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Does anyone find that taking piriton or phenergan makes their tics better or worse? (The more modern antistamines cause less sedation because they have less effect on the brain so we wouldn't expect them to have much effect on tics).
As is so often the case this is a preliminary finding- what is now needed is a search for the HDC mutation in other people with TS who are not members of this one family.
Moving on to the second study, from Columbia, that is not particularly novel, but once more implicates and confirms the involvement of the dopamine system. Neurotransmitters are released from nerve cells (neurons) at a gap called a synapse and then pass on the nerve impulse to the next nerve cell by attaching to a specific "receptor". In this study of 69 TS patients the gene for one of the dopamine receptors (called DRD2) was examined and it was found that people with TS were more likely to have particular variants thereby suggesting that dopamine dysfunction is important in TS.
The third study is more novel, using newer concepts. When James Watson and the late Francis Crick made their famous Nobel Prize winning discovery of the genetic code in the 1960s and the gene for Huntington's disease was subsequently identified in the 1980s it looked like we had cracked the code to every genetic disease, given enough time. In recent years it has become apparent that there is a lot about our DNA that is not yet fully understood.
Whilst the genetic code tell us what proteins are made in cells, our chromosomes also contain vast tracts of DNA that are “non-coding”- i.e. are not used to produce proteins but may be involved in the regulation of cellular function in other ways that are not yet well understood. Another aspect of our DNA that could be significant is that certain sections of it are deleted or duplicated in different individuals- this is called copy number variants (CNV).
Thousands of these variants have been identified. In this study of 111 TS patients, 10 of them were found to have one of five rare CNVs that were not found in controls. The basic logic is similar to the second paper- trying to find genetic variations that mark out people with TS, without having to find large familes with multiple affected members. Three of these five CNVs have also previously been found in autism, schizophrenia and ADHD. The suggestion is that some CNVs may be present in a spectrum of neuropsychiatric problems, not just TS.
As the study was relatively small and can be technically criticised in some other ways, this again can only be considered a preliminary pointer and not a ready-made breakthrough. There will be much more of this kind of work in future- including from the American TSAs International Genetic Consortium.
]]>1) Quality of life in TS
There has been increasing interest in trying to assess the 'quality of life' experienced by people with TS and their families- because measuring the severity of tics or other aspects like ADHD or OCD may not tell the whole story.
For instance, some people with quite severe tics are not particularly bothered by them, whilst others with fairly mild tics are greatly distressed by them- what matters is the impact on the individual. There is already a questionnaire specially for quality of life in TS that some members may have helped to test out when it was being developed by Professor Robertson, Dr. Cavanna and others.
This new German study used generic standard measures (rather than the new TS scale) and also looked at depression. The results showed a significantly reduced quality of life in adult patients with TS and this was worse according to age, severity of symptoms and the presence of depression. All this is predictable but important in showing how much having TS affects people, so we can try and demonstrate this to the outside world and also address reversible factors that could make them function better- e.g. depression.
2) MRI imaging in TS
There are very many studies of various kinds of brain scanning in TS. Scans in individual patients are not useful as they are normal, but research uses average results from groups of patients to see what differences can be found with 'normal controls' i.e. people who do not have TS or other diagnoses.
It is becoming easier to draw general conclusions from this body of work, but each individual study can sometimes be hard to interpret. There are two recent new ones.
An American study uses an MRI technique to look at circuits in the brain by examining how water molecules move around (if they are trapped in a nerve circuit then they can't move around so much). Like many previous studies of various types the conclusion was that the abnormality lies in the parts of the brain that are known to be critical in controlling movement- known as cortico-striatal circuits between the motor part of the surface of the brain and certain deep parts of the brain called the basal ganglia.
A second study from Spain used more conventional MRI methods to look at the structural appearance of the brain and identified subtle abnormalities caused by expanded spaces around blood vessels in patients compared to normal controls. The area affected is also in part of the basal ganglia called the substantia nigra-in fact the part that Parkinson's disease affects, although there is no clinical link between the two conditions. The trouble with this is that these spaces around blood vessels in the brain are usually considered a normal variant that don't cause any symptoms, but the authors hypothesise that when they are in the substantia nigra in TS they may be more significant.
]]>Many diseases including movement disorders have been found to be caused by mutations in single genes, for instance Huntington's disease and rare types of young-onset Parkinson's disease. Other diseases also have at least partly a genetic cause which is not yet fully explained, e.g. Tourette's and "normal" late onset Parkinson's. Many diseases probably have a variety of genes that could be involved rather than one single disease-causing gene and TS is almost certainly in this category.
One approach to this is to look for susceptibility genes. These are genetic variations that can be present in normal people but are more likely to be present in people with the disease. There are already a number of known susceptibility genes for Parkinsons.
This new study from Montreal demonstrates a susceptibility gene for people with Tourettes. Of note is that the gene involved, called BTBD9 is also known to be a susceptibility factor for another neurological condition, Restless Legs Syndrome (RLS). There is no strong clinical link between the two conditions although another report from Montreal has suggested some overlap and incidentally it appears that Dr. Georges Gilles de la Tourette himself was aware of the symptoms of RLS.
The treatment for RLS is similar to the treatment for Parkinson's- drugs to boost dopamine brain function, whereas for tics we are normally trying to block dopamine although there have also been trials of Parkinson's drugs in TS. The main point is that dopamine function appears to be a significant factor in both TS and RLS.
The RLS gene was found more in patients without OCD, ie "pure" TS. So, no closer to a gene test for TS or understanding the cause of TS but perhaps another peek into the multiple factors that decide if a person has TS or not.
]]>On 23 October a meeting was held in London convened by Professor Gavin Giovannoni and funded by the European Science Foundation. There were 28 participants from around Europe and the discussion was around a proposed study into the link between streptococcus infection and neuropsychiatric disorders which we hope will go ahead on a Europe-wide basis in due course.
There has also been a couple of new papers- one for and one against this elusive link:
This paper shows that, in 45 cases, streptococcal infection predicted an increase in tic and obsessional symptoms and, interestingly, increased the effect of social stress which is also very important. It was concluded that a minority of children with TS are indeed sensitive to Strep.
This is a study by Dr. Harvey Singer, who has been more sceptical about the link with streptococcus. In this study his group found that there was no difference in antibodies found in TS and non-TS cases. This is the kind of study where different groups can spend a long time debating the different methods used and whether one lab's result can be replicated at another lab or not- it is still very difficult to define the underlying science here.
2) Deep Brain Stimulation
TA members will already have heard of this study on deep brain stimulation via the TA newsletter.
This is a follow up study of Italian patients who had DBS surgery two years ago. After the two years the treatment appeared to maintain its effectiveness for tics and neuropsychiatric symptoms.
In the UK a study at Birmingham and London is starting. I have certainly met patients with very severe TS who nonetheless don't like the idea of surgery. It may be that the option when available is less popular than was expected.
You may like to take a look at this accompanying article which is written for patients.
3) Cognitive function and self-perception in a children with Tourette Syndrome in Sweden
This Swedish paper is worth mentioning as Dr. Khalifa has been conducting excellent population-based work in which TS cases are found ("ascertained") in schools rather than in clinics, removing the bias of a sample that has come to see a doctor.
This is a study of 25 children with TS. One third had cognitive problems and negative self-perceptions and this was not related to the severity of their tics. This is an important indicator of the significance of the 1% frequency of TS in children- it may be important even in "mild" cases where the tics are not bad enough to go to a specialist.
4) TS caused by alignment of the jaw?
This study focuses on a treatment that some dentists in the UK have been interested in trying, following publication overseas. In my personal opinion the hypothesis that TS is due to a reflex triggered off by the alignment of the jaw and not due to a brain problem is incorrect and not based on sound hypotheses or clinical trials. It has appeared in the dental and not the neurological literature to date. I am open to my opinion being changed if there were to be a high quality clinical trial.
If any members or readers have been treated using this method perhaps they could contact Tourettes Action to let us know your experiences and how much you were charged?
]]>In the paper the authors suggest that milder cases may be less likely to be associated with streptococcus, meaning their negative result could still be correct even allowing for this factor, but I don’t think we are in a position to be sure of this. These issues are inevitable when information that has been collected in the past is reviewed (a retrospective study) - but to collect the data that is needed on an ongoing basis (a prospective study), although more powerful, is very challenging and expensive to organise.
Debate about the significance of streptococcal infection and anti-basal ganglia antibodies is certain to continue, with researchers in the UK being important contributors. In the meantime, treatments aimed at the immune system or antibiotics against the bacterium itself in patients who do not have an active infection should be considered experimental in the view of most clinicians.
This study is by a major author from Texas, Dr. Joseph Jankovic. As described below there are very many small scale studies of drug treatment, but this one is better than the majority as it is a "double blind placebo controlled study". This means that some patients received dummy pills (placebo) and neither the doctors assessing the patients nor the patients themselves knew which was which (although sometimes it is possible to guess, a factor that must be borne in mind). There are certainly cases where a drug looks promising when used in a few patients, but a proper placebo trial like this later shows that to be mere illusion.
Rather than a standard dopamine blocking drug, this was a study of an epilepsy drug called Topiramate. Only 29 patients were tested, mainly males and both children and adults and over a period of less than three months. On average, patients taking the drug improved in terms of the number and severity of their tics compared to the placebo group. This kind of study doesn't give us hard evidence about how this drug compares with other drugs and the fact that different patients react differently is always a problem in TS. However, it is an indication that this drug might be worth trying.
2) Complementary and alternative medicine use in Gilles de la Tourette syndrome
This is a study about the use of complementary (CAM) therapies. Using questionnaire of 100 patients or parents there was a high frequency of use of at least one kind of CAM (64%). These included prayer (study done in Chicago), vitamins, massage, dietary supplements, chiropractic manipulation, meditation, yoga, acupuncture, hypnosis, homeopathy etc- basically anything. Most people initiated these strategies without telling their doctor.
It would be interesting to know if a similar picture exists in the UK. Whilst there isn't evidence that any of these treatments help TS and additionally for most of them there is no scientific rationale to explain how they possibly could, it isn't possible to say that nobody has benefited from going down this route. Even placebos help patients, especially if they have faith that they might. Moreover some of these therapies may promote relaxation, which in itself is a legitimate strategy, although we do know that relaxation therapy alone is inferior to a package including Habit Retraining Therapy (HRT, see below).
]]>Also in June the yearly International Movement Disorder Society Symposium was held in Paris, but I wasn't there. Several posters concerning TS were presented.
To set the scene for our new research blog I'll briefly summarise the broad messages I took away from New York. In this entry I will generally not be crediting individual researchers by name.
1) Genetics
It has long been known that in most cases TS appears to be inherited with other family members having either TS, tics or obsessionality. However it has not proved possible to track down the genes involved, probably because there are several that cause vulnerability to TS. The current approach is Genome Wide Association Study (GWAS). Using new technology it is possible to screen for hundreds of thousands of minor genetic variations and blood from over 1000 TS cases has been analysed in this way. The advantage of this approach is that we don't need to know what we are looking for in advance, the disadvantage is the huge number of TS cases needed to get powerful results. Currently more are being sought and that may include some from the UK (the work is in the US).
Preliminary results have identified 7 possible regions of DNA that may be significant and this is being further investigated. Previous results from 2007 using pairs of siblings one with TS and one without TS but only looking at less than 400 variations in DNA also identified a region of interest on chromosome number 2 that is still being looked at.
2) Neural circuitry and Neurosurgery
One of the mysteries of TS is what is actually happening in the brain to cause the symptoms as people with TS have no obvious abnormalities of the structure of the brain on brain scans or post-mortem examination (although very few brains have been examined in this way- if you would like to donate your brain after you have died then the office can give you details!). On the other hand there may be some subtle abnormalities of the size of certain parts of the brain including circuits that control movement (called the basal ganglia) and connections between the left and right brain (called the corpus callosum).
The emerging concept is that TS is not caused by an abnormality of one part of the brain (as for instance happens in a stroke whose effects are focal) but of malfunction of the whole circuits that control movement and are also involved in emotion (so can also cause OCD). An important publication of the last few years was a post-mortem study showing certain kinds of brain cells ("parvalbumin positive") are reduced in a part of this circuit called the caudate nucleus. These cells have regulatory and control functions on the whole circuit and could be abnormal due to an abnormality of the development of the brain.
Whilst normal clinical brain scans (MRI or CT) do not show any problem in people with TS, research scans showing the function of the brain are capable of showing differences although these are very hard to interpret. This can include the activity of different parts of the brain in terms of firing of brain cells and release of certain neurotransmitter chemicals. One presentation at the meeting showed a new approach of looking at the development of connectivity of different parts of the brain- children with TS seemed to be lagging behind by about 3 years.
The new treatment of Deep Brain Stimulation (DBS) may be a way to correct the malfunctioning circuits, by the surgical insertion of stimulator wires into the brain- early results are very encouraging but this is still an experimental treatment and not routinely performed in the UK.
3) Epidemiology (how common is TS)
TS was thought to be rare until the 1970s but by the 1980s it was though to affect 1 in every 2000 people. Over the last 20 years it has become apparent that it is actually more common than that. It affects about 1% of schoolchildren, although some of these are very mild they can still have associated features like OCD and ADHD. The amount of TS found depends on how it is counted.
Recent and new epidemiology data was presented. Firstly a couple of very large American studies which both seemed to underestimate the amount of TS. A telephone survey in which 64 000 random telephone calls were made- only 0.3% had a diagnosis of TS made by a doctor (so there must be a lot who had TS but did not have a diagnosis because it was mild or because they hadn't seen a doctor). The other study was of Medicaid and private insurance companies in the US- also showing a low rate of TS of 0.5 per 1000 amongst 10 million children! This seems to be because in America neurology doctors are not paid if they see a psychiatry patient and TS is classified as a mental disorder, so the doctors naturally call it something else! Let's hope President Obama succeeds in reforming the system there.
An excellent study from Sweden was presented (by Anne-Liis von Knorring, you can find the summary on the internet). This took a different approach predicted to identify higher numbers- looking at children in school and seeing how many actually have TS. She had a figure of around 0.5% overall but the interesting feature was that when association with OCD and ADHD was looked at, this comorbidity was most common in TS and chronic vocal tics, less common in Chronic Multiple Tics (CMT, persistent tics but no vocal tics) and not very common in Transient Tic Disorder (tics that disappear with age, very common in boys- seen far more often than TS).
4) Neuroimmunology
TS probably can't be explained by genes alone- but we don't have a very good understanding of other important factors. One theory is that throat infections with a bacteria called streptococcus (which is very common in children, about 30% have it at some time) may sometimes trigger off an immune response that attacks the brain (autoimmunity) causing TS or related disorders in genetically vulnerable individuals. An antibody called "anti basal ganglia antibody" or ABGA has been identified in a subgroup of patients who have a sudden onset of a TS like condition after throat infection and ABGA is also found in about 25% of people with "normal" TS, but the significance of this is highly controversial. It may mean that antibiotics or treatments affecting the immune system may be helpful for people with TS but there is not good proof of this so far.
Presentations at the meeting on this topic included one by British (alright, originally South African) speaker Professor Gavin Giovannoni who has been supported by Tourettes Action. We heard closely argued data from several other speakers and overall the jury is still out- I won't go into detail here but we will cover future developments on the blog.
5) Drug treatments and animal models
For most patients with severe tics in the UK the main treatment is with drugs. The effect of drugs tend to be a bit variable from person to person and as we all know they are not usually anywhere near 100% effective. The characteristics of TS make it difficult to conduct good clinical trials, providing the solid evidence needed to decide which are the best treatments. We know that small trials are often positive and this can be disproved with the larger trials ("placebo controlled, double blind) that are difficult to conduct. Many drugs have been tried but we usually recommend clonidine or dopamine blocking drugs (like sulpiride or aripiprazole).
I am afraid this most important field is essentially a little stagnant at the moment. In general drug companies are not interested in developing drugs for TS. The Government funding body in the US (NIH) rejected applications for larger trials for TS, and this may be because of the emphasis that has been put on people succeeding despite having tics, and TS not being life-threatening. It seems unlikely that very much more reliable, effective and tolerable drugs are immediately on the way although people with TS may benefit from drug development for other conditions- novel drugs in other areas of neuropsychiatry could also provide something new for TS, if we can persuade the medical authorities of the need to allow off-license prescribing.
Another problem is the absence of a good animal model- meaning an animal system that through genetic engineering or brain surgery seems to resemble a person with TS either in a literal sense or in certain measurable characteristics, or in any case to the extent that drugs can be tested in the animal to predict if they will work for humans who actually have the disease. However at the meeting we did also hear about progress with animal models, this kind of work could be important in future.
6) Behavioural treatments
This area has increased rapidly in importance in the last few years, but in the UK we are badly lagging behind.
It has been known for some time that certain behavioural techniques delivered by experienced clinical psychologists can be as helpful for tics as drugs. These include habit retraining therapy (HRT) and exposure response prevention (ERP). The basic principle of HRT is for troublesome tics to be countered by a competing physical movement, and for ERP for suppression of tics in response to premonitory sensations (the feeling or urge that most patients have prior to ticcing, that gets better when they tic in response). The old view that suppressing tics is bad has been replaced by the current concept that suppressing tics actually makes the urge to tic reduce over time.
There are recent trials using a new acronym CBIT which is Comprehensive Behavioural Intervention for Tics. It consists of several elements: psychoeducation, HRT, functional intervention (identifying exacerbating and relieving factors), a reward system (for complying with CBIT, not for tic reduction) and relaxation training.
At the meeting we heard the results of the child CBIT study, and the adult results are awaited. Over 50% of children had a good response compared to 18% in the control group who received only the education and support elements.
We know that access to clinical psychologists is very patchy in the UK and worse than that there are hardly any psychologists who are experienced in these specialised techniques for tics. Tourettes Action is concerned about this. One possible but inadequate solution is to have a look at the books written by Douglas Woods and colleagues, available on Amazon, Doug is one of the primary researchers on these studies and the books for parents and for adults as well as therapists outlines principles that may help in self-management.
6) Impact of TS
People in the UK may be interested to see this survey of American TSA members including 670 adults, 740 parents and 420 children.
Some selected stats:
10 % adults quit job because of tics
17% avoided job interview
21% asked to leave a public place
Regarding treatments:
Children:
Adults:
And drugs:
Children:
Adults:
Interesting as we tend to avoid haloperidol in the UK due to side effects- newer drugs are preferred.
So I hope this summary of the New York meeting is interesting- it will be longest entry in the blog for a long time to come. Watch out for updates on new reports of interest....
]]>The first entry to follow shortly will be an update from the International Scientific Symposium in New York which was held in June, summarising several areas of the scientific literature.
The future plan for the blog is for newly published individual reports to be highlighted and put in context.
We hope this is a useful service and would welcome your comments to help@tourettes-action.org.uk.