Schizophrenia and Infections: The Eyes Have It

Abstract

The visual tract is prominently involved in schizophrenia, as evidenced by perceptual distortions and a type of nystagmus found in many individuals affected. Genetic explanations for these abnormalities have been suggested. This study proposes an alternate explanation based on infection. Several infectious agents thought to be associated with some cases of schizophrenia are known to cause both infection of the fetus and abnormalities of the eye. Toxoplasma gondii is examined in detail, and rubella, cytomegalovirus, varicella-zoster virus, and herpes simplex virus more briefly. Careful ophthalmic assessments, including funduscopy and direct examination of tissues for infectious agents, will clarify the role of such agents in ocular aspects of schizophrenia.

Introduction

Visual changes are common in schizophrenia. Several authors have described perceptual distortions of colors, the intensity of light, and shapes, especially in the early stages of the illness.^1–3 Difficulties in face recognition; misreading the facial expressions of others; misidentifying individuals as people known earlier in life; and believing that one’s parents have been replaced (Capgras syndrome) have also been described. Such reports suggest that parts of the visual tract—eyes, optic tract, and occipital cortex—may be involved in the schizophrenia disease process. This suggestion is supported by recent reviews.^4,5

This article will review selected structural and functional eye abnormalities found in schizophrenia and other psychiatric disorders. It will then examine some infections of the eye and central nervous system to demonstrate how such infections might account for the eye abnormalities.

Eye Abnormalities in Schizophrenia

The most studied eye abnormalities in schizophrenia include the following.

Nystagmus.

Abnormal “ocular pursuit-reactions” were described in individuals with dementia praecox in 1908 by Diefendorf and Dodge.⁶ Such involuntary, repetitive eye movements are a type of nystagmus which may be caused by abnormalities of the optic tract, brain, inner ear or by some drugs. This research was carried forward by Couch and Fox⁷ and White,⁸ then popularized by Holzman et al⁹ who focused on smooth pursuit eye movements (SPEM), said to occur in 50%–85% of individuals with schizophrenia, 40% of individuals with bipolar disorder, and 8% of the general population. SPEM dysfunctions have also been described in children with autism, attention deficit hyperactivity disorder (ADHD), and reading disorders.¹⁰

Disorders of SPEM can be measured in a variety of ways^11,12 and have been described in antipsychotic-naïve patients as well as in those on medication.¹³ In some cases, antipsychotics improve SPEM function.¹⁴ By 2008, there were over 200 publications on eye movement abnormalities in individuals with schizophrenia, making it one of the most extensively studied and replicated findings for this disease.¹¹

Strabismus.

Strabismus is a misalignment in which both eyes are not looking in the same direction. The deviant eye may be directed inward (esotropia) or outward (exotropia). Strabismus occurs in 1%–5% of the general population and may be caused by genetic or environmental factors, including complications of pregnancy.

There are multiple reports of strabismus occurring in individuals with schizophrenia, including an intriguing case in which a man’s strabismus coincided with the waxing and waning of his psychotic symptoms.¹⁵ In 2004, Toyota et al¹⁶ reported that strabismus occurred in 46 of 346 (13%) individuals with schizophrenia, all of whom had constant exotropia, compared with 27 of 542 (5%) of controls (OR, 20.6; 95% CI, 5.03–56.2). Two years later, they confirmed these findings with an additional sample.¹⁷

An alternate approach was taken by Schiffman et al who prospectively followed up 265 Danish children who had had a standard eye exam, including 90 children who had a parent diagnosed with schizophrenia. They reported that “children who later developed a schizophrenia-spectrum disorder had significantly higher eye exam scale and strabismus scale scores” compared with the controls.¹⁸ A study in Minnesota followed up 407 children who had strabismus. Children with exotropia, but not esotropia, “were 3.1 times more likely to develop a psychiatric disorder than were control subjects.” These included 3 cases of psychoses and significant increases in individuals with ADHD, adjustment disorder, and learning disabilities.¹⁹ A similar study of adults with various types of strabismus reported a significant association between some types and anxiety disorder, psychiatric hospitalization, and psychiatric medication use.²⁰

Impaired Visual Acuity.

Many psychiatric medications affect visual acuity, so this must be considered when assessing eye function. A Finish study assessed visual acuity in 56 individuals with schizophrenia, 72 with other nonaffective psychosis, 38 with affective psychosis, and 6422 other individuals.²¹ After adjusting for age and sex, schizophrenia had approximately 5-fold odds (P < .0001) of having visual impairment for distance and approximately 6-fold odds (P < .0001) for near vision. The other 2 diagnoses were associated with much less impairment. The use of antipsychotics in general was not associated with visual impairment but the use of phenothiazines, when examined separately, was associated with impairment of near vision. In a separate study, this research group reported that the visual impairment experienced by individuals with schizophrenia significantly impaired their activities of daily living and social functioning.²²

Finally, a Swedish study of 110 children of women with psychosis assessed their visual acuity at age 4, then followed them until age 22.²³ The children with impaired visual acuity at age 4 had a significantly increased incidence of schizophrenia-spectrum disorders at age 22 (P = .003), but no increased incidence of depression, anxiety disorder, personality disorder, or substance abuse, the other conditions studied.

Corneal Temperature.

Shiloh et al²⁴ reported that the temperature of the cornea in drug-free individuals with schizophrenia is significantly higher than those on antipsychotic medication or normal controls. They also reported that the corneal temperature fluctuated with the patients’ symptoms.²⁵ Human body temperature is thought to be influenced by dopamine levels, perhaps by its effect on the hypothalamus.²⁶

Blindness and Schizophrenia.

Congenitally blind people have a markedly decreased rate of schizophrenia, although recent studies suggest this is only true if the cause of the blindness is cortical, not in the eye.^27,28

Other Eye Abnormalities.

A variety of other eye abnormalities have been described in individuals with schizophrenia. Karson et al²⁹ reported that drug-free individuals with schizophrenia have an increased blink rate. Electrophysiological studies using visual evoked potentials have shown deficits in visual processing and perceptual organization.^30,31 Electroretinograph studies have reported differences between individuals with schizophrenia and controls in a-wave and b-wave activity.⁵ Structurally, there have been reports of both retinal venule widening and retinal nerve fiber layer thinning associated with schizophrenia.⁵

Possible Explanations

The perceptual distortions commonly found in schizophrenia have been widely assumed to be psychological in origin, part of the person’s delusions and thinking disorder. By contrast, multiple studies have assessed eye tracking in the first-degree relatives and viewed eye tracking as a marker of genetic vulnerability.^32,33 Specific genes, such as RGS4 and the catechol-O-methyltransferase (COMT) gene, have been suggested as genetic links between schizophrenia and eye tracking,^34,35 but no gene or chromosomal region has been conclusively implicated. Specific genetic defects have also been proposed to explain the occurrence of strabismus in schizophrenia^36,37 and the protective effect of congenital cortical blindness.²⁷

An ancillary, though not mutually exclusive, explanation for the occurrence of eye abnormalities in schizophrenia is infectious agents in the eye and/or central nervous system. Such infections may occur in utero or after birth and may involve a variety of infectious agents. As examples of how infections could explain the eye symptoms in schizophrenia, Toxoplasma gondii will be examined in detail and selected viruses more briefly.

Toxoplasma gondii

Toxoplasma gondii, the causative agent of toxoplasmosis, is a parasite for which felines are the complete host. It can infect any warm-blooded animal, and is one of the world’s most successful parasites, infecting approximately 30% of all humans. It may be transmitted to humans congenitally or by infective oocysts by way of contaminated water; sandboxes or loose soil; cat litter boxes; unwashed vegetables from contaminated gardens; or tissue cysts through raw or undercooked meat from infected animals. Congenital transmission occurs when pregnant women become infected and T. gondii crosses the placenta to infect the fetus, which it does approximately 10%–20% of the time following primary infection.³⁸ The majority of pregnant women who become infected are asymptomatic; the others have mild, flu-like symptoms. Transmission of T. gondii in the first trimester of pregnancy often results in severe damage to the fetus, including fetal death, but transmission later in pregnancy usually results in less apparent infections. Most infants with congenital infection appear normal at birth.³⁹

Previous studies have established links between T. gondii and schizophrenia. Approximately 80 studies have assessed IgG and/or IgM antibodies to T. gondii in individuals with schizophrenia. Most found a significant increase in antibodies in patients compared with controls; 3 meta-analyses reported ORs of 2.71,⁴⁰ 1.81,⁴¹ and 1.68.⁴² Four other studies reported that adults with schizophrenia were significantly more likely as a child to have lived in a home with cats, thus increasing exposure to infection with T. gondii.^43–46 Exposure to T. gondii has also been associated with other psychiatric conditions such as generalized anxiety disorder⁴⁷ and suicidality⁴⁸ as well as cognitive decline in the elderly.⁴⁹

The brain and the eye are among the organs most commonly infected in human toxoplasmosis. In the United States, approximately 21000 individuals develop toxoplasmosis-associated ocular lesions each year.⁵⁰ Geographic differences of T. gondii are marked; ie, in the United States only about 2% of T. gondii-infected individuals develop the ocular form, whereas in parts of Brazil, where other strains prevail, as many as 20% will develop the ocular form.⁵⁰ These differences may be related to differences in strains or other unidentified genetic or environmental factors.⁵¹

In the eye, the most common form of toxoplasmosis is retinochoroiditis in which the retina and choroid are involved, usually leaving one or more retinal scars that can be visualized by careful funduscopic exam. Toxoplasmosis is said to be “the most common cause of posterior uveitis in immunocompetent subjects.”⁵² We are not aware of any study that has assessed individuals with schizophrenia for retinal scars that would indicate a past T. gondii infection.

Other manifestations of ocular toxoplasmosis include the following:

1. Nystagmus: Six studies of congenital toxoplasmosis with ocular symptoms have noted the occurrence of nystagmus in between 2% and 27% of cases.^53–58 The nystagmus was described as “horizontal and pendular…a jerk-type of nystagmus.”⁵⁸

2. Strabismus: Strabismus is a relatively common consequence of congenital toxoplasmosis, occurring in between 26% and 29% in 4 studies.^55–58

3. Impaired visual acuity: Given the high prevalence of retinochoroditis in congenital toxoplasmosis, it is not surprising to find that visual acuity is often impaired. In 4 studies of such individuals, impairment of visual acuity (ie, “blurred vision”) has been reported as occurring in between 24% and 79% of cases.⁵⁹

4. Excess dopamine: The human retina contains cells that produce dopamine, and many retinal neurons have dopamine receptors that can be activated by retinal transmission. Toxoplasma gondii infection can result in increased levels of dopamine generated by the organism or host cells, although this is not a universal finding.^60,61 It is known that excess dopamine can produce hyperintense color perception and “higher contrast sensitivity.”⁵ Thus, ocular infections with T. gondii might explain some of the perceptual distortions experienced in schizophrenia as well as the increased corneal temperature. Certain strains of T. gondii can also affect the expression of GABA, glutamate, serotonin, and norepinephrine in cell cultures, with different stains having different effects on the various neurotransmitters.⁶²

5. Complement activation and neuronal connectivity: Recent studies in animal models indicate that chronic T. gondii infection can activate components of the complement system⁶³ and alter synaptic functioning and neural connectivity.⁶⁴ These findings are of interest in light of recent findings indicating polymorphisms in the human complement gene and levels of complement proteins in the blood and cerebrospinal fluid as risk factors for schizophrenia.^65,66

   Regarding the schizophrenia protective effect of congenital cortical blindness, this may be similar to the schizophrenia protective effect of rheumatoid arthritis. Such protective effects might be explained if the same or a similar infectious agent caused both conditions; having one condition would thereby confer immunity to getting the second.⁶⁷

Other aspects of ocular toxoplasmosis are also of interest for schizophrenia. Congenital retinochoroiditis, usually asymptomatic at birth, may become symptomatic anytime in childhood or early adulthood.⁶⁸ However, the majority of cases of ocular toxoplasmosis, at least in the United States and Europe, are likely to be acquired postnatally and to become symptomatic “in the second and third decade of life.”^69,70

Other Infections

Toxoplasma gondii has been discussed in detail to illustrate how an infectious agent could explain many of the ocular symptoms in schizophrenia, but other infectious agents could also do so. Congenital rubella, ie, has been associated with an increased incidence of autism, mood disorders, and schizophrenia-spectrum disorders.⁷¹ It commonly produces cataracts and may also produce retinopathy, strabismus, nystagmus, microphthalmia, glaucoma, and amblyopia.⁷² The amblyopia may then produce contour integrations deficits which occur in schizophrenia.³¹

Congenital infectious with herpes viruses such as cytomegalovirus,⁷³ varicella-zoster virus,⁷⁴ and herpes simplex virus type 2 (HSV-2)⁷⁵ are also associated both with later psychosis and ocular symptoms. Cytomegalovirus may produce chorioretinitis, retinopathy, strabismus, nystagmus, and optic atrophy.⁷⁶ Varicella-zoster virus may produce chorioretinitis, nystagmus, cataracts, anisocoria, and microphthalmia.⁷⁷ Similarly, HSV-2 may produce acute retinal necrosis up to 30 years after the initial infection.^78,79

Discussion

In recent years, the importance of inflammation in the schizophrenia disease process has become evident. The most prominent finding from genetic studies points to the involvement of the major histocompatibility complex on chromosome 6, a region heavily involved in the immune response, including the response to infectious agents.⁸⁰ Research on C-reactive protein and other markers of inflammation have increasingly suggested that this is an integral part of the schizophrenia disease process.^81,82 It thus seems reasonable to consider infectious agents as an alternate explanation for the eye findings.

Other known infectious agents, and presumably many still unknown agents, can also cause ocular symptoms. The Zika virus, which causes ocular abnormalities in 35% of infected offspring, is a recent addition to the list.⁸³ The best way to ascertain the possible role of such infectious agents in schizophrenia is to perform careful ophthalmologic assessments, including funduscopic examinations, on individuals with this disease. Patients who have obvious eye signs, such as nystagmus and strabismus, should be of special interest. Obtaining fluid from the vitreous would facilitate studies of antibodies, infectious agents, and inflammatory markers, thereby increasing the chances of identifying a specific infectious agent and allowing appropriate therapy to be initiated.^84,85

If T. gondii or other infectious agents are proven to be responsible for many of the eye abnormalities that occur in schizophrenia, it will modify our thinking about some of the perceptual distortions experienced by patients. Such distortions may be biological rather than psychological in origin, based on illusions rather than delusions. Furthermore, the treatment of the underlying infection might lead to improvement in visual symptoms, markedly improving the quality of life of some individuals with schizophrenia.