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BackgroundSpectrum of chronic orthostatic intolerance without orthostatic hypotension includes postural tachycardia syndrome (POTS), with orthostatic tachycardia and hypocapnic cerebral hypoperfusion (HYCH), without orthostatic tachycardia. This study compared autonomic, cerebrovascular, and neuropathic features of POTS and HYCH.MethodsThis retrospective study evaluated patients with orthostatic intolerance referred for autonomic testing. Analyzed data included surveys (Survey of Autonomic Symptoms, Compass-31, Neuropathy Total Symptom Score-6, Central Sensitization Inventory) and autonomic tests (Valsalva maneuver, deep breathing, sudomotor and tilt tests), cerebrovascular (cerebral blood flow velocity (CBFv) monitoring in the middle cerebral artery), respiratory (capnography), neuropathic (skin biopsies for assessment of small fiber neuropathy) and invasive cardiopulmonary exercise testing (iCPET).ResultsA total of 127 HYCH, 125 POTS, and 42 healthy controls were analyzed. Compared HYCH to POTS patients, there was no difference in the duration of symptoms, the prevalence of younger women, comorbidities, sensory and autonomic complaints, central sensitization syndrome, supine/standing norepinephrine levels, inflammatory markers and medical therapy except for gastrointestinal medication. Autonomic testing showed widespread but similar abnormalities in POTS and HYCH that included: reduced orthostatic CBFv and end-tidal CO2, preload failure (assessed in 16/19 POTS/HYCH), mild autonomic failure, and frequent small fiber neuropathy.ConclusionHYCH and POTS are syndromes of orthostatic intolerance with cerebral hypoperfusion associated with reduced orthostatic cerebral blood flow, hypocapnia, mild autonomic failure and small fiber neuropathy of a similar degree and distribution; except for tachycardia in POTS. Similarities in peripheral domain abnormalities that affect heart rate suggest that orthostatic tachycardia in POTS is driven by the central nervous system overcompensation of orthostatic challenge. These findings provide additional evidence that HYCH and POTS represent a spectrum of the same disorder. Reduced orthostatic cerebral blood flow is a key unifying feature of HYCH and POTS.

Abstract Autonomic symptom questionnaires are frequently used to assess dysautonomia. It is unknown whether subjective dysautonomia obtained from autonomic questionnaires correlates with objective dysautonomia measured by quantitative autonomic testing. The objective of our study was to determine correlations between subjective and objective measures of dysautonomia. This was a retrospective cross-sectional study conducted at Brigham and Women’s Faulkner Hospital Autonomic Laboratory between 2017 and 2023 evaluating the patients who completed autonomic testing. Analyses included validated autonomic questionnaires [Survey of Autonomic Symptoms (SAS), Composite Autonomic Symptom Score 31 (Compass-31)] and standardized autonomic tests (Valsalva maneuver, deep breathing, sudomotor, and tilt test). The autonomic testing results were graded by a Quantitative scale for grading of cardiovascular reflexes, sudomotor tests and skin biopsies (QASAT), and Composite Autonomic Severity Score (CASS). Autonomic testing, QASAT, CASS, and SAS were obtained in 2627 patients, and Compass-31 in 564 patients. The correlation was strong between subjective instruments (SAS vs. Compass-31, r = 0.74, p

Coronavirus disease (COVID-19) is a novel highly contagious infectious disease caused by the coronavirus SARS-CoV2. The virus affects the human respiratory and other systems, and presents mostly as acute respiratory syndrome with fever, fatigue, dry cough, myalgia and dyspnea. The clinical manifestations vary from no symptoms to multiple organ failure. Majority of patients fully recover. Several postinfectious presumably autoimmune complications of COVID-19 affecting the brain or peripheral large nerve fibers have been reported. This report describes a post COVID-19 patient who developed chronic fatigue, orthostatic dizziness and brain fog consistent with orthostatic hypoperfusion syndrome (OCHOS), a form of orthostatic intolerance, and painful small fiber neuropathy (SFN). Initially, the patient was diagnosed with.OCHOS (detected by the tilt test with transcranial Doppler monitoring) and SFN (confirmed by skin biopsy), and both OCHOS/SFN were attributed to Post Treatment Lyme Disease Syndrome of presumed autoimmune etiology. Patient recovered on symptomatic therapy. COVID-19 triggered exacerbation of OCHOS/SFN responded to immunotherapy with intravenous immunoglobulins. This case suggests that post COVID-19 syndrome may present as an autoimmune OCHOS/SFN and that early immunotherapy may be effective. Further studies are necessary to confirm the link between OCHOS/SFN and COVID-19 disease as well as to confirm the benefit of immunotherapy.

Background: Small fiber neuropathy (SFN) is a common health problem. SFN is associated with loss of small fibers, either sensory, autonomic or both. Reduced autonomic sudomotor sweat gland nerve fiber density (SGNFD) and sensory epidermal nerve fiber density (ENFD) can be seen in SFN. Electrochemical skin conductance (ESC) is a non-invasive test for measurement of sudomotor function. This study evaluated the diagnostic accuracy of ESC to detect abnormal SGNFD and ENFD.Methods: This was a retrospective blinded study of participants referred for evaluation of SFN. The primary outcome measure was the specificity and sensitivity of ESC to diagnose loss of small fibers using SGNFD and ENFD as reference tests. The secondary outcome measures were the correlation between ESC and neuropathy severity, pain, and autonomic clinical scales.Results: Two hundred ten patients were enrolled in the study, age (mean ± sd) 45.5 ± 16.1 years, men/women = 52/158. ESC adjusted for weight (ESC/kg) was reduced in subjects with abnormally low SGNFD (normal/abnormal, ESC/kg = 1.19 ± 0.31/0.94 ± 0.37 μS/kg, p < 0.0001) and abnormally low ENFD (normal/abnormal ESC/kg 1.20 ± 0.37/1.04 ± 0.33 μS/kg, p < 0.0011). ESC/kg correlated with SGNFD (ρ = 0.39, p < 0.0001) and ENFD (ρ = 0.47, p < 0.0001). ESC/kg did not correlate with symptom scales. ESC/kg had 64% sensitivity and 77% specificity (ROC 0.73, p = 0.0001) to predict abnormal SGNFD and 69% sensitivity and 55% specificity (ROC 0.63, p = 0.0017) to predict abnormal ENFD. In comparison, SGNFD had 50.1% sensitivity and 85.1% specificity to predict abnormal ENFD (ROC 0.69, p = 0.0001).Conclusion: ESC/kg has modest accuracy to detect SGNFD loss. ESC may be a useful test in characterization of small fiber neuropathy.

Parkinson disease (PD) is associated with cognitive impairment. We aimed to determine the effects of intranasal insulin (INI) on cognition and motor performance in PD. This was a proof of concept, randomized, double-blinded, placebo-controlled trial evaluating the effects of 40 international units (IU) of insulin or saline once daily for four weeks on cognitive and functional performance. Of 16 subjects enrolled, eight in the INI group and six in the placebo group completed verbal fluency (FAS), Unified Parkinson Disease Scale (UPDRS), and modified Hoehn and Yahr scale (HY, PD severity) at baseline and post-treatment and were included in the analyses. After treatment, the INI group had a better total FAS score (p = 0.02) (41 ± 8.2 vs. 30.8 ± 7.1, mean ±SD, p = 0.02) compared to the placebo group. The INI group also had improved HY (p = 0.04) and UPDRS-Motor (Part III) (p = 0.02) scores when compared to baseline. One INI treated patient with multiple system atrophy (MSA) remained stable and did not show disease progression. The placebo group had no change. INI administration was well tolerated and there were no hypoglycemic episodes or serious study related adverse events or medications interactions. INI is safe in PD and MSA patients and may provide clinically relevant functional improvement. Larger studies are warranted to determine the INI effect in treatment of cognitive and motor impairment in Parkinson disease. Trial Registration: ClinicalTrial.gov NCT02064166.

ObjectivesTo examine whether post-treatment Lyme disease syndrome (PTLDS) defined by fatigue, cognitive complaints and widespread pain following the treatment of Lyme disease is associated with small fiber neuropathy (SFN) manifesting as autonomic and sensory dysfunction.MethodsThis single center, retrospective study evaluated subjects with PTLDS. Skin biopsies for assessment of epidermal nerve fiber density (ENFD), sweat gland nerve fiber density (SGNFD) and functional autonomic testing (deep breathing, Valsalva maneuver and tilt test) were performed to assess SFN, severity of dysautonomia and cerebral blood flow abnormalities. Heart rate, end tidal CO2, blood pressure, and cerebral blood flow velocity (CBFv) from middle cerebral artery using transcranial Doppler were monitored.Results10 participants, 5/5 women/men, age 51.3 ± 14.7 years, BMI 27.6 ± 7.3 were analyzed. All participants were positive for Lyme infection by CDC criteria. At least one skin biopsy was abnormal in all ten participants. Abnormal ENFD was found in 9 participants, abnormal SGNFD in 5 participants, and both abnormal ENFD and SGNFD were detected in 4 participants. Parasympathetic failure was found in 7 participants and mild or moderate sympathetic adrenergic failure in all participants. Abnormal total CBFv score was found in all ten participants. Low orthostatic CBFv was found in 7 participants, three additional participants had abnormally reduced supine CBFv.ConclusionsSFN appears to be associated with PTLDS and may be responsible for certain sensory symptoms. In addition, dysautonomia related to SFN and abnormal CBFv also seem to be linked to PTLDS. Reduced orthostatic CBFv can be associated with cerebral hypoperfusion and may lead to cognitive dysfunction. Autonomic failure detected in PTLDS is mild to moderate. SFN evaluation may be useful in PTLDS.

The objective of the study was to identify markers of hypocapnic cerebral hypoperfusion (HYCH) in patients with orthostatic intolerance (OI) without tachycardia and without orthostatic hypotension. This single center, retrospective study included OI patients referred for autonomic evaluation with the 10 min tilt test. Heart rate, end-tidal CO2 (ET-CO2), blood pressure, and cerebral blood flow velocity (CBFv) from middle cerebral artery were monitored. HYCH was defined by: (1) Symptoms of OI; (2) Orthostatic hypocapnia (low ET-CO2); (3) Abnormal decline in orthostatic CBFv due to hypocapnia; 4) Absence of tachycardia, orthostatic hypotension, or other causes of low CBFv or hypocapnia. Sixteen subjects met HYCH criteria (15/1 women/men, age 38.5±8.0 years) and were matched by age and gender to postural tachycardia patients (POTS, n = 16) and healthy controls (n = 16). During the tilt, CBFv decreased more in HYCH (-22.4±7.7%, p

Purpose: Electrochemical skin conductance (ESC) using reverse iontophoresis and chronoamperometry has been used to evaluate abnormal function of small fibers. How ESC correlates with loss of small fibers in skin is unclear.Methods: This was a prospective, blinded study. The primary outcome measure was the correlation between ESC at the feet and results of skin biopsies including epidermal nerve fiber density (ENFD) and sweat gland nerve fiber density (SGNFD) at the distal leg. ESC, ENFD and SGNFD data were normalized by adjusting for weight. The secondary outcome measures were the correlation between ESC and the following variables: quantitative sudomotor axon reflex test (QSART) and symptom scales (neuropathy, pain and autonomic).Results: 81 patients ((mean±sd): age=53.3±17.3, men/women=25/56 were enrolled in the study. ESC was reduced in subjects with abnormally low ENFD (ENFD normal/abnormal, ESC = 1.17±0.27/0.87±0.34 µSiemens/kg, p

Digital advising requires that the diversity of people and departments in a college or university share a unified approach to advising. This shared vision of advising necessitates university-wide support from top-level administrators as well as faculty/staff involvement in advising delivery. This article describes the process of adopting digital advising as a practice that helped transform the institution.