Cervical dystonia (CD) has long been considered to be a motor disorder. However, CD seems to represent an extremely heterogeneous condition. Indeed, it has become clear that beyond motor manifestations, patients with CD may also complain of non motor symptoms, including psychiatric disorders, pain, cognitive and sleep disorders. Non-motor symptoms represent an important determinant of quality of life and a source of disability in CD. Previous studies aimed to disentangle the complex relationship between motor and non motor symptoms have yielded conflicting results. In addition several CD subtypes have been so far identified only considering motor features. Therefore, the role of non-motor symptoms in determining clinical heterogeneity in CD is still unclear. The first line of treatment for motor symptoms in CD is botulinum toxin (BoNT) injection therapy. Conversely, no study has so far investigated whether the treatment with BoNT may also improve non-motor burden in CD.On this background, the main aim of this study is to identify clinical CD subtypes on the basis of motor and non-motor symptoms. A second aim of this study is to longitudinally evaluate the effect of BoNT treatment on motor and non-motor symptoms. Finally, the last aim is to explore the relationship between motor features, as tested by kinematic techniques, and non-motor symptoms in CD. For these purposes, we will enroll 80 CD patients and 80 healthy controls. We will investigate five clinical domains, including motor symptoms, psychiatric disturbances, sleep disorders, cognitive impairment and pain, by using standardized clinical scales and kinematic recording of dystonic movements. These domains will be used as variables in a k-means cluster analysis. A correlation analysis between kinematic data and non-motor manifestations will be performed. Finally we will perform a longitudinal evaluation by assessing non-motor symptoms severity before and 1 and 3 months after botulinum toxin injection.
In the present project we will aim to clarify the relevance and the role of non-motor manifestations in CD clinical and pathophysiological heterogeneity by using novel clinical and neurophysiological approaches.
The first element of novelty of our study will be the application of clustering techniques to identify CD clinical subtypes by combining motor and non-motor variables. Previous studies have identified CD subtypes by considering a priori hypothesis and by applying a monodimensional approach, where single motor features were used as the sole classification factors. To overcome these limitations, in our study we will perform a k means cluster analysis, a hypothesis free approach, that involves clustering algorithms with the goal of finding hidden patterns or groupings in a dataset. This will allow to describe data-driven multidimensional subtypes, reflecting the clinical complexity of the disease.
The second element of novelty of our study is that we will look for possible correlations between non-motor symptoms and quantitative data of motor impairment, coming from a kinematic evaluation of dystonic movements. By performing an objective measurement of dystonic symptoms we will add new insight on the controversial relationship between motor and non-motor domains in CD.
A further point of strength of the present study will be the longitudinal evaluation of the effects of botulinum toxin on CD motor and non-motor symptoms, simultaneously. This approach has relevant clinical and pathophysiological implications. Non-motor symptoms represent a relevant source of disability in CD and non satisfactory treatments are currently available. It is therefore pivotal to identify new therapeutic strategies for CD non-motor symptoms management. The observation that botulinum toxin may improve non-motor manifestations severity could represent the first step for novel therapeutic approach in CD. In addition, testing simultaneously the effects of botulin toxin on motor and non-motor symptoms will contribute to clarify the relationship between these clinical domains in CD. From a pathophysiological perspective, the observation that botulinum toxin may modulate non-motor symptoms severity will shed light on the currently debated central effects of botulinum toxin. Indeed, beyond a peripheral action of botulinum toxin, some evidences coming from experimental neurophysiological studies (blink reflex, motor and somatosensory evoked potentials) seem to support a central action of botulinum toxin in humans.
Overall, the present study has relevant pathophysiological, clinical and therapeutic implications and will increase our knwoledge on the role of non-motor symptoms in CD, thus representing the first step for new strategies aimed at improving CD disability and quality of life.