2.1 Modes of Transmission

This chapter introduces Toxoplasma gondii, the cause of toxoplasmosis. It discusses the many ways it can be transmitted and what is known about human infections, especially those affecting the brain, the pregnant uterus, and the eyes. It details the evidence linking this parasite to psychosis and estimates the percentage of psychosis cases that may be caused by it. It also briefly discusses the evidence linking toxoplasmosis to other conditions: epilepsy, brain cancer, rheumatoid arthritis, and motor vehicle accidents.

It has been called “one of the most successful parasites on Earth” and yet is one of medicine’s best kept secrets. It is “remarkable in its ability to infect nearly any nucleated cell in any warm-blooded animal” and infects most species of mammals and birds. An estimated one third of the world’s humans are infected although this varies widely by country, depending on dietary habits and exposure to cats. A 2014 survey in the United States reported that 11% of the population, or approximately 40 million Americans, have antibodies to this parasite indicating past infection [1,2,3,4].

For almost a century after its discovery, it remained largely unknown. It was given a tongue-twisting name, Toxoplasma gondii, which was in fact inadvertently misspelled—the North African rodent in which it was discovered in 1908 was a gundi, not a gondi. It is a protozoan parasite, not bacteria or viruses which were the infectious agents of greatest interest in the twentieth century. The most noteworthy protozoan is the malaria parasite; T. gondii, as it is commonly abbreviated, is a second cousin to the malaria parasite, but, like famous humans, second cousins don’t get much press. It was not until 1938 that T. gondii was known to be transmitted from a pregnant woman to her fetus and to cause severe problems with brain development. And it was not until the late 1960s that cats were identified as the specific host for this parasite. T. gondii has to be eaten by a cat to complete its life cycle in the cat’s intestine.

It begins its life cycle when a cat, usually as a kitten, becomes infected. Although the cat usually has no symptoms, it excretes in its feces up to 50 million infective T. gondii oocysts per day for an average of 8 days. At any given time approximately 1% of cats are infective and excreting oocysts. The oocysts are remarkably hearty and can survive for long periods in soil or water, as will be described in Chap. 7. Wherever the cat defecates may become contaminated with infectious oocysts. Since cats prefer loose soil for defecation, this often includes gardens, children’s sandboxes, and animal feed piles in barns. After 24 hours the oocysts dry out and are thought by some researchers to become aerosolized, thus floating in the air and capable of being inhaled. Water becomes contaminated when cat feces deposited on the ground is carried into streams by rainwater or when cat litter is flushed down the toilet.

The variety of ways in which humans can become infected with T. gondii is impressive and not widely appreciated. Best known is the fact that pregnant women who become infected can pass the parasite on to their developing fetus, thus being an example of congenital transmission. For many years it was believed that a woman could only congenitally transmit T. gondii on one occasion. It is now known that at least occasionally she can become reinfected with a different strain of the parasite or become chronically infected. Similarly well known is the risk of becoming infected from contact with cat litter. However, it is usually not physical contact with cat litter that is the risk but rather breathing in the aerosolized T. gondii oocysts that may float in the air once the infected cat feces dry out. Therefore it is recommended that pregnant women not change cat litter. Recent studies have even identified T. gondii oocysts in the air near outside locations where cats frequently defecate. An outbreak of toxoplasmosis among 37 patrons of a cat-infested riding stable in Georgia was thought to have been caused by people inhaling the oocysts. Many people are also aware that one can become infected with toxoplasmosis by gardening or children playing in loose soil or sand in which infected cats have defecated. In one such outbreak, seven preschool-age children from an extended family in Alabama became infected after playing in sand piles which had been contaminated by infected cats. In another outbreak, four children from one family became infected with toxoplasmosis, presumably from exposure to infected family cats [5,6,7,8,9].

It is also reasonably well known that one can acquire toxoplasmosis by eating undercooked or raw meat. Many such outbreaks have been documented, such as five students in New York who all ate undercooked hamburger on the same night. Cows, sheep, pigs, and other animals become infected, for example, by eating animal feed in which an infected cat has defecated. T. gondii then develops cysts in the animal’s muscle tissue that can infect humans if the meat is undercooked. Raw fruits and vegetables that have not been properly washed are additional sources of infection. In recent years, it has become clear that infected drinking water is also a major source of toxoplasmosis infection. Over 200 waterborne outbreaks have been documented, including 1 in Victoria, British Columbia, in which 100 people became clinically infected with toxoplasmosis [10,11,12,13,14].

Other possible modes of transmission of the T. gondii parasite to humans are still being explored. In a few cases, it has been passed on as part of an organ transplantation from an infected person. A recent study reported T. gondii infection in 2% of fleas from dogs and cats, raising the possibility that humans could become infected by petting them. A study of infectious agents left on the keypads of automated teller machines (ATMs) in New York City identified T. gondii on 1 of the 66 ATMs studied, perhaps left by someone who had been gardening prior to using the ATM. The possible sexual transmission of T. gondii is also under investigation; it has been shown to occur in dogs and sheep, and, since T. gondii oocysts have occasionally been found in the seminal fluid of men, it seems likely that sexual transmission also occurs in humans [15,16,17,18,19].

2.2 What Is Known Regarding Human Infections?

Given the fact that 11% of the American population is infected with Toxoplasma gondii, what symptoms do they have when they are infected? Fortunately in the vast majority of cases, they have very minor symptoms or no symptoms at all. For those who have symptoms, they are usually flulike, with fever, malaise, and often with enlarged lymph nodes. Such symptoms can be effectively treated with standard antiparasitic drugs. Thus most people who are infected with T. gondii are unaware that they are infected because doctors do not routinely test for it.

There are three major exceptions to this otherwise benign clinical picture. The first is cerebral toxoplasmosis. When T. gondii gets into the brain, it often causes major problems because we have no effective medications for toxoplasmosis that cross the blood-brain barrier and, thus, no effective treatments. Cerebral toxoplasmosis may affect individuals who are immunosuppressed, either because of having a disease such as HIV-AIDS or because of treatment for cancer or an organ transplant. For such individuals an initial infection with T. gondii or reactivation of the latent infection can result in severe toxoplasmosis, especially of the brain. Prior to the availability of effective treatments for AIDS, cerebral toxoplasmosis accounted for many deaths of these patients. Studies estimate a total of 1400 hospital visits and 71 deaths per year attributable to toxoplasmosis in the United States, two thirds of which are for cerebral toxoplasmosis [20, 21].

The second exception is when an infection with T. gondii takes place in a pregnant woman. It has been known for many years that this can cause severe problems for the developing fetus, and for this reason, pregnant women are tested for toxoplasmosis infection by their obstetricians. If the infection takes place early in the pregnancy, the consequences may be especially severe, including spontaneous abortion, a stillborn child, or brain damage. Such damage may include an enlarged skull (hydrocephalus), calcifications of the brain tissue, or other brain damage producing seizures and/or decreased IQ, including mental retardation. It has been estimated that congenital toxoplasmosis infections occur in approximately 1 in 10,000 births in the United States, or approximately 3800 per year. Studies from France and Brazil that have provided a longer follow-up of possible cases have reported congenital infection rates up to ten times higher than the US study [22,23,24].

The third exception is that T. gondii is known to be a common cause of eye disease and, in fact, said to be “the most common retinal infection in the United States.” Such infections occur commonly following congenital transmission, but they may also occur following infection in children and adults. For example, during the Canadian waterborne outbreak referred to above when 100 people became clinically symptomatic with toxoplasmosis, 20 of them had eye symptoms. Such symptoms may include eye pain, sensitivity to light, decreased vision, strabismus (“crossed eyes”), and nystagmus (“dancing eyes”), with severe cases even producing loss of vision. Either one or both eyes may be infected. It has been estimated that approximately 4800 individuals “develop symptomatic ocular toxoplasmosis each year in the United States” [25].

2.3 Fatal Attraction

Up until the turn of the twenty-first century, it was thought that the extent of human effects of T. gondii was confined to immunosuppressed individuals, congenital infections, and eye disease. Then in 2000 T. gondii was catapulted to public attention. In a highly publicized experiment, Joanne Webster and her colleagues at Oxford demonstrated that T. gondii was capable of altering the brains of rats, thus making it more likely that the T. gondii-infected rat would be eaten by a cat, thereby completing the life cycle of the parasite. It was, as the authors noted, a “fatal attraction.” Specifically, rats were put in a room with cat urine in one corner and rabbit urine in another. Normal rats have a strong, hardwired aversion to cat urine, but the T. gondii-infected rats were actually attracted to it. This is an example of the manipulation hypothesis in evolutionary biology whereby “a parasite may alter the behavior of its host but for its own benefit, usually by enhancing its transmission rate.” Another example is the malaria parasite which, when it infects humans, makes them more attractive to mosquitos which then further disseminate the parasite [26, 27].

The Oxford experiment caught the attention of the scientific community, resulting in headlines such as “How Your Cat is Making You Crazy” and “Can You Really Catch Madness from Your Cat?” Neuroscientist Robert Sapolsky and his colleagues at Stanford were among the first to replicate the study. They additionally demonstrated that the effect of the parasite on the rat brain was highly specific for only cat urine. The rat’s reaction to the urine of other animals was not affected nor in general was its anxiety or fear altered. Sapolsky et al. claimed that “the behavioral syndrome produced by T. gondii does not have any precedent in neuroscience research.” In a 2002 essay entitled “Bugs in the Brain,” Sapolsky called the specificity of the brain manipulation by T. gondii “flabbergasting”:

This is akin to someone getting infected with a brain parasite that has no effect whatsoever on thoughts, emotions, SAT scores or television preferences but, to complete its life cycle, generates an irresistible urge to go to the zoo, scale a fence and try to French kiss the pissiest looking polar bear [28,29,30].

In the two decades since Webster et al. reported that rats infected with T. gondii had significant changes in their behavior, behavioral changes associated with T. gondii have been reported in three other animal species. Wild red foxes exhibit facial muscle twitching, constant pacing, decreased fear of humans, and increased affection in what has been called the dopey fox syndrome. Hyena cubs that were infected with T. gondii were reported to have less fear of lions, as measured by their willingness to approach them, and to be 3.9 times more likely to be killed by them compared to cubs not infected. And chimpanzees, man’s closest relatives, were shown to lose their innate aversion toward the urine of leopards, their only natural predator, when the chimpanzees become infected with T. gondii [31,32,33,34].

Such studies inevitably raised questions about the effects that T. gondii might be having on humans. Beginning in the 1990s, Jaroslav Flegr and his colleagues in Prague undertook a series of studies of personality characteristics comparing people who were, or were not, infected with T. gondii. They reported a variety of personality traits associated with this parasitic infection, which are more common in males and included being more “expedient, suspicious, jealous, and dogmatic.” Such studies also have been carried out by other researchers, including in the United States; a 2018 summary of the studies claimed that the major personality characteristics of human T. gondii infection are greater impulsivity and aggressiveness. These studies raise the question of whether there are subgroups of Americans, among the 40 million so infected, who are unusually suspicious, impulsive, aggressive, etc. because they are infected with T. gondii. In one follow-up study, it was also reported that students who majored in business and people who start their own businesses were more likely than controls to be infected with T. gondii. Several recent studies have also suggested that toxoplasmosis may be responsible for causing mild cognitive impairment in some otherwise healthy people [35,36,37,38,39].

2.4 What Is the Evidence for Toxoplasmosis and Psychosis?

The 2000 publication by Webster et al. demonstrating that T. gondii can significantly change the behavior of animals was of great interest to those of us who had been researching infectious agents as a possible cause of schizophrenia and other psychoses. We were aware of reports that individuals infected with T. gondii occasionally had symptoms of psychosis. We were also aware of reports, beginning as early as 1953, that psychiatric patients often had increased antibodies to T. gondii compared to controls, indicating past infection. Almost all of these early studies had been carried out in Eastern Europe or China and were relatively unknown in Western Europe or America. In 1995 we published a paper asking “Could Schizophrenia Be a Viral Zoonosis Transmitted from House Cats?” [40].

The question was thus raised whether Toxoplasma gondii might be causing some cases of human psychosis, including people diagnosed with schizophrenia and bipolar disorder. Since it has been established that infectious agents in general can cause psychosis, as summarized in Chap. 1, it seemed like a reasonable question to ask. The following is the evidence supporting this possibility.

2.4.1 T. gondii Can Cause Psychotic Symptoms

It has been known for many years that T. gondii can cause delusions, auditory hallucinations, and other psychotic symptoms. As early as 1951, shortly after it had been first established that T. gondii could infect humans, a woman working with toxoplasmosis in a laboratory became infected, confirmed by a skin test. Among her symptoms were difficulties in concentrating or in following a conversation and feelings of being “far away, as if my body wasn’t there.” In 1966 a Dutch psychiatrist reported that “psychiatric disturbances were very frequent” in adults who acquired toxoplasmosis, occurring in 24 of 114 (21%) of the reviewed cases. Another Dutch researcher noted that “the literature not infrequently focuses attention on psychoses with schizophrenia or schizophreniform features that accompany chronic toxoplasmosis or that acquired in childhood or early in adult life.” Among the cases was another laboratory worker who had become infected with T. gondii and then developed delusions and hallucinations. In more recent years, symptoms of psychosis have also frequently been seen in individuals with AIDS who develop a toxoplasmosis infection of the brain [41,42,43].

Relevant to the possible relationship between toxoplasmosis and psychosis is a clinical case on which I recently consulted. Two brothers, born 2 years apart, both developed schizophrenia in their teenage years. Although the mother had no known history of having had toxoplasmosis, the older brother had been diagnosed with toxoplasma eye disease at age 4. Since it is now known that congenital toxoplasmosis can be transmitted by an infected mother to more than one offspring, as noted above, this could theoretically produce multiple cases of psychosis in a family. If so, it would give schizophrenia or bipolar disorder the appearance of being a genetic disease when in fact it was really an infectious disease. In further support of such reasoning, eye symptoms, such as impaired visual acuity, nystagmus, and strabismus, are commonly found in individuals with schizophrenia as well as in toxoplasmosis eye disease. Retinal abnormalities are especially common in both schizophrenia and in toxoplasmosis eye disease [9, 44,45,46,47,48].

2.4.2 Among Individuals with Schizophrenia, Those Who Are Infected with T. gondii Have Been Shown to Have More Severe Symptoms

In one study, 57 individuals with schizophrenia who were infected with T. gondii were compared to 194 individuals with schizophrenia who were not infected. The infected group had more severe symptoms, were on higher doses of antipsychotic medications, and had been hospitalized longer. Another study of 94 individuals with schizophrenia reported a highly significant association between being infected with T. gondii and having a continuous and more severe course. In a third study, 210 inpatients, all of whom had had schizophrenia for at least 5 years, were divided into 100 who were characterized as treatment resistant and 110 who were not treatment resistant. Among the treatment resistant, 70% were found to be infected with T. gondii compared to 36% of the nontreatment-resistant group. A study of 246 individuals with schizophrenia reported that those infected with toxoplasmosis were sicker, especially with more negative symptoms, than those not infected. A study of 600 individuals with first-episode schizophrenia reported significantly more delusions and hallucinations among those infected with T. gondii. Finally, a meta-analysis of 13 such studies concluded that “T. gondii infection has a modest effect on severity of positive and total symptoms in schizophrenia among those in the early stages of the disorder.” It therefore appears that T. gondii infection is associated with a more severe form of schizophrenia [49,50,51,52,53,54].

2.4.3 Individuals with Psychosis, Compared to Controls, Are Significantly More Likely to Have Antibodies Against T. gondii, Indicating Past Infection

To date there have been approximately 100 such studies of individuals with schizophrenia, of which at least 80 have reported a significant association. For example, a 2012 meta-analysis of 38 studies, including 6067 individuals with schizophrenia and 8715 controls, reported an odds ratio of 2.7; in other words, a person who has been infected with T. gondii is 2.7 times more likely to have schizophrenia compared to a person who has not been infected. Similarly, a 2015 meta-analysis of 42 studies reported an odds ratio of 1.8. The single largest study, involving 81,962 blood donors in Denmark, reported a significant association between antibodies to T. gondii and a diagnosis of schizophrenia with an odds ratio of 1.5. When the data analysis was restricted to cases in which infection with T. gondii definitely preceded the onset of schizophrenia, the odds ratio was even higher: IRR 2.8 [55,56,57].

Similarly, there have been approximately 20 T. gondii antibody studies for individuals with bipolar disorder. One meta-analysis of 11 such studies reported a significant odds ratio of 1.5. A second meta-analysis of eight such studies, including five new ones, reported an odds ratio of 1.3. Most recently, the largest study done to date, involving 1207 bipolar patients and 745 controls, failed to find an association between T. gondii infection and bipolar disorder. Because only approximately one quarter of patients with bipolar disorder have psychotic symptoms, compared to all patients with schizophrenia, one would expect to find a weaker association [56, 58].

Other antibody studies have been carried out to ascertain whether a past infection with T. gondii, as assessed by having antibodies, can predict who is more likely to later develop psychosis. Five studies have assessed antibodies in women before they gave birth or in the newborn; four of the studies reported that the offspring of the women and the newborns who had antibodies to T. gondii, especially those with the highest titers, were significantly more likely to later develop schizophrenia or other psychoses. A recent review of these studies concluded: “The evidence provided by these newer studies strengthens the support for an association between prenatal exposure to T. gondii antibodies and risk of psychosis.” An especially interesting study that used T. gondii antibodies to predict the later development of psychosis was carried out in China where 7126 entering university students were tested for T. gondii antibody. By the end of 4 years, 84 students had developed psychosis. The entering students who had had evidence of past T. gondii infection (IgG antibodies) were 2.6 times more likely to develop psychosis; those who had evidence of a recent infection (IgM antibodies) were 5 times more likely to develop psychosis compared to the entering students who had not been infected by T. gondii [59,60,61,62,63,64].

2.4.4 Individuals with Schizophrenia or Bipolar Disorder, Compared to Controls, Are Significantly More Likely as a Child to Have Lived in a Home with a Cat

The first such study, published in 1995, included 165 individuals with schizophrenia or bipolar disorder and 165 matched controls. Those with schizophrenia or bipolar disorder were significantly more likely to have lived in a household with a cat, especially from ages 6 to 10. A follow-up study with 264 cases and 528 matched controls similarly reported a statistically significant excess of cat ownership between birth and age 13 among the individuals who later developed schizophrenia or bipolar disorder. A third study involving 2125 individuals with schizophrenia or bipolar disorder and 4847 controls reported a similar statistically significant difference—51% of the cases had owned a cat between birth and age 13 compared to 43% of the controls. All three of these studies were done in the United States using the membership of the National Alliance on Mental Illness (NAMI) [65,66,67].

There have been seven attempts to replicate these findings. In Turkey 300 hospitalized patients with schizophrenia were compared with 300 controls (150 blood donors and 150 nonpsychotic psychiatric outpatients) on family cat ownership in childhood, birth to age 13. Among those with schizophrenia, a statistically significant 59% had owned cats in childhood compared to 8% of the controls. In Tunisia, 200 individuals with serious mental illness were compared with 200 well-matched controls. Among the 101 patients diagnosed with schizophrenia, 59% had owned a cat during childhood compared to 38% of the controls, a statistically significant difference (Oumaima Inoubli, et al. “Childhood Cat Ownership is a Risk Factor for Schizophrenia at an Early Age,” submitted for publication). In Canada, 1986 adults were asked about psychotic experiences and cat ownership prior to age 13. Those who reported having had psychotic experiences were significantly more likely to have owned a rodent-hunting (outside) cat in childhood than those who owned a non-rodent-hunting (inside) cat or no cat at all. In Finland cat ownership from birth up to the age of 7 was assessed in the northern Finland birth cohort. Cat ownership in early childhood was not significantly associated with the small number of 55 individuals diagnosed with schizophrenia but was significantly associated with the much larger group of 4866 individuals who were assessed for having schizotypal personality traits at age 31 [68,69,70].

In the Czech Republic, researchers collected online, self-reported data on Facebook from 8864 individuals regarding cat contact. Those who self-reported a diagnosis of bipolar disorder, but not schizophrenia, were significantly associated with having more cats in the house but not with cat ownership in childhood. In the United States, a large cohort of 396 individuals with schizophrenia and 381 with bipolar disorder were compared to 594 controls on cat and dog ownership in childhood. Overall cat ownership was not a risk factor for either disease, but dog ownership was a significant protective factor against the development of schizophrenia. Finally, a study in England examined cat ownership at ages 4 and 10 in individuals who had some self-reported psychotic-like thinking at age 13. The initial association was statistically significant but was no longer significant when the researchers controlled for household crowding and poverty. Since household crowding and poverty have been clearly shown to increase the transmission of T. gondii, it may be argued that controlling for these factors is not appropriate and would weaken any association that did exist. In summary, among ten studies of cat ownership in childhood and the later development of psychotic symptoms, six studies reported a significant association, two reported mixed results, and two studies were negative [71,72,73,74].

In fact it is surprising that it is possible in any study to find a significant association between cat ownership in childhood and psychosis. Children can become infected in many different locations that are contaminated with T. gondii oocysts, including play areas at school, a babysitter’s house, a friend’s house, or a public park. Even if a child became infected in a sandbox at their own home, they would not necessarily have to have owned a cat; cats from the neighborhood may well be responsible for the oocyst contamination.

2.5 How Many Cases of Psychosis Might Be Caused by T. gondii?

Overall, the evidence suggests that T. gondii might cause some cases of psychosis. Is there any way to estimate how many cases this might be? In 2014, Dr. Gary Smith in the School of Veterinary Medicine at the University of Pennsylvania published a paper in which he tried to answer this question specifically for schizophrenia. Using data from the T. gondii antibody studies discussed above, he estimated the population attributable fraction of cases of schizophrenia that were likely to be caused by the parasite to 21% with a possible range from 14% to 31%. Regarding the annual incidence of schizophrenia, the most recent international data suggests that it is approximately 14.6 cases per hundred thousand population. Based on the US population of 330 million, that rate would translate into 48,100 new cases of schizophrenia each year. And 21% of that would be approximately 10,300 cases attributable to T. gondii [75, 76].

Nobody has yet done a similar study to calculate the population attributable fraction of cases of affective psychosis, which would include bipolar disorder and severe depression with psychotic features, but let us assume that it is also 21%. The annual incidence of affective psychosis is 7.1 per hundred thousand population. That rate translates into approximately 23,400 new cases of affective psychosis each year, of which 4900 would be attributable to T. gondii. Altogether, then, the protozoal parasite that causes toxoplasmosis might be responsible for approximately 15,000 new cases of psychosis in the United States each year.

In fact, estimating the population attributable fraction of cases of psychosis that may be caused by T. gondii is very difficult because there are so many unknowns. Some of these unknowns include the following:

  • Inaccurate testing : It has become increasingly clear that the tests being used to ascertain whether or not a person has been infected with T. gondii are often not accurate. This is especially true for individuals, such as those with schizophrenia or bipolar disorder, who are taking antipsychotic medications which are thought to suppress the immune response. This was demonstrated most clearly in a study in which 39 individuals with schizophrenia who had never been treated and 36 individuals with schizophrenia who were being treated were compared with 73 normal controls. On T. gondii antibody testing, of both the serum and cerebrospinal fluid, the patients who had never been treated had statistically significant higher antibody levels then the controls. The patients who were being treated had lower antibody levels than those who were not being treated, slightly but not significantly higher than normal controls. This suggests that for individuals receiving antipsychotic medication, many are being classified falsely as not being infected with T. gondii. This is also true for individuals being immunosuppressed; for example, in a study of AIDS patients, 16% of those known to be infected with T. gondii tested negative for antibodies. Other studies have shown that antibodies to T. gondii may wane over time even in individuals with live cysts in the brain. Of special concern was a recent study in mice in which male mice whose sperm was infected with T. gondii altered the behavior of their offspring through RNA changes, even though the offspring themselves had no antibodies to toxoplasmosis. Whether or not this also happens in humans is not known [77,78,79,80,81].

  • Host genetics : For most infectious agents, it is known that some people are genetically more susceptible to becoming infected, while others are genetically more resistant. This is also true for T. gondii. For example, it has been shown that if an individual has a particular gene (HLA-DQ3), that person will be more susceptible to getting toxoplasmosis that affects the brain. On the other hand, if a person has a different gene (HLA-DQ1), that person will be more resistant to such infections [82].

  • Immune status : The effectiveness of a person’s immune system in fighting off assaults by infectious agents varies widely among individuals and also in a given individual over time. Thus if you also have the flu when you are exposed to T. gondii, your immune system may be weakened. This principle has been demonstrated by individuals with AIDS who have impaired immune systems and in whom T. gondii often causes major brain infections.

  • Form of infectious agent : T. gondii may infect people as an oocyst (e.g., in contaminated water) or as a tissue cyst (for example, in undercooked lamb). In mice it has been shown that infections with oocysts lead to more severe disease than infections with tissue cysts. Similarly, according to one toxoplasmosis expert, “circumstantial evidence suggests that oocyst-induced infections in humans are clinically more severe than tissue cyst-acquired infections” [83].

  • Strain : T. gondii is known to have many strains, some being much more pathogenic than others. Type I, II, and III strains have been most widely studied, but almost 200 other genotypes have been identified. Different strains are known to have markedly different effects on animals; for example, type I kills mice, but types II and III do not. In humans, type I is thought to cause most cases of congenital toxoplasmosis as well as eye disease. In an important study of 91 women who had had toxoplasmosis and gave birth to individuals who developed psychosis, an association was statistically significant for women who had been infected with a type I strain, but not for those infected with type II or III strains. It has also been shown in humans that different strains affect brain neurotransmitters and neuropeptides very differently, so it would be expected that different strains would have different psychiatric effects. Sorting this out is made more difficult by the fact that a person may become infected with more than one strain [63, 84,85,86,87,88].

  • Timing of infection: For many infectious agents, it is known that the specific timing of the infection in human development is a major determinant in the outcome. For example, the polio virus may have a very different effect if it infects a 2-year-old rather than a 12-year-old. Timing is also thought to be important for T. gondii. Studies in mice reported very different outcomes, including the effects on neurotransmitters, when mice were infected as juveniles or as adults. The importance of timing is also suggested by congenital toxoplasmosis; the outcome of first trimester infections is much worse than the outcome of third trimester infections [89].

  • Breed of cat: The susceptibility of cats to infection by T. gondii varies significantly by breed. A study carried out in Finland on 1121 cats representing 8 different breeds reported a threefold difference in Toxoplasma seropositivity. The cats with the highest rate of infection were Persians at 60%, and those with the lowest rate were Burmese at 19%; the other 6 breeds had intermediate rates. In general the longhaired breeds were twice as likely to be infected as the shorthaired breeds. Since cat breeds tend to be regionally popular and to change over time, this would be another variable that would affect the prevalence of toxoplasmosis. Thus two countries could have the same number of cats, but, because they favor different breeds, one country could have twice as much toxoplasmosis as the other [90].

In summary, there is still much we do not understand regarding human infections with T. gondii. This parasite has provided many surprises so far and is likely to provide still more.

2.6 Other Diseases and Conditions

As interest in Toxoplasma gondii has increased in the last two decades, researchers have looked for associations of this parasite with other diseases and conditions. Given the propensity of T. gondii to infect the brain and the reports of its association with psychosis, researchers have looked especially at diseases and conditions associated with the brain. These have included autism, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, cerebral palsy, and suicidal behavior. Among the studies the diseases and conditions that show the strongest associations with T. gondii are epilepsy, brain cancer, rheumatoid arthritis, and motor vehicle accidents.


Since 1995, 16 studies have been published looking for an association between toxoplasmosis and epilepsy. A 2015 meta-analysis of 6 of these studies, with a total of 1280 subjects with epilepsy and 1608 controls, reported a positive association with an odds ratio of 2.25, p = 0.005. The authors concluded that “despite the limited number of studies and lack of high-quality data, toxoplasmosis should continue to be regarded as an epilepsy risk factor.” A recent meta-analysis that included all 16 studies, with 3771 epileptic patients and 4026 healthy controls, reported an odds ratio of 1.72, p = 0.001 [91, 92].

Brain cancer

Since 1967 there have been five case-control and two epidemiological published studies on the relationship between infection with T. gondii and brain cancer. A study in Minnesota of 24 meningiomas, tumors of the covering of the brain, and 77 gliomas, tumors of the brain substance, reported that both were increased in individuals infected with T. gondii, but this only achieved statistical significance for the 35 gliomas categorized as astrocytomas (p < 0.01). A study in Australia looked for infection in 53 individuals with meningiomas and 117 with gliomas. The former showed a significant association (p < 0.02; OR 2.09), but the latter showed no increase. A Korean study examined 93 brain cancers, including 12 meningiomas, 14 astrocytomas, and 31 glioblastomas; all 3 were significantly associated with T. gondii infection at the p < 0.05 level. Most recently two prospective studies were published, meaning that the blood was collected to ascertain T. gondii status before the brain tumor was diagnosed. A small study of 37 gliomas from the United States and a large study of 328 gliomas from Norway both reported a significant association with toxoplasmosis infection (OR 2.70 and OR 1.32 respectively). In summary, two out of the three studies of meningiomas and four out of the five studies of gliomas reported a statistically significant association between the brain cancer and infection with T. gondii [93,94,95,96].

The first of the two epidemiological studies was published in 2012 and involved data from 37 countries. The national incidence of brain cancers was compared to the national rate of T. gondii seropositivity. The authors reported a significant association, specifically “infection with T. gondii was associated with a 1.8-fold increase in the risk of brain cancers.” The authors attempted to replicate these findings by comparing similar data for the 22 administrative regions of France. They reported a similar significant association but only for men age 55 and over and women age 65 and over with the magnitude of the effect increasing with age [97, 98].

Rheumatoid arthritis

Perhaps the most interesting association of T. gondii with other diseases is with rheumatoid arthritis. Eight studies have reported an increased prevalence of T. gondii antibodies in individuals with this disease. A meta-analysis of these studies, with 1244 patients and 2799 controls, reported an odds ratio of 3.30, p < 0.0001. Another study reported that individuals with rheumatoid arthritis, compared to controls, have had more exposure to cats. This association is especially interesting because rheumatoid arthritis and schizophrenia share several epidemiological features, and it has been noted in many studies that the two diseases are mutually exclusive, i.e., once you get either rheumatoid arthritis or schizophrenia, you almost never get the other. This suggests that T. gondii or another pathogen may cause some cases of both diseases with the clinical outcome differing because of genetic predisposition, timing of the initial infection, strain difference, or other factor [99, 100].

Motor vehicle accidents

Laboratory work with mice infected with T. gondii established the fact that the parasite causes a slowing of their reaction time. Therefore in 2001 Jaroslav Flegr and his colleagues in Prague compared the reaction time of 60 human subjects infected with the parasite and 56 subjects not infected. Those infected had a significantly longer reaction time. Based on these findings, Flegr et al. wondered whether this might have practical implications, such as increasing the rate of vehicular accidents in individuals who were infected [101].

Flegr et al. compared 146 drivers who had caused an accident and pedestrians who had been hit by a vehicle with 446 local residents. The drivers and pedestrians were significantly more likely to be infected with T. gondii with an odds ratio of 2.65 (p < 0.0001). Since that study was published, ten other studies have been done in Denmark, Poland, Russia, Czech Republic, Turkey, Mexico, and New Zealand, half reporting positive results and half reporting negative results. The largest of these was the Danish study involving 2724 drivers in accidents and 6294 matched control blood donors and reported “a very weak association between traffic accidents and toxoplasmosis” (OR 1.11; p = 0.054). A meta-analysis done on all the studies reported an odds ratio of 1.69 (p = 0.003) [102,103,104].

Such data should always be approached with caution, however, since correlations do not necessarily indicate causation. As one observer noted, “Think of people who enjoy rare steaks and also tend to drive recklessly in fast cars. Consuming rare meat raises their chances of [toxoplasmosis] infection and reckless driving makes their chances of an accident more likely, but personal taste could explain the link between infections and accidents rather than parasite control” [105].

In summary, Chap. 1 established the fact that many human diseases are transmitted to us by infectious agents from animals as well as the fact that infectious agents can cause psychosis. Chapter 2 has proposed that Toxoplasma gondii, a protozoan parasite carried by cats, may cause some cases of psychosis, specifically schizophrenia and bipolar disorder. Is there additional evidence that might support such a claim? Historically cats have a very unusual and distinctive history. For 400 years they were used for rodent control but kept in the barn, socially shunned as agents of Satan and on religious holidays tortured and killed. Then over the next 400 years, they slowly became pets for humans, then companions and finally family members. The relationship between cats and humans, and thus human exposure to Toxoplasma gondii, changed radically over the eight centuries. If there really is a relationship between this parasite and human psychosis, wouldn’t we expect to see some correlation between the changing relationship between cats and humans and the incidence of psychosis?

Among English-speaking nations, there is only one country which has sufficient data to address this question. England has extensive anecdotal data on the status of cats because its writers embraced them as pets and wrote about them. It also has extensive information on the incidence and prevalence of psychosis, usually referred to as madness or insanity. It is thus to England that we now turn for the next three chapters to ascertain whether there is any correlation between the rise of cats and the rise of madness.