Improving the evidence base for treatment of Postural Orthostatic Tachycardia Syndrome (POTS)

Abstract

Postural tachycardia syndrome (POTS) is a chronic debilitating condition characterized by symptoms of light-headedness, fatigue, palpitations, pre-syncope, sleep disturbances, cognitive impairment and brain fog in conjunction with an exaggerated increase in heart rate (HR) when upright, despite maintenance of a normal blood pressure (BP). There is little high-level evidence to inform current guidelines for the investigation and management of POTS, at least in part due to the lack of biological markers to provide clarity on diagnosis and to quantify severity of disease. The objectives of the work described in this thesis was to highlight the gaps in evidence for therapeutic modalities currently available for the treatment of patients with POTS and to study the value of transcranial doppler (TCD) measures of cerebral blood flow velocity (CBFv) during orthostatic and cognitive stress for future therapeutic trials in patients with POTS. The rationale behind use of TCD measurement of CBFv relates to the hypothesis that periodic reduction in cerebral blood flow (CBF) due to inadequate compensation for changes in orthostatic pressure may explain the almost universal symptom of mental clouding described by patients with POTS. Since many patients with POTS describe mental clouding even when recumbent, we hypothesized that regulation of CBF in response to cognitive activation in the absence of orthostatic stress may also be dysfunctional. We therefore studied CBF during both orthostatic and cognitive stress in patients with POTS. An overview of the pathophysiology and co-morbidities associated with POTS is provided in Chapter 1 followed by a systematic review of the efficacy and quality of evidence for therapies currently utilised in the management of patients with POTS (Chapter 2). The results of our pilot study of CBFv in patients with POTS, and controls, is reported in Chapter 3. The contents of these 3 chapters have been published in peer reviewed journals. In our pilot study, the effect of a visual stimulus on CBFv was measured using a handheld duplex TCD. We replicated the methodology previously used to demonstrate a reduction in neurovascular coupling (as demonstrated by a reduced CBFv response to a visual stimulus) in a study of patients with spinal cord injuries. (1) The rationale for replicating this methodology was the authors’ attribution of the reduced neurovascular coupling in patients with spinal cord injury to disruption in the patients’ autonomic feedback loops. As autonomic dysfunction has long been suspected to underlie the pathophysiology of POTS,(2) we considered the robust findings generated through the relatively simple methodology described by Phillips might prove useful in the study of patients with POTS. Unfortunately, this was not the case. Instead, we found similar changes in CBFv in our patient and control groups in response to the brief visual stimulus. As a result of the negative findings from our pilot study (in which a brief visual stimulus was used), in subsequent studies we measured changes in CBFv during a prolonged cognitive stress. Not only was this stimulus a better reflection of the conditions during which patients typically experienced “brain fog” but it also allowed us to measure the effect of fatigue on symptoms scores, CBFv responses, and on cognitive performance. As a result of difficulty in maintaining the angle of insonation in the posterior cerebral artery (PCA) over this prolonged cognitive stress (due to the small diameter of the PCA), we developed a protocol in which CBFv changes were measured in the middle cerebral artery (MCA). As a reduction in CBF may relate to hypocapnia in association with hyperventilation or increased tidal volume,(3),(4),(5) we included the measurement of respiratory rate and end tidal carbon dioxide (ETCO2) in studies with more prolonged stimuli. The results of our study of CBFv responses to orthostatic and prolonged cognitive stress in POTS and control groups are reported in Chapter 4. In this study, we demonstrated that prolonged cognitive stress was associated with a greater reduction in CBFv in the MCA in the patient group when compared with controls. We also studied the effect of midodrine, an alpha adrenergic agonist, on CBFv in the MCA in patients with POTS undergoing orthostatic and prolonged cognitive stress. Participants in this study were selected based on their previous symptomatic improvement in response to midodrine. We set out to determine if this symptomatic response was associated with an improvement in CBFv response to prolonged cognitive stress. The results of this study (reported in Chapter 5) were inconclusive. Whilst patients reported a significant improvement in symptom severity, and we detected an improvement in reaction time during cognitive testing following midodrine, we did not demonstrate an improvement in hemodynamic or CBFv responses to cognitive or orthostatic stress following administration of midodrine. This negative study could reflect a placebo effect in reporting of symptomatic improvement or that the study was underpowered to demonstrate a difference in CBFv response, however it suggests that TCD measurement of CBFv in the MCA in response to orthostatic and prolonged cognitive stress may not be as useful as we had hoped as an objective marker of response for future therapeutic trials in patients with POTS. In Chapter 6 we report on the use of plasma exchange therapy as a novel intervention in treatment resistant POTS. The use of plasma exchange in POTS was based on positive repsonses to plasma exchange in patients with a related condition (autoimmune autonomic ganglionopathy) (6) as well as reports of auto-antibodies in the sera of patients with POTS. (7). The clinical course, cognitive and CBFv reponses to orthostatic and cognitive stress in a patient treated with acute and maintenance plasma exchange therapy are suggestive of some improvement with plasma exchange however the brief duration of response following each treatment and the lack of response in other patients did not support plasma exchange as a viable long term option for POTS. Further studies are needed to evaluate TCD assessment of CBFv in POTS patients to define its utility in clinical practice. It would be of interest to study the CBFv response to prolonged cognitive stress after orthostatic stress in both POTS and control groups. A comparison of CBFv response to cognitive challenge measured by TCD with regional blood flow response using fMRI during an identical cognitive challenge would provide further insight into the utility of TCD as a tool to measure outcomes in clinical trials. As we advance our knowledge on the pathophysiology underlying this condition, a biomarker that correlates well with POTS symptom severity will be immensely valuable for clinicians managing this complex syndrome.