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SUMMARY This review recapitulates the head-up tilt test, which is commonly used for evaluation of orthostatic syndromes and dysautonomia. Tilt test evaluates autonomic system responses to orthostatic stress. Established tilt testing includes monitoring of heart rate and blood pressure; adding capnography and cerebral blood flow monitoring expands its diagnostic yield and allows assessing cerebral blood flow regulation. Common syndromes detectable by the tilt test are neurally mediated syncope (vasodepressor, cardiovagal, or mixed), orthostatic hypotension, postural orthostatic tachycardia syndrome, hypocapnic cerebral hypoperfusion, and orthostatic cerebral hypoperfusion syndrome. This review describes relevant physiology, tilt test protocols, diagnostic criteria for orthostatic syndromes, grading test results, diagnostic accuracy, limitations of the tilt test, and safety considerations.

Mast cell disorders including hereditary alpha tryptasemia (HαT) and idiopathic mast cell activation syndrome (MCAS) can be associated with neurologic symptoms such as orthostatic intolerance, pain, and cognitive impairment. The origin of these symptoms is not well understood.To characterize neurologic findings in patients with HαT and MCAS through objective measurements.Patients with a confirmed diagnosis of HαT or MCAS with neurologic symptoms were referred for standardized autonomic testing encompassing Valsalva maneuver, deep breathing, sudomotor and tilt tests with cerebral blood flow velocity (CBFv) determination, and skin biopsies for small fiber neuropathy (SFN).There were 15 patients with HαT (age 44.4 ± 15.9 years), 16 with MCAS (34.4 ± 15.5), and 14 matched controls who were evaluated. Baseline serum tryptase level was increased in patients with HαT when compared with patients with MCAS (14.3 ± 2.5 ng/mL vs 3.8 ± 1.8; P.001) and neurologic symptoms were similar between the 2 groups. When compared with controls, orthostatic CBFv was reduced in HαT (-24.2 ± 14.3%; P.001) and MCAS (-20.8 ± 5.5%; P.001). Reduced nerve fibers consistent with SFN were found in 80% of patients with HαT and 81% of those with MCAS. Mild-to-moderate dysautonomia was detected in all patients with HαT and MCAS when results of sympathetic, parasympathetic, and sudomotor tests were combined.We provide evidence of reduced orthostatic CBFv and SFN associated with mild-to-moderate autonomic dysfunction in patients with HαT and MCAS. Our findings suggest that comprehensive autonomic testing may be helpful to explain neurologic symptoms and guide treatment in patients with HαT and MCAS.

Type 2 diabetes mellitus (T2DM) increases the risk of dementia. Intranasal insulin (INI) has emerged as treatment for T2DM-related cognitive impairment. This randomized, doubled blind trial consisted of 24-week treatment with 40 IU of intranasal insulin (Novolin® R) or placebo (sterile saline) once daily and 24-week follow-up period. T2DM and control participants > 50 years old and able to walk for 6 minutes, were enrolled. The primary outcomes were INI effect on cognition and normal and dual task walking. A total of 244 participants (122 women; 65.8 ± 9.1 years old) were randomized in the four groups (57 DM-INI, 58 DM-Placebo, 65 Control-INI, 64 Control-Placebo). Of 223 at baseline, 174 completed treatment (84 DM [70% of planned enrollment] and 90 controls [100%]), and 156 (69 DM) completed the follow-up. In T2DM, INI did not improve cognitive outcomes or depression as compared to placebo. In controls, INI improved verbal learning during on-treatment (p=0.03) and post-treatment (p=0.03) periods (Mixed Models). DM-INI group had faster normal walking at baseline and on-treatment (p Disclosure V. Novak: Advisory Panel; Spouse/Partner; Endonovo Therapeutics, Inc., Consultant; Spouse/Partner; Dysimmune Foundtation, Other Relationship; Spouse/Partner; Oxford University Press. L. Aponte becerra: None. L. H. Ngo: Consultant; Self; Five Islands Consulting, Other Relationship; Self; Radiological Society of America. C. Mantzoros: Advisory Panel; Self; Amgen Inc., GENFIT, Intercept Pharmaceuticals, Inc., Novo Nordisk, Regeneron Pharmaceuticals Inc. P. Novak: Other Relationship; Self; Dysimmune Foundation, Endonovo Therapeutics, Oxford Press. R. Mcglinchey: None. W. Dai: None. V. Lioutas: Consultant; Self; QMetis. S. Buss: Consultant; Self; Kinto Care. C. B. Fortier: None. F. Khan: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK103902); U.S. Food and Drug Administration (IND107690); Novo Nordisk (ISS-001063), Medtronic (NERP15-0310); World Health Organization (UTN-U111-1175-1588)

Effective recruitment and retention strategies in clinical trials are essential to achieve the enrollment goals. We aimed to identify baseline characteristics predicting dropouts and analyze the effect of retention strategies within the MemAID elderly cohort. The trial consisted of 12 visits during 24 weeks of INI/placebo treatment and 24 weeks of follow-up. Retention strategies were implemented 2 years after the beginning of the study and included incentives (meals, stipend, transportation), revised eligibility criteria, and flexibility in scheduling. A total of 244 participants (122 female; 65.8 ± 9.1 years old, 115 diabetes (DM)) were randomized, and completed baseline (223), treatment (174), and follow-up (156). After randomization, 65 participants (27%, 30 DM [46%]) dropped out. Dropouts occurred earlier in the study (19.6% cumulative failure at 100 days) as compared to later (25.3% cumulative failure at 300 days). Cox models showed no risk of dropout with DM diagnosis, but increased risk (p Disclosure F. Khan: None. D. F. Isaza-pierotti: None. P. Novak: Other Relationship; Self; Dysimmune Foundation, Endonovo Therapeutics, Oxford Press. C. Mantzoros: Advisory Panel; Self; Amgen Inc., GENFIT, Intercept Pharmaceuticals, Inc., Novo Nordisk, Regeneron Pharmaceuticals Inc. L. H. Ngo: Consultant; Self; Five Islands Consulting, Other Relationship; Self; Radiological Society of America. V. Novak: Advisory Panel; Spouse/Partner; Endonovo Therapeutics, Inc., Consultant; Spouse/Partner; Dysimmune Foundtation, Other Relationship; Spouse/Partner; Oxford University Press. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK103902); U.S. Food and Drug Administration (IND107690); Novo Nordisk (ISS-001063), Medtronic (NERP15-0310); World Health Organization (UTN-U111-1175-1588)

INI has emerged as a potential treatment for T2DM-related functional decline and is safe in adults without T2DM. However, INI safety in T2DM-IDDM is unknown. We aimed to demonstrate safety of long-term INI use in T2DM-IDDM MemAID participants. We screened 86 participants with T2DM-IDDM, 14 were randomized (9 INI/5 Placebo), 9 started treatment (5 INI [60±14 years, 2 Female]; 4 Placebo [68±2 years, 1 Female]). Of those, 2-INI and 3-Placebo participants completed 24 weeks of treatment and 24 weeks of follow-up. Participants underwent one week of continuous glucose monitoring (CGM)(Medtronic IPro2) at baseline and after INI (Novolin® R ) or placebo initiation. HbA1c, fasting plasma and capillary glucose, and insulin were measured throughout the study. Insulin levels were unchanged across the study. In 2 INI-treated participants, HbA1c, fasting plasma and capillary glucose declined from baseline, but the average values were similar during treatment and follow up, and comparable to 3 placebo-treated participants. Both INI-treated participants had adjustments of IDDM regimens. Capillary glucose did not decline 2 hours after INI administration, and there were no interactions between INI and subcutaneous insulin. There were no INI-related serious adverse events. Of 13 hypoglycemia (HG) episodes across the study, 2 asymptomatic level-1 HG (15.4%) occurred in INI group and 7 (53.8%) in placebo group. There were 2 asymptomatic level-2 HG (15.4%) in both INI and placebo groups. INI therapy was not associated with serious adverse events or HG in older participants with T2DM-IDDM. This study may pave the way towards future larger studies evaluating the safety of concomitant administration of INI and subcutaneous insulin (NCT02415556). Disclosure L. Aponte becerra: None. B. Galindo mendez: None. F. Khan: None. C. Mantzoros: Advisory Panel; Self; Amgen Inc., GENFIT, Intercept Pharmaceuticals, Inc., Novo Nordisk, Regeneron Pharmaceuticals Inc. P. Novak: Other Relationship; Self; Dysimmune Foundation, Endonovo Therapeutics, Oxford Press. V. Lioutas: Consultant; Self; QMetis. L. H. Ngo: Consultant; Self; Five Islands Consulting, Other Relationship; Self; Radiological Society of America. Memaid investigators (j. trevino): n/a. V. Novak: Advisory Panel; Spouse/Partner; Endonovo Therapeutics, Inc., Consultant; Spouse/Partner; Dysimmune Foundtation, Other Relationship; Spouse/Partner; Oxford University Press. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK103902); U.S. Food and Drug Administration (IND107690); Novo Nordisk (ISS-001063), Medtronic (NERP15-0310); World Health Organization (UTN-U111-1175-1588)

SUMMARY The autonomic nervous system is a complex neural network that controls several organ systems. Its assessment includes a detailed history of autonomic functions, clinical examination, and autonomic tests. Most widely used is a battery of tests that assess cardiovascular reflex autonomic and sudomotor tests, which include deep breathing (assesses parasympathetic function), Valsalva maneuver, tilt test (both assess parasympathetic and adrenergic functions), and sudomotor testing for the evaluation of postganglionic sudomotor fibers. These basic tests represent a foundation of autonomic testing. Nevertheless, the autonomic nervous system also controls organ systems not directly assessed by basic tests. This review describes a number of auxiliary autonomic tests that can be used in addition to basic autonomic tests or can be used independently to explore particular autonomic functions or to answer a specific clinical question. The auxiliary tests described in this review evaluate cardiovascular, thermoregulatory, gastrointestinal, genitourinary, eye, and exocrine functions. These tests are cold pressor test, sustained handgrip maneuver, reverse tilt test, venoarteriolar reflex, laser Doppler flare imaging, microneurography, neck suction, lower body negative pressure, venous occlusion plethysmography, pharmacologic assessment of postganglionic sympathetic outflow, plasma norepinephrine, sympathetic skin response, video cinefluoroscopic swallowing test, esophageal manometry test, small bowel manometry test, wireless motility capsule test, urodynamic studies, penile plethysmography, intracavernosal papaverine injection, infrared video pupillography, corneal confocal microscopy, pupillary response to dilute pilocarpine and hydroxyamphetamine, Schirmer test, tear osmolarity test, and salivary secretion test. The protocol of each test is described in detail. This review can be used as a quick reference for the auxiliary autonomic tests.

Mast cells (MCs) are important in intestinal homeostasis and pathogen defense but are also implicated in many of the clinical manifestations in disorders such as irritable bowel syndrome. The utility of specifically staining for MCs in order to quantify and phenotype them in intestinal biopsies in patients with gastrointestinal (GI) symptoms is controversial and is not a widely adopted practice. Whether or not intestinal MCs are increased or have a unique phenotype in individuals with hereditary alpha-tryptasemia (HαT), who have extra copies of the mast cell tryptase gene TPSAB1 and typically elevated baseline serum tryptase levels >8ng/mL is not known. We examined the duodenal biopsies of 17 patients with HαT and compared them to 15 patients with mast cell activation syndrome who had baseline serum tryptases

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., Highlights • Post COVID-19 syndrome is associated with fatigue, brain fog and pain. • Orthostatic cerebral hypoperfusion syndrome (OCHOS) can be responsible for fatigue and brain fog in post COVID-19 syndrome. • Small fiber neuropathy (SFN) can be responsible for pain in post COVID-19 syndrome. • OCHOS and SFN in post COVID-19 syndrome may have autoimmune basis and early immunotherapy with intravenous immunoglobulins may be effective.

Background Hereditary alpha-tryptasemia (HαT) is an autosomal dominant genetic trait characterized by multiple copies of the alpha-tryptase gene at the TPSAB1 locus. Previously described symptomatology involves multiple organ systems and anaphylaxis. The spectrum of mast cell activation symptoms is unknown, as is its association with specific genotypes. Objective To describe clinical, laboratory, and genetic characteristics of patients referred for the evaluation of mast cell activation–related symptoms and genotype-confirmed HαT. Methods We retrospectively describe clinical characteristics, baseline tryptase, and tryptase genotype in 101 patients. Patients were referred for mast cell activation–related symptoms and underwent genotyping to confirm diagnosis of HαT. Results Of 101 patients, 80% were female with average tryptase of 17.2 ng/mL. Tryptase was less than 11.4 ng/mL in 8.9% and greater than 20 ng/mL in 22.3% (range 6.2-51.3 ng/mL). KIT D816V mutation was negative in all subjects tested. 2α:3β was the most common genotype but did not correlate with tryptase levels. Unprovoked anaphylaxis was noted in 57% of the subjects with heterogeneous genotypes. Most common symptoms include gastrointestinal, cutaneous, psychiatric, pulmonary, cardiovascular, and neurologic. A total of 85% of patients were taking H1- or H2-antihistamines with partial symptom relief. Omalizumab was effective at suppressing anaphylaxis or urticaria in 94% of the patients. Conclusion HαT encompasses a broad range of baseline tryptase and should be considered in patients with symptoms of mast cell activation and tryptase levels greater than 6.2 ng/mL. Patients may present with complex symptomatology including cutaneous, gastrointestinal, neurologic, and psychiatric symptoms and anaphylaxis, some of which respond to omalizumab.

ObjectiveTo evaluate the safety and efficacy of l-serine in humans with hereditary sensory autonomic neuropathy type I (HSAN1).MethodsIn this randomized, placebo-controlled, parallel-group trial with open-label extension, patients aged 18–70 years with symptomatic HSAN1 were randomized to l-serine (400 mg/kg/day) or placebo for 1 year. All participants received l-serine during the second year. The primary outcome measure was the Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNS). Secondary outcomes included plasma sphingolipid levels, epidermal nerve fiber density, electrophysiologic measurements, patient-reported measures, and adverse events.ResultsBetween August 2013 and April 2014, we enrolled and randomized 18 participants, 16 of whom completed the study. After 1 year, the l-serine group experienced improvement in CMTNS relative to the placebo group (−1.5 units, 95% CI −2.8 to −0.1, p = 0.03), with evidence of continued improvement in the second year of treatment (−0.77, 95% CI −1.67 to 0.13, p = 0.09). Concomitantly, deoxysphinganine levels dropped in l-serine-treated but not placebo-treated participants (59% decrease vs 11% increase; p < 0.001). There were no serious adverse effects related to l-serine.ConclusionHigh-dose oral l-serine supplementation appears safe in patients with HSAN1 and is potentially effective at slowing disease progression.Clinicaltrials.gov identifierNCT01733407.Classification of evidenceThis study provides Class I evidence that high-dose oral l-serine supplementation significantly slows disease progression in patients with HSAN1.

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.

Currently available techniques for the evaluation of small fiber neuropathy and related sudomotor function remain suboptimal. Electrochemical skin conductance (ESC) has recently been introduced as a simple noninvasive and fast method for the detection of sudomotor dysfunction. The purpose of this review is to synthesize and appraise research using ESC measurements for sudomotor evaluation in adults. Electronic databases including MEDLINE and Google Scholar were searched (up to March 13, 2017). The search strategy included the following terms: "electrochemical skin conductance,” “Sudoscan,” and “EZSCAN.” Evidence was graded according to defined quality indicators including (1) level of evidence; (2) use of established tests as reference tests (e.g., quantitative sudomotor axon test [QSART], sympathetic skin responses [SSR], thermoregulatory sweat test [TST], and skin biopsies to assess sudomotor and epidermal small fibers); (3) use of consecutive/non-consecutive subjects; and (4) study design (prospective/retrospective). A total of 24 studies met the inclusion criteria. These were classified into preclinical, normative, comparative/diagnostic, or interventional. ESC measurement properties, diagnostic accuracy, and similarities to and differences from established tests were examined. ESC measurements expand the arsenal of available tests for the evaluation of sudomotor dysfunction. The advantages and disadvantages of ESC versus established tests for evaluating sudomotor/small fiber function reviewed herein should be used as evidence to inform future guidelines on the assessment of sudomotor function.

Background Type 2 diabetes mellitus (T2DM) accelerates brain aging and increases the risk for dementia. Insulin is a key neurotrophic factor in the brain, where it modulates energy metabolism, neurovascular coupling, and regeneration. Impaired insulin-mediated brain signaling and central insulin resistance may contribute to cognitive and functional decline in T2DM. Intranasal insulin (INI) has emerged as a potential therapy for treating T2DM-related cognitive impairment. Methods/design Ongoing from 2015, a prospective, two-center, randomized, double-blind, placebo-controlled trial of 210 subjects (120 T2DM and 90 non-diabetic older adults) randomized into four treatment arms (60 T2DM-INI, 60 T2DM-Placebo, 45 Control-INI, and 45 Control-Placebo) evaluating the long-term effects of daily intranasal administration of 40 International Units (IU) of human insulin, as compared to placebo (sterile saline) over 24 weeks and 24 weeks of post-treatment follow-up. Study outcomes are: 1) long-term INI effects on cognition, daily functionality, and gait speed; 2) identifying a clinically relevant phenotype that predicts response to INI therapy; 3) long-term safety. Conclusion This study addresses an important knowledge gap about the long-term effects of intranasal insulin on memory and cognition in older people with T2DM and non-diabetic controls, and may provide a novel therapeutic target for prevention and treatment of cognitive and functional decline and dementia. Trial Registration NCT02415556

The tilt provoked most of the patient’s symptoms, including dizziness, nausea and loss of consciousness, which was consistent with postural tachycardia syndrome and neurally mediated syncope of mixed type.

The tilt test provoked this patient’s typical waxing and waning spells associated with palpitations and dizziness. Testing showed mild adrenergic dysfunction of unclear clinical significance and small fiber neuropathy. Anxiety can mimic and exaggerate symptoms of orthostatic intolerance.

Small fiber neuropathy, mixed, length-dependent can be autoimmune even if no antineuronal antibodies can be found. Yet the seronegative small fiber neuropathy may still respond to therapy with immune globulins.

This patient has a history of Lyme disease with persistent cognitive and sensory symptoms, and he may have posttreatment Lyme disease syndrome (PLDS). The autonomic testing showed small fiber neuropathy and cerebral autoregulatory failure.

Autonomic testing revealed length-dependent small fiber neuropathy affecting sensory fibers. Repeated titer of acetylcholine ganglionic antibody was negative, but repeated epidermal nerve fiber density testing showed progressive deterioration. Symptoms improved with intravenous immune globulin therapy.

Dizziness can be associated with cerebral autoregulatory failure and hypovolemia, which can be detected by pulse pressure collapse during the Valsalva maneuver.

Small fiber neuropathy is associated with adrenergic failure. Anxiety is common and occasionally can be identified as a transient elevation of heart rate, blood pressure, and cerebral blood flow velocity.

In this patient, autonomic tests were positive for small fiber neuropathy, mixed, length-dependent. Clinical workup was positive for ganglionic acetylcholine receptor antibody. Patient subsequently improved with immunotherapy with intravenous immunoglobulins.

The testing for this patient showed minimal dysautonomia, small fiber neuropathy, and orthostatic cerebral hypoperfusion syndrome (OCHOS). Small fiber neuropathy can be due to vitamin B12 deficiency. Mild dysautonomia is not suggestive of Parkinson’s disease or multiple system atrophy.

The tilt provoked syncope. Patient confirmed that the symptoms of dizziness during the tilt test were very similar to her complaints. Small fiber neuropathy can be associated with multiple sclerosis.

This patient is an example of a typical autonomic failure associated with diabetes mellitus. Autonomic testing showed generalized autonomic failure with orthostatic hypotension and severe small fiber neuropathy affecting both sensory and autonomic fibers.

Initial orthostatic hypotension (IOH)is characterized by a rapid decrease in blood pressure in response to standing up quickly, with restoration of blood pressure in less than a minute. IOH is not associated with autonomic failure.

Recurrent hypertensive crisis, dizziness, and headaches may be associated with cerebral autoregulatory failure, which can be detected by a transcranial Doppler.

The patient has history of mast cell activation syndrome (MCAS) in which mast cells inappropriately release active substances including leukotriene and histamines, triggering symptoms of flushing and orthostatic intolerance. Small fiber neuropathy was length-dependent, mild, affecting predominantly sensory fibers. Tilt test showed postural tachycardia syndrome (POTS).

The tilt test showed severe orthostatic cerebral hypoperfusion syndrome (OCHOS) with reduced cerebral blood flow velocity. OCHOS is associated with reduced orthostatic cerebral blood flow velocity without orthostatic hypotension or arrhythmia.

Orthostatic hypertension is a syndrome associated with a rise in orthostatic blood pressure, for example in essential hypertension, diabetes, and dysautonomia. Therapy with calcium channel blockers may reduce hypertension and also may improve cerebral perfusion since calcium channel blockers dilate cerebral vessels.

This chapter describes a characteristic pattern of neurally mediated mixed syncope on the tilt test.

Patient became unresponsive during the first minute of the tilt; she was tachycardic but the blood pressure and cerebral blood flow were stable. Psychogenic pseudosyncope can be superimposed on postural tachycardia syndrome (POTS). Pseudosyncope, small fiber neuropathy, and POTS can be associated with hypermobile Ehlers-Danlos syndrome.

In this patient, cerebral blood flow velocity (CBFv) was reduced by 38% during the tilt. Decline in CBFv was due to hypocapnia-induced cerebral vasoconstriction, typical for hypocapnic cerebral hypoperfusion (HYCH). Patient reported dizziness, shortness of breath, and confusion during the tilt. Blood pressure during tilt showed prominent oscillations characteristic of hypovolemia.

A 61-year-old man presents with a progressive exertional dyspnea, fatigue, orthostatic intolerance, and weakness. Autonomic testing was normal. However, there was evidence of respiratory failure associated with tachypnea and hypocapnia. Respiratory failure is characteristic of amyotrophic lateral sclerosis (ALS).

This chapter describes a characteristic pattern of neurally mediated mixed syncope on the tilt test with prolonged asystole.

Tilt test has shown mild postural tachycardia syndrome (POTS), hypovolemic form. There was no evidence of autonomic failure.

Autonomic testing showed mixed small fiber neuropathy, which can be responsible for both sensory complaints and dysautonomia. Dysautonomia was generalized, but mild and was associated with mild orthostatic intolerance. The patient has generalized hypermobility spectrum disorder (GHSD).

The tilt test can be useful in the evaluation of anxiety and to differentiate anxiety from orthostatic intolerance.

A basic understanding of the functional and physiological structure of the autonomic nervous system (ANS) is essential in interpreting test results. This chapter summarizes the functional anatomy of the ANS. The ANS has been divided into the central autonomic system (CAN), also called preganglionic system, and the peripheral (or postganglionic system), which includes the parasympathetic system, sympathetic system, and enteric system. The anatomy and functions of the ANS and its various divisions are explained. Also described is the anatomy and functions of the baroreceptor reflex (BR), which is important in controlling the heart rate and blood pressure.

The autonomic testing revealed vasodepressor syncope. The decline in blood pressure while the heart rate remains unchanged is characteristic for vasodepressor syncope. Treatment consists of volume expansion with high fluid and high salt intake.

The testing showed a typical postural tachycardia syndrome (POTS) pattern but was negative for small fiber neuropathy. Although the patient has marfanoid habitus, she tested negative for the fibrillin-1 gene mutation which underlies the Marfan syndrome; she is more likely for positive for Ehlers-Danlos syndrome.

This chapter describes a unique vasodepressor syncope with minimal prodromes associated with loss of cerebral autoregulation.

The tilt test showed a combination of anxiety, postural tachycardia syndrome (POTS), and presyncope. The POTS in this patient was mild, but anxiety may exacerbate symptoms.

Autonomic testing showed mixed small fiber neuropathy, which can be responsible for both sensory complaints and dysautonomia. Dysautonomia was generalized but mild. The patient has generalized hypermobility spectrum disorder (GHSD).

This is an example of a typical autonomic failure associated with diabetes mellitus. Autonomic testing showed generalized autonomic failure with orthostatic hypotension and severe small fiber neuropathy affecting both sensory and autonomic fibers.

This case presents characteristic symptoms of painful small fiber neuropathy which was confirmed by abnormal skin biopsy. Painful small fiber neuropathy can have autoimmune cause and may respond to intravenous immunoglobulin (IVIG).