 Thank you to the Brain Foundation for the opportunity to speak to you today. My name is Dr. Joel Marmeri and I'm a movement disorders fellow at the Sir Vincent's Hospital in Sydney. As I'm sure you're all aware, the Brain Foundation provides support for individuals and research teams to conduct high quality research into neurological disorders and brain disease. First and foremost I wish to express my thanks to the Brain Foundation for its ongoing support of our research into the topic that I wish to speak to you about today, that being the topic of dystonia. Now this isn't by any means meant to be a comprehensive review of dystonia given our time restraints but I hope I can introduce you to the main concepts that underlie dystonia, its subtypes, as well as introduce you to our current understanding of the causes of dystonia and provide a brief update on existing and newly evolving treatment strategies. As with any medical condition it's actually often quite interesting to look back and reflect on how our understanding of that condition has changed with time. Now we currently recognise dystonia by definition as a movement disorder that's characterised by sustained or intermittent muscle contractions causing abnormal or from repetitive movements, postures or both. Interestingly it wasn't always this way, now whilst dystonia has likely existed as long as the human brain has, the term was first coined in 1911 by German neurologist and psychiatrist Dr. Heinrich Oppenheim, where he described a condition in four children that he termed a dystonia muscularum deformens in his paper about a peculiar cramping sickness in children and adolescents. Whilst our definition and understanding of dystonia has certainly evolved and improved over time, many of those astute observations that Dr. Oppenheim made in 1911 remain true to this day. Specifically he noted that the abnormal movements that were seen with dystonia occurred in the absence of any weakness and were often initiated or worsened by voluntary action. Now our current definition of dystonia is most recently updated in 2013 and I've outlined that for you on this slide. It's important to note that the involuntary movements that we see in dystonia are not due to the actual nerves or the muscles themselves but rather abnormal electrical signals that are generated in the brain telling those muscles to contract. Now there isn't a lot of data on the exact prevalence of dystonia in Australia but it's probably around three per one thousand individuals and the sub-prevalence of focal forms of dystonia is again probably about ten times greater than that of generalised forms and I'll outline what they are shortly. Whilst this is our definition of dystonia, in order for specialists to better investigate and treat our patients what we really need is a good classification system for all of these syndromes. So currently we classify dystonia according to separate axes. Now the first are the clinical characteristics of the dystonia and this includes things like the age of onset, the regions of the body that might be affected, how that dystonia has changed over time as well as the presence of other neurological features that are associated with that dystonia. Now additionally we also classify the dystonic syndrome according to whether there is a known or an identifiable cause. Now this helps us to indicate whether the dystonia that we're seeing is occurring alongside part of another neurodegenerative condition and a good example of this is the dystonia that we can see associated with things like Parkinson's disease, whether that dystonia is due to a previous injury to the brain or indeed if there is no identifiable evidence of either degeneration or a lesion in that brain. Further we can also then classify the cause of dystonia according to whether it is inherited or acquired and this assists us in differentiating those forms of dystonia where there is an identifiable genetic cause such as in the DYT gene abnormalities or whether that dystonia has been acquired during the course of life. Whilst it does seem a little nebulous at first glance it's really important to obtain an accurate diagnosis and classification because that then helps us to target an individual's investigations and guide both the individual and the clinician together in making decisions regarding their treatment regimen. So if we have an idea of what the dystonia is or the next logical question that follows is well okay well what causes it. I wish I had a simple straightforward answer that really isn't one but what we know is that dystonia can be associated with damage to or degeneration of multiple regions of the brain. Now this includes the basal ganglia, the thalamus, the cortex, the brainstem and the cerebellum however what we do also know is that dystonia can occur in the absence of there being clear cell damage or degeneration. Given that dystonia seems to occur as a result of abnormalities in multiple different areas of the brain as you can see there we're increasingly viewing dystonia as a network disorder. Now that can arise from abnormalities in one or more areas of that brain network rather than it being any abnormality with one specific site in the brain alone. It's also likely that genetic predisposition and then lifetime environmental factors play a role in the development of dystonia. But when we sit down and we have a look at the brain function of individuals with dystonia compared to individuals who do not have dystonia we find a couple of differences. Using special electrophysiologic and imaging tests we can identify abnormalities in the processing of sensory information. We see changes in how the sensory and the motor systems are mapped out in the brain in addition to abnormalities in motor control, motor inhibition and in neuroplasticity that is the ability of the brain to change based on the stimulus that it's provided with. Having noted how we define and classify the dystonia as well as briefly reviewing what we know about its pathophysiology I then thought it was important to review what can dystonia look like. Now if you or a family member or someone you know has dystonia it's important to note it might look completely different to that of another individual with dystonia. What we spoke about earlier is sort of that underlying characterizing feature of dystonia are the sustained or intermittent muscle contractions resulting in abnormal movements, postures or both. Now these movements are often repetitive and they can be patterned, they can be twisting or even tremulous. Dystonia is often but not always, are worsened by voluntary action and there's evidence of muscle overflow activation. There are some forms of dystonia such as blepharospasm which involves the eyes or laryngeal dystonia involving the vocal cords that are associated purely with involuntary muscle contraction and no abnormal posturing. Others on the other hand can have quite a significant tremulous component and this is known as a dystonic tremor. There are some forms of dystonia that are exquisitely task specific and they only occur when an individual is performing a certain task so a good example of this is writer's cramp which we see that only comes out when an individual tries to write something down or musician's dystonia which again the individual may have no evidence of dystonia otherwise but as soon as they attempt to play their musical instrument their dystonia comes out. Now these dystonic syndromes can be focal where they affect one region of the body only, they can be segmental where you have two or more attached parts of the body involved, they can be generalized involving the whole body they might even be multifocal where there are multiple areas of the body that aren't sort of located next to each other are involved or you can actually even develop something like a hemi dystonia which involves one part of the body or one half of the body. I don't have the capacity here to go into all of the clinical features of dystonia that I'd like to but one really interesting phenomenon to talk about is the gest antagonist which translates I think literally from the French for an antagonizing gesture. This is actually quite a clever sensory trick that individuals develop where if they experience dystonia in a body part sometimes touching that body part can actually markedly reduce their dystonia and in some individuals even thinking about performing that action can have a drastic benefit on their dystonia and that's probably again due to that sensory feedback mechanism that then dampens their motor outflow. So with all of that in mind how does your doctor diagnose you with dystonia and what can we then do together to help provide options in terms of treatment. Now dystonia primarily really is diagnosed on the basis of its clinical features by an experienced movement disorder specialist or a neurologist. There's no specific test that's used to identify dystonia and that's important but what we might consider are certain blood tests, imaging modalities or in some individuals even think about things like genetic testing to identify whether there's a possible underlying cause of that dystonia. Now as I said whilst these investigations are an important adjunct to diagnosis and can be important in identifying potential causative factors or things that can be addressed directly the diagnosis really is based on the clinical history that's provided by the individual and that includes going into previous brain trauma, perinatal history, developmental history as well as previous exposures particularly just certain forms of medications. We then use that information alongside a good physical examination and that allows us to establish an accurate diagnosis of dystonia and this is really important because there are some conditions that do mimic dystonia that may not necessarily fit under the spectrum of dystonia itself. So as I mentioned I'm sure you can appreciate it's the type of dystonia that really helps guide our treatment options so I won't be able to go into all of this in great detail but what I'd like to do is outline the general options that exist as well as a general therapeutic approach and how these can be tailored to the individual based on their diagnostic classification. Now the options that I'm presenting here are primarily for the adult patient with dystonia because that's primarily what my experience is in. If we start with oral medications now these can be effectively employed as part of the overall regimen for management of dystonia particularly in individuals with more generalized forms. So the first medication I've listed there is levodopa which is a form of dopamine replacement you might be familiar with that being sort of the cardinal underlying treatment for Parkinson's disease. Now this isn't necessarily required in every individual but in a small subset of individuals they may have a condition called doper responsive dystonia and this particular subset can really benefit quite markedly from levodopa therapy so that's something that your neurologist or specialist may discuss with you. There are other medication options these can include things like clonazepam or the anti-colonergic class of drugs tetrabenazine or if there's coexisting spasticity baclofen is often considered as well. Many of these medications do have varying personal efficacy what works for one person may not work for the next and they also have quite marked variability in terms of personal tolerance as well as a side effect profile so they all need to be really prescribed under very close supervision and again ideally I think with the input of a movement disorder specialist. One of the most effective forms of treatment particularly for the focal and segmental subtypes of dystonia is botulinum toxin so you might be familiar with it botulinum toxin is a potent neurotoxin that causes local muscle weakness and prevents the release of neurotransmitters that signal muscle contraction. There are multiple different forms or types of botulinum toxin each has a slightly different formulation and potency but they all work via a very similar mechanism. Now this form of treatment has been extensively studied and used most frequently in forms of focal dystonia so things like blepharospasm, cervical dystonia, laryngeal dystonia or focal dystonia that affects either the upper or the lower limbs. It can though also be implemented as part of a more general treatment regimen for individuals with those generalized forms of dystonia. Again treatment tolerability is often limited by side effects and sometimes they're not necessarily side effects they're just related to how the medication works that is by over weakening the muscles that are injected or sometimes the botulinum toxin can actually diffuse into neighboring structures or muscles. There are some other side effects that do occur with botulinum toxin and these really need to be discussed with your specialist when considering this as a form of appropriate treatment for you or your family member. Outside of medication options there are very important adjunctive therapies that need to be employed alongside dystonia. Now as with all of these options again these are not curative they don't change the underlying brain signals but they form very important parts of an individual's treatment regimen so these include things like physiotherapy and physical retraining strategies. These can be really important in attempting to reprogram movement in individuals with generalized focal and tusk specific forms of dystonia. They're also very important to prevent physical complications that may develop from the dystonic syndrome. Speech therapy I've put there now whilst actually over exercising dystonic muscles can sometimes worsen forms of dystonia. Speech therapists are really important in terms of the management of laryngeal dystonia often from its initial diagnosis individuals may present to a speech therapist with their laryngeal dystonia and they can also be really really effective in assisting to retrain unhelpful strategies that were developed in in sort of an effort to compensate for the laryngeal dystonia like a whispering or certain pitch changes. That's all really important parts of our treatment and we're certainly very well engaged with our allied health in terms of managing these patients. In the last few minutes I just wanted to draw attention to something that we have a particular interest on in this Invinced Hospital from both a clinical and a research perspective and these are the surgical therapies for dystonia. Now these fall primarily under two separate categories those being deep brain stimulation and lesional therapies. Now these treatments are not necessarily for everyone and they're often indicated for severe dystonia that is unable to be adequately controlled with either medications or botulinum toxin. They're generally more commonly implemented in segmental or generalized forms of dystonia but they can be considered for certain focal forms of dystonia and we'll talk about that. Deep brain stimulation involves the insertion of very thin wires into parts of the brain that control movement. Using a small pacemaker like device we are then able to deliver electrical signals to the parts of the brain that modulate and control movement and by doing this we can actually attempt to block the abnormal electrical activity that is driving the underlying dystonia. Now whilst it does require open brain surgery the advantage of this option is it allows us to titrate the electrical signals to that individual with an aim of achieving the best outcome with minimal side effect profile. Deep brain stimulation really is one of the most effective forms of treatment for certain forms of generalized and cervical dystonic syndrome and there's good evidence of effect in many of the genetic forms of generalized dystonia but I will caveat here by saying that there are some dystonic syndromes that deep brain stimulation is not appropriate for and it can worsen the dystonia so this needs to be something that if you're considering this treatment option needs to be discussed really closely with your neurologist and your neurosurgeon. Just the last thing that I wanted to go into again with time constraints is a new evolving treatment option particularly for focal dystonia. So I mentioned before lesional therapies is an option as a surgical treatment for dystonia and it can be used to interrupt the pathways that carry the abnormal signals again in the brain that are driving the dystonia. With the advent of new technology recently what we're able to do is accurately map those pathways out in the brain and target them and create small highly accurate lesions within the brain without requiring an incision or any irradiation. Now the way that we achieve this is with a technique known as MRI guided focused ultrasound. Now this is currently FDA and TGA approved for the use of treatment of certain tremor disorders. In short what we do is we identify those parts of the brain that are thought to play a critical role in generating the dystonia and then we're able after we identify those we're able to deliver highly focused beams of ultrasound energy to that specific region. Now what this results in is the generation of thermal energy at those at that point where those ultrasound beams converge right at our target site in an aim to disrupt these pathways. Now I often like to explain this as an allegas to using a magnifying glass to focus the beams of sunlight at a specific focal point. What you'll know is that if you can focus it right at a specific point you can generate heat but you can pass your hand between those beams of ultrasound between those beams of sunlight and that focal point without causing any harm. So in 2021 there was a pilot study undertaken in Tokyo Japan using this method to treat individuals with forms of focal task specific upper limb dystonia including individuals with riders cramp and musicians dystonia and the authors published quite promising results. So we're currently recruiting to conduct a clinical trial at St Vincent's Hospital in Sydney and we're again looking at this form of treatment in individuals with focal hand dystonia. We're aiming to further establish this modality as a method of treatment for dystonia and also trying to obtain a better understanding of the changes in the brain that are evident in these individuals. So I just wanted to say thank you again to the Brain Foundation for their ongoing support of all of the research efforts conducted around Australia as well as specifically again for supporting our research. I've left my contact details there on the presentation if anybody should have any questions about anything that I've discussed or questions about dystonia or indeed our clinical trial and research that we're performing at St Vincent's please feel free to contact me. But thank you again all of you for all of your time and thank you again to the Brain Foundation for its ongoing assistance and just a note of the references used for the presentation. Thank you very much.