Essential tremor (ET) is an heterogeneous condition. It is still unknown whether ET should be considered a specific disease entity or whether under the definition of ET there are multiple disease entities. Patients with different ET subtypes, likely have a specific pattern of clinical, motor and non motor symptoms, including cognitive and psychiatric abnormalities. In addition, the various ET subtypes likely have pathophysiological differences, as assessed by neurophysiological and neuroimaging investigations. Clinical and pathophysiological differences of the various ET subtypes may also affect the responsiveness to pharmacological treatment, including propranolole. The aim of the study is to provide a systematic characterization of the clinical features of ET patients and a deeper insight into the pathophysiological mechanisms of these conditions. Finally, the results of the study would also allow a better comprehension on the use of propanol in the therapeutic management of ETpatients.
The first novel feature of the project is the investigation of the clinical characteristics, including motor and non-motor symptoms, in a large sample of patients with a diagnosis of ET, according to the standard criteria. Our hypothesis is that under the classification of ET there are different ET subtypes possibly characterized by different clinical features. We expect possible differences between: (i) ART vs. ET or (ii) patients with family history of ET in comparison to patients without a family history and finally (iii) between patients with isolated tremor affecting one body segment and those with tremor involving different body segments.
Another novel aspect of the project is the assessment of possible pathophysiological differences in a large sample of patients with ET. Our hypothesis is that patients with different ET subtypes will show different motor and sensory abnormalities, as assessed by neurophysiological techniques (including kinematic analysis of tremor and assessment of STDT) or neuroimaging investigations. Previous investigations in our laboratory indeed showed that STDT values were normal in patients with essential tremor (Tinazzi et al., 2013), whereas they were increased in patients with upper limb tremor associated with cervical dystonia. In a recent study, from our laboratory, in patients diagnosed as having ET according to clinical criteria, STDT values differed in patients with and without family history for ET, being higher in those with a sporadic form of ET. Moreover, analyzing STDT values according to the body part affected by tremor we found that in patients with ET with upper limb involvement STDT values were normal whereas in those with isolated head tremor STDT values were increased (Conte et al., 2015). STDT investigation may therefore clarify whether ET subtypes may show different STDT values. Neuroimaging measures would provide additional evidence for structural and functional changes in specific brain sites and circuits, possibly related to different ET subtypes.
The third aim of the study is to further investigate the therapeutic role of propranonol in patients with different ET subtypes. Several studies have been designed to identify factors potentially useful in predicting the therapeutic outcomes. Murray et al. (1976) observed that propranolol treatment in ET has a better outcome in younger patients and in those with shorter disease duration. Differently, Teravainen et al. (1976) and Larsen (1980) observed an higher efficacy of propranolol administration in older patients and in those characterized by lower tremor frequency. We predict that the responsiveness to propranonol might reflect the pathophysiological heterogeneity of the various conditions .
In summary, ET has long been investigated in clinical, neurophysiological and neuroimaging studies and several sub-classifications have been proposed (Deuschl et al., 2015). However, this is the first study assessing the possible clinical motor and non-motor features and the pathophysiological mechanisms of ET, as assessed by neurophysiological and neuroimaging investigations, in a large sample of patients, focusing on the possible distinguishing features among the various ET subtypes, including difference in the therapeutic responsiveness to propranolole administration in these patients.