New insights into identifying children at risk for autoimmune brain disorders

Reported on 11th August 2009

A new study by researchers at Columbia University Mailman School of Public Health's Center for Infection and Immunity indicates that pediatric obsessive-compulsive disorder (OCD), Tourette syndrome and/or tic disorder may develop from an inappropriate immune response to the bacteria causing common throat infections.
The mouse model findings, published online by Nature Publishing Group in this week's Molecular Psychiatry, support the view that this condition is a distinct disorder, and represent a key advance in tracing the path leading from an ordinary infection in childhood to the surfacing of a psychiatric syndrome. The research provides new insights into identifying children at risk for autoimmune brain disorders and suggests potential avenues for treatment.

OCD and tic disorders affect a significant portion of the population. More than 25% of adults and over 3% of children manifest some features of these disorders. Until now, scientists have been unable to convincingly document the association between the appearance of antibodies directed against Group A beta-hemolytic streptoccoccus (GABHS) in peripheral blood and the onset of the behavioral and motor aspects of the disorder. As a result, treatment strategies were restricted to targeting symptoms rather than causes.

Strep throat bacteria, or GABHS, are known to cause autoimmune disorders such as Sydenham chorea, with symptoms such as fever and uncontrolled tics of the face or extremities in susceptible individuals, prompting some scientists to suspect that GABHS could play a role in a syndrome known as Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS), a rapid-onset and episodic form of OCD and tic disorders observed in some children. The latest study by CII researchers supports the hypothesis that some neuropsychiatric syndromes may be triggered by direct action of GABHS-associated antibodies on the brain. Whether environmental factors other than GABHS can lead to similar effects is as yet unknown.

Using a mouse model of PANDAS, Mady Hornig, MD, associate professor of epidemiology at Columbia University Mailman School of Public Health, and colleagues demonstrate this suspected link between GABHS antibodies and the psychiatric symptoms of the disorder. Immunizing mice with an inactivated form of the bacteria, CII researchers found that the mice exhibited repetitive behaviors reminiscent of children with PANDAS. Injection of antibodies from the immunized mice into the bloodstream of non-immunized mice replicated these behaviors.

"These findings illustrate that antibodies alone are sufficient to trigger this behavioral syndrome," said Dr. Hornig. "Our findings in this animal model support and may explain results of Swedo and colleagues in treating children with PANDAS using plasmapheresis or intravenous immunoglobulin (IVIg). They may also have implications for understanding, preventing or treating other disorders potentially linked to autoimmunity, including autism spectrum, mood, attentional, learning, and eating disorders."

"This work provides strong corroboration for a link between exposure to infection, development of an autoimmune response, and the onset of repetitive behaviors and deficits in attention, learning, and social interaction," says CII Director W. Ian Lipkin, MD, John Snow Professor of Epidemiology, and professor of Neurology and Pathology at Columbia University. "Further investigations in this strep-triggered, autoimmune mouse model of PANDAS will promote the discovery of more effective interventions for these disabling disorders and guide the development of robust prevention strategies."

Dr. Susan Swedo, a senior investigator at NIMH who has been a leader in research into PANDAS, provides commentary on the work in this issue of Molecular Psychiatry, where the authors' work is also featured on the journal's cover.

The Center for Infection and Immunity at the Mailman School is dedicated to global research and training programs focused on pathogen surveillance and discovery, and to understanding how gene-environment-timing interactions contribute to health and disease. www.cii.columbia.edu

www.mailman.columbia.edu

Victory for children with Tourette syndrome

Reported on 3rd August 2006

The Department of Education has announced the final regulations enforcing Part B of the Individuals with Disabilities Education Act (IDEA) law, which was reauthorized by Congress.
Tourette Syndrome (TS) is now listed as a disability under the category of Other Health Impaired (OHI). This new categorization is the result of over two decades of vigorous advocating for this classification by the national Tourette Syndrome Association (TSA). The announcement was made today by the U.S. Secretary of Education, Margaret Spellings, in Washington, D.C. at an invitation-only public announcement meeting.

"This is a tremendous victory for children with TS," said Monte Redman, TSA's Chairman of the Board, "allowing them to become socially and academically successful, ensuring that they reach their full potential."

TSA, through its unyielding efforts, has been steadfast in lobbying for this designation. The Association has held hundreds of meetings on Capitol Hill, with the Department of Education and with the office of the First Lady Laura Bush, and over the years members have sent thousands of letters to Congress explaining the necessity and value of having TS listed under OHI. Additionally, TSA members -- parents, children and teens with TS -- participated in the Department of Education's public hearings, making personal, heartfelt statements demonstrating how the OHI designation would improve the education of these children.

Travis Stecher, 18, recipient of The TSA 2005 Outstanding Youth Achievement Award, spoke so passionately before the Department of Education during a California hearing in July 2005 that they interrupted the hearing to specially acknowledge his testimony.

In her overview of the new regulations, Secretary Spellings specifically acknowledged Tourette Syndrome as an example of one of the changes that were made, pointing out that TS is a neurological disorder, not a behavioral issue.

Judit Ungar, TSA President along with TSA Board Member, Nancy Baker, and her 11-year-old daughter, Jackie, attended the private meeting to report back to TSA members about the new classification, the direct result of their unwavering support and campaigning for this regulatory change.

"For many students this classification under OHI will result in appropriate services making it possible for children with TS to remain in a general education setting," said Judit Ungar. "For some students with significant symptoms, this classification may eliminate the necessity for costly residential placements."

Marked by involuntary twitching and vocal tics, TS is an inherited condition frequently misunderstood and misdiagnosed, affecting more than 200,000 Americans. Founded in 1972, the TSA has a three-pronged mission of education, research and service and directs a network of 31 chapters and more than 150 support groups across the country.

http://www.tsa-usa.org/

Children with Tourette's better at mental grammar skills

Reported on 16th July 2007

Children with Tourette's syndrome may have to put up with some unwanted movement and verbal tics, but neuroscientists at Georgetown University Medical Center and the Kennedy Krieger Institute have found that they are much quicker at processing certain mental grammar skills than are children without the disorder.
They say the findings, reported in the current issue of the journal Neuropsychologia, suggest that abnormalities in the brain linked to tics in Tourette's syndrome may also result in a range of rapid behaviors -- and, possibly, superior skills -- than had been appreciated before.

"These children were particularly fast, as well as largely accurate, in certain language tasks. This tells us that their cognitive processing may be altered in ways we have only begun to explore, and moreover in a manner that may provide them with performance that is actually enhanced compared that of typically-developing children, said the study's senior investigator, Michael Ullman, Ph.D., professor of neuroscience, psychology, neurology and linguistics.

According to the National Institutes of Health (NIH), about 200,000 Americans have the most severe form of Tourette's syndrome, but as many as 10 percent of Americans have a milder form. The most common initial symptom is a facial tic, and other tics -- sudden, rapid, repeated movement or vocalization -- may follow. Tics can include eye blinking, repeated throat clearing or sniffing, arm thrusting, kicking, shoulder shrugging, or jumping, but coprolalia, which is involuntary use of obscene words or swearing, is only rarely associated with Tourette's syndrome.

This nervous system disorder is linked to structural and functional abnormalities in the basal ganglia and frontal cortex area of the brain, which result in decreased inhibition of frontal activity, leading to hyperkinetic behaviors and development of tics, Ullman says. The disorder is also associated with abnormalities in the way that chemical substances, such as hormones and neurotransmitters, help nerve cells talk to each other.

In this study, Ullman, along with first author Matthew Walenski, PhD, and Stewart Mostofsky, MD, decided to study two different aspects of language as a way to broaden understanding of this disorder.

These two basic aspects of language, "rule governed" and ,idiosyncratic, knowledge, depend on distinct neurobiological processes. Rule-governed knowledge involves the procedural memory system that depends on frontal/basal-ganglia area circuits in the brain; in language, it is used to combine parts of words together according to the grammatical rules of the language (for example, putting walk and ed together to form a regular past tense.) In contrast, idiosyncratic knowledge depends on declarative memory, and is learned and processed in the hippocampus and other temporal lobe areas in the brain. This kind of memory allows us to learn that a word is linked to an object (such as the word ,cat, to its meaning furry animal), and also is used to learn irregular past tense word forms (as in spring and sprang).

Some previous evidence suggested that aspects of procedural memory may be abnormal in Tourette's syndrome, whereas declarative memory remains largely spared, but the contrast between the two forms of language knowledge had not been studied before. In this study, eight children, age 8-17, with Tourette's syndrome and eight typically developing children of the same ages without the disorder were given tasks that included producing past tense forms. All of the children had a normal IQ. The investigators found that children with Tourette's syndrome were significantly faster than the control group in producing rule-governed past tenses (like slip-slipped) that depend on grammar and procedural memory but not in producing irregular or other unpredictable past tenses (such as bring-brought) that are stored in declarative memory.

The two groups of children were then given a picture-naming task to test motor skill and conceptual knowledge. Those with Tourette's syndrome responded significantly faster than the control group in naming pictures of objects that can be manipulated (such as hammer), and thus depend on motor skill knowledge, but not in naming pictures of non-manipulated objects (like elephant), which depend only on conceptual knowledge. The motor skill knowledge associated with manipulated objects also depends on procedural memory. But unlike in the past tense task, where some accuracy was lost to the speed of the response, there was no loss of accuracy in the picture-naming test by children with the disorder.

"This may mean that the brain abnormalities we see in Tourette's syndrome may lead not only to tics but also to a much wider range of unsuppressed and rapid behaviors," Ullman said. The researchers are now developing new language and memory tests for patients with Tourette's syndrome.

http://gumc.georgetown.edu

New experimental treatment for Tourette's syndrome

Reported on 2nd December 2008

The University of Rochester Medical Center (URMC) is leading a multi-center clinical research study of a new experimental treatment for Tourette's syndrome. The study will examine whether or not a drug that alters the chemical activity in the brain can alleviate the symptoms of the disease.
Tourette's syndrome (TS) is a neurological disorder characterized by multiple, repeated tics. These tics generally consist of abrupt and involuntary vocal outbursts or muscular jerks. Symptoms usually begin at an early age and can increase in frequency and severity over time. Many individuals with TS have a mild form of the disease and do not require medical intervention unless the tics interfere with normal daily function.Patients with more severe forms of TS are currently treated with various antipsychotic drugs

"While the precise mechanism that causes Tourette's is unknown, we have long observed that the neuro-chemical dopamine is overly active in individuals with the disease," said URMC neurologist Roger Kurlan, M.D., the study's principal investigator. "This chemical imbalance in the brain may play a role in the disease and, consequently, the drugs that are currently used to treat the disease are known to suppress dopamine production.However, these drugs are also associated with severe side effects that often deter their use."

Kurlan and his colleagues are studying a drug called Mirapex (pramipexole). The drug is approved by the Food and Drug Administration for use in patients with Parkinson's disease and restless leg syndrome.Mirapex is a dopamine agonist; it stimulates dopamine production in the brain. Small pilot studies with the drug in TS patients have shown good outcomes and few side effects. Mirapex is investigational in patients with Tourette's syndrome.

"It would seem to be counter-intuitive to stimulate more chemical activity in the brain when we know that there already is an imbalance in Tourette's patients," said Kurlan. "However, we believe that this might actually cause the dopamine receptors in the brain to adapt and desensitize so that they start reacting less to the overactive dopamine."

Kurlan is the head of the Tourette's Syndrome Study Group, an international network of researchers who are involved in almost every major clinical study of the disease. It was work by Kurlan and his colleagues in 2001 in schools in Monroe County, New York that demonstrated that TS is far more prevalent than previously realized.His research found that 1 in 4 children in special education programs in the region's schools exhibited some form of tics or TS. Kurlan and his colleagues were also instrumental in establishing the hereditary nature of disease which helped dispel the previously held notion that TS was a psychological disorder.

Kurlan and his colleague Jonathan Mink, M.D., Ph.D. also run one of the larger TS clinics in the country; at any one time, URMC physicians are following more than 2,000 TS patients from across upstate New York and northern Pennsylvania.

URMC is seeking the families of children or adolescents who are bothered by their tics to participate in the study.The study is being funded by Mirapex's manufacturer, Boehringer Ingelheim Pharmaceuticals, and there is no cost to participants.The study lasts for 6 weeks, with the option for patients to continue the medication for a longer period.

http://www.urmc.rochester.edu

Researchers examine link between Tourette syndrome and ADHD

Reported on 15th April 2009

The most disabling aspect of Tourette syndrome is that in 90% of cases, it exists in conjunction with another disorder.
The most frequent co-occurring condition in people with Tourette is attention deficit hyperactivity disorder (ADHD), though the cause of this association is uncertain. Having one disorder can be disabling enough, but having two means coping with more than twice the disability.

New research published in the April 13 edition of the Journal of Developmental and Behavioural Pediatrics by University of Calgary and University of Toronto researchers looked at nearly 400 children with Tourette syndrome to try to understand the connection between these two disorders. Their findings show that while Tourette and ADHD have a major genetic component, there are potentially preventable perinatal factors that increase the risk of a co-occurring diagnosis of ADHD in children with Tourette.

"We know that perinatal stress is a risk factor for ADHD alone. If you were low birth weight, if your mother smoked during pregnancy, or if you were born prematurely, all these things increase the risk of ADHD," says Dr. Tamara Pringsheim, Director, Calgary Tourette Syndrome Clinic, a University of Calgary Faculty of Medicine professor and lead author on the study.

To examine the link between Tourette and ADHD, the researchers looked at a population of children that had Tourette syndrome with or without ADHD and compared rates of perinatal risk factors such as low birth weight, prematurity, and maternal smoking in each group. Researchers found that the children exposed to these perinatal risks were two to three times as likely to develop Tourette syndrome with ADHD, suggesting that these factors play a role in the development of ADHD in children with Tourette as well.

Pringsheim, a neurologist and researcher says the important information from this research is for people at risk genetically for Tourette syndrome to take precautions when planning a family by "not smoking, trying to ensure a healthy weight for the baby, and receiving appropriate medical care." Quality of life in children with Tourette syndrome is most importantly determined by the severity of ADHD symptoms; anything one can do to minimize the chances of a co-occurring diagnosis of ADHD will allow children a greater chance of success and happiness in their life.

Laura Locke is a board member of the Tourette Syndrome Foundation of Canada and became involved with the foundation when her son was diagnosed with Tourette syndrome at the age of 10. "Research into Tourette syndrome is vital. We have seen the difference it can make to have accurate information about this disorder and better medications," she says.

Tourette syndrome has a great spectrum of severity. People with Tourette have motor and vocal tics -- rapid, repetitive, meaningless movements and sounds. Common motor tics include forceful blinking, opening the eyes wide, head shaking and grimacing, while the most common vocal tics are sniffing, throat clearing and grunting. Some people are very mildly affected, while others have more severe symptoms which make the disorder more noticeable and disabling. It is believed that Tourette syndrome affects about 1 in 100 people; however, many people do not seek medical attention for the disorder because the symptoms are so mild.

"There are a lot of misconceptions out there about people who suffer from Tourette. The images we see on TV and movies are completely false. I have some patients who have severe tics, but less than 10% of patients with Tourette syndrome swear. It's uncommon," says Pringsheim.

http://www.ucalgary.ca/

Deep brain stimulation for psychiatric disorders

Reported on 30th June 2009

Pioneering therapeutic trials to investigate the effectiveness of deep brain stimulation (DBS) in hard-to-treat depression, obsessive-compulsive disorder (OCD) and Tourette's syndrome are underway at multiple medical centers around the world, according to a review in the June 2009 issue of Mayo Clinic Proceedings.
"Deep brain stimulation has long been seen as valuable for controlling movement disorders," according to the review, written by Susannah Tye, Ph.D., Mark Frye, M.D., from the Mayo Clinic Department of Psychiatry and Psychology, and Kendall Lee, M.D., Ph.D., Mayo Clinic Department of Neurosurgery. "It now is being investigated for hard-to-treat psychiatric disorders," according to the authors.

"Early results indicate the effect on depression and obsessive compulsive disorder is beneficial, but the therapy needs further study," Dr. Lee says. The potential for this breakthrough treatment is enormous in reducing the toll of mental illness on patients, their families and society, according to the review. Unlike electroshock therapy (ECT), which stimulates the entire brain, DBS stimulates specific parts of the brain. DBS is thought to be functionally equivalent to creating a lesion on the brain, but with the advantage of being adjustable and reversible.

"It is like implanting a pacemaker for the brain," says Dr. Lee. The patient is awake during deep brain stimulation surgery while a neurosurgeon implants the electrodes. Patients are able to give immediate feedback. Additionally, patients do not feel any pain during the implantation procedure since the brain is without pain receptors.

In the developed world, major depression is second only to cardiovascular disease in premature mortality and time lived with disability according to the review. In persons aged 15 to 44 years, depression is the most disabling medical illness in the United States. The prevalence of major depression, known to be a chronic and relapsing illness, is approximately 17 percent, affecting almost 1 in 5 persons.

Medications and psychiatric therapy can effectively treat many patients with major depression; however, up to 20 percent of these patients fail to respond to these non-surgical therapeutic interventions. "DBS is not a miracle cure and should not be used to treat all depression," says Dr. Lee. "It should be reserved for those patients who have treatment-resistant depression, and approved by a multi-disciplinary team." Ongoing advances in DBS technologies represent an important new field that could greatly advance the understanding of psychiatric neurobiology, according to the review.

Deep brain stimulation: New treatment option for people with severe Tourette syndrome

Reported on 27th October 2009

Deep brain stimulation may be a safe and effective treatment for Tourette syndrome, according to research published in the October 27, 2009, print issue of Neurology®, the medical journal of the American Academy of Neurology.

"Our findings hold promise for helping people with severe Tourette syndrome, who are in need of new treatment options to improve their quality of life," said study author Andrea Cavanna, MD, of the University of Birmingham, in the United Kingdom.

It is estimated that two million Americans are affected by Tourette syndrome, which is a neurological disorder characterized by uncontrolled movements and vocalizations, or tics, lasting more than a year. The first symptoms of Tourette syndrome are almost always noticed in childhood and some common tics include eye blinking, facial grimacing, shoulder shrugging and head or shoulder jerking. People who have Tourette syndrome often also have obsessive-compulsive disorder (OCD), depression, anxiety or attention deficit hyperactivity disorder (ADHD).

The study involved 15 people with severe Tourette syndrome and OCD who were an average age of 30 and continued to have severe symptoms after trying medications and psychobehavioral treatments. They also had high levels of depression and anxiety at the start of the study. The participants were followed and tested for two years after deep brain stimulation, which involves a surgically implanted brain pacemaker that sends electrical impulses to certain parts of the brain.

The study found that the participants experienced 52 percent fewer tics on average and a 26 to 33 percent improvement in the symptoms of OCD, depression and anxiety two years after deep brain stimulation began. Deep brain stimulation had no significant effect on thinking abilities in the study.

"Despite having only 15 patients in this study, it is the largest to date on the effectiveness of deep brain stimulation as a treatment for Tourette syndrome," said Cavanna. "The results showed that all 15 people who were assessed after two years' treatment experienced improvements in disabling tics and neurological problems, which is encouraging. Unfortunately three patients from the original group of 18 were no longer part of the study at follow up and this limits the ability to generalize our findings. More research needs to be done to confirm that deep brain stimulation is a safe and effective treatment for Tourette syndrome."

Deep brain stimulation is FDA approved for the treatment of essential tremor, Parkinson's disease and dystonia.

Source: The American Academy of Neurology