There is always an understandable concern about possible side effects and indeed mild problems (e.g. drowsiness) are not uncommon. These drugs can also cause other involuntary movements and these are the sorts of problems we really do not want to see in our patients. These movements can be of various types (eg. tremor, muscle spasm or dystonia) and usually get better when the drug is stopped.

However there are some movements, especially around the face, called tardive dyskinesias that can continue despite the drug being withdrawn. It has always been felt that although this has been reported in patients treated for TS that the problem is rather rare. This study (http://onlinelibrary.wiley.com/doi/10.1002/mds.23894/full) looks at over 500 patients treated with neuroleptics. Reassuringly none of these people developed dyskinesias. As it is known that around 3-8 % of people given similar drugs for schizophrenia could be expected to develop dyskinesias in a one year period.  The conclusion is that patients with Tourette's seem to be less vulnerable to this difficult problem and neuroleptic usage should not be restricted because of this concern.

Secondly, one of those things that parents and patients knew already where medical science is catching up. We hear very often about a hypersensitivity to various sensory stimulations which sometimes bother people with TS as much as the tics. This study (http://www.ncbi.nlm.nih.gov/pubmed/22038938) by one of the premier American researchers in movement disorders, looked at 19 adults with TS and 19 "normal" volunteers.  A questionnarie showed that 80% of the people with TS described heightened sensitivity to external stimuli including all the senses (ie. visual, touch, smell etc). Intense stimuli seemed less annoying than faint repetitive stimulation.  However the TS people and the non-TS people had the same ability to detect various very faint stimuli, so people with TS were not in fact suffering from an ability to be over-sensitive.  People with TS did seem to have a tendency to rate stimuli at the lower end of the scales used. The difference must be in the processing of the sensory information in the brain.

Lastly this month, a new topic that is often raised on the helpline- sleep and Tourette's. A German researcher, Ari Rothenberger has been interested in this area and attended our symposium held in Oxford a few years ago to talk about this aspect. From our forums we know people have been talking about insomnia, night terrors, hypnogogic hallucinations (like dreaming once you have woken up) and ticcing in sleep. The brain goes through various stages of activity when asleep and there are indications that this might be altered in people with TS.  It was traditionally thought that tics usually resolved in sleep but we now know that they can occur in all phases of sleep. The literature indicates a lower "sleep efficiency" (http://www.ncbi.nlm.nih.gov/pubmed/17537072), longer to get to sleep, longer asleep, increased "arousal phenomena" eg including non-tic movements during sleep (http://www.ncbi.nlm.nih.gov/pubmed/12842228), and increased tics during dreaming phases (rapid eye movement or REM sleep) (http://jnnp.bmj.com/content/70/2/192.abstract).

The severity of daytime tics may be related to how disrupted sleep becomes. It is interesting that forum members have mentioned hypnogogic hallucinations as this is not well documented in the medical literature- however it reflects another variation in arousal and often occurs in patients with narcolepsy who tend to fall alseep very easily in the day- but there is no link between narcolepsy and TS.

No doubt there will be future further work to outline the differences in sleep in TS- but for people who are having bothersome problems there is no evidence to guide best treatment in TS- so the best approach would be to analyse the clinical problem from a Sleep Medicine perspective, although for some patients the big problem may be lack of control of severe tics that impedes sleep. Unfortunately getting expert advice in Sleep Medicine can be variable according to where you live. Your neurologist may also be able to help.



As a whole, psychosocial research in TS is increasing- and our own Tourettes Action BIG Lottery consortium with Professor Georgina Jackson at Nottingham University should give further information about the experience of schoolchildren which can be used to help them with the challenges of taking TS to school in future.

This month I have been asked to talk about "intrusive thoughts", which have regularly cropped up on the helpline. This refers to unwanted, often unpleasant thoughts that can repeatedly come into a person's mind. We understand that this can be very difficult to talk about. The thoughts can be distressing and embarrassing to explain, for example with violent or sexual themes. Very often this kind of symptom is explained by OCD. There is a large literature on how common OCD is in TS and how it differs from "pure" OCD. The parts of the brain involved in causing OCD is probably closely related to the cause of tics- i.e. in circuits connecting the cerebral cortex, basal ganglia and thalamus. There can be other ways of thinking about unwanted thoughts- sometimes people with TS refer to "mental tics". Most people with tics feel an urge to tic then a sense of relief after ticcing- but having an obsessive thought or performing an obsessive action does not bring this kind of relief. The separation between the two may not be very useful as OCD is generally thought to be part of TS. OCD is defined as being distressing and includes compulsions (e.g. repetitively checking the door is locked) and obsessions (thoughts) lasting for more than an hour a day. However, very many people with TS have a milder version of this that we often call obsessive compulsive behaviour (OCB) - i.e. not bad enough to be diagnosed as OCD but essentially the same thing. Treatment of OCD in people with TS is the same as for "pure" TS. Intrusive thoughts can respond to a combination of cognitive behavioural treatment (CBT) and medication with a group of drugs called serotinin reuptake inhibitors (SSRIs) that are well known for their use for depression. To treat OCD high doses are often needed. Treatment is often effective and probably more reliable than medications for tics. Unlike tics other people cannot see thoughts, which is why OCD has been called the invisible disease. Perhaps the main message is that it is worth discussing intrusive thoughts so they can be addressed. Psychiatrists for children or adults are best placed to assess the problem.

Lastly for this month- look out for Dr. Andrew Clempson's update on dental treatments for TS. We are watching the area closely and look forward to hearing more about the forthcoming American TSA clinical trial. The expected cost of treatment in the US for paying patients is around $3000. We have heard of some good and some poor experiences of members and a fairly wide range of financial costs. Until there is high quality trial data (i.e. placebo controlled, see previous blogs) it is not possible to know how effective and durable the treatments are, and they remain difficult to explain on scientific grounds.



The attacks are described as being started off by trivial triggers followed by remorse afterwards. The area is associated with the work of Cathy Budman. In her 2003 study of 48 children with TS who had rage attacks, four different causative factors triggering the attacks were identified: "specific urge resolution, environmentally secure reactivity, nonspecific urge resolution or labile non-resolving". This could have implications for approaches to help the children although the terminology may be off-putting.

Budman's earlier studies (http://www.ncbi.nlm.nih.gov/pubmed/9862602, http://www.ncbi.nlm.nih.gov/pubmed/11026181) described associated features in simpler terms. Many children with rages were found to have only mild tics and they had more comorbidities including both ADHD and OCD. It's probably a mistake to consider rages in TS as a very distinct type of problem or behaviour- there is likely to be a relationship to the impulsivity that underlies other aspects of the condition and reflecting the other comorbidities seen in these patients.

Another more recent study from the same group which was primarily about the use of aripiprazole for TS did show that some patient's rages improved with the treatment. The drug paroxetine may also help, but is not now usually used in children. Although it is an antidepressant (and similar to other drugs that are used in children), rages are not particularly associated with mood problems.

Whilst this is essentially all that has been documented in the medical literature about the problem, more important in individual cases is probably the assessment of an interested child psychiatrist who may be able to recommend practical measures to help. Like so much in Tourette's for complex cases with difficult problems we have a long way to go to find better treatment methods.

On a more light-hearted note, the history of TS has attracted a lot of interest over the years (articles easily obtainable on Google). This is partly because of the time and place- the 1880s at the Salpêtrière Hospital in Paris. Gilles de la Tourette's boss was Professor Charcot, a very important figure in the history of medicine, neurology and psychiatry. Freud was another of his students at one point. The first case of what became known as Tourette syndrome was described in 1825 by Itard, and this case was later included in the series of further patients published by Gilles de la Tourette in 1885. He didn't really become famous until 70 years after his horrible death in 1904 from syphilis of the brain (which was a common way to die at the time). From the kind of man he was, one suspects he would be delighted that his name is now well-known all over the world and not just by doctors.

The only problem is that Hugh Rickards and Andrea Cavanna have now made it clear that patients with TS were described 12 years earlier by another doctor, Trousseau. I'd suggest we change the Charity's name to Trousseau's Action, but Suzanne Dobson our Chief Executive has quite a powerful left hook. After all, Trousseau is still famous amongst doctors for his other contributions to medicine, but if Gilles de la Tourette wasn't remembered for TS he would now most likely be virtually unknown.

PANDAS

Firstly, some PANDAS (http://www.ncbi.nlm.nih.gov/pubmed/21411742). This study looked at the antibodies that that can be found in the blood and bind to the brain in PANDAS, in 25% of TS and also in the original long-described autoimmune neuropsychiatric condition triggered off by streptococcus, Sydenham's chorea ("St. Vitus's dance"). What anti-basal ganglia antibodies antibodies (ABGA) actually do has remained controversial, and the identification of the proteins they target has not answered the problem. In this study live cultured neurons were used and the researchers looked for antibodies that stick to the cell surface in the blood of patients with the three conditions. They were present in Sydenham's chorea but not in TS or PANDAS suggesting that the former is autoimmune (as always thought) but weakening the hypothesis for PANDAS and TS. However we do know that the ABGA antibodies in PANDAS target proteins that can be inside the cells rather on the surface although antibodies normally do act by binding to surface proteins. So the debate goes on…..

Genes

We've discussed genes a lot below. There isn't a single gene for TS, although in rare individual families there may be. Here is another example: http://www.ncbi.nlm.nih.gov/pubmed/21520241, showing three gene variants not only in the original three-generation family but also in one of the genes in another family. The wider significance of this is not clear- but presumably this group or others will screen for these variants in more patients. Meanwhile it seems likely that for most people with TS multiple genes each of little individual effect are what raises the risk of having the condition- perhaps triggered off by other factors, for instance streptococcal infection.

Aripiprazole

Now, to treatment. Aripiprazole has become a frequently used drug for tics all over the world. The worry with drugs of this class is the possibility of the dopamine blocking effect causing secondary movement disorders, which sometimes can be irreversible. These are called "extrapyramidal side effects" or EPS. A study from Texas (http://www.ncbi.nlm.nih.gov/pubmed/20818603) shows that in a clinic devoted to this problem, in about 3.5% the drug involved was aripiprazole. The patients would mostly not have had TS, and the figures given don't tell us about the drugs involved in the other 96.5% of them. EPS with other similar drugs in TS has always seemed to be relatively rare, and we do often use lower doses than the other uses of the drugs. In an unpublished series of patients from my clinic in London and also patients from Sicily 5 out of 42 patient developed the kind of problem with aripiprazole- but in each case the EPS got better when the aripiprazole was reduced and none of the patients were children. This is disappointing as aripiprazole is a newer drug which is supposed to be less prone to EPS than older drugs like haloperidol or sulpiride. It is possible that it is not actually the case. We need to stay aware of the issue in clinical practice, but if you or your child is currently taking aripiprazole there is no need to panic- please don't stop the tablets!

Neurosurgery

Finally- neurosurgical treatment. Deep brain stimulation (DBS) continues to be experimental in TS but may end up as a standard therapy for selected severe cases. This series of 5 patients (http://www.ncbi.nlm.nih.gov/pubmed/21538528) is a study of where exactly the electrodes should be placed in the brain. This does remain a major problem- it is not yet known where the optimal placement is or should be. The significance of this paper is the UK involvement, as very few patients have received the treatment so far. For more information on DBS see http://dbs.tsa-usa.org/ from the USA Tourette Syndrome Association. Tourettes Action encourages anyone in the UK considering DBS to take part in the London/Birmingham trial or ask their surgeon to join in the TSA registry available via the website- the more patients that are documented in the medical literature the sooner we will have the answers we need.



Many parents or people with tics have felt that diet can influence the tics and / or hyperactivity- with the classic popular advice to avoid coca cola and such like. In fact there has been little hard evidence to back this up, although an older study from Germany certainly confirmed the impression using questionnaires.

It is sometimes difficult to go from impressions of people actually dealing with the condition at home to hard evidence in medical journals because there are so many sources of bias. Whether diet, including elements like sugar and caffeine, is relevant to ADHD has been debated for some time with previous overall conclusions appearing to be broadly negative.

The current study from Holland may trump this as it is published in the Lancet, and was a fairly rigorously controlled trial of 100 children. Half of them were allocated to a restricted elimination diet. 30 out of 50 children on the diet had a good improvement and the majority of those got worse again when various foods were re-introduced.  The conclusion was that this strict form of diet elimination could be useful in identifying a subset of children who could benefit from it on a more long-term basis, but that it is not useful to do blood tests for food allergy to find these children. It is inadvisable to design a diet for a child without professional input.

Gene expression in TS

The blog has included several entries on genetics and how the newest techniques have been applied to TS. To recap, as no "major gene" which causes TS has been identified (and doesn't seem to exist) a major current way forward is to look at all the DNA of many people with and without TS to look for smaller differences that might increase the chances of having TS. This won't lead to a gene test for TS but when these several genes are identified it will allow us to look at their functions which could give clues as to the ultimate cause of the condition. 

But what do genes do?  The DNA of genes is translated into RNA which is then translated into proteins. Many of these proteins are the building blocks for the body and many others regulate the whole system so that the right protein is expressed in the right time and place.  It is now possible to look at gene expression using automated chips that identify specific sequences of RNA showing which genes are actually turned on or "expressed".

Two recent studies, in Brain Research and Pharmacogenomics, have used this sort of technique to look at the genes relating to dopamine and three other neurochemical systems- noradrenaline, GABA and ACh. The broad conclusions- that these systems are all relevant as the expression of certain genes was related to control of tics by medication or different to control subjects without TS.

That TS is connected to changes in neurotransmitters is not surprising but this technique which looks at the expression of genes rather than the genes themselves is simply another route which may eventually help build a more specific case for what is happening in the brain and how it can be put right.

This study describes an automatic electronic device to measure tic activity. This could be useful in studies of treatment in allowing a longer assessment period without the person being watched by a researcher or video camera.

This could be useful and better than scales filled out by a doctor, but doesn't get around the problem of measuring what really matters to an individual patient. To do this it is more important to try and make a measurement of quality of life (QOL) rather than just severity of tics. A questionnaire to measure QOL has already been designed and Tourettes Action members may have helped in that project. A new English and Italian publication has now looked what factors contributed to a good or poor QOL in TS patients. This was confined by the design of the QOL questionnaire- for instance some of the questions relate to obsessionality, concentration or happiness so OCD, ADHD and depression automatically have an important influence on the results. Interestingly the severity of tics measured by other methods did not cause worse QOL.

Lastly, this American study using an internet questionnaire of over 200 children and their parents looked at the impairment caused by tics and did find a correlation (relationship) of increasing tic severity and physical, social, family, academic and psychological functioning, with comorbidies like OCD or ADHD making the situation worse.

One could say the these two studies disagree- the English result is that more severe tics are not that important for a poorer good quality of life, while the American results say the opposite. The problem comes down to what is actually being measured when we talk about QOL. Some may say the problem with severe tics is the attitude of other people rather than TS itself but, in the end, if people feel impaired as a result, then we need to continue to try and find ways of supporting them. I suspect there will never be one way of measuring TS that works for everyone and for every research purpose, and this is a very real problem in assessing the effectiveness of treatments.

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961109-9/abstract

Our May blog covered the same approach in TS (see below). ADHD is big news in the media for reasons different to the sometime fascination with TS. As many will appreciate, some newspapers and TV psychologists wage war on ADHD with the view that it isn't really a medical disorder, but all to do with environment and parenting. For parts of the media this press-released paper became all about "proof" for whether it is actually a genuine condition or not- because if children with ADHD have genetic differences then the conclusion may be that ADHD have a biological cause.

This approach of scanning thousands of genes for subtle differences in large numbers of patients is now being applied right across medicine- to conditions which, like TS, do not have a simple, single, abnormal gene. These conditions may have a more complex pattern of vulnerability which is not the same for each person - for instance multiple sclerosis (MS) or high blood pressure. This approach is unlikely to give us a blood test for the condition but may teach us more about the causes of diseases, by pointing to the range of genes that are involved. For example, for MS there is already evidence implicating the immune system, confirming that the body's own immunity to infections may be attacking nerve cells in that disease.

Autoimmunity has also been implicated in TS with the PANDAS / streptococcal research covered below (but there is NO link between TS and MS). A new paper has taken a different approach by looking at autoimmune disease in the mothers of children with TS or OCD.

http://www.ncbi.nlm.nih.gov/pubmed/20864184

The common autoimmune diseases cause thyroid problems, vitiligo (de-pigmentation of patches of skin), rheumatoid arthritis and vitamin B12 deficiency. These problems tend to be more common in women affecting about 5% in the USA. In the mothers of over a hundred children with OCD (some with tics) the figure was raised to 18%, and higher still when the child was thought to have PANDAS. This could indicate a link between mothers with autoimmune diseases and vulnerability to an autoimmune cause of TS in certain cases. Still no smoking gun though.....

Measurement of intelligence is full of pitfalls and can stir controversy. The problem with intelligence is what is it and how can we measure this proposed innate property without actually measuring other things like education and social background which are far from innate. The problems aside, IQ is clinically important as Learning Disability is defined by measurement using standard scales like the Wechsler Intelligence Scale for Children (WISC). Children (and adults) can have learning problems without being classified as having a disability- for instance a child with a high IQ might also have ADHD which could make it difficult for them to perform well in exams despite being very intelligent.

An "average" IQ is set at 100, but 50% of us have an IQ below this value and the other 50% of us are above this value. The higher or lower the score the fewer people will be left. This is called a "normal distribution", sometimes called a "bell curve", which is a common characteristic of biological measurements. Height and weight also follow normal distributions whereas other qualities like eye colour can't be measured in this way because blue eyes can be inherited and for these purposes blue isn't a merely a pale kind of brown!

Whilst we see many children with TS who have learning difficulties, and SEN schools have more TS children than mainstream schools it has previously been felt to be the case that people with TS have an "average" IQ meaning they follow the same normal distribution and are not more likely to have an IQ lower than 100 than a randomly selected child. However there have been previous suggestions that certain types of IQ might be more likely to be impaired in TS as the tests can be split into verbal and non-verbal (performance) types.

A recent Danish study has returned to this issue in 266 children who went through these kinds of tests. The average verbal IQ was 93 and the performance IQ was 87 with a combined score of 89. An earlier onset of tics seemed to affect the performance IQ.

What does this mean? Probably not a great deal- TS children on average had a slightly lower IQ than other children but the difference was only slight and there is confirmation that performance IQ tends to be a bit lower than verbal IQ in TS. This certainly doesn't exclude individuals with TS having very high IQ's!

Moving on to another biological measurement with a normal distribution: weight. As covered before one of the side effects of the neuroleptic medications often used for tics is weight gain, including older ones like haloperidol and sulpiride and newer ones like risperidone and others. A group in Chicago looked at weight and body mass index (BMI) in almost 200 patients, both children and young adults.

A comparison of those treated with neuroleptics and those not on drugs showed that both older and newer neuroleptics were associated with a higher than average BMI of over 0.5 (healthy BMI is below about 25 so not all these patients were technically overweight they were just slightly heavier than expected). Unpublished data (so treat with caution) from my clinic showed that children with TS, both treated and untreated, were slightly heavier than average but there was less effect on weight with the drug aripiprazole. This is consistent with the known properties of this drug, which is now one of the most widely used for TS.

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.