The Infection Connection

PSYCHOLOGY HAS LONG HELD THAT MENTAL ILLNESS IS BORN OF ADVERSE EXPERIENCES.MORE RECENTLY, RESEARCH HAS POINTED THE FINGER AT FLAWED GENES. NOW A THIRD CULPRIT MAY BE EMERGING: INVASION BY BACTERIA AND VIRUSES.

Eight-year-old Seth broke from the grasp of Jane, his harried mother, for the third time in 10 minutes. Tearing across the emergency room, he stopped short, transfixed by a piece of paper lying on the floor. His red-rimmed eyes seemed to bulge from their sockets and his mouth twitched violently, as if he were in pain. Indifferent to Jane's pleas to stop, he proceeded to pick up from the floor every piece of paper, no matter how filthy, with hands that were reddened and raw. It was the state of his hands that had precipitated the trip to the hospital: Seth had spent most of the night in the bathroom, washing them over and over.

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With his head jerking spasmodically and his fingers pecking at pieces of paper and cigarette butts, the boy resembled some strange overgrown bird. Then, suddenly terrified, he flew back to Jane and began pulling on her arm. "Mommy, Mommy, let's leave!" he whimpered. "They're going to kill us. They're coming!"

Jane tried her best to calm him, but she too was beginning to panic. Two days before, Seth had been a perfectly normal little boy whose most serious health problems were the occasional cold or sore throat. He had become mentally ill overnight.

What caused Seth's anxiety, his tics, his obsessive-compulsive behavior? Astonishingly, it was probably that minor sore throat, his doctors concluded. Today, scientists are increasingly coming to recognize that the bacteria and viruses that frequently invade our bodies and cause sore throats and other minor ailments may also unleash a host of major mental and emotional illnesses, including anorexia, schizophrenia and obsessive-compulsive disorder.

It is a theory sharply at odds with earlier views of the genesis of psychological illness. Followers of Freud long held that mental and emotional trouble is primarily the result of poor parenting, especially by mothers. Indeed, until about 30 years ago, psychoanalysts frequently placed the blame for schizophrenia on "schizophrenogenic" mothers. Obsessive-compulsive disorder, also, was put at Mom's door. "It was thought to be the result of harsh toilet training," observes Susan Swedo, M.D., chief of pediatrics and developmental neuropsychiatry at the National Institutes of Mental Health. But such theories, which added immeasurable guilt to the burdens of parents with mentally ill offspring, have turned out to have little evidence to back them up, most experts now agree.

Instead, in recent years, the focus has shifted to genes as the main source of mental illness. Faulty DNA is thought to be at least partly responsible for, among other problems, anxiety and panic disorders, schizophrenia, manic depression and antisocial personality disorder, which is characterized by impulsive, excessively emotional and erratic patterns of interpersonal behavior.

Yet genetics doesn't appear to wholly account for the occurrence of major psychiatric ailments. If heredity alone were to blame, identical twins would develop schizophrenia with a high degree of concordance, but in fact in only 40% of cases in which one identical twin has the disease does the other twin have it as well. Autism, though it has been observed to run in families, also strikes five of every 10,000 children apparently arbitrarily. Nor can depression and other affective disorders be completely explained by damaged DNA. Says Ian Lipkin, Ph.D., a neuroscientist and microbiologist at the University of California at Irvine: "Genetics doesn't hold the key to understanding how to fit these square pegs into round holes."

Bacteria and viruses may be that key, but scientists have been slow to grasp the idea. Consider the case of syphilis, which is caused by the bacterium Treponema pallidum. In its final, or tertiary, stage, the disease can precipitate psychiatric problems like dementia, mania, depression, delusions and Tourette's like tics. Though some scientists suspected a connection between infection with the bacterium and the mental disturbances that may take three to five decades to emerge, the link became widely accepted only in the 1940s after the introduction of the antibiotic penicillin as a treatment for syphilis. In the interim, patients with syphilis who later developed psychiatric problems were often institutionalized as crazy. But even with the link established, Freud's theories were in ascendance and few scientists were willing to consider that microbes might be a common source of other mental illness.

Now, decades later, infection has emerged as a prime suspect in psychological illnesses. The inadequacy of genetic and experiential explanations has prompted scientists to look elsewhere--and their gaze has come to rest on physical ailments, such as heart disease, cancers and ulcers, that in some cases have an infectious origin. Could the same be true, they wonder, for mental and emotional ills?

Improved technology has made it easier to find out. Since active only when inside other living creatures, microbes are notoriously hard to grow, and therefore study, in the lab, but scientists' ability to do so has increased steadily over the last few decades. Other tools have allowed researchers to see their quarry more clearly. For about a decade, microbiologists have used a technique called polymerase chain reaction, or PCR, to replicate a small piece of genetic material over and over until it forms a quantity large enough to study--and large enough to show the lingering traces of an infection. A new variant of PCR, called representational difference analysis, introduced in 1994, allows scientists to go one step further and compare the differences between two separate pieces of DNA (including healthy and diseased segments, for instance). And the refinement of electron microscopes has permitted researchers to follow the "footprints" left by infection in patients' cerebrospinal fluid.

The introduction of CAT scans in the early 1970s has been another leap forward. Before then, only an X-ray--or an autopsy--could reveal damage to the brain, and then only in its grossest form. CAT scans show subtle changes that can be tracked over time, giving researchers a more accurate sense of a microbe's impact. MRI, developed in the early 1980s, has added three-dimensionality to pictures of the brain, and PET scans, invented soon after, have added motion. Now bacteria and viruses can be caught red-handed.

Still, teasing out the tie between microbes and psychological problems has proved a difficult task, in no small part because of the cunning and guile of the pathogens themselves, which have many ways of attacking our bodies and brains.

T. pallidum, syphilis' causative bacterium, proceeds in straightforward fashion: it attacks and kills brain cells. After entering the body--usually through sexual intercourse, or through the mother's placenta into her fetus--the bacterium travels along the lymph system until it arrives at the brain. Once it lodges there, it spares few structures, inflaming some neurons and stripping the myelin, or insulation, from others. (Without myelin, nerve impulses are slowed or stopped altogether.)

Other microbes are more devious. The human immunodeficiency virus, for example, which can cause anxiety, delirium, psychosis and suicidal impulses, uses a Trojan horse strategy. Instead of directly attacking brain cells, it infects macrophages, the immune-system enforcers that roam the bloodstream, engulfing foreign cells that may pose a threat to the body. After hitching a macrophage ride into the brain, HIV cranks out cytokines, protein peptides that kill off neurons. The virus Chlamydia pneumoniae may use a similar trick--slipping into the brain and manufacturing cytokines--to cause Alzheimer's disease.

Streptococcal bacteria, like those that cause strep throat, take yet a different tack. As they invade the body, they automatically trip the body's defense alarm, calling up the immune system's antibody soldiers. But once the skirmish begins, the bacteria camouflage themselves within that very immune system. Like a wolf in sheep's clothing, they disguise themselves through molecular mimicry, cloaking themselves in proteins that imitate the body's own proteins, and thereby elude attack. For reasons scientists don't yet understand, the antibodies of some people--perhaps those with a genetic predisposition--then turn on their bodies' own tissues, assailing neurons the basal ganglia. These structures, located between the more primitive lower brain and the higher cortical centers, help interpret information from the senses and are key to healthy emotions and behavior.

The self-destruction instigated by streptococcal bacteria can be particularly dangerous to young children. Because their immune systems are "naive," or underdeveloped, "their bodies mount a vigorous response to streptococci, but it is not terribly effective, and their antibodies wind up injuring their own neurons instead of the bacteria," explains Swedo. She believes that such self-induced damage leads some children to develop obsessive-compulsive disorder.

In an experiment conducted earlier this year, Swedo replaced the blood plasma of 28 children who suffered from OCD (and who had elevated levels of streptococcus antibodies) with healthy donor plasma, reasoning that such a switch would remove the trouble-making antibodies. Within a month, the incidence of ties declined by half, and their other OCD symptoms were reduced by 60%. "That was really gratifying," says Swedo. "It means that OCD is a medical illness, and if you catch it before there is scarring in the brain, you can cure it."

OCD isn't the only mental illness associated with streptococcus. Though anorexia nervosa has been tied to a distorted body image, societal pressure to be thin, discomfort with developing sexuality, and other emotional and cultural factors, doctors have also noted that the eating disorder sometimes appears or worsens after a case of strep throat. Streptococcus has been implicated as well in Tourette's syndrome and in Sydenhams chorea, which makes the arms and legs of those afflicted jerk in a manner often likened to dancing.

Researchers think that the seeds of yet other mental illnesses may be planted while a fetus is still in the womb, when the pregnant mother-to-be becomes infected. Flu epidemics have been followed a generation later by waves of schizophrenia in England, Wales, Denmark, Finland and other countries, and a recent study published in the New England Journal of Medicine reports higher rates of schizophrenia among children born in crowded areas in cold weather--conditions hospitable to respiratory ailments.

Scientists suspect that in such cases a virus, such as the one that causes influenza or a newer candidate, the Borna virus, may insinuate itself into the fetal brain at a crucial stage of development. The microbe then subtly deranges the brain's neural connections in a process that becomes apparent only as the brain reaches full maturity, in early adulthood. In people with schizophrenia, parts of the brain--the cortex, thalamus, limbic system and basal ganglia--shrink, while crevices and fluid-filled spaces enlarge by as much as half, and the brain's chemical balance shifts. Such changes might well be the terrible legacy of a prenatal virus.

Microbes that cause mental illness can also enter the body another way--on one's fork. In the mid-1990s, an outbreak of Creutzfeldt-Jakob disease struck fear into meat-eaters, especially in England, where 35 people died after eating infected beef. While alive, the victims of what was dubbed "mad cow disease" exhibited bizarre symptoms such as continual screaming, inappropriate laughter, failure to bathe and compulsive walking.

Scientists theorized that the "mad cows" became infected because they were fed on sheep afflicted with the disease known as scrapie, but a similar infection endemic to cows may be to blame. (Scrapie in sheep, bovine spongiform encephalitis in cows and Creutzfeldt-Jakob disease in humans are all believed to be caused by what's known as a prion, or infectious protein, which acts in a manner similar to a virus.) Contaminated human growth hormone, corneal transplants and surgical instruments have also been suspected of communicating the disease to humans. Earlier this year, the British medical journal The Lancet reported that multiple surgeries and living on a farm are risk factors for CJD. Though the disease is considered rare, Yale neuropathologist Laura Manueldis, M.D., who thinks that the causative agent is actually a small virus rather than a prion, suspects that CJD is more common than we believe, and is often misdiagnosed as Alzheimer's.

Why doesn't every child with a strep throat develop an anxiety disorder? Or dementia strike every adult with syphilis? Our bodies protect us from most invasions by unfriendly microbes, but the vulnerable-those with poor health, weakened immune systems or, perhaps, genetic susceptibility--are less equipped to fend off the viruses and bacteria that may eventually cause mental illness.

Continuing research is likely to bring more effective vaccines and antibiotics, but prevention and treatment will have to be every bit as shrewd as the infectious agents themselves, which spread and reproduce in seemingly countless ways. More worrisome is the fact that illness-causing organisms may be outwitting our antimicrobial strategies. With the development of antibiotics and antivirals, researchers had hoped to vanquish viruses and bacteria once and for all. But they underestimated the wily ingenuity of these microbes, which soon produced strains resistant to the new miracle medicines.

Likewise, scientists at one time believed that infectious agents evolved to become less potent, if only to ensure their own survival: the longer an infected host stays alive, after all, the greater the number of people who can be exposed to the pathogen, and the more likely the microbe is to reproduce itself. But recent research has turned up a less reassuring reality: under some conditions, microbes can flourish with increased virulence in crowded modern cities. These densely populated areas can maintain dangerous pathogens that otherwise might whip through a community and then have nowhere else to go.

To fight these pathogens successfully, doctors will have to tailor the treatments to the specific disease. Sometimes, for example, they may want to relieve an infected patient's fever and inflammation; at other times, fever must be left alone to kill off heat-sensitive viruses. Syphilis can be cured with penicillin, and doctors have had some success in prescribing antibiotics to people with anorexia. Other illnesses require more involved treatment, such as Swedo's plasma replacement for children with OCD, and some ailments cannot be helped much at all. The only way to treat HIV dementia, for example, is to try to slow the replication of the virus itself. No current therapy does this permanently, and many HIV-positive patients still suffer psychiatric symptoms. (In fact, suicide is a leading cause of death among the HIV-infected.) There's no treatment for Creutzfeldt-Jakob disease beyond palliative care, and by the time influenza-induced schizophrenia becomes apparent, the neurological damage is already done.

Still, science continues to offer hope that one day such infectious agents will be controlled or even eliminated. That day can't come too soon for Swedo, a pediatrician by training. "When I practiced medicine at Memorial Hospital in Chicago, I saw parents suffer horribly when they lost their children to leukemia," she says. "When I came to the NIMH, I began to see parents lose their children to OCD and schizophrenia. These parents' grief is so much more profound. The fact that their children's illnesses are socially unacceptable makes their pain almost unbearable." Now that we know many psychiatric ills begin with a microbe, rather than a suffocating mother or remote father, "we can start treating mentally ill people without the shame and blame. We can treat them medically."

WHAT YOU CAN DO

Since we know so little about the viruses and bacteria that cause some types of mental illness, it makes sense to avoid them when you can. Here, advice on preventing infection from leading scientists (much of which sounds uncannily like Mom's):

o Eat a healthy diet.

o Get plenty of sleep.

o Reduce stress.

o Get a flu shot each fall.

o Be aware that sex with multiple partners raises your risk of infection.

o Wash your hands frequently. (Though you might be tempted to use one of the many antibacterial soaps on the market, such cleansers may promote the growth of drug-resistant "superbugs.")

o Don't eat meat that isn't well-cooked, or if you have any questions about how it was stored or prepared.

o Find out whether you have any physical conditions that increase your risk of infection, and discuss preventive steps with your doctor. If, for example, you have a prolapsed mitral valve (a valve in the heart that doesn't close properly, increasing risk of infection), your doctor may recommend that you take antibiotics before having dental work done.

o Pay attention to your body. Even minor symptoms--fever, chills, a sore neck--can mean you're doing battle with an infection, and you should discuss them with your doctor. Pay special attention to your children's symptoms.

o If you are prescribed antibiotics, finish the entire course of therapy.

o If you work in a medical setting--even as a technician or clerk--be sure to seek vaccinations against hepatitis and other pathogens you may acquire from patients.

o If you're pregnant, take special care to avoid respiratory ailments such as influenza. Avoid contact with cat litter, which can harbor Toxoplasma, a microbe that can cause birth defects or even spontaneous abortion.

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