The Postural Tachycardia Syndrome: a multi-system condition. Clinical features, pathophysiology, genetics and novel treatment
Creators: name: Iodice, Valeria
Publisher: name: Imperial College London
Year: 2013

description: Autonomic dysfunction is a common presentation of various neurological disorders and has a heterogeneous aetiology and pathophysiology. PoTS is a very common form of orthostatic intolerance characterized by excessive increases in heart rate during orthostatic stress without orthostatic hypotension and is often associated with the Joint Hypermobility Syndrome (JHS); the most common heritable disorder of connective tissue. However, information is still limited in PoTS with regards to the clinical presentation and quality of life, pathophysiology, the responses to treatment and possible genetic contributions. As part of this thesis a novel autonomic function scoring scale was generated and validated to quantify the degree of autonomic impairment (CAF score), which was able to differentiate patients with different autonomic disorders and quantify the degree of autonomic overactivity in patients with PoTS. An autonomic and quality of life self-administered questionnaire (AQQoL) was also developed in order to assess a range of autonomic symptoms, allied features, familial autonomic dysfunction and the relative quality of life in a large cohort of patients with autonomic disorders. This instrument was found to be helpful in detecting autonomic, non-cardiovascular and quality of life impairments in patients with autonomic disorders and could inform future longitudinal studies in patients with a wide range of autonomic disorders. PoTS might be a genetic disorder with a likely multifactorial and polygenic pathophysiology and possible variable expressivity. Using the AQQoL and further investigations 21 families with PoTS and JHS were described for the first time. In order to further understand the pathophysiology of PoTS and JHS, peripheral small nerve fibre function and morphology, using the skin biopsy technique, were evaluated. A subgroup of patients with PoTS and JHS have an underlying small fibre neuropathy and associated abnormalities of Collagen IV in basement membranes and blood vessels in the skin indicating that multiple pathophysiological mechanisms could coexist in the same patients and that the skin biopsy is a valuable tool to differentiate PoTS sub-groups. Diagnosing PoTS can be challenging and tests, in addition to the traditional orthostatic stressors, such as liquid meal challenge, modified exercise and heat challenge tests, can be of value in the assessment of these patients. In particular, the liquid meal challenge test is also helpful in determining whether drugs such as the somatostatin analogue, Octreotide, can reduce postural tachycardia and symptoms of orthostatic intolerance pre- and post-prandially. Similarly, for the first time, the beneficial effect of 50 mcg of Octreotide on orthostatic hemodynamic responses before and after food ingestion in PoTS was shown. PoTS is a complex multi-system disorder that may cause significant autonomic morbidity and impairment of quality of life. The pathophysiology is heterogeneous and in our patient cohort is likely to be linked to connective tissue disorders, such as JHS and genetic factors. A more extensive autonomic assessment, including the evaluation of hemodynamic responses to daily stimuli, may be important for establishing definitive diagnostic criteria for PoTS. The management of these patients needs a multi-step pharmacological approach and in the most severe cases requires specific targeting, with medications such as Octreotide for example, which might be beneficial in reducing postural tachycardia and orthostatic intolerance.