Autonomic function testing in the COVID-19 pandemic: an American Autonomic Society position statement.

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.

Ellagitannins: Bioavailability, Purification and Biotechnological Degradation.

The ellagitannins are a group of phenolic compounds with biological activities. Ellagic acid is the product obtained from hydrolysis of ellagitannins. Information related to the biosynthesis of ellagitannins still been scarce and confused. The ellagitannins are obtained from plants and their purification process implies mainly the use of chromatographic techniques. The ellagitannin acyl hydrolase (EAH) also known as ellagitannase is an enzyme capable of hydrolyzing the ester bonds of ellagitannins and the consequent releasing of ellagic acid. Information about the EAH is not clear because the enzyme had showed different activities due to the low purity or complexity of substrates and there is no available information about the biochemical, physicochemical and molecular characteristics of EAH. The present review describes information related to the sources, biosynthesis and the purification of ellagitannins and a current assessment on the production of ellagitannase.

An Unusual Postoperative Neuropathy: Foot Drop Contralateral to the Lateral Decubitus Position.

Postoperative neuropathy is often related to surgical positioning or improper padding during surgery. However, other causes should be considered, particularly when the deficit does not correlate with a positioning error. A case is presented of a 15-year-old girl who experienced postoperative foot drop contralateral to the lateral decubitus position. Further evaluation led to a clinical diagnosis of hereditary neuropathy with liability to pressure palsies that predisposed the patient to the injury. Anesthesiologists should suspect hereditary neuropathy with liability to pressure palsies in patients presenting for multiple nerve decompression surgeries and be vigilant in the perioperative handling of these susceptible individuals.

Effects of patient-controlled abdominal compression on standing systolic blood pressure in adults with orthostatic hypotension.

OBJECTIVE: To assess the effects of patient-controlled abdominal compression on postural changes in systolic blood pressure (SBP) associated with orthostatic hypotension (OH). Secondary variables included subject assessments of their preferences and the ease-of-use. DESIGN: Randomized crossover trial. SETTING: Clinical research laboratory. PARTICIPANTS: Adults with neurogenic OH (N=13). INTERVENTIONS: Four maneuvers were performed: moving from supine to standing without abdominal compression; moving from supine to standing with either a conventional or an adjustable abdominal binder in place; application of subject-determined maximal tolerable abdominal compression while standing; and while still erect, subsequent reduction of abdominal compression to a level the subject believed would be tolerable for a prolonged period. MAIN OUTCOME MEASURES: The primary outcome variable included postural changes in SBP. Secondary outcome variables included subject assessments of their preferences and ease of use. RESULTS: Baseline median SBP in the supine position was not affected by mild (10mmHg) abdominal compression prior to rising (without abdominal compression: 146mmHg; interquartile range, 124-164mmHg; with the conventional binder: 145mmHg; interquartile range, 129-167mmHg; with the adjustable binder: 153mmHg, interquartile range, 129-160mmHg; P=.85). Standing without a binder was associated with an -57mmHg (interquartile range, -40 to -76mmHg) SBP decrease. Levels of compression of 10mmHg applied prior to rising with the conventional and adjustable binders blunted these drops to -50mmHg (interquartile range, -33 to -70mmHg; P=.03) and -46mmHg (interquartile range, -34 to -75mmHg; P=.01), respectively. Increasing compression to subject-selected maximal tolerance while standing did not provide additional benefit and was associated with drops of -53mmHg (interquartile range, -26 to -71mmHg; P=.64) and -59mmHg (interquartile range, -49 to -76mmHg; P=.52) for the conventional and adjustable binders, respectively. Subsequent reduction of compression to more tolerable levels tended to worsen OH with both the conventional (-61mmHg; interquartile range, -33 to -80mmHg; P=.64) and adjustable (-67mmHg; interquartile range, -61 to -84mmHg; P=.79) binders. Subjects reported no differences in preferences between the binders in terms of preference or ease of use. CONCLUSIONS: These results suggest that mild (10mmHg) abdominal compression prior to rising can ameliorate OH, but further compression once standing does not result in additional benefit.

Decreased orthostatic adrenergic reactivity in non-dipping postural tachycardia syndrome.

Whether non-dipping - the loss of the physiologic nocturnal drop in blood pressure - among patients with postural tachycardia syndrome (POTS) is secondary to autonomic neuropathy, a hyperadrenergic state, or other factors remains to be determined. In 51 patients with POTS (44 females), we retrospectively analyzed 24-hour ambulatory blood pressure recordings, laboratory indices of autonomic function, orthostatic norepinephrine response, 24-hour natriuresis and peak exercise oxygen consumption. Non-dipping (<10% day-night drop in systolic blood pressure) was found in 55% (n=28). Dippers and non-dippers did not differ in: 1) baseline characteristics including demographic and clinical profile, sleep duration, daytime blood pressure, 24-hour natriuresis, and peak exercise oxygen consumption; 2) severity of laboratory autonomic deficits (sudomotor, cardiovagal and adrenergic); 3) frequency of autonomic neuropathy (7/23 vs. 8/28, P=0.885); 4) supine resting heart rate (75.3±14.0bpm vs. 74.0±13.8bpm, P=0.532); or 5) supine plasma norepinephrine level (250.0±94.9pg/ml vs. 207.0±86.8pg/ml, P=0.08). However, dippers differed significantly from non-dippers in that they had significantly greater orthostatic heart rate increment (43±16bpm vs. 35±10bpm, P=0.007) and significantly greater orthostatic plasma norepinephrine increase (293±136.6pg/ml vs. 209±91.1pg/ml, P=0.028). Our data indicate that in patients with POTS, a non-dipping blood pressure profile is associated with a reduced orthostatic sympathetic reactivity not accounted for by autonomic neuropathy.

Multiple system atrophy: prognostic indicators of survival.

Neurological and autonomic presentation in multiple system atrophy (MSA) may predict early mortality. Quantification of early autonomic failure as a mortality predictor is lacking. Early neurological and autonomic clinical features were retrospectively reviewed in 49 MSA cases (median age at onset, 56.1 years; 16 women) confirmed by autopsy at Mayo Clinic. When available, the 10-point composite autonomic severity score derived from the autonomic reflex screen provided quantification of the degree of autonomic failure and thermoregulatory sweat test quantitated body surface anhidrosis. Symptoms at onset were autonomic in 50%, parkinsonian in 30%, and cerebellar in 20% of cases. Survival (median [95% confidence interval]) was 8.6 [6.7-10.2] years. Survival was shorter in patients with early laboratory evidence of generalized (composite autonomic severity score ≥ 6) autonomic failure (7.0 [3.9-9.8] vs. 9.8 [4.6-13.8] years; P = 0.036), and early requirement of bladder catheterization (7.3 [3.1-10.2] vs. 13.7 [8.5-14.9] years; P = 0.003) compared with those without these clinical features. On Cox proportional analysis, prognostic indicators of shorter survival were older age at onset (hazard ratio [95% confidence interval], 1.04 [1.01-1.08]; P = 0.03), early requirement of bladder catheterization (7.9 [1.88-38.63]; P = 0.004), and early generalized (composite autonomic severity score ≥ 6) autonomic failure (2.8 [1.01-9.26]; P = 0.047). Gender, phenotype, and early development of gait instability, aid-requiring ambulation, orthostatic symptoms, neurogenic bladder, or significant anhidrosis (thermoregulatory sweat test ≥ 40%) were not indicators of shorter survival. Our data suggest that early development of severe generalized autonomic failure more than triples the risk of shorter survival in patients with MSA.

Autoimmunoreactive IgGs against cardiac lipid raft-associated proteins in patients with postural orthostatic tachycardia syndrome.

Lipid rafts are specialized plasma membrane microdomains that serve as platforms for integrating cellular signal transductions. We have recently reported that autoantibodies against cardiac membrane proteins are present in patients with postural orthostatic tachycardia syndrome (POTS). In this study, we examined the presence of autoimmunoreactive IgGs against lipid raft proteins in these patients. IgGs were purified from the sera of 10 patients and 7 normal controls. Cardiac lipid raft preparations were isolated from normal human heart tissue. The lipid raft-associated proteins were resolved by 2-dimensional gel electrophoresis and immunoblotted against IgGs from each subject. Protein spots that reacted specifically with patient IgGs were identified by nano-liquid chromatography-mass spectrometry/mass spectrometry. Thirty-four such protein spots, and 72 unique proteins were identified. The targets of autoimmunoreactive IgGs include proteins associated with caveolae structure, adrenergic signaling, calcium signaling, cytostructures, chaperone and energy metabolism. Multiple pathways were involved including those that regulate caveolae-mediated signaling, oxidative phosphorylation, fatty acid metabolism, protein ubiquitination, and cardiac ß-adrenergic signaling. Our results suggest that cardiac lipid raft-associated proteins are targets of autoimmunoreactive IgGs from patients with POTS. Autoimmunity may play a role in the pathogenesis of POTS.

Peripheral neuropathy incidence in inflammatory bowel disease: a population-based study.

OBJECTIVE: Our aim was to determine the incidence of peripheral neuropathy in a population-based inflammatory bowel disease (IBD) cohort from Olmsted County, Minnesota. METHODS: We retrospectively ascertained neuropathy incidence in a population-based cohort of adult persons newly diagnosed with IBD between 1940 and 2004 in Olmsted County, Minnesota, using the medical records linkage system of the Rochester Epidemiology Project. The Kaplan-Meier method was used to estimate the cumulative incidence of neuropathy. RESULTS: A total of 772 Olmsted County residents aged 18 to 91 years were diagnosed with IBD. After 12,476 person-years, 9 patients developed neuropathy, providing an overall incidence rate of 72 (95% confidence interval [CI] 33-137) cases per 100,000 IBD person-years. The cumulative incidence rates after 10, 20, and 30 years were 0.7% (95% CI 0.0%-1.3%), 0.7% (95% CI 0.0%-1.5%), and 2.4% (95% CI 0.6%-4.6%), respectively. Neuropathy was diagnosed after 1 to 44 years from IBD onset. Only 2 patients had active bowel disease at the time of neuropathy onset. The clinical spectrum consisted of 1) monophasic immune radiculoplexus neuropathy (comorbid diabetes in 2 of 4 patients) and 2) chronic distal sensorimotor polyneuropathy (comorbid diabetes in 2 of 5 patients). CONCLUSIONS: Our population-based study suggests that neuropathy is uncommon in the patient population of IBD. Radiculoplexus neuropathy and sensorimotor polyneuropathy were both observed, commonly during periods of bowel disease inactivity. Clinicians should consider other etiologies of neuropathy in patients with IBD.

Autoimmunoreactive IgGs from patients with postural orthostatic tachycardia syndrome.

PURPOSE: Autoantibodies are implicated in the pathogenesis of cardiovascular diseases and cardiac arrhythmias. In this pilot study, we tested the hypothesis that autoantibodies are present in patients with postural orthostatic tachycardia syndrome (POTS). EXPERIMENTAL DESIGN: Seven control subjects (6 F:1 M, average age 36.1 years) and ten patients with the diagnosis of POTS (7 F: 3 M, average age 35.1 years) provided informed consent and 30 mL of venous blood. Human heart membrane proteins were resolved by 2DE and immunoblotted against purified IgGs from controls and patients. RESULTS: Eighteen protein spots immunoreactive specifically against patient IgGs were detected and they were excised from gels, trypsin-digested, and analyzed by nanoLC-electrospray MS/MS. Forty unique proteins were identified and these include proteins that are associated with cardiac hypertrophy (mimecan, myozenin), cardiac remodeling (periostin), cardiomyopathy (desmin, desmoplakin), cell survival (laminin), structural integrity (filamin), chaperone proteins (crystalline, HSP70), mitochondrial enzymes, and channel proteins. Ingenuity Pathway Analysis showed multiple pathways were involved including those that regulate energy metabolism, redox, fibrosis, cardiac hypertrophy, and degeneration. CONCLUSIONS AND CLINICAL RELEVANCE: Autoantibodies are present in patients with POTS. These autoantibodies cross-react with a wide range of cardiac proteins and may induce alterations in cardiac function. Autoimmune pathogenetic mechanisms should be further explored in these patients.

A prospective, 1-year follow-up study of postural tachycardia syndrome.

OBJECTIVE: To prospectively evaluate patients who met standard criteria for postural tachycardia syndrome (POTS), at baseline and 1-year follow-up, using standard clinical and laboratory methods to assess autonomic function. METHODS: Fifty-eight patients met the study criteria (orthostatic symptoms and a heart rate increment of ≥ 30 beats/min on head-up tilt) and completed 12 months of follow-up. All patients were enrolled and completed the study from January 16, 2006, through April 15, 2009. Patients underwent standardized autonomic testing, including head-up tilt, clinical assessment, and validated questionnaires designed to determine the severity of autonomic symptoms. RESULTS: Patients were predominantly young females (n=49, 84%), with 20 patients (34%) reporting an antecedent viral infection before onset of symptoms. More than one-third (37%) no longer fulfilled tilt criteria for POTS on follow-up, although heart rate increment on head-up tilt did not differ significantly at 1 year (33.8 ± 15.1 beats/min) compared with baseline (37.8 ± 14.6 beats/min) for the entire cohort. Orthostatic symptoms improved in most patients. Autonomic dysfunction was mild as defined by a Composite Autonomic Severity Score of 3 or less in 55 patients (95%) at baseline and 48 patients (92%) at 1 year. CONCLUSION: To our knowledge, this is the first prospective study of the clinical outcomes of patients with POTS. Orthostatic symptoms improved in our patients, with more than one-third of patients no longer fulfilling tilt criteria for POTS, although the overall group change in heart rate increment was modest. Our data are in keeping with a relatively favorable prognosis in most patients with POTS.

Amyloid-like IgM deposition neuropathy: a distinct clinico-pathologic and proteomic profiled disorder.

Some patients with immunoglobulin paraproteinemic neuropathy have intra-nerve deposits that morphologically mimick amyloid, but do no stain with Congo red. Patients with amyloid-like deposits were identified. The nerve amyloid-like aggregates were studied by laser microdissection and dual mass spectrometry. Three male patients, all with IgM gammopathy, and neuropathy were identified. Follow-up, disease duration was 5, 19, and 7 years, respectively. All had progressive asymmetric sensory-onset distal axonal polyneuropathy with late motor involvement. Autonomic symptoms occurred in only one after 13 years of symptoms. None had clinical cardio-renal involvement. One had skin papules with dermal amyloid-like deposits. Endoneurial amyloid-like deposits had granulo-fibrillar ultrastructure. Mass spectrometry of laser-dissected deposits identified IgM pentameric macroglobulin (heavy, light, and joining chains) without amyloid-associated proteins including absent apolipoprotein E and serum amyloid P-component. Amyloid-like neuropathy has distinct clinical, pathologic, and proteomic features which expand the spectrum of IgM neuropathies. Patients have favorable survival, relative absence of autonomic features, and distinct proteomic profiles of the infiltrative protein in nerve.

Unexpected neuroimaging abnormalities in patients with apparent C8 radiculopathy: broadening the clinical spectrum.

INTRODUCTION: C8-root impingement by C7/T1 lesions on neuroimaging studies is not consistently observed in C8 radiculopathy. We hypothesized that C7 or T1 root lesions (with a pre- or postfixed plexus) or cervical myelopathy might explain some "C8 radiculopathies" without C8 root compression. METHODS: Retrospective analysis of cervical neuroimaging in 31 consecutive patients with EMG-confirmed C8 radiculopathy. RESULTS: Five patients (16%) had C8-root compression at C7/T1. Of those without C8-root compression, 5 (16%) had C7-root compression at C6/7, one (3%) had T1-root compression at T1/T2, 7 (23%) had cervical cord compression at or above the C6/7 level, 4 (13%) had intramedullary cervical lesions, and 9 (29%) had mild or nonspecific findings. CONCLUSIONS: C8 radiculopathy without C8-root compression may be due to C7-root compression in the setting of a "prefixed" brachial plexus, upper cervical cord compression with vascular compromise of the distal cervical spinal cord ("myelopathic hand"), or intramedullary cervical cord lesions.

Immune trigeminal sensory neuropathy with esophageal achalasia: improvement with long-term immunotherapy.

We report a patient who developed subacute facial-predominant numbness and anhidrosis, oral incoordination, and esophageal achalasia with resultant cachexia. Great auricular nerve biopsy showed extensive epineurial perivascular inflammatory infiltrates. Sensation, sweating, and swallowing improved with pulse intravenous methylprednisolone given over 5 years. We suggest that the patient's deficits, including achalasia, were due to an immune-mediated sensory and autonomic neuropathy and that, in such cases, pathologic studies of the great auricular nerve may be diagnostically informative.

Extraparenchymal neurocysticercosis in Albuquerque, New Mexico.

BACKGROUND: neurocysticercosis (NCC) prevalence is increasing throughout the United States mainly because of immigration from Latin America. Clinicians may fail to recognize the extraparenchymal disease because they do not consider the diagnosis. METHODS: to analyze neuroimaging and clinical characteristics of extraparenchymal NCC, we retrospectively reviewed all such cases presenting to a major general medical school hospital in the State of New Mexico. RESULTS: eleven (30%) of our 37 cases of NCC diagnosed using standard criteria from 1998 through 2004 had extraparenchymal disease. On neuroimaging, 36% of the patients lacked parenchymal cysts, 64% had intraventricular cysticerci, 64% had subarachnoid cysticerci, and 64% had hydrocephalus due to either basal arachnoiditis or direct obstruction of intraventricular pathways. Lumbar puncture was performed in 6 patients. All had a cerebrospinal fluid (CSF) pleocytosis, none had CSF or blood eosinophilia, and CSF antibody to NCC could be absent while present in serum. Response to treatment was frequently suboptimal. CONCLUSIONS: extraparenchymal NCC is more frequent than previously thought. Because clinicians outside the Southwest United States are often unfamiliar with NCC as a cause of chronic meningitis, chronic ventriculitis, or hydrocephalus without obvious cysts, the diagnosis of extraparenchymal NCC often depends on the correct interpretation of neuroimaging.

Preventing and treating orthostatic hypotension: As easy as A, B, C.

Orthostatic hypotension is a chronic, debilitating illness that is difficult to treat. The therapeutic goal is to improve postural symptoms, standing time, and function rather than to achieve upright normotension, which can lead to supine hypertension. Drug therapy alone is never adequate. Because orthostatic stress varies with circumstances during the day, a patient-oriented approach that emphasizes education and nonpharmacologic strategies is critical. We provide easy-to-remember management recommendations, using a combination of drug and nondrug treatments that have proven efficacious.

Isolated facial diplegia and very late-onset myopathy in two siblings: atypical presentations of facioscapulohumeral dystrophy.

We report two elderly siblings with atypical myopathic weakness due to facioscapulohumeral dystrophy (FSHD). The proband presented with isolated facial diplegia, and her brother developed late onset facial and limb-girdle weakness. Both siblings had a 4q35 deletion with the same residual fragment size (25 kb) confirming FSHD. This report highlights the clinical heterogeneity and intrafamily variability of FSHD.

Severe long-standing dysimmune sensory neuronopathy responsive to etanercept.

Sensory neuronopathy in association with connective tissue disease is a disabling disorder for which there is no well-established therapy. Various immunosuppressive agents, plasmapheresis, and intravenous immunoglobulin have shown only anecdotal or modest beneficial effects. Tumor necrosis factor alpha is a proinflammatory cytokine that mediates TH1-cell inflammatory responses and is a plausible contributor to dorsal root ganglion injury in sensory neuronopathy. We describe a patient with severe painful and ataxic sensory neuronopathy in association with systemic lupus erythematosus, who showed marked and sustained improvement on etanercept, a tumor necrosis factor alpha inhibitor, despite a chronic and progressive course that was refractory to several immunomodulatory interventions. We review the therapeutic potential of tumor necrosis factor alpha blockade in immune-mediated neuropathies and the reported neurologic complications from its use, most notably central and peripheral demyelination.