Случаи психиатрической манифестации рассеянного склероза

Psychiatric disturbances, such as psychosis, have been often described during the course of multiple sclerosis (MS),1 but rarely at onset of the disease.2 In our work, we present two patients with psychotic disorders at onset of relapsing-remitting MS.

The first patient, a 26-year-old woman, was diagnosed with schizoaffective disorder after the acute appearance of auditory hallucinations and confusion; she was treated with antipsychotic drugs, without significant results. One year later, the patient developed weakness in the left leg and widespread paraesthesia. MR images showed demyelinating lesions in the white matter of the left temporal horn and in the dorsal spine. We made a diagnosis of MS,3 and she started glatiramer acetate treatment to prevent further relapses. To date, after 12 months from the beginning of treatment, the patient shows no relevant neurological and psychiatric alterations.

The second patient, a 30-year-old man, presented (2 years before our observation) with an episode characterized by psychomotor agitation with identity disturbances diagnosed as borderline personality disorder, and he started treatment with olanzapine without results. After a few months, he was referred to our department because of the development of lower-limb weakness and urge-incontinence. An MRI showed several lesions in the subcortical white matter and in the periventricular regions. All findings supported the diagnosis of MS, and the patient started beta-interferon treatment, with progressive clinical improvement, both in neurological and then in psychiatric alterations.

The exact percentage of psychiatric onset of MS is still unknown, but the number of MS patients with psychiatric onset may exceed 1%: in our experience, 2 among a cohort of 148 MS subjects had a psychiatric onset, about 1.3%. In our two cases, only the presence of abnormalities at the neurological examination induced clinicians to consider MS as cause of psychiatric disturbance.

Several reports highlight the association of psychotic symptoms with the presence of demyelinating lesions in the left temporal lobe. In our patients, one had temporal lesions, and the other had periventricular plaques, without significant relationship with the temporal lobe. In our opinion, it is not possible to establish a direct relationship between the sites of cerebral lesions and the psychiatric manifestations observed in MS.

After the psychiatric episode, both patients started long-term treatment with glatiramer acetate or beta-interferon. As reported in literature, glatiramer acetate also results in relief of affective disorders,4 whereas beta-interferon increases anxiety and depression.5 Nevertheless, in our patient, the administration of beta-interferon probably contributed to stabilizing the clinical picture.

Although studies on the prevalence of psychiatric onset of MS are few, we conclude that it may occur in more than 1% (in our experience, about 1.3%) and that, in previously healthy people with acute psychotic disorders, even the presence of the slightest neurological abnormality justifies a cranial MRI examination. Further studies are necessary to evaluate the factors that influence the development of psychiatric disorders in MS and the relationship between disease-modifying drugs and psychiatric disorders.

Psychiatric Onset Of Multiple Sclerosis: Description Of Two Cases

Инфекционная теория шизофрении: вирус HERV-W

By the 1980s he began working with Robert Yolken, an infectious-diseases specialist at Johns Hopkins University in Baltimore, to search for a pathogen that could account for these symptoms. The two researchers found that schizophrenics often carried antibodies for toxoplasma, a parasite spread by house cats; Epstein-Barr virus, which causes mononucleosis; and cytomegalovirus. These people had clearly been exposed to those infectious agents at some point, but Torrey and Yolken never found the pathogens themselves in the patients’ bodies. The infection always seemed to have happened years before.

Torrey wondered if the moment of infection might in fact have occurred during early childhood. If schizophrenia was sparked by a disease that was more common during winter and early spring, that could explain the birth-month effect. “The psychiatrists thought I was psychotic myself,” Torrey says. “Some of them still do.”

While Torrey and Yolken were chasing their theory, another scientist unwittingly entered the fray. Hervé Perron, then a graduate student at Grenoble University in France, dropped his Ph.D. project in 1987 to pursue something more challenging and controversial: He wanted to learn if new ideas about retroviruses—a type of virus that converts RNA into DNA—could be relevant to multiple sclerosis.

Robert Gallo, the director of the Institute of Human Virology at the University of Maryland School of Medicine and co­discoverer of HIV, had speculated that a virus might trigger the paralytic brain lesions in MS. People had already looked at the herpes virus (HHV-6), cytomegalovirus, Epstein-Barr virus, and the retroviruses HTLV-1 and HTLV-2 as possible causes of the disease. But they always came up empty-handed.

Perron learned from their failures. “I decided that I should not have an a priori idea of what I would find,” he says. Rather than looking for one virus, as others had done, he tried to detect any retrovirus, whether or not it was known to science. He extracted fluids from the spinal columns of MS patients and tested for an enzyme, called reverse transcriptase, that is carried by all retroviruses. Sure enough, Perron saw faint traces of retroviral activity. Soon he obtained fuzzy electron microscope images of the retrovirus itself.

By the time Perron made his discovery, Torrey and Yolken had spent about 15 years looking for a pathogen that causes schizophrenia. They found lots of antibodies but never the bug itself. Then Håkan Karlsson, who was a postdoctoral fellow in Yolken’s lab, became interested in studies showing that retroviruses sometimes triggered psychosis in AIDS patients. The team wondered if other retroviruses might cause these symptoms in separate diseases such as schizophrenia. So they used an experiment, similar to Perron’s, that would detect any retrovirus (by finding sequences encoding reverse transcriptase enzyme)—even if it was one that had never been catalogued before. In 2001 they nabbed a possible culprit. It turned out to be HERV-W.

Several other studies have since found similar active elements of HERV-W in the blood or brain fluids of people with schizophrenia. One, published by Perron in 2008, found HERV-W in the blood of 49 percent of people with schizophrenia, compared with just 4 percent of healthy people. “The more HERV-W they had,” Perron says, “the more inflammation they had.” He now sees HERV-W as key to understanding many cases of both MS and schizophrenia. “I’ve been doubting for so many years,” he says. “I’m convinced now.”

Through this research, a rough account is emerging of how HERV-W could trigger diseases like schizophrenia, bipolar disorder, and MS. Although the body works hard to keep its ERVs under tight control, infections around the time of birth destabilize this tense standoff. Scribbled onto the marker board in Yolken’s office is a list of infections that are now known to awaken HERV-W—including herpes, toxoplasma, cytomegalovirus, and a dozen others. The HERV-W viruses that pour into the newborn’s blood and brain fluid during these infections contain proteins that may enrage the infant immune system. White blood cells vomit forth inflammatory molecules called cytokines, attracting more immune cells like riot police to a prison break.

In one experiment, Perron isolated HERV-W virus from people with MS and injected it into mice. The mice became clumsy, then paralyzed, then died of brain hemorrhages. But if Perron depleted the mice of immune cells known as T cells, the animals survived their encounter with HERV-W. It was an extreme experiment, but to Perron it made an important point. Whether people develop MS or schizophrenia may depend on how their immune system responds to HERV-W, he says. In MS the immune system directly attacks and kills brain cells, causing paralysis. In schizophrenia it may be that inflammation damages neurons indirectly by overstimulating them. “The neuron is discharging neurotransmitters, being excited by these inflammatory signals,” Perron says. “This is when you develop hallucinations, delusions, paranoia, and hyper-suicidal tendencies.”

Gene studies have failed to provide simple explanations for ailments like schizophrenia and MS. Torrey’s theory may explain why. Genes may come into play only in conjunction with certain environmental kicks. Our genome’s thousands of parasites might provide part of that kick.

“The ‘genes’ that can respond to environmental triggers or toxic pathogens are the dark side of the genome,” Perron says. Retroviruses, including HIV, are known to be awakened by inflammation—possibly the result of infection, cigarette smoke, or pollutants in drinking water. (This stress response may be written into these parasites’ basic evolutionary strategy, since stressed hosts may be more likely to spread or contract infections.) The era of writing off endogenous retroviruses and other seemingly inert parts of the genome as genetic fossils is drawing to an end, Perron says. “It’s not completely junk DNA, it’s not dead DNA,” he asserts. “It’s an incredible source of interaction with the environment.” Those interactions may trigger disease in ways that we are only just beginning to imagine.

Torrey and Yolken hope to add a new, more hopeful chapter to this story. Yolken’s wife, Faith Dickerson, is a clinical psychologist at Sheppard Pratt Health System in Baltimore. She is running a clinical trial to examine whether adding an anti-infective agent called artemisinin to the drugs that patients are already taking can lessen the symptoms of schizophrenia. The drug would hit HERV-W indirectly by tamping down the infections that awaken it. “If we can treat the toxoplasmosis,” Torrey says, “presumably we can get a better outcome than by treating [neurotransmitter] abnormalities that have occurred 14 steps down the line, which is what we’re doing now.”

The Insanity Virus