This article reviews the clinical, neurophysiologic, and neuropathologic findings in patients presenting with small fiber neuropathies. Emphasis is placed on recent updates to the literature, but also on understanding the differential diagnosis and initial evaluation of patients with small fiber neuropathy. There have been several updates in the literature about diseases associated with small fiber neuropathy. First, treatment-induced neuropathy in diabetes mellitus is an iatrogenic small fiber neuropathy linked to overly rapid correction in blood glucose levels in the setting of chronic hyperglycemia. Second, several novel mutations to sodium channels have been identified in patients presenting with idiopathic small fiber neuropathy that may significantly alter our understanding and future treatment of small fiber neuropathy. Third, antibodies against voltage-gated potassium channels appear to be associated with a much higher incidence of pain than would be expected, although the mechanism has not been established. Fourth, the link between glucose dysregulation, metabolic syndrome, and neuropathy continues to grow. Finally, several other disorders, including postural orthostatic tachycardia syndrome, have been postulated to be associated with small fiber neuropathies. Small fiber neuropathies are a heterogeneous group of disorders that may present with a variety of sensory or autonomic symptoms. Recent reports highlight a number of new causes of small fiber neuropathy that continue to reduce the number of remaining idiopathic cases.

Postural orthostatic tachycardia syndrome (POTS) is associated with many symptoms including orthostatic intolerance, fatigue, palpitations, and cognitive dysfunction. Treatment, which typically consists of exercise, increased dietary sodium and fluids, compression garments, and medications for orthostatic intolerance, frequently produces unsatisfactory results. The authors report the case of a 26-year-old woman who presented with a 6-year history of severe fatigue, orthostatic intolerance, heat intolerance, cognitive dysfunction, and diffuse pain. She had previously injured her jaw on an obstacle course. Results of a standing test were consistent with POTS. After standard medical therapy was unsuccessful, the patient was referred for osteopathic manipulative treatment. At her 18-month follow-up, the patient's symptoms had improved dramatically. Physicians should consider osteopathic evaluation and manipulative treatment when caring for patients with POTS.

To evaluate the prevalence of joint hypermobility (JH) and comorbid conditions in children and young adults referred to a tertiary care neurogastroenterology and autonomic disorders clinic for functional gastrointestinal complaints. This was a retrospective chart review of 66 new patients aged 5-24 years who fulfilled at least 1 pediatric Rome III criteria for a functional gastrointestinal disorder (FGID) and had a recorded Beighton score (n = 45) or fibromyalgia tender point score (n = 45) based on physician examination. Comorbid symptoms were collected and autonomic testing was performed for evaluation of postural tachycardia syndrome (POTS). The median patient age was 15 years (range, 5-24 years), 48 (73%) were females, and 56% had JH, a significantly higher rate compared with population studies of healthy adolescents (P < .001; OR, 10.03; 95% CI, 5.26-19.13). POTS was diagnosed in 34% of patients and did not correlate significantly with hypermobility. Comorbid conditions were common, including sleep disturbances (77%), chronic fatigue (93%), dizziness (94%), migraines (94%), chronic nausea (93%), and fibromyalgia (24%). JH and other comorbid symptoms, including fibromyalgia, occur commonly in children and young adults with complex FGIDs. POTS is prevalent in FGIDs but is not associated with hypermobility. We recommend screening patients with complex FGIDs for JH, fibromyalgia, and comorbid symptoms such as sleep disturbances, migraines, and autonomic dysfunction.

Postural changes in 258 patients with pulmonary arteriovenous malformations (PAVMs) reviewed between 2005 and 2013 were evaluated prospectively using validated pulse oximetry methods. Of the 257 completing the test, 75 (29%) demonstrated orthodeoxia with an oxygen saturation fall of at least 2% on standing. None described platypnoea (dyspnoea on standing). The heart rate was consistently higher in the erect posture: 74 (29%) had a postural orthostatic tachycardia of ≥20 min(-1), and in 25 (10%) this exceeded 30 min(-1). Orthostatic tachycardia was more pronounced in PAVM patients than controls without orthodeoxia (age-adjusted coefficient 5.5 (95% CIs 2.6, 8.4) min(-1), p<0.001). For PAVM patients, the age-adjusted pulse rise was 0.79 min(-1) greater for every 1% greater drop in oxygen saturation on standing (p<0.001). In contrast to the postural orthostatic tachycardia syndrome, in this population, there was a trend for more pronounced orthostatic tachycardia to be associated with better exercise tolerance.

We described a heterogenous group of children disabled by postural tachycardia syndrome (POTS) and evident orthostatic hypertension (OHT). Twenty patients met the diagnostic criteria for POTS + OHT. Their clinical characteristics were compared with those in 76 patients with POTS alone and 20 healthy age-matched controls. Multivariate logistic regression analysis was used to identify independent risk factors for POTS + OHT. Supine systolic blood pressure (SBP) was lower in the POTS + OHT group than in the POTS group (p < 0.05). Compared with the POTS group, the POTS + OHT group showed markedly increased upright SBP, upright heart rate (HR) and HR changes (p < 0.05). Headache was more common in the POTS + OHT group than in the POTS group (p < 0.05). Logistic regression analysis revealed that low supine SBP and headache were independent risk factors for OHT in POTS patients. Headache and low supine SBP were the main clinical characteristics of a novel syndrome of POTS associated with OHT.

Our objective was to examine the differences in cardiac autonomic function in Postural Tachycardia Syndrome (POTS) versus inappropriate sinus tachycardia (IST). Subjects (IST, n = 8; POTS, n = 12) were studied using standard measurements of the autonomic reflex screen, baroreflex function and spectral analysis. Data was compared to age/gender-matched controls (n = 20). The components of the autonomic reflex screen did not differ between groups. The exception was the significant but expected difference in postural heart rate increment on head-up tilt in POTS (47.9 ± 13.8; n = 12) compared to IST (30.9 ± 9.7; n = 8; p = 0.008). Accordingly the Orthostatic Intolerance Scale showed significantly greater orthostatic symptoms in POTS (2.6 ± 0.5; n = 12) versus IST patients (0.4 ± 0.5; n = 8; p < 0.001). Conversely, IST patients had a significantly higher resting heart rate (96 ± 12; n = 8) when compared to POTS patients (73 ± 12; n = 12; p = 0.001). There was a significant difference in vagal baroreflex sensitivity (BRSv) in POTS (8.21 ± 2.3, n = 12) compared to IST patients (5.30 ± 2.94, n = 8, p = 0.036) during the Valsalva maneuver. Only POTS subjects showed a significant increase in sympathovagal balance (LF/HF) with tilt (FFT, 8.29 ± 6.38; AR, 7.84 ± 5.24) compared to the supine position (FFT, 2.25 ± 1.75; AR, 1.99 ± 1.38; p < 0.05) for both frequency domains. Differences in cardiac autonomic function contribute to changes in positional and non-positional heart rate in postural tachycardia syndrome versus inappropriate sinus tachycardia. These findings shed further light on the autonomic dysfunction underlying POTS and IST.

Healthy subjects with asymptomatic postural tachycardia (≥30 bpm) at baseline were evaluated over a 1-year period to determine whether they developed orthostatic symptoms. Subjects were evaluated at baseline and at 1 year using the autonomic reflex screen and autonomic symptom profile (ASP). Heart rate increment on HUT did not differ at baseline (40.6 ± 7.5 bpm) or at 1 year (37.1 ± 11.1 bpm; n = 26; p > 0.05). Orthostatic symptoms measured by the ASP did not reveal significant orthostatic dysfunction throughout follow-up (baseline, 7.88 ± 7.61; 1 year, 9.04 ± 6.64; n = 26; p > 0.05). The ten autonomic domains of the ASP did not reveal a change in autonomic symptoms from baseline (13.56 ± 13.66) to 1-year follow-up (15.12 ± 11.62; n = 26; p > 0.05). Cardiovagal function was unchanged between baseline and follow-up for both heart rate variability to deep breathing (baseline, 23.9 ± 11.6 bpm; 1 year, 23.0 ± 9.3 bpm; n = 26; p > 0.05) and Valsalva ratio (baseline, 2.16 ± 0.39; 1 year, 2.15 ± 0.33; n = 26; p > 0.05). These findings further argue that heart rate criteria (≥30 bpm) for Postural Tachycardia Syndrome (POTS) are not appropriate in younger individuals and higher postural heart rates do not predispose individuals to the development of POTS.

Postural tachycardia syndrome (POTS) is characterized clinically not only by an exaggerated increase in heart rate (HR), but an associated cognitive impairment that disables many patients. Modafinil might be effective in improving the cognitive symptoms, but modafinil may stimulate the sympathetic nervous system and worsen tachycardia in POTS. We tested the hypothesis that modafinil would worsen tachycardia and orthostatic symptoms in POTS. Patients with POTS (n = 54) underwent a randomized crossover trial with modafinil 100 mg versus placebo. Heart rate and systolic blood pressure (SBP) were measured seated and standing before modafinil or placebo administration and then hourly for 4 hours. Over 4 hours, standing HR was not significantly different between the modafinil and placebo groups (analysis of variance [ANOVA] Pdrug = 0.328), but seated SBP was significantly higher in the modafinil group (mean [SD], 109 [12] mm Hg vs 104 [10] mm Hg; P = 0.004). Modafinil also significantly increased both the seated SBP (ANOVA Pdrug = 0.004) and the standing SBP (ANOVA Pdrug = 0.041) over time. There was no significant difference between modafinil and placebo over the 4-hour period with regard to POTS symptom burden scores (14 [12] vs 14 [12]; P = 0.962). Modafinil did not significantly worsen standing HR or acute orthostatic symptoms in patients with POTS compared with the placebo group and improved upright blood pressure. Therefore, modafinil could be tested as a potential treatment for the cognitive impairment in POTS.

Hyperadrenergic postural tachycardia syndrome (POTS) is the main phenotype of POTS. The aim of this study was to present our single-center experience of hyperadrenergic POTS in children and adolescents. Thirty-seven patients who met the diagnostic criteria for POTS were enrolled in our study. Their orthostatic serum norepinephrine levels were determined by high-performance liquid chromatography. In a retrospective analysis, based on clinical and serum norepinephrine criteria, we analyzed the clinical features of POTS cases between the POTS-alone group and the hyperadrenergic POTS group. Nineteen patients (51.35%) met the diagnostic criteria for hyperadrenergic POTS and 18 patients were assigned to the POTS-alone group. Compared with the POTS-alone patients, dizziness, headache and tremulousness were more frequent in patients with hyperadrenergic POTS (P < 0.05). During the tilt table test, children with hyperadrenergic POTS had a greater increment of systolic blood pressure and heart rate than POTS-alone patients. Patients with hyperadrenergic POTS should be identified and differentiated from those with neuropathic POTS. Hyperadrenergic POTS in children and adolescents should be considered when POTS patients suffer from frequent dizziness, headache, and tremulousness. In head-up tilt testing, children and adolescents with hemodynamic characteristics of hyperadrenergic POTS had greater increments of systolic blood pressure and heart rate.

Postural tachycardia syndrome (POTS) is a disorder of orthostatic intolerance characterized by excessive tachycardia of unknown etiology. Our objective in this study was to evaluate the correlation between C-fiber involvement as shown by skin biopsy and adrenergic cardiac metaiodobenzylguanadine (MIBG) uptake in POTS patients. Skin biopsies of 84 patients with POTS were examined by Protein Gene Product 9.5 (PGP9.5) immunohistochemistry and were compared with MIBG myocardial scintigraphy imaging data. Mean intraepidermal nerve fiber (IENF) density was in the lower normal age-adjusted range, 7.2 ± 2.9/mm (normal ≥ 7/mm), and was slightly below the normal range in 45% of POTS patients. MIBG uptake was reduced in 21% of patients. Low IENF density correlated with reduced cardiac MIBG uptake (r = 0.39, P = 0.001). A subset of neuropathic POTS patients may harbor mild small fiber neuropathy with abnormalities of unmyelinated nerve fibers in the skin associated with reduced myocardial postganglionic sympathetic innervation.

Brain "fog" is a constellation of symptoms that include reduced cognition, inability to concentrate and multitask, as well as loss of short and long term memory. Brain "fog" characterizes patients with autism spectrum disorders (ASDs), celiac disease, chronic fatigue syndrome, fibromyalgia, mastocytosis, and postural tachycardia syndrome (POTS), as well as "minimal cognitive impairment," an early clinical presentation of Alzheimer's disease (AD), and other neuropsychiatric disorders. Brain "fog" may be due to inflammatory molecules, including adipocytokines and histamine released from mast cells (MCs) further stimulating microglia activation, and causing focal brain inflammation. Recent reviews have described the potential use of natural flavonoids for the treatment of neuropsychiatric and neurodegenerative diseases. The flavone luteolin has numerous useful actions that include: anti-oxidant, anti-inflammatory, microglia inhibition, neuroprotection, and memory increase. A liposomal luteolin formulation in olive fruit extract improved attention in children with ASDs and brain "fog" in mastocytosis patients. Methylated luteolin analogs with increased activity and better bioavailability could be developed into effective treatments for neuropsychiatric disorders and brain "fog."

Postural Tachycardia Syndrome (PoTS) represents a disorder of the autonomic nervous system that results in symptoms of orthostatic intolerance. Despite having a severe impact on the patient's quality of life, the current treatment options for PoTS are based on limited evidence. Subsequently, this results in clinicians having to utilise a variety of treatment regimens in the hope of successfully providing symptomatic relief. However, the options available for PoTS are not without significant side effects that can worsen an already debilitating condition. Our cases provide a further novel treatment option for clinicians to consider in PoTS refractory to established treatments.

To explore the point prevalence of painful temporomandibular disorders (TMD) in a well-characterized clinical cohort of postural orthostatic tachycardia syndrome (PoTS) sufferers and to understand the functional and physiologic impact of this comorbidity on the patient. Patients with PoTS were retrospectively recruited from a previous study conducted in a UK hospital setting. Data had previously been collected on several parameters, including sociodemographic, physiologic, and functional. The participants were mailed a highly sensitive (99%) and specific (97%) self-report screening instrument for painful TMD. Simple descriptive statistics with Fisher Exact and Kruskal-Wallis tests were used to examine the data and draw inferences from it. A total of 36 individuals responded (69% response rate). Just under half (47%) of the sample screened positive for painful TMD. There was no significant difference between the screening result for TMD or previously reported headaches or joint pain (P < .05). Chronic fatigue syndrome (CFS) was diagnosed by the Fukuda Criteria in 44% of the total sample and in 56% of those with painful TMD. There were no significant differences in physiologic parameters in CFS and TMD. TMD caused a significant decrease in quality of life as measured by the Patient-Reported Outcomes Measurement Information System, Health Assessment Questionnaire (P < .05). TMD are common in patients with PoTS. They have a significant, additional impact on patients' quality of life and should therefore be screened for at an early stage in PoTS.

We evaluated the cortical morphology in patients with orthostatic intolerance. Thirty patients with orthostatic intolerance, as well as age- and sex-matched normal controls, were enrolled in this study. We divided the patients into orthostatic hypotension (n = 22) and postural tachycardia syndrome (n = 8) groups based on their response to a head-up tilt table test. We analyzed whole-brain T1-weighted MRI images using FreeSurfer 5.1. The measures of cortical morphology were compared between the groups. The cortical thickness in the right hemisphere, including the medial orbitofrontal, peri-calcarine, post-central, inferior temporal, and lateral occipital cortex, and in the peri-calcarine cortex of the left hemisphere was thinned in patients with orthostatic hypotension compared to normal controls. The other measures of cortical morphology, including the surface area, volume, and curvatures, did not differ between patients with orthostatic hypotension and normal controls. However, none of the measures of cortical morphology differed between patients with postural tachycardia syndrome and normal controls. We demonstrated that the cortical morphology significantly changed in patients with orthostatic hypotension but not in patients with postural tachycardia syndrome compared to normal controls. These findings support the hypothesis that orthostatic intolerance is a heterogeneous syndrome.

Postural tachycardia syndrome (PoTS), a form of dysautonomia, is characterized by orthostatic intolerance, and is frequently accompanied by a range of symptoms including palpitations, lightheadedness, clouding of thought, blurred vision, fatigue, anxiety, and depression. Although the estimated prevalence of PoTS is approximately 5-10 times as common as the better-known condition orthostatic hypotension, the neural substrates of the syndrome are poorly characterized. In the present study, we used magnetic resonance imaging (MRI) with voxel-based morphometry (VBM) applying the diffeomorphic anatomical registration through exponentiated lie algebra (DARTEL) procedure to examine variation in regional brain structure associated with PoTS. We recruited 11 patients with established PoTS and 23 age-matched normal controls. Group comparison of gray matter volume revealed diminished gray matter volume within the left anterior insula, right middle frontal gyrus and right cingulate gyrus in the PoTS group. We also observed lower white matter volume beneath the precentral gyrus and paracentral lobule, right pre- and post-central gyrus, paracentral lobule and superior frontal gyrus in PoTS patients. Subsequent ROI analyses revealed significant negative correlations between left insula volume and trait anxiety and depression scores. Together, these findings of structural differences, particularly within insular and cingulate components of the salience network, suggest a link between dysregulated physiological reactions arising from compromised central autonomic control (and interoceptive representation) and increased vulnerability to psychiatric symptoms in PoTS patients.

POTS is a global public-health disease, but predictor for therapeutic response to metoprolol in children with POTS is lacking. This study was designed to investigate predictive value of plasma C-type natriuretic peptide (CNP) in the therapeutic efficacy of metoprolol on postural tachycardia syndrome (POTS) in children. Totally 34 children with POTS and 27 healthy children were included in the study. The head-up test or head-up tilt test was used to check heart rate and blood pressure from supine to upright in subjects. A double antibody (competitive) sandwich immunoluminometric assay was used to detect plasma CNP. Metoprolol was used to treat children with POTS. The difference in plasma concentrations of CNP between responders and non-responders was compared. An ROC curve was used to analyze plasma CNP to predict efficacy of metoprolol on POTS in children. Plasma CNP in children with POTS was significantly higher than that of healthy children [(51.9 ± 31.4) vs. (25.1 ± 19.1) pg/ml, P <0.001]. Plasma CNP in responders to metoprolol was significantly higher than non-responders [(59.1 ± 33.5) vs. (34.8 ± 16.7) pg/ml, P = 0.037] before treatment. The ROC curve showed that area under the curve was 0.821 (95% CI 0.642-0.999). The cut-off value of plasma CNP > 32.55 pg/ml yielded a sensitivity of 95.8% and specificity of 70% in predicting therapeutic efficacy of metoprolol on POTS children. Plasma CNP might serve as a useful predictor for the therapeutic efficacy of metoprolol on POTS in children.

This review explores the proposal that vulnerability to psychological symptoms, particularly anxiety, originates in constitutional differences in the control of bodily state, exemplified by a set of conditions that include Joint Hypermobility, Postural Tachycardia Syndrome and Vasovagal Syncope. Research is revealing how brain-body mechanisms underlie individual differences in psychophysiological reactivity that can be important for predicting, stratifying and treating individuals with anxiety disorders and related conditions. One common constitutional difference is Joint Hypermobility, in which there is an increased range of joint movement as a result of a variant of collagen. Joint hypermobility is over-represented in people with anxiety, mood and neurodevelopmental disorders. It is also linked to stress-sensitive medical conditions such as irritable bowel syndrome, chronic fatigue syndrome and fibromyalgia. Structural differences in "emotional" brain regions are reported in hypermobile individuals, and many people with joint hypermobility manifest autonomic abnormalities, typically Postural Tachycardia Syndrome. Enhanced heart rate reactivity during postural change and as recently recognized factors causing vasodilatation (as noted post-prandially, post-exertion and with heat) is characteristic of Postural Tachycardia Syndrome, and there is a phenomenological overlap with anxiety disorders, which may be partially accounted for by exaggerated neural reactivity within ventromedial prefrontal cortex. People who experience Vasovagal Syncope, a heritable tendency to fainting induced by emotional challenges (and needle/blood phobia), are also more vulnerable to anxiety disorders. Neuroimaging implicates brainstem differences in vulnerability to faints, yet the structural integrity of the caudate nucleus appears important for the control of fainting frequency in relation to parasympathetic tone and anxiety. Together there is clinical and neuroanatomical evidence to show that common constitutional differences affecting autonomic responsivity are linked to psychiatric symptoms, notably anxiety.

Gastrointestinal symptoms are common in the postural orthostatic tachycardia syndrome (POTS). However, few studies have evaluated gastrointestinal transit in POTS. Our primary objectives were to evaluate gastrointestinal emptying and the relationship with autonomic dysfunctions in POTS. We reviewed the complete medical records of all patients aged 18 years and older with POTS diagnosed by a standardized autonomic reflex screen who also had a scintigraphic assessment of gastrointestinal transit at Mayo Clinic Rochester between 1998 and 2012. Associations between specific gastric emptying and autonomic (i.e., cardiovagal, adrenergic, and sudomotor) disturbances were evaluated. Among 163 patients (140 women, mean [± SEM] age 30 [± 1] years), 55 (34%) had normal, 30 (18%) had delayed, and 78 (48%) had rapid gastric emptying. Fifty-eight patients (36%) had clinical features of physical deconditioning, which was associated (p = 0.02) with rapid gastric emptying. Associations with delayed gastric emptying included vomiting, which was more common (p < 0.003), and anxiety or depression, which was less common (p = 0.02). The tilt-associated increase in heart rate and reduction in systolic BP at 1 min was associated (p < 0.05), being greater in patients with delayed gastric emptying. Two-thirds of patients with POTS and GI symptoms had abnormal, most frequently rapid gastric emptying. Except for more severe adrenergic impairment in patients with delayed gastric emptying, the pattern of autonomic dysfunction did not discriminate among gastric emptying groups. Further studies are necessary to ascertain whether extravascular volume depletion and/or deconditioning contribute to POTS in patients with gastrointestinal symptoms.

Postural tachycardia syndrome (POTS) is characterized by symptoms of orthostatic intolerance. Antibodies of acetylcholine receptor (AChR-ab) affect acetylcholine transmission between the ganglia and result in imbalance of the autonomic nervous system in POTS. This study was designed to analyze the clinical characteristics of POTS patients with AChR-ab positive and explore the value of AChR-ab in children with POTS. In 82 children with POTS, twenty patients (24.39%) were found as AChR-ab positive. Their clinical characteristics and hemodynamic responses to orthostatic changes were compared with the remaining 60 patients with negative AChR-ab. Symptoms of POTS children with AChR-ab positive were significantly severe than those of AChR-ab negative patients (p = 0.001). Preceding infection was predominant in patients with AChR-ab positive compared with that of patients with AChR-ab negative (p < 0.001). Syncope and fatigue were more common in the AChR-ab positive patients (p < 0.05). The change of upright heart rate was increased significantly in AChR-ab positive patients compared with AChR-ab negative cases (p = 0.013). Multiple logistic regression analysis revealed that preceding infection (OR 22.356, 95% CI 2.151-34.920), syncope (OR 11.570, 95% CI 2.098-63.810), and fatigue (OR 11.145, 95% CI 1.658-74.911) were independent risk factors for POTS with AChR-ab positive. In conclusion, POTS with positive AChR-ab was a heterogeneous disorder. Preceding infection, syncope and fatigue were their main clinical characteristics.

Mental clouding is an almost universal complaint among patients with postural tachycardia syndrome (POTS) but remains poorly understood. Thus, we have determined whether POTS patients exhibit deficits during neuropsychological testing relative to healthy subjects. A comprehensive battery of validated neuropsychological tests was administered to 28 female POTS patients and 24 healthy subjects in a semi-recumbent position. Healthy subjects were matched to POTS patients on age and gender. Selective attention, a primary outcome measure, and cognitive processing speed were reduced in POTS patients compared with healthy subjects (Ruff 2&7 Speed t-score: 40±9 compared with 49±8; P=0.009; Symbol Digit Modalities Test t-score: 45±12 compared with 51±8; P=0.011). Measures of executive function were also lower in POTS patients (Trails B t-score: 46±8 compared with 52±8; P=0.007; Stroop Word Color t-score: 45±10 compared with 56±8; P=0.001), suggesting difficulties in tracking and mental flexibility. Measures of sustained attention, psychomotor speed, memory function or verbal fluency were not significantly different between groups. The present study provides evidence for deficits in selective attention and cognitive processing in patients with POTS, in the seated position when orthostatic stress is minimized. In contrast, other measures of cognitive function, including memory assessments, were not impaired in these patients, suggesting selectivity in these deficits. These findings provide new insight into the profile of cognitive dysfunction in POTS and provide the basis for further studies to identify clinical strategies to better manage the mental clouding associated with this condition.

The pathogenesis of postural orthostatic tachycardia syndrome (POTS) is poorly understood. However, it has been suggested that altered immune activity or denervation of the autonomic system following illness may be an important trigger. Patients infected with Lyme disease have a small incidence of post-Lyme disease syndrome that share similar characteristics to POTS. We report a short series of two women who present with persistent symptoms of orthostatic intolerance consistent with POTS after treated Lyme disease.

This study aimed at examining three tilt angle-based positive responses and the time to positive response in a head-up tilt test for children with orthostatic intolerance, and the psychological fear experienced at the three angles during head-up tilt test. A total of 174 children, including 76 boys and 98 girls, aged from 4 to 18 years old (mean 11.3±2.8 years old), with unexplained syncope, were randomly divided into three groups, to undergo head-up tilt test at the angles of 60°, 70° and 80°, respectively. The diagnostic rates and times were analysed, and Wong-Baker face pain rating scale was used to access the children's psychological fear. There were no significant differences in diagnostic rates of postural orthostatic tachycardia syndrome and vasovagal syncope at different tilt angles during the head-up tilt test (p>0.05). There was a significant difference, however, in the psychological fear at different tilt angles utilising the Kruskal-Wallis test (χ2=36.398, p<0.01). It was mildest at tilt angle 60° utilising the Kolmogorov-Smirnov test (p<0.01). A positive rank correlation was found between the psychological fear and the degree of tilt angle (r(s)=0.445, p<0.01). Positive response appearance time was 15.1±14.0 minutes at 60° for vasovagal syncope children. There was no significant difference in the time to positive response, at different tilt angles during the head-up tilt test for vasovagal syncope or for postural orthostatic tachycardia syndrome. Hence, it is suggested that a tilt angle of 60° and head-up tilt test time of 45 minutes should be suitable for children with vasovagal syncope.

With the safety of human papilloma virus vaccine (HPVv) being questioned, this article aims to assess the risks and benefits of the commercially available HPVv. Within the last decade, two vaccines (Gardasil and Cervarix) have been put on the market to prevent infection with the most oncogenic HPV subtypes. Both vaccines contain aluminum adjuvants that are meant to cause a hyper stimulated immune response to prevent HPV infection. The purpose of this paper is to consider the safety of these two vaccines based on the data from the U.S. Vaccine Adverse Event Reporting System (VAERS) and case reports. The current HPVv are both effective and generally safe. However, it should be noted that autoimmune side effects have been reported in several studies. Further research should be done to understand the relationship between HPVv and autoimmunity.

Central obesity and hyperinsulinaemia of polycystic ovary syndrome (PCOS) are associated with chronic sympathetic over activity. To evaluate the autonomic functions and to indicate the superiority, if any, for those functions in the diagnosis of sympathetic over activity in PCOS women. Sixty-four PCOS patients and 40 women served as the control group were studied. The two groups were subdivided according to the body mass index (BMI) into two obese and non-obese groups. Waist:hip ratio (WHR), plasma epinephrine level was estimated, sympathetic skin response (SSR); postural orthostatic tachycardia syndrome, heart rate variability (HRV), and valsalva ratio were measured in both groups. Compared to the control group, obese PCOS patients demonstrated higher BMI and WHR, reduced palmar SSR latency and higher amplitude, altered HRV, higher plasma epinephrine level, and rapid pulse rate. Moreover, non-obese patients show reduced palmar SSR latency and higher amplitude, higher plasma epinephrine level, and higher pulse rate. BMI and WHR of the patients were positively correlated with plasma epinephrine level; while the HRV was negatively correlated WHR. Women with PCOS exhibits altered autonomic function and sympathoexcitation is more pronounced in obese than non-obese patients; therefor the SSR could be useful auxiliary electrophysiological test to predict autonomic dysfunction in those patients. Receiver operating characteristics curve demonstrate the pulse rate in standing position as the autonomic function test that is superior to others in predicting sympathetic over activity in those patients.

Postural orthostatic tachycardia syndrome (POTS) is the most common of several types of dysautonomia, characterized by dysfunction of the autonomic nervous system manifesting with symptoms of orthostatic intolerance with or without associated orthostatic hypotension and excessive autonomic excitation. Given the numerous presenting musculoskeletal symptoms of POTS and its known associations with other clinical entities like Ehlers-Danlos syndrome, POTS constitutes an unusual treatment challenge of which the orthopaedic surgeon and other related healthcare providers should be aware. We describe two patients with a diagnosis of POTS and musculoskeletal manifestations. The first is a 13-year-old boy with a concurrent diagnosis of Ehlers-Danlos syndrome and worsening back pain. The patient had resolution of his musculoskeletal symptoms after treatment with a Boston Overlap LSO brace and physical therapy and resolution of his cardiovascular symptoms after pharmacologic treatment. The second patient is a 17-year-old girl with an L1 vertebral hemangioma and pain of sudden onset radiating to her lower extremities. Her symptoms were controlled with therapy and gabapentin. POTS is a poorly understood and controversial clinical entity with lack of awareness and knowledge regarding the syndrome by the majority of medical specialists. Its complex and wide range of clinical presentation has led to being commonly mistaken with malingering, depression and anxiety disorders. Review of the literature did not yield any previous studies addressing POTS and the special considerations for the orthopaedic surgeon caring for these patients; previous studies of large patient series focus on investigating the pathologic substrate of POTS and the efficacy of various treatment modalities on the cardiovascular dysregulation. These two cases show that understanding and knowledge of this syndrome and its comorbidities should guide any diagnostic approach or therapeutic intervention by the orthopaedic surgeon caring for patients with this syndrome. It is important that the surgeon is aware of the benefits of detailed patient education and physical conditioning, the increased perioperative complications, and the need for specialized anesthesia.