytoarchitectural histopathologic changes found in bovine spongiform encephalopathy. The presence of vacuoles, i.e. microscopic “holes” in the gray matter, gives the brain of BSE-affected cows a sponge-like appearance when tissue sections are examined in the lab.

Different hypotheses exist for the origin of prion proteins in cattle. Two leading hypotheses suggest it may have jumped species from the disease scrapie in sheep, or that it evolved from a spontaneous form of “mad cow disease” that has been seen occasionally in cattle for many centuries. In the fifth century BC, Hippocrates described a similar illness in cattle and sheep, which he believed also occurred in man. Publius Flavius Vegetius Renatus recorded cases of a disease with similar characteristics in the fourth and fifth centuries. Recent research suggests mad cow disease is caused by a genetic mutation within a gene called the prion protein gene. The research shows, for the first time, that a 10-year-old cow from Alabama with an atypical form of bovine spongiform encephalopathy had the same type of prion protein gene mutation as found in human patients with the genetic form of Creutzfeldt–Jakob disease, also called genetic CJD, for short. Besides having a genetic origin, other human forms of prion diseases can be sporadic, as in sporadic CJD, as well as foodborne. They are contracted when people eat products contaminated with mad cow disease. This form of Creutzfeldt-Jakob disease is called variant CJD.

Variant Creutzfeldt-Jakob Disease

Variant Creutzfeldt–Jakob Disease (vCJD) is a fatal neurological disorder which is caused by prions.

Learning Objectives

Generalize the role of prions in Creutsfeldt-Jakob disease

Key Takeaways

Key Points

  • Bovine spongiform encephalopathy (BSE) is believed to be the cause of variant Creutzfeldt–Jakob (vCJD); BSE is a prion disease that affects cattle. In both humans and cattle the disease causes large holes in the brain.
  • The prion the misfoled protein that causes vCJD has two conformations: one is the native form and is water soluble; the other is the disease form, which is water insoluble.
  • The misfolded prion proteins can cause other normally folded pre-prion proteins to become prions, which disrupts the native proteins disrupting function leading to cell death.
  • There is no known treatment for vCJD, except avoiding BSE contaminated meat.

Key Terms

  • Creutzfeldt–Jakob disease: a rare, progressive, currently fatal disease of the nervous system, characterized by dementia and loss of muscle control; a prion disease, apparently transmissible from animals to humans by eating infected tissue, as well as from tissue interchanges among humans
  • prion: A self-propagating misfolded conformer of a protein that is responsible for a number of diseases that affect the brain and other neural tissue.
  • transmembrane: traversing a cellular membrane

Creutzfeldt–Jakob disease, or CJD, is a degenerative neurological disorder (brain disease) that is incurable and invariably fatal. CJD is occasionally called a human form of mad cow disease (bovine spongiform encephalopathy or BSE), even though classic CJD is not related to BSE. However, given that BSE is believed to be the cause of variant Creutzfeldt–Jakob disease (vCJD) in humans, the two are often confused. In CJD, the brain tissue develops holes and takes on a sponge-like texture. This is due to a type of infectious protein called a prion. Prions are misfolded proteins which replicate by converting their properly folded counterparts.

image

A tonsil biopsy: The brown staining is for the prion protein responsible for variant Creutzfeldt–Jakob disease prion.

Transmissible spongiform encephalopathy diseases are caused by prions. Thus, the diseases are sometimes called prion diseases. Other prion diseases include Gerstmann–Sträussler–Scheinker syndrome (GSS), fatal familial insomnia (FFI) and Kuru in humans; as well as bovine spongiform encephalopathy (BSE, commonly known as mad cow disease) in cattle, chronic wasting disease (CWD) in elk and deer, and Scrapie in sheep. Alpers’ syndrome in infants is also thought to be a transmissible spongiform encephalopathy caused by a prion.

The prion that is believed to cause Creutzfeldt–Jakob exhibits at least two stable conformations. One, the native state, is water-soluble and present in healthy cells. As of 2007, its biological function is presumably in transmembrane transport or signaling. The other conformational state is relatively water-insoluble and readily forms protein aggregates. People can also acquire CJD genetically through a mutation of the gene that codes for the prion protein (PRNP). This occurs in only 5–10% of all CJD cases.

The CJD prion is dangerous because it promotes refolding of native proteins into the diseased state. The number of misfolded protein molecules will increase exponentially and the process leads to a large quantity of insoluble protein in affected cells. This mass of misfolded proteins disrupts cell function and causes cell death. Mutations in the gene for the prion protein can cause a misfolding of the dominantly alpha helical regions into beta pleated sheets. This change in conformation disables the ability of the protein to undergo digestion. Once the prion is transmitted, the defective proteins invade the brain and are produced in a self-sustaining feedback loop.

Chronic Fatigue Syndrome

Chronic fatigue syndrome (CFS) is the most common persistent fatigue syndrome that affects people.

Learning Objectives

Recognize the major symptoms associated with chronic fatigue syndrome

Key Takeaways

Key Points

  • CFS is typified by extreme fatigue even in the absence of any type of exertion, and can affect people of all ages.
  • There can be many non-fatigue symptoms associated with CFS, with many people exhibiting several different symptoms.
  • While no direct association has been shown between a given virus and CFS, the onset of CFS is often preceded with viral infection type symptoms.

Key Terms

  • orthostatic: Of, or relating to upright posture.
  • morbid: Of, or relating to disease.
  • prevalence: the total number of cases of a disease in the given statistical population at a given time, divided by the number of individuals in the population
  • encephalomyelitis: Inflammation of the brain and spinal cord.

Chronic fatigue syndrome (CFS) is the most common name used to designate a significantly debilitating medical disorder or group of disorders. Generally defined by persistent fatigue accompanied by other specific symptoms for a minimum of six months in adults (and 3 months in children/adolescents), not due to ongoing exertion, not substantially relieved by rest, and not caused by other medical conditions. The disorder may also be referred to as myalgic encephalomyelitis (ME), post-viral fatigue syndrome (PVFS), chronic fatigue immune dysfunction syndrome (CFIDS), or several other terms.

image

Chronic fatigue syndrome: Sufferers of chronic fatigue syndrome experience tiredness and unrefreshing sleep.

Biological, genetic, infectious and psychological mechanisms have been proposed for the development and persistence of symptoms but the etiology of CFS is not understood and may have multiple causes. There is no diagnostic laboratory test or biomarker for CFS. Symptoms of CFS include post-exertional malaise; unrefreshing sleep; widespread muscle and joint pain; sore throat; headaches of a type not previously experienced; cognitive difficulties; chronic, often severe, mental and physical exhaustion; and other characteristic symptoms in a previously healthy and active person. Persons with CFS may report additional symptoms such as muscle weakness, increased sensitivity to light, sounds and smells, orthostatic intolerance, digestive disturbances, depression, and cardiac and respiratory problems. It is unclear if these symptoms represent co-morbid conditions or are produced by an underlying etiology of CFS. CFS symptoms vary from person to person in number, type, and severity.

The majority of CFS cases start suddenly, usually accompanied by a “flu-like illness” while a significant proportion of cases begin within several months of severe adverse stress. An Australian prospective study found that after infection by viral and non-viral pathogens, a sub-set of individuals met the criteria for CFS, with the researchers concluding that “post-infective fatigue syndrome is a valid illness model for investigating one pathophysiological pathway to CFS”. However, accurate prevalence and exact roles of infection and stress in the development of CFS are currently unknown.