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The National Institutes of Health hosted a workshop in 2019 to build consensus around the current state of understanding of the pathophysiology of postural orthostatic tachycardia syndrome (POTS) and to identify knowledge gaps that must be addressed to enhance clinical care of POTS patients through research. This second (of two) articles summarizes current knowledge gaps, and outlines the clinical and research priorities for POTS. POTS is a complex, multi-system, chronic disorder of the autonomic nervous system characterized by orthostatic intolerance and orthostatic tachycardia without hypotension. Patients often experience a host of other related disabling symptoms. The functional and economic impacts of this disorder are significant. The pathophysiology remains incompletely understood. Beyond the significant gaps in understanding the disorder itself, there is a paucity of evidence to guide treatment which can contribute to suboptimal care for this patient population. The vast majority of physicians have minimal to no familiarity or training in the assessment and management of POTS. Funding for POTS research remains very low relative to the size of the patient population and impact of the syndrome. In addition to efforts to improve awareness and physician education, an investment in research infrastructure including the development of standardized disease-specific evaluation tools and outcome measures is needed to facilitate effective collaborative research. A national POTS research consortium could facilitate well-controlled multidisciplinary clinical research studies and therapeutic trials. These priorities will require a substantial increase in the number of research investigators and the amount of research funding in this area.

Patients with idiopathic REM-sleep behavior disorder (iRBD) are at substantial risk of progressive neurodegenerative disease of α-synuclein pathology. Longitudinal studies have demonstrated that abnormal α-synuclein deposition occurs early in the course of disease and may precede the appearance of motor symptoms by several decades. This provides rationale for the use of a reliable biomarker to both follow disease progression and to assess treatment response, once disease-modifying treatments become available. Tissue α-synuclein has emerged as a promising candidate, however the utility of α-synuclein detection in tissues accessible to biopsy in iRBD remains unclear. This article summarizes the current literature on the role of tissue biopsy in iRBD, with specific focus on its potential role as a biomarker of disease progression and its role in future clinical trials.

Background Post-ganglionic sudomotor abnormalities are common in Parkinson's disease (PD), however data in clinically isolated REM sleep behavior disorder (iRBD) are limited. Objective To determine the prevalence of sudomotor abnormalities in a cohort of patients with iRBD. Methods We performed a retrospective review of patients seen in our autonomic clinic who underwent testing with the quantitative sudomotor axon reflex test (QSART). We identified three groups for comparison: 1.) iRBD, 2.) PD with RBD (PDwRBD) 3.) PD without RBD (PDwoRBD). Results PDwRBD (n = 27) patients demonstrated the greatest sudomotor abnormalities (sudomotor CASS 1.44 ± 1.24), followed by PDwoRBD (n = 23, 0.57 ± 0.5) and iRBD (n = 20, 0.55 ± 0.94) (p = 0.015). Twenty percent of patients with iRBD had an abnormal result, compared to 67% PDwRBD and 35% PDwoRBD. Discussion Sudomotor abnormalities are common in patients with iRBD, supporting the concept that peripheral autonomic impairment occurs early in the course of disease.

Although there are reports of narcolepsy type 1 caused by lesions of the central nervous system, there are far fewer reports of narcolepsy type 2 (NT2) caused by discrete brain lesions. We report a case of a patient in whom NT2 was diagnosed after a viral illness, and inflammatory lesions in the right thalamus and amygdala were found. In addition, symptoms of autonomic impairment developed and postural tachycardia syndrome was subsequently diagnosed in this patient. To our knowledge this is the first reported case of NT2 resulting from central nervous system lesions in these discrete locations, as well as the first reported case of postural tachycardia syndrome associated with narcolepsy.

Fatigue is common in POTS, and patients often report unrefreshing sleep. These symptoms are directly correlated with a reduced quality of life, however the treatment of sleep disorders in this population remains a challenge. This article will review the current literature on the prevalence of sleep disorders in POTS, their association with the underlying pathophysiology of POTS, and current treatment paradigms.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia frequently affecting patients with synucleinopathies, but its exact prevalence in multiple system atrophy (MSA) is unclear. Whether questionnaires alone are sufficient to diagnose RBD is also unknown. We performed a cross-sectional study of patients with probable MSA from six academic centers in the US and Europe. RBD was ascertained clinically and with polysomnography; we also performed a meta-analysis according to PRISMA guidelines for studies published before September 2014 that reported the prevalence of RBD in MSA. A random-effects model was constructed using weighted prevalence proportions. Only articles in English were included. Studies were classified into those that ascertained the presence of RBD in MSA clinically and with polysomnography. Case reports or case series (≤5 patients) were not included. Forty-two patients completed questionnaires and underwent polysomnography. Of those, 32 (76.1 %) had clinically suspected RBD and 34 (81 %) had polysomnography-confirmed RBD. Two patients reported no symptoms of RBD but had polysomnography-confirmed RBD. The primary search strategy yielded 374 articles of which 12 met the inclusion criteria. The summary prevalence of clinically suspected RBD was 73 % (95 % CI, 62–84 %) in a combined sample of 324 MSA patients. The summary prevalence of polysomnography-confirmed RBD was 88 % (95 % CI, 79–94 %) in a combined sample of 217 MSA patients. Polysomnography-confirmed RBD is present in up to 88 % of patients with MSA. RBD was present in some patients that reported no symptoms. More than half of MSA patients report symptoms of RBD before the onset of motor deficits.

Neurogenic orthostatic hypotension is a highly prevalent and disabling feature of autonomic failure due to both peripheral and central neurodegenerative diseases. Community-based epidemiological studies have demonstrated a high morbidity and mortality associated with neurogenic orthostatic hypotension. It is due to impairment of baroreflex-mediated vasoconstriction of the skeletal muscle and splanchnic circulation and is caused by damage or dysfunction at central and/or peripheral sites in the baroreflex efferent pathway. Nonpharmacological and pharmacological interventions may be implemented to ameliorate the symptoms of orthostatic intolerance and improve quality of life. Many patients will be adequately treated by education, counseling, removal of hypotensive medications, and other nonpharmacological interventions, whereas more severely afflicted patients require pharmacological interventions. The first stage of pharmacological treatment involves repletion of central blood volume. If unsuccessful, this should be followed by treatment with sympathomimetic agents.

Sleep is a complex homeostatic function, regulated in part by control nuclei of the autonomic nervous system. When sleep is disrupted, symptoms of autonomic impairment may emerge. In addition, many primary disorders of autonomic dysfunction can disrupt sleep. This chapter will briefly review the anatomy of the autonomic and sleep systems, the physiology of autonomic function during normal sleep, and some of the techniques used to measure autonomic function during sleep. Autonomic disorders with prominent sleep impairment are reviewed, including postural tachycardia syndrome and the disorders of α-synuclien deposition.

Kleine-Levin syndrome is a rare recurrent hypersomnia associated with symptoms of behavioral and cognitive impairment. This article reviews common presenting symptoms, differential diagnosis, diagnostic workup, and potential treatment options. Current updates on functional imaging studies and long-term neuropsychological studies are reviewed.

Lumbar drains are frequently used in clinical neuroscience and are often managed in the neurointensive care unit. Complications are generally rare, and intracranial venous thrombosis (IVT) and infarction has not been reported. We report the case of a 45-year-old woman who developed a cerebrospinal fluid (CSF) leak after spinal surgery. Fifteen hours after placement of a lumbar drain she developed pure alexia and color agnosia caused by left lateral sinus thrombosis with hemorrhagic infarction in the posterior inferior left temporal lobe. We review the literature on the association of IVT with injury to the spinal dura, and we propose a mechanism whereby the lumbar drain may facilitate its development. We found 29 cases in which spinal dural injury was followed by IVT. The association is not coincidental, because nearly all cases were associated with post-dural puncture headache, which occurs in only a minority of cases of dural puncture. Injury to the spinal dura alters the distribution of craniospinal elasticity causing profound intracranial CSF hypotension on assuming the erect posture. This causes acute dilation of cerebral veins resulting in both orthostatic headache and venous stasis. We propose that placement of the lumbar drain and elevation of the head of the bed aggravated intracranial CSF hypotension and facilitated IVT. When a lumbar drain is placed for treatment of a spinal CSF leak, the patient should remain flat in bed. Any patient with post-dural injury headache that intensifies after an initial plateau, persists for longer than a week, or loses its orthostatic character should be evaluated for intracranial sinus or venous thrombosis.

Patients with postural tachycardia syndrome (POTS) often describe symptoms of fatigue, sleepiness, and lack of refreshing sleep. We aimed to provide further objective measures of sleep in patients with POTS. POTS patients (n = 18) were selected based on autonomic testing and evaluation at our center. Controls (n = 16) of similar age, gender, and BMI were selected from new patients referred to the Stanford Sleep Disorders Clinic for any sleep-related complaint. All patients underwent polysomnography and completed several sleep questionnaires and a 2-week sleep diary. POTS patients and control subjects were of similar age (27 ± 10.2 vs. 29 ± 5.4 years, p = 0.92) and Body Mass Index (21 ± 3.8 vs. 24 ± 4.1, p = 0.14). The majority of subjects in both groups were females (72 % POTS vs. 81 % controls). POTS patients scored higher on subjective fatigue scales but not sleepiness scales. POTS patients scored in the normal range on the BDI and the “evening” category on the MEQ. Their sleep diaries were not different from controls. With the exception of mild OSA, slightly reduced %REM and prolonged REM latency, their PSG data were normal and no different from controls. It is unlikely that the sleep-related complaints of POTS patients are the result of a primary sleep disorder unique to POTS. We propose that a combination of factors such as body fatigue, chronic pain, and other somatic symptoms common in POTS patients might be the underlying reason for sleep-related symptoms in POTS.

The autonomic nervous system plays an important role in the coordination of many important physiologic functions during sleep. Many patients with untreated sleep disorders will describe symptoms of autonomic impairment, and a majority of patients with autonomic impairment have some form of sleep disorder. This article will explore possible explanations for this connection, as well as review the current literature on autonomic impairment in common primary sleep disorders including obstructive sleep apnea, insomnia, restless legs syndrome, periodic limb movement disorder, narcolepsy, and rapid eye movement sleep behavior disorder.

Autonomic nervous system (ANS) dysfunction as a cause of disease is an increasingly recognized health problem, not only in the field of neurology, but also in cardiology, gastroenterology, endocrinology, urology, psychiatry, and primary care medicine. Patients may present with a myriad of symptoms including orthostatic intolerance, recurrent syncope, labile blood pressure, disorders of sweating and thermoregulation, neurogenic bladder, sexual dysfunction, gastrointestinal dysmotility, pupil abnormalities, and sleep disorders. These symptoms may, in turn, be a consequence of genetic (e.g., hereditary sensory and autonomic neuropathies, transthyretin amyloidosis), neurodegenerative (e.g., Parkinson disease [PD], multiple system atrophy [MSA]), autoimmune (e.g., autoimmune ganglionopathies), or acquired disorders (e.g., spinal cord lesions, type 2 diabetes). Although autonomic symptoms may be among the most debilitating features of these progressive conditions, they are often treatable. Autonomic disorders specialists require a comprehensive knowledge of the anatomy, physiology, and pharmacology of the ANS, understanding of the pathophysiology and management of acute and chronic autonomic conditions, and expertise in the performance and interpretation of clinical and laboratory evaluation of the ANS. The authors thank Dr. Horacio Kaufmann for reviewing an earlier version of this manuscript.

It is not yet clear what exact mechanisms are at work in hibernating animals that prevent clot formation and maintain tissue perfusion under conditions of very slow blood flow and increased blood viscosity brought about by the low temperatures. It has been shown that the total amino acid pool increases more then two fold in hibernating animals with taurine accounting for about 50% of this increase [Storey et al., Proc Natl Acad Sci USA 1988; 85(21): 8350-4]. This work investigates the effect of taurine on platelets and the plasma coagulation system. Taurine was added at different concentrations in the range between 5 and 25 mM to donor plasma. Using STA/STA Compact coagulation analyzer the following tests were performed: prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time (TT). At the highest concentration tested (25 mM) taurine prolonged TT by 9%. The prolongation was statistically significant but not clinically significant retaining TT within normal limits (16.7-20.7 s). PT and APTT remained unchanged by taurine. The effect of taurine on platelets was assessed by platelet aggregation by thrombin, extent of platelet shape change (ESC) induced by ADP, and thrombelastography. Taurine at 5 mM final concentration inhibited platelet aggregation by 10%. Increasing taurine concentration to 25 mM did not result in a further augmentation of the inhibitory effect. ESC was unaffected by taurine. Clot strength determined by thrombelastography also remained unchanged by taurine.

Kleine-Levin syndrome is a recurrent hypersomnia associated with symptoms of hyperphagia, hypersexuality, and cognitive impairment. This article reviews the current available research and describes common clinical symptoms, differential diagnosis, and acceptable workup and treatment. Although deficits have traditionally been thought to resolve between episodes, functional imaging studies and long-term neuropsychological testing in select patients have recently challenged this notion. This may suggest that Kleine-Levin syndrome is not as benign as previously considered.

Autoimmune autonomic ganglionopathy (AAG) and myasthenia gravis (MG) are both autoimmune channelopathies mediated by antibodies directed against nicotinic acetylcholine receptors. While both diseases target acetylcholine receptors, skeletal muscle and ganglionic receptor subtypes have key immunologic and genetic distinctions, and reports of patients with both AAG and MG are rare. We report a patient with antibody-confirmed AAG and elevated levels of ACh binding antibodies that did not meet clinical or electrodiagnostic criteria for MG. We presume that his skeletal muscle nAChR seropositivity was a false positive, perhaps due to the cross reactivity of the patient's ganglionic nAChR antibodies with skeletal nAChR subtypes.