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Motor cortex stimulation (MCS) was introduced in 1985 and has been tested extensively for different types of peripheral and central neuropathic pain syndromes (eg, central poststroke pain, phantom limb pain, trigeminal neuropathic pain, migraines, etc). The motor cortex can be stimulated through different routes, including subdural, epidural, and transcranial.In this review, we discuss the current uses, surgical techniques, localization techniques, stimulation parameters, and clinical outcomes of patients who underwent chronic MCS for treatment-resistant pain syndromes.A broad literature search was conducted through PubMed to include all articles focusing on MCS for pain relief (keywords: subdural, epidural, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, motor cortex stimulation, pain).Epidural MCS was the most widely used technique and had varying response rates across studies. Long-term efficacy was limited, and pain relief tended to decrease over time. Subdural MCS using similar stimulation parameters demonstrated similar efficacy to epidural stimulation and less invasive methods, such as repetitive transcranial magnetic stimulation (rTMS), which have been shown to provide adequate pain relief. rTMS and certain medications (ketamine and morphine) have been shown to predict the long-term response to epidural MCS. Complications tend to be rare, the most reported being seizures during subdural or epidural stimulation or hardware infection.Scientific evidence supports the use of MCS for treatment of refractory neuropathic pain syndromes. Further studies are warranted to elucidate the specific indications and stimulation protocols that are most amenable to the different types of MCS.

Abnormalities in orthostatic blood pressure changes upon active standing are associated with morbidity, mortality, and reduced quality of life. However, over the last decade, several population-based cohort studies have reported a remarkably high prevalence (between 25 and 70%) of initial orthostatic hypotension (IOH) among elderly individuals. This has raised the question as to whether the orthostatic blood pressure patterns in these community-dwelling elderly should truly be considered as pathological. If not, redefining of the systolic cutoff values for IOH (i.e., a value ≥ 40 mmHg in systolic blood pressure in the first 15 s after standing up) might be necessary to differ between normal aging and true pathology. Therefore, in this narrative review, we provide a critical analysis of the current reference values for the changes in systolic BP in the first 60 s after standing up and discuss how these values should be applied to large population studies. We will address factors that influence the magnitude of the systolic blood pressure changes following active standing and the importance of standardization of the stand-up test, which is a prerequisite for quantitative, between-subject comparisons of the postural hemodynamic response.

Approximately 80% of Americans identify as religious. As physicians caring for patients with COVID-19, we have seen both positive and negative effects of religious activity during the pandemic. Religious worship generally supports close social interaction, which provides many benefits, especially in mental health, but it can also contradict infection control measures. These forces do not necessarily have to be in opposition to each other. Herein, we present three case vignettes of religious patients who were infected with and recovered from COVID-19. We review the potential benefits and risks of religious activity in the current pandemic, as supported by the medical literature. Finally, we offer some thoughts on how to engage with patients so that the benefits of both religious activity and public health measures are optimized.

Purpose Post-COVID-19 syndrome is a poorly understood aspect of the current pandemic, with clinical features that overlap with symptoms of autonomic/small fiber dysfunction. An early systematic analysis of autonomic dysfunction following COVID-19 is lacking and may provide initial insights into the spectrum of this condition. Methods We conducted a retrospective review of all patients with confirmed history of COVID-19 infection referred for autonomic testing for symptoms concerning for para-/postinfectious autonomic dysfunction at Mayo Clinic Rochester or Jacksonville between March 2020 and January 2021. Results We identified 27 patients fulfilling the search criteria. Symptoms developed between 0 and 122 days following the acute infection and included lightheadedness (93%), orthostatic headache (22%), syncope (11%), hyperhidrosis (11%), and burning pain (11%). Sudomotor function was abnormal in 36%, cardiovagal function in 27%, and cardiovascular adrenergic function in 7%. The most common clinical scenario was orthostatic symptoms without tachycardia or hypotension (41%); 22% of patients fulfilled the criteria for postural tachycardia syndrome (POTS), and 11% had borderline findings to support orthostatic intolerance. One patient each was diagnosed with autoimmune autonomic ganglionopathy, inappropriate sinus tachycardia, vasodepressor syncope, cough/vasovagal syncope, exacerbation of preexisting orthostatic hypotension, exacerbation of sensory and autonomic neuropathy, and exacerbation of small fiber neuropathy. Conclusion Abnormalities on autonomic testing were seen in the majority of patients but were mild in most cases. The most common finding was orthostatic intolerance, often without objective hemodynamic abnormalities on testing. Unmasking/exacerbation of preexisting conditions was seen. The temporal association between infection and autonomic symptoms implies a causal relationship, which however cannot be proven by this study.

Aim of the study. Multiple system atrophy (MSA) and spinocerebellar ataxia (SCA) share similar symptomatology. We describe a rare occurrence of familial MSA that proved to be SCA6 upon genetic analysis. Materials and methods. Eighty MSA patients were enrolled in our study; blood samples were collected and genetic screening of the familial case for known SCA loci was performed. Results. A 68-year-old woman presented with recurrent and severe episodes of light-headedness, imbalance, frequent falls, neck and lower back stiffness, subjective arm and leg weakness, and numbness and tingling in both feet. One year later, her condition had declined; she experienced more falls, worsening instability, again more generalised but still subjective weakness, impaired fine motor movements, slurred speech, difficulty swallowing, episodes of choking, bladder incontinence, and constipation. Clinical suspicion included parkinsonism, MSA, and SCA. The patient was enrolled in our MSA study and was found to have 22 and 12 CAG repeats in CACNA1A. The other 79 clinical MSA patients were negative for SCA6 screening. Conclusions and clinical implications. While MSA and SCA may have similar presentations during early disease stages, the presence of both conditions on the list of differential diagnoses can be a diagnostic dilemma. Further analysis will aid in developing a biomarker to distinguish between the two conditions and guide proper management.

Introduction Genetic variants in the glucocerebrosidase (GBA) gene have been previously associated with susceptibility to synucleinopathies. The risk is well-established in Lewy body disease but is not as confirmed for multiple system atrophy (MSA). We aim to evaluate associations between exonic variants in GBA and risk of neuropathologically-confirmed multiple system atrophy (MSA). Methods Sanger gene sequencing of GBA was performed on 167 pathologically confirmed MSA patients collected at Mayo Clinic Florida Brain Bank, and data were extracted from whole-genome sequencing of 834 clinical controls. Common GBA variants were assessed for association with MSA. Rare GBA variants (and also all GBA variants) were collapsed together and evaluated for association with MSA risk using a gene-burden test. Results A total of 17 exonic GBA variants were observed, including a novel p.Q112X variant that is likely pathogenic in a patient with mixed parkinsonism-cerebellar subtype MSA. The more common p.N409S and p.L483P variants that recessively cause Gaucher's disease (GD), and are associated with risk of Lewy body disease, were not observed. When collapsing across all GBA variants, the presence of any GBA variant was significantly more frequent in MSA patients than in controls (OR = 1.90, P = 0.031). However, this association was driven by p.T408M, which had a significantly higher frequency in MSA patients compared to controls (OR = 4.21, P = 0.002). There was no significant association with risk of MSA for the p.E365K variant (OR = 0.79, P = 0.72). Conclusions Other than the specific GBA p.T408M variant, coding GBA variants are not associated with risk of MSA.

Background: Abnormal aggregates of α‐synuclein are pathologic hallmarks of multiple system atrophy (MSA) and Lewy body disease (LBD). LBD sometimes coexists with MSA, but the impact of co‐pathology, particularly diffuse LBD, on presentation of MSA has not been studied. We aimed to determine the frequency and clinicopathologic features of MSA with LBD (MSA+LBD). Methods: Using hematoxylin & eosin and α‐synuclein‐immunostained slides, we assessed the distribution and severity of LBD in 230 autopsy‐confirmed MSA patients collected from 1998 to 2018. Alzheimer‐type pathology was assessed to assign the likelihood of clinical presentations of dementia with Lewy body (DLB) using the consensus criteria for DLB. We reviewed medical records to characterize clinicopathologic features of MSA+LBD. Genetic risk factors for LBD, including APOE ε4 allele and mutations in GBA, SNCA, LRRK2, and VPS35, were analyzed. Results: LBD was observed in 11 MSA patients (5%); seven were brainstem type, three were transitional type, and one was diffuse type. The latter four had an intermediate or high likelihood of DLB. Three of the four had an antemortem diagnosis of Parkinson’s disease with dementia (PDD) or clinically probable DLB. Two patients had neuronal loss in the substantia nigra, but not in striatal or olivocerebellar systems with widespread glial cytoplasmic inclusions, consistent with minimal change MSA. In these cases, LBD was considered the primary pathology, and MSA was considered coincidental. APOE ε4 allele frequency was not different between MSA+LBD and MSA without LBD. Two of nine MSA+LBD patients had a risk variant of GBA (p.T408M and p.E365K). Conclusions: Although rare, MSA with transitional or diffuse LBD can develop clinical features of PDD or DLB. Minimal change MSA can be interpreted as a coincidental, but distinct, α‐synucleinopathy in a subset of patients with diffuse LBD.

Purpose of review Autonomic disorders offer a fascinating view of the complexity of the nervous system. Their impact on human health ranges from benign to severe. Deciphering autonomic symptoms and signs draws on the cognitive skills and personal interest in the plight of patients that first attracted many physicians to the field of neurology. This article provides tools to sharpen those skills. Recent findings Autonomic neuroscience and accumulated clinical knowledge have led to the categorization of autonomic disorders into specific syndromes that can be identified on the basis of clinical phenotypes and physiologic responses to standardized stimuli in the autonomic laboratory. A key development has been the ability to distinguish neurogenic orthostatic hypotension from other causes of hypotension. Quantification of sudomotor responses has proven valuable in the diagnosis of thermoregulatory disorders and small fiber neuropathies such as those related to diabetes mellitus. Increasing attention has focused on autonomic failure as a defining feature of neurodegenerative α-synucleinopathies, especially multiple system atrophy. As awareness of autonomic disorders has increased, the once obscure term dysautonomia has entered into common parlance. Summary With appropriate knowledge and experience, neurologists can diagnose autonomic dysfunction accurately and with confidence. The opportunity to play an important role in caring for patients with autonomic disorders is worth the effort.

Geniculate neuralgia (GN) is an uncommon, but severe, condition that is characterized by excruciating paroxysmal pain in the seventh cranial nerve's cutaneous distribution of general somatic afferent fibers carried through the nervus intermedius (NI). GN becomes a surgical disease in refractory cases of pain after exhaustive medical management. Surgical intervention in the form of microvascular decompression and nerve sectioning has been investigated with good patient outcomes. Despite this, there are limited guidelines on either technique's appropriateness in specific operative scenarios. In our 30-year experience in GNs surgical management, we have found that a detailed knowledge of the NIs anatomy, variants, and intraoperative surgical anatomic findings are the key to choosing the most appropriate intervention, and may provide the answer to why some patients fail to experience pain relief after surgery. These anatomic variants also may explain why many patients commonly do not experience side effects related to the visceral efferent and special afferent fibers after nerve sectioning.

The greatest challenges to the management of trigeminal neuralgia and other cranial neuralgias result from gaps in our understanding of the mechanisms generating and maintaining the symptoms, patient assessment, methods for measuring outcomes, lack of adequately powered controlled trials, and inherent limitations of drug and surgical treatments. There are in vitro and in vivo experimental models that remain underused in the field. Human genetic tests have identified candidate genes in trigeminal neuralgia families. Imaging methods, especially diffusion tensor imaging and some neurophysiological tests, can be used to phenotype patients at group level. Large-scale pivotal controlled trials are needed to better understand the relative effectiveness of pharmacological and surgical interventions. Disease-specific registries maintained by multiple centres are recommended that help to standardize and improve patient management. More study is needed to understand patient decision-making processes and the role of patient support groups.

Sodium chloride, or common table salt, for millennia has played a prominent role in human affairs. Salt is also a key molecule for regulating intravascular fluid volume in patients with orthostatic disorders. In this first article of a special issue of the journal focusing on salt and the autonomic nervous system, the historical and physiologic significance of salt is reviewed, highlighting its importance to society and to medicine. The relevance of salt both for civilization and for autonomic physiology penetrates into nearly every aspect of life and health. Replacing salt that has been depleted or administering salt to expand intravascular volume is considered standard treatment for patients with orthostatic hypotension and syndromes of orthostatic intolerance. The potential longterm effects of added salt, including effects unrelated to intravascular volume, have been insufficiently studied in patients with autonomic disorders. A salient concern is the potential increased risk of developing hypertension. Underappreciated aspects of salt include its ability to increase anxiety and through nonosmotic mechanisms to contribute to local tissue inflammation. Salt may be either salubrious or detrimental, or possibly both at the same time, depending on the clinical conditions. Reconciling these opposite effects in clinical practice requires weighing benefits against potential risks, assessing what is known alongside what is uncertain, and titrating treatment decisions to the particular needs of each individual patient.

Abnormalities in orthostatic blood pressure changes upon active standing are associated with morbidity, mortality, and reduced quality of life. However, over the last decade, several population-based cohort studies have reported a remarkably high prevalence (between 25 and 70%) of initial orthostatic hypotension (IOH) among elderly individuals. This has raised the question as to whether the orthostatic blood pressure patterns in these community-dwelling elderly should truly be considered as pathological. If not, redefining of the systolic cutoff values for IOH (i.e., a value ≥ 40 mmHg in systolic blood pressure in the first 15 s after standing up) might be necessary to differ between normal aging and true pathology. Therefore, in this narrative review, we provide a critical analysis of the current reference values for the changes in systolic BP in the first 60 s after standing up and discuss how these values should be applied to large population studies. We will address factors that influence the magnitude of the systolic blood pressure changes following active standing and the importance of standardization of the stand-up test, which is a prerequisite for quantitative, between-subject comparisons of the postural hemodynamic response.

Assessment of cardiovagal function can be reliably and reproducibly performed using noninvasive tests of cardiovascular function. Measurement of heart rate responses to deep breathing assesses the integrity of afferent and efferent vagal pathways. Measuring heart rate response to Valsalva assesses the vagal component of the baroreflex and should be done with simultaneous recording of arterial pressure. Using heart rate recordings from the Valsalva maneuver, the Valsalva ratio can be computed from the maximal heart rate response to phase II and the minimal heart rate response during phase IV, while baroreflex sensitivity can be measured by plotting each heart interval against the preceding systolic blood pressure value, leading to the slope of the simple linear regression. Quantitative grading of cardiovagal function can be performed using the composite autonomic severity scale. The following chapter describes the physiology, methodology, clinical utility, and shortcomings of the most clinically used tests of cardiovagal function.

ObjectiveTo evaluate the pattern and severity of autonomic dysfunction in autopsy-confirmed progressive supranuclear palsy (PSP) compared to α-synuclein pathology.MethodsAutopsy-confirmed cases of 14 patients with PSP, 18 with multiple system atrophy (MSA), and 24 with Lewy body disease (LBD) with antemortem autonomic testing were reviewed retrospectively. All patients underwent comprehensive clinical evaluations by a movement disorder specialist, formal autonomic testing, and postmortem examinations at Mayo Clinic.ResultsThe absence of orthostatic hypotension (OH) was the strongest autonomic parameter that distinguished PSP from α-synucleinopathies (0% vs 69%, p < 0.0001). Tests of adrenergic failure, which distinguish neurogenic OH, also differentiated PSP from other groups. These included the pressure recovery time (p = 0.0008), adrenergic impairment score (p = 0.001), and magnitude of change of systolic (p = 0.0002) and diastolic (p = 0.0001) blood pressures (BPs) during upright tilt. In addition, REM sleep behavior disorder was seen less frequently (p = 0.006) in PSP (33%) compared to MSA (87%) and LBD (90%). Antemortem clinical diagnostic accuracy for these phenotypically variable disorders was 57% for PSP and 83% for α-synucleinopathies.ConclusionOur results suggest that the cardiovascular adrenergic system, which sustains BP during standing, is relatively unaffected, if not spared, in PSP. These findings increase our understanding of the clinical signature of PSP and have the potential to improve diagnostic accuracy in atypical parkinsonisms by distinguishing PSP from the α-synucleinopathies.

Human papillomavirus (HPV) vaccination has been anecdotally connected to the development of dysautonomia, chronic fatigue, complex regional pain syndrome and postural tachycardia syndrome. To critically evaluate a potential connection between HPV vaccination and the above-noted conditions. We reviewed the literature containing the biology of the virus, pathophysiology of infection, epidemiology of associated cancers, indications of HPV vaccination, safety surveillance data and published reports linking HPV vaccination to autonomic disorders. At this time, the American Autonomic Society finds that there are no data to support a causal relationship between HPV vaccination and CRPS, chronic fatigue, and postural tachycardia syndrome to other forms of dysautonomia. Certain conditions are prevalent in the same populations that are vaccinated with the HPV vaccine (peri-pubertal males and females). This association, however, is an insufficient proof of causality.

Supine hypertension commonly occurs in patients with neurogenic orthostatic hypotension due to autonomic failure. Supine hypertension promotes nocturnal sodium excretion and orthostatic hypotension, thus, interfering with quality of life. Perusal of the literature on essential hypertension and smaller scale investigations in autonomic failure patients also suggest that supine hypertension may predispose to cardiovascular and renal disease. These reasons provide a rationale for treating supine hypertension. Yet, treatment of supine hypertension, be it through nonpharmacological or pharmacological approaches, may exacerbate orthostatic hypotension when patients get up during the night. Fall-related complications may occur. More research is needed to define the magnitude of the deleterious effects of supine hypertension on cardiovascular, cerebrovascular, and renal morbidity and mortality. Integration of more precise cardiovascular risk assessment, efficacy, and safety data, and the prognosis of the underlying condition causing autonomic failure is required for individualized management recommendations.

This perspective piece on head-up tilt table testing is part of a series on autonomic function testing. The tilt table can be a useful diagnostic test, but methodologies vary, and the results are sometimes misinterpreted. The intent here is not to review comprehensively the utility of various tilt table testing protocols but to convey a number of general points that may give perspective and have practical clinical value, based on an understanding of autonomic physiology and our long clinical and research experience in the evaluation of autonomic disorders. The goals of tilt table testing are to assess orthostatic hypotension (OH), chronic orthostatic intolerance (COI), and unexplained syncope. The testing is useful for distinguishing neurogenic from non-neurogenic OH, identifying failure of the sympathetic noradrenergic system in autonomic neuropathies and ganglionopathies, and assessing baroreflex-sympathoneural function in α-synucleinopathies. For COI, the testing can provide objective data related to the patient's symptoms, diagnose postural tachycardia syndrome (POTS), and distinguish POTS from other causes of tachycardia. Provocative tilt table testing can help understand bases for recurrent transient loss of consciousness in patients with syncope, distinguish neurally mediated syncope from psychogenic pseudosyncope, and separate syncope-related convulsion from epileptic seizures. For each of these purposes, the goals, formats, endpoints, and clinical utility are different. As for any autonomic test, tilt table findings must be interpreted in the context of the patient's clinical presentation.

Background Multiple system atrophy (MSA) presents with various combinations of autonomic dysfunction, parkinsonism, and cerebellar ataxia. Although clinical diagnostic criteria have been widely used, the sensitivity and specificity are suboptimal. This study aims to provide evidence supporting the revision of the current diagnostic criteria for MSA. Methods Medical records of 171 patients with autopsy-confirmed MSA in the Mayo Clinic brain bank were reviewed with regard to their clinical features and diagnoses. Pathologic features, including concomitant pathologies (i.e., Alzheimer-related and Lewy-related pathologies), were also assessed. Results The cohort included 133 MSA-parkinsonian type, 36 MSA-cerebellar type, and 2 unclassified MSA patients who did not show significant motor symptoms. Twenty-three patients (13%) were not clinically diagnosed with MSA, but instead with progressive supranuclear palsy, Parkinson's disease (PD), PD with dementia (PDD), or dementia with Lewy bodies (DLB). Three patients with PDD and DLB also had concomitant Lewy body pathology. Six patients had late-onset MSA, with an age of onset greater than 75 years. Erectile dysfunction was frequent in male patients (60/63; 95%) in all age ranges. REM sleep behavior disorder (RBD) was present in 82 patients (48%) and was the initial symptom in 13 patients. Cognitive impairment was present in 60 patients (35%), but was an initial symptom in only two patients. Conclusions Our findings support the conclusion that late-onset presentation should not exclude MSA. The findings of this large autopsy-based cohort provides valuable insights for improving clinical criteria for MSA.

Evaluation of disorders of the autonomic nervous system is both an art and a science, calling upon the physician's most astute clinical skills as well as knowledge of autonomic neurology and physiology. Over the last three decades, the development of noninvasive clinical tests that assess the function of autonomic nerves, the validation and standardization of these tests, and the growth of a large body of literature characterizing test results in patients with autonomic disorders have equipped clinical practice further with a valuable set of objective tools to assist diagnosis and prognosis. This review, based on current evidence, outlines an international expert consensus set of recommendations to guide clinical electrodiagnostic autonomic testing. Grading and localization of autonomic deficits incorporates scores from sympathetic cardiovascular adrenergic, parasympathetic cardiovagal, and sudomotor testing, as no single test alone is sufficient to diagnose the degree or distribution of autonomic failure. The composite autonomic severity score (CASS) is a useful score of autonomic failure that is normalized for age and gender. Valid indications for autonomic testing include generalized autonomic failure, regional or selective system syndromes of autonomic impairment, peripheral autonomic neuropathy and ganglionopathy, small fiber neuropathy, orthostatic hypotension, orthostatic intolerance, syncope, neurodegenerative disorders, autonomic hyperactivity, and anhidrosis.

Hydration with water and salt is the mainstay of treatment for autonomic nervous system disorders that impair orthostatic tolerance. The goal is to expand intravascular volume to compensate for the downward displacement of blood volume that occurs when standing and thereby sustain cerebral perfusion and restore quality of life. Despite strong consensus recommendations for salt supplementation as standard treatment of these disorders, published evidence of benefit is relatively weak, and no randomized clinical trials have occurred. This review summarizes the physiological rationale for hydration and evaluates the literature on oral and intravenous hydration in the treatment of neurogenic orthostatic hypotension, postural tachycardia syndrome, and recurrent vasovagal syncope. We conclude that oral salt replacement is indicated for treatment of neurogenic orthostatic hypotension because these patients have excessive renal sodium excretion, and for treatment of chronic orthostatic intolerance because these patients are often hypovolemic. As not all patients are able to tolerate sufficient oral hydration, there is also a role for intravenous volume-loading in severe cases of postural tachycardia syndrome. We offer guidance, based on review of the literature and the clinical judgment of a cardiologist and neurologist with experience treating autonomic disorders, regarding the option of ongoing intravenous hydration for treatment of severe, refractory cases of postural tachycardia syndrome.

PURPOSE: Investigate single nucleotide variants and short tandem repeats in 44 genes related to spinocerebellar ataxia in clinical and pathologically defined cohorts of multiple system atrophy. METHODS: Exome sequencing was conducted in 28 clinical multiple system atrophy patients to identify single nucleotide variants in spinocerebellar ataxia -related genes. Novel variants were validated in two independent disease cohorts, 86 clinically diagnosed multiple system atrophy patients and 166 pathological multiple system atrophy cases. Expanded repeat alleles in spinocerebellar ataxia genes were evaluated in 36 clinically diagnosed multiple system atrophy patients; CAG/CAA repeats in TATA-Box Binding Protein (TBP, causative of SCA17) were screened in 216 clinical and pathological multiple system atrophy patients and 346 controls. RESULTS: No known pathogenic spinocerebellar ataxia single nucleotide variants or pathogenic range expanded repeat alleles of ATXN1, ATXN2, ATXN3, CACNA1A, AXTN7, ATXN8OS, ATXN10, PPP2R2B, and TBP were detected in any clinical multiple system atrophy patients. However, four novel variants were identified in four spinocerebellar ataxia-related genes across three multiple system atrophy patients. Additionally, four multiple system atrophy patients (1.6%) and one control (0.3%) carried an intermediate length 41 TBP CAG/CAA repeat allele (OR=4.11, P=0.21). There was a significant association between occurrence of a repeat length of longer alleles (>38 repeats) and an increased risk of multiple system atrophy (OR=1.64, P=0.03). CONCLUSION: Occurrence of TBP CAG/CAA repeat length of longer alleles (>38 repeats) is significantly associated with increased multiple system atrophy risk. This discovery warrants further investigation and supports a possible genetic overlap of multiple system atrophy with SCA17.

COVID-19 is a global pandemic that is wreaking havoc with the health and economy of much of human civilization. In this document from the American Autonomic Society, we identify the potential risks of exposure to patients, physicians, and allied healthcare staff. We provide guidance for conducting autonomic function testing safely in this environment.

Renaissance England witnessed a series of brief epidemics of a rapid and often fatal illness, the predominant feature of which was a disturbance of the autonomic nervous system. Profuse sweating was both an emblematic and ominous sign of this Sudor Anglicus. Its story is medically fascinating as well as historically noteworthy. Possible sites of pathological involvement include the hypothalamus, serotonergic neurons in the brainstem or spinal cord, autonomic ganglia, peripheral sympathetic nerves, neuroeffector junctions, or eccrine glands. Of candidate etiologic agents, a virus is most likely, given the seasonal variation, geographic clustering, and pattern of spread of the epidemics. Hantaviruses, enteroviruses, influenza, and others provide clinical comparisons, but a definitive match with known viruses has remained elusive.

This article reviews disorders of sweating, including hyperhidrosis and anhidrosis due to central or peripheral autonomic nervous system causes.Disorders of thermoregulation and sweating may manifest with hyperhidrosis or hypohidrosis/anhidrosis. Primary disorders of hyperhidrosis may significantly impact quality of life yet tend to be benign. Many sweating disorders present with compensatory hyperhidrosis due to areas of anhidrosis. Anhidrosis may occur due to either central or peripheral damage to the autonomic nervous system. The thermoregulatory control of sweating involves central pathways from the hypothalamus to the brainstem and then spinal cord as well as projections to peripheral structures, including the sympathetic chain ganglia, peripheral nerves, and eccrine sweat glands. Disruption at any point of this pathway may lead to impaired sweating. Characterization of sweating dysfunction helps localize different autonomic disorders to guide diagnosis and may allow for evaluation of treatment effect.Sweating dysfunction manifests in myriad ways, including essential hyperhidrosis, complete anhidrosis with heat intolerance, and compensatory hyperhidrosis due to anhidrosis, and often indicates involvement of underlying central or peripheral autonomic dysfunction.

Introduction We assessed patients’ perceptions of physician empathy during telemedicine consultations as compared to in-person consultations during clinical encounters for acute stroke. Methods This prospective cohort study was undertaken at a comprehensive stroke centre hub in collaboration with a distant community hospital spoke site. Eligible participants presented to hub or spoke emergency departments with suspected acute stroke within three hours of symptom onset. Participants were evaluated at the hub site in person or at the remote site via telemedicine by the same group of neurologists. Following acute care decisions, single-visit data including participant-reported assessments of physician empathy were collected within 24 h. The primary outcome was the Consultation and Relational Empathy score. The secondary outcome for the telemedicine cohort was the Telemedicine Patient Satisfaction Measure score. Results Between 31 May 2013–13 March 2019, 70 patients completed the study. Fifty patients were seen by telemedicine and 20 patients were seen in person. Median Consultation and Relational Empathy scores (with a possible score of 10–50) were 49 (range 27–50) for telemedicine and 45 (range 26–50) for in-person consultations (Wilcoxon rank sum p = 0.18). Each item of the Consultation and Relational Empathy questionnaire was rated very good or excellent by at least 87% of participants in the telemedicine group. The median Telemedicine Patient Satisfaction Measure score was 54 (range 12–60), with each item rated agree or strongly agree by at least 84% of participants. Discussion We found no difference between telemedicine and in-person visits in patient perception of physician empathy in acute stroke care. Therefore, we conclude that empathy can be conveyed by facial expression, voice and attentiveness in a telemedicine encounter and, in the setting of acute stroke care, does not require physical touch or proximity.

Orthostatic hypotension (OH) is a common yet often overlooked condition. Particularly debilitating is neurogenic orthostatic hypotension (nOH) caused by deficient neurotransmission of norepinephrine, which is the primary neurotransmitter released at sympathetic peripheral vascular nerve terminals in response to orthostatic stress.In this review, the author summarizes and critiques established and emerging pharmacologic approaches for the management of nOH. Two drugs are currently approved. Midodrine, an αChemical pharmacotherapy of nOH is best individualized to the needs and condition of each patient and guided by the underlying pathophysiology, severity of orthostatic incapacity, and minimization of comorbidities such as nSH. The goal of therapy is to maintain cerebral perfusion and increase the patient's ability to engage in upright daily activities. Advances in pharmacogenetics and ambulatory devices hold promise.

Background Rare coding variants ABI3_rs616338-T and PLCG2_rs72824905-G were identified as risk or protective factors, respectively, for Alzheimer’s disease (AD). Methods We tested the association of these variants with five neurodegenerative diseases in Caucasian case-control cohorts: 2742 AD, 231 progressive supranuclear palsy (PSP), 838 Parkinson’s disease (PD), 306 dementia with Lewy bodies (DLB) and 150 multiple system atrophy (MSA) vs. 3351 controls; and in an African-American AD case-control cohort (181 AD, 331 controls). 1479 AD and 1491 controls were non-overlapping with a prior report. Results Using Fisher’s exact test, there was significant association of both ABI3_rs616338-T (OR = 1.41, p = 0.044) and PLCG2_rs72824905-G (OR = 0.56, p = 0.008) with AD. These OR estimates were maintained in the non-overlapping replication AD-control analysis, albeit at reduced significance (ABI3_rs616338-T OR = 1.44, p = 0.12; PLCG2_rs72824905-G OR = 0.66, p = 0.19). None of the other cohorts showed significant associations that were concordant with those for AD, although the DLB cohort had suggestive findings (Fisher’s test: ABI3_rs616338-T OR = 1.79, p = 0.097; PLCG2_rs72824905-G OR = 0.32, p = 0.124). PLCG2_rs72824905-G showed suggestive association with pathologically-confirmed MSA (OR = 2.39, p = 0.050) and PSP (OR = 1.97, p = 0.061), although in the opposite direction of that for AD. We assessed RNA sequencing data from 238 temporal cortex (TCX) and 224 cerebellum (CER) samples from AD, PSP and control patients and identified co-expression networks, enriched in microglial genes and immune response GO terms, and which harbor PLCG2 and/or ABI3. These networks had higher expression in AD, but not in PSP TCX, compared to controls. This expression association did not survive adjustment for brain cell type population changes. Conclusions We validated the associations previously reported with ABI3_rs616338-T and PLCG2_rs72824905-G in a Caucasian AD case-control cohort, and observed a similar direction of effect in DLB. Conversely, PLCG2_rs72824905-G showed suggestive associations with PSP and MSA in the opposite direction. We identified microglial gene-enriched co-expression networks with significantly higher levels in AD TCX, but not in PSP, a primary tauopathy. This co-expression network association appears to be driven by microglial cell population changes in a brain region affected by AD pathology. Although these findings require replication in larger cohorts, they suggest distinct effects of the microglial genes, ABI3 and PLCG2 in neurodegenerative diseases that harbor significant vs. low/no amyloid ß pathology. Electronic supplementary material The online version of this article (10.1186/s13024-018-0289-x) contains supplementary material, which is available to authorized users.

To survey online patient ratings of physicians practicing autonomic medicine. Online patient review scores of US physician members of the American Autonomic Society were compared to scores of US physicians in general and to indices of professional expertise. The 68 autonomic physicians who had been rated scored 3.80 ± 0.82 on a composite five-star scale, in which 5 was the most favorable score, as compared to 3.84 ± 0.98 for all US physicians (no significant difference, p = 0.8). Scores correlated inversely with autonomic physicians’ number of scientific publications (p = 0.01), h-index (p = 0.01), and m-index (p = 0.0004). Scores of diplomates of the United Council for Neurologic Subspecialties certified in autonomic disorders or who were ranked in the top 1% of US physicians by Castle Connolly had scores comparable to those of other autonomic physicians. Scores did not correlate with physician gender, number of reviews, or years in practice. A quality patient experience, accurate diagnosis, and appropriate treatment are goals shared by patients and autonomic specialists. In this study, patient reviews of autonomic physicians were comparable to those of physicians across specialties. Metrics of greater autonomic expertise were associated with equal or lower patient satisfaction scores. In conclusion, compiled subjective reviews are a useful but incomplete indicator of autonomic physician quality and expertise. An ideal profile would combine clinical and nonclinical indicators of professional competence. Reliable information is needed to empower autonomic patients to make truly informed healthcare choices.

Sympathetic neuroimaging is based on the injection of compounds that either radiolabel sites of the cell membrane norepinephrine transporter (NET) or that are taken up into sympathetic nerves via the NET and radiolabel intra-neuronal catecholamine storage sites. Detection of the radioactivity is by planar or tomographic radionuclide imaging. The heart stands out among body organs in terms of the intensity of radiolabeling of sympathetic nerves, and virtually all of sympathetic neuroimaging focuses on the left ventricular myocardium. The most common cardiac sympathetic neuroimaging method worldwide is 123I-metaiodobenzylguanidine (123I-MIBG) scanning. 123I-MIBG scanning is used routinely in Europe and East Asia in the diagnostic evaluation of neurogenic orthostatic hypotension (nOH), to distinguish Lewy body diseases (e.g., Parkinson disease with orthostatic hypotension (OH), pure autonomic failure) from non-Lewy body diseases (e.g., multiple system atrophy) and to distinguish dementia with Lewy bodies from Alzheimer's disease. In the USA, 123I-MIBG scanning has been approved by the Food and Drug Administration for the evaluation of pheochromocytoma and some forms of heart failure-but not for the above-mentioned differential diagnoses. Positron emission tomographic methods based on imaging agents such as 18F-dopamine are categorized as research tools, despite more than a quarter century of clinical experience with these modalities. Considering that 123I-MIBG scanning is available at most academic medical centers in the USA, cardiac sympathetic neuroimaging by this methodology merits consideration as an autonomic test, especially in patients with nOH.

Catechols are a class of compounds that contain adjacent hydroxyl groups on a benzene ring. Endogenous catechols in human plasma include the catecholamines norepinephrine, epinephrine (adrenaline), and dopamine; the catecholamine precursor DOPA, 3,4-dihydroxyphenylglycol (DHPG), which is the main neuronal metabolite of norepinephrine; and 3,4-dihydroxyphenylacetic acid (DOPAC), which is the main neuronal metabolite of dopamine. In the diagnostic evaluation of patients with known or suspected dysautonomias, measurement of plasma catechols is rarely diagnostic but often is informative. This review summarizes the roles of clinical catechol neurochemistry in autonomic function testing.

Background Dysregulation of the specialized lipid metabolism involved in myelin synthesis and maintenance by oligodendrocytes has been associated with the unique neuropathology of MSA. We hypothesized that apolipoprotein E, which is associated with neurodegeneration, may also play a role in the pathogenesis of MSA. Objective This study evaluated genetic associations of Apolipoprotein E alleles with risk of MSA and α-synuclein pathology, and also examined whether apolipoprotein E isoforms differentially affect α-synuclein uptake in a oligodendrocyte cell. Methods One hundred sixty-eight pathologically confirmed MSA patients, 89 clinically diagnosed MSA patients, and 1,277 control subjects were genotyped for Apolipoprotein E. Human oligodendrocyte cell lines were incubated with α-synuclein and recombinant human apolipoprotein E, with internalized α-synuclein imaged by confocal microscopy and cells analyzed by flow cytometry. Results No significant association with risk of MSA or was observed for either Apolipoprotein E ɛ2 or ɛ4. α-Synuclein burden was also not associated with Apolipoprotein E alleles in the pathologically confirmed patients. Interestingly, in our cell assays, apolipoprotein E ɛ4 significantly reduced α-synuclein uptake in the oligodendrocytic cell line. Conclusions Despite differential effects of apolipoprotein E isoforms on α-synuclein uptake in a human oligodendrocytic cell, we did not observe a significant association at the Apolipoprotein E locus with risk of MSA or α-synuclein pathology. © 2018 International Parkinson and Movement Disorder Society.

The most important autonomic function test-the autonomic medical history-is the patient's account, interpreted by a clinician skilled in asking the right questions, of symptoms during daily activities that relate to the autonomic nervous system. The chronology and pattern of these symptoms combine to create a portrait of autonomic function or dysfunction. We summarize the steps in obtaining a comprehensive autonomic medical history.

Background This study aimed to determine the frequency of transactive response DNA binding protein 43 kDa pathology in PSP, the clinical features of patients with this pathology, and genetic risk factors for it. Methods Hippocampal sections were screened with immunohistochemistry for transactive response DNA binding protein 43 kDa in 945 PSP cases. A subset of 261 cases that were negative in hippocampus was screened in the amygdala. The density and disruption of this pathology, as well as regional tau burden, and clinical and genetic characteristics were analyzed. Results We observed transactive response DNA binding protein 43 kDa pathology in 47 cases in the hippocampus and an additional 9 cases that only affected the amygdala. Hippocampal sclerosis was the strongest risk factor, followed by Alzheimer's disease pathology, argyrophilic grain disease, and older age at death. Five stages of transactive response DNA binding protein 43 kDa pathology were identified in PSP: Stage A had pathology only in the amygdala (16%); stage I had pathology confined to the hippocampus and entorhinal cortex (9%); stage II included both regions of stage A and I (38%); stage III spread further to medial occipitotemporal gyrus (20%); and stage IV had pathology in the dorsolateral frontal lobe (18%). Anatomical areas vulnerable to PSP pathology had varying degrees of this pathology in stage II and later. PSP with transactive response DNA binding protein 43 kDa pathology were older at disease onset and had lower median MMSE scores; however, the latter was driven by concurrent pathologies. Conclusions Distribution and clinical characteristics of transactive response DNA binding protein 43 kDa pathology in PSP were influenced by concurrent pathologies. This is the first study to observe that PSP-vulnerable regions are also susceptible to this non-tau pathology. © 2016 International Parkinson and Movement Disorder Society.

Glossopharyngeal neuralgia (GPN) is a condition characterised by sudden, severe pain in the distribution of the glossopharyngeal nerve. It can be triggered by talking, yawning, coughing and swallowing. Classically, patients experience a unilateral lancinating and excruciating pain described as electrical shock-like pain in the areas around the ear, tongue, or the mandibular angle. Uncommon manifestations include cardiac arrhythmias and syncope during pain episodes. Surgery is indicated in refractory cases. Bilateral GPN is rare, and definitive surgical treatment for bilateral GPN has not yet been reported. In this case report, a young woman with bilateral GPN who underwent staged surgery bilaterally is described. She did not develop life-threatening cardiac abnormalities postoperatively.

Multiple system atrophy (MSA) is a rare sporadic, progressive parkinsonism characterised by autonomic dysfunction. A recent genome-wide association study reported an association at the Elongation of Very Long Fatty Acids Protein 7 (ELOVL7) locus with MSA risk. In the current study four independent and unrelated cohorts were assessed, consisting of pathologically confirmed MSA cases, Parkinson’s disease (PD) cases, and two unrelated, healthy control groups. All exons of ELOVL7 were sequenced in pathologically confirmed MSA cases; data for PPMI samples and Biobank controls was extracted from whole genome sequence. Coding variants in ELOVL7 were extremely rare, and we observed no significant association of ELOVL7 coding variants with risk of MSA.

Background The objectives of this study were to elucidate any potential association between α-synuclein pathology and cognitive impairment and to determine the profile of cognitive impairment in multiple system atrophy (MSA) patients. To do this, we analyzed the clinical and pathologic features in autopsy-confirmed MSA patients. Methods We retrospectively reviewed medical records, including neuropsychological test data, in 102 patients with autopsy-confirmed MSA in the Mayo Clinic brain bank. The burden of glial cytoplasmic inclusions and neuronal cytoplasmic inclusions were semiquantitatively scored in the limbic regions and middle frontal gyrus. We also assessed concurrent pathologies potentially causing dementia including Alzheimer's disease, hippocampal sclerosis, and cerebrovascular pathology. Results Of 102 patients, 33 (32%) were documented to have cognitive impairment. Those that received objective testing, deficits primarily in processing speed and attention/executive functions were identified, which suggests a frontal-subcortical pattern of dysfunction. Of these 33 patients with cognitive impairment, 8 patients had concurrent pathologies of dementia. MSA patients with cognitive impairment had a greater burden of neuronal cytoplasmic inclusions in the dentate gyrus than patients without cognitive impairment, both including and excluding patients with concurrent pathologies of dementia. Conclusions The cognitive deficits observed in this study were more evident on neuropsychological assessment than with cognitive screens. Based on these findings, we recommend that clinicians consider more in-depth neuropsychological assessments if patients with MSA present with cognitive complaints. Although we did not identify the correlation between cognitive deficits and responsible neuroanatomical regions, a greater burden of neuronal cytoplasmic inclusions in the limbic regions was associated with cognitive impairment in MSA. © 2016 International Parkinson and Movement Disorder Society