Tafamidis for autonomic neuropathy in hereditary transthyretin (ATTR) amyloidosis: a review Abstract Purpose Autonomic dysfunction is a very common, early and distressing aspect of hereditary transthyretin (ATTR) amyloidosis leading to significant loss of quality of life and morbidity for patients. Although the clinical variability of ATTR has been well characterized as neuropathic, cardiac or mixed phenotype, the extent of autonomic involvement remains poorly understood. Despite the fact that the autonomic nervous system has not been specifically evaluated in any of the clinical trials of tafamidis, and that, for some primary and secondary endpoints used in these trials, the behavior cannot be separated from non-autonomic items, an attempt was made to use published material to indirectly access the efficacy of tafamidis in treating dysautonomia. Methods Literature review summarizing the results of primary and secondary endpoints related to the autonomic features used in the original tafamidis trials, the post hoc publications, and real-world data, on the effect of tafamidis on autonomic dysfunction in patients with ATTR amyloidosis. Results There is some evidence that indirectly demonstrates that tafamidis is safe and could slow or arrest the progression of autonomic neuropathy in patients with ATTR amyloidosis, in addition to its well-described effects to ameliorate sensory-motor peripheral neuropathy. Conclusion Although the current evidence is scarce, tafamidis might be effective in arresting the progression of autonomic neuropathy in patients with ATTR amyloidosis. Tafamidis might be more effective at the early stage of the disease; however, individual responses must be monitored.

Novel RNA-targeted therapies for hereditary ATTR amyloidosis and their impact on the autonomic nervous system Abstract Purpose Transthyretin-mediated hereditary amyloidosis (hATTR amyloidosis) is a multisystemic disease with heterogeneous clinical presentation. Hallmarks of the disease are sensory-motor and autonomic neuropathy and cardiomyopathy. Two disease-modifying drugs, inotersen (an antisense oligonucleotide) and patisiran (a small interfering RNA agent), were recently approved for the treatment of hATTR polyneuropathy. We here review the results of the RNA-targeted therapy clinical trials with special emphasis on the endpoints measuring autonomic symptoms and function. Methods Literature review. We used the terms “autonomic neuropathy”, “dysautonomia”, “autonomic symptoms”, “oligonucleotides”, “inotersen” and “patisiran” in patients with hATTR amyloidosis. Results In the NEURO-TTR (inotersen) clinical trial, the modified NIS+7 score (mNIS+7) remained stable in 36% of the patients in the inotersen arm (defined as a change of less than 2 points), and 50% of patients had improved quality of life (Norfolk-QOL-DN score) after 15 months. In the APOLLO patisiran trial, 74% of the patients showed stabilization of the neuropathy, defined as a < 10 points increase on mNIS+7, and 51% of patients showed an improvement of quality of life (Norfolk QOL-DN), favoring patisiran at 18 months. Patients on patisiran had a reduced burden of autonomic dysfunction as measured by the COMPASS-31, and a stabilization of nutritional status, suggesting an effect on gastrointestinal autonomic function. Conclusions Clinical trials of inotersen and patisiran showed that these agents were able to halt the progression of the disease, with some patients even reducing the burden of polyneuropathy, and improving qualify of life. The information on their impact on autonomic parameters is limited, warranting further dedicated studies.

Orthostatic heart rate does not predict symptomatic burden in pediatric patients with chronic orthostatic intolerance Abstract Purpose Postural orthostatic tachycardia syndrome (POTS) in adults is defined as symptoms of chronic orthostatic intolerance (COI) and autonomic dysfunction (AD) with heart rate (HR) increase of 30 beats per minute (bpm), or HR > 120 bpm, during prolonged upright position. However, in adolescents, POTS is defined as symptoms of OI and AD with HR increase of ≥ 40 bpm, based on tilt table data. We assessed frequency of COI symptoms in pediatric patients versus HR criteria on prolonged standing to evaluate using criteria of increased HR of 30–39 bpm versus ≥ 40 bpm in our POTS Program. Methods Patients with COI with symptoms for > 3 months plus HR increase of ≥ 30 bpm on 10 min stand aged ≤ 18 years at diagnosis were included. Patients were divided into two groups: those with HR increase of 30–39 bpm, and those with HR increase of ≥ 40 bpm or upright HR of > 120 bpm. A total of 28 symptoms described prior to diagnosis were evaluated using chi-square testing to assess for significant differences. Results Only insomnia was found to be significantly different between the two groups. The other 27 symptoms showed no significant difference as a function of HR. Conclusion There are minimal statistically significant differences and no clinical differences between patients as a function of HR increase during standing. Thus, a 40-bpm threshold for adolescents on standing test may be too high, or a specific HR criteria threshold is neither predictive nor definitive in diagnosing POTS.

Quantitative magnetic resonance evaluation of the trigeminal nerve in familial dysautonomia Abstract Purpose Familial dysautonomia (FD) is a rare autosomal recessive disease that affects the development of sensory and autonomic neurons, including those in the cranial nerves. We aimed to determine whether conventional brain magnetic resonance imaging (MRI) could detect morphologic changes in the trigeminal nerves of these patients. Methods Cross-sectional analysis of brain MRI of patients with genetically confirmed FD and age- and sex-matched controls. High-resolution 3D gradient-echo T1-weighted sequences were used to obtain measurements of the cisternal segment of the trigeminal nerves. Measurements were obtained using a two-reader consensus. Results Twenty pairs of trigeminal nerves were assessed in ten patients with FD and ten matched controls. The median (interquartile range) cross-sectional area of the trigeminal nerves in patients with FD was 3.5 (2.1) mm2, compared to 5.9 (2.0) mm2 in controls (P < 0.001). No association between trigeminal nerve area and age was found in patients or controls. Conclusions Using conventional MRI, the caliber of the trigeminal nerves was significantly reduced bilaterally in patients with FD compared to controls, a finding that appears to be highly characteristic of this disorder. The lack of correlation between age and trigeminal nerve size supports arrested neuronal development rather than progressive atrophy.

The Schellong test: detecting orthostatic blood pressure and heart rate changes in German-speaking countries

The microbiome in autonomic medicine and other updates in recent autonomic research

Autonomic dysfunction in myalgic encephalomyelitis and chronic fatigue syndrome: comparing self-report and objective measures

Physical activity and dietary interventions in diabetic neuropathy: a systematic review Abstract Purpose Diabetic neuropathy is a common and disabling disorder, and there are currently no proven effective disease-modifying treatments. Physical activity and dietary interventions in patients with diabetes and diabetic neuropathy have multiple beneficial effects and are generally low risk, which makes lifestyle interventions an attractive treatment option. We reviewed the literature on the effects of physical activity and dietary interventions on length-dependent peripheral neuropathy and cardiac autonomic neuropathy in diabetes. Methods The electronic database PubMed was systematically searched for original human and mouse model studies examining the effect of either dietary or physical activity interventions in subjects with diabetes, prediabetes, or metabolic syndrome. Results Twenty studies are included in this review. Fourteen studies were human studies and six were in mice. Studies were generally small with few controlled trials, and there are no widely agreed upon outcome measures. Conclusions Recent research indicates that dietary interventions are effective in modifying diabetic neuropathy in animal models, and there are promising data that they may also ameliorate diabetic neuropathy in humans. It has been known for some time that lifestyle interventions can prevent the development of diabetic neuropathy in type 2 diabetes mellitus subjects. However, there is emerging evidence that lifestyle interventions are effective in individuals with established diabetic neuropathy. In addition to the observed clinical value of lifestyle interventions, there is emerging evidence of effects on biochemical pathways that improve muscle function and affect other organ systems, including the peripheral nerve. However, data from randomized controlled trials are needed.

Induced pluripotent stem cells in multiple system atrophy: recent developments and scientific challenges Abstract Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disease, with no known genetic cause to date. Oligodendroglial α-synuclein accumulation, neuroinflammation, and early myelin dysfunction are hallmark features of the disease and have been modeled in part in various preclinical models of MSA, yet the pathophysiology of MSA remains elusive. Here, we review the role and scientific challenges of induced pluripotent stem cells in the detection of novel biomarkers and druggable targets in MSA.

Complex regional pain syndrome: a focus on the autonomic nervous system Abstract Purpose Although autonomic features are part of the diagnostic criteria for complex regional pain syndrome (CRPS), the role of the autonomic nervous system in CRPS pathophysiology has been downplayed in recent years. The purpose of this review is to redress this imbalance. Methods We focus in this review on the contribution of the autonomic nervous system to CRPS pathophysiology. In particular, we discuss regional sympathetic and systemic autonomic disturbances in CRPS and the mechanisms which may underlie them, and consider links between these mechanisms, immune disturbances and pain. Results The focused literature research revealed that immune reactions, alterations in receptor populations (e.g., upregulation of adrenoceptors and reduced cutaneous nerve fiber density) and central changes in autonomic drive seem to contribute to regional and systemic disturbances in sympathetic activity and to sympathetically maintained pain in CRPS. Conclusions We conclude that alterations in the sympathetic nervous system contribute to CRPS pathology. Understanding these alterations may be an important step towards providing appropriate treatments for CRPS.