Autonomic reflex tests

Autonomic reflex tests using sensitive and reproducible measurements have been used at more medical centers as a feasible and reliable neurophysiological diagnostic tool in the United States. Autonomic reflex tests have improved diagnosis process for autonomic neuropathies and largely evaluate cardiovascular and sudomotor autonomic reflexes. The two autonomic systems have a few advantages over other systems. Neuronal pathways relevant to the autonomic reflex tests have been relatively well studied in human and animal models. Hemodynamic parameters and sweat measures can be monitored continuously and easily quantified. The tests can be performed as an outpatient basis through non-invasive methods without sedation of patients.

Cardiovascular assessment in the autonomic reflex test consists of evaluation for cardiovagal function, sympathetic adrenergic function, and hemodynamic response to orthostatic stress. Cardiovagal function can be evaluated by analyzing heart rate changes to various stimuli. For a beat-to-beat heart rate monitoring, intervals between two neighboring R waves of QRS complexes on a continuous electrocardiogram are recorded with each heartbeat. Common stimuli to induce cardiovagal activities are deep breathing, Valsalva maneuver, and active standing. Deep and slow breaths at 5–6 times per minute maximize changes in heart rates or heart rate variability. Inspiration increases heart rate through vagal tone withdrawal and expiration decreases heart rate with vagal activation ( Fig. 10.1A ). The exact mechanism of the cardiovagal activities to the breathing cycles is largely unknown in humans although stretch receptors in the chest wall (Hering-Breuer reflex) and cardiac stretch receptors (Bainbridge reflex) play important roles in animals. It is believed that the breathing frequency at 5–6 breaths per minute create a maximum synchrony in the cardiovagal neurons in the brainstem resulting in the highest heart rate variability. There are various methods to measure heart rate changes. And patient’s heart range change is compared to age-specific normative data. A Valsalva maneuver produces dynamic changes in blood pressure and heart rate secondary to cardiovagal and sympathetic activities. Valsalva ratio, which reflects how rapidly heart rate drops following discontinuation of the Valsalva maneuver, is another measure of cardiovagal function. It will discussed later with sympathetic adrenergic measures. A 30:15 ratio (of heart rate) to an active standing is a third measure for cardiovagal function. With an active standing from a supine position, there is an acute shift in blood volume due to gravity and exercising muscle that draw in blood. Heart rate increases rapidly as a compensatory mechanism in order to minimize blood pressure drop secondary to the shift, then decreases with recovery of blood pressure . Heart rate reaches its peak at approximately 12 s after standing up. A 30:15 ratio is obtained by dividing an increased heart rate at 15 s after standing by a decreased heart rate at 30 s. It is also estimated by measuring a 15th RR interval and a 30th RR interval. However, because time to a peak heart rate can be different between healthy subjects and patients , a ratio of an absolute maximum to a minimum heart rate after standing can be used and increases sensitivity.

Deep breathing and Valsalva Maneuver. During a deep breathing test for cardiovagal evaluation (A, B), a subject is asked to take slow and deep breaths at 5–6 times per minutes. Heart rate (*) and the chest wall movement (arrow) are recorded simultaneously. Deep breathing in a healthy subject reveals normal heart rate variability seen as wide fluctuations in heart rate in sync with breathing (A). When cardiovagal function is severely impaired, heart rate rarely changes despite the good respiratory effort (B). A Valsalva maneuver changes heart rate (C, E) and blood pressure (D, F). Blood pressure during and after a Valsalva maneuver has four distinct phases (D). In a healthy subject, blood pressure has recovery during late phase 2 (2 L) following a drop during early phase 2 (2E). And blood pressure response shows overshooting (rapid increment in blood pressure above the baseline) during phase 4 (D). Numbers in D indicates four phases of blood pressure response including early phase 2 (2E) and late phase 2 (2 L). With the overshooting, heart rate drops abruptly from a maximum (*) to a lowest point (**), from which a Valsalva ratio can be measured (C). In autonomic failure, blood pressure fails to recover during phase 2 and overshooting is not seen (F) and the heart does not respond to the dropping blood pressure showing absent or minimal changes in heart rate (E). In (D) and (F), arrows indicate onsets and endings of forced expiration with its pressure. Heart rate and blood pressure are recorded and displayed by using WR-TestWorks software.

Sympathetic adrenergic function is assessed by recording beat-to-beat blood pressure in response to a Valsalva maneuver, active standing and passive standing on a tilt-table. With a volume clamped method of Peňáz, arterial blood pressure can be measured in a non-invasive and continuous way. For a Valsalva maneuver, a subject is asked to blow through a closed tube at expiratory pressure of 40 mmHg for 15 s. Blood pressure waveform during a Valsalva maneuver has four distinct phases ( Fig. 10.1D ). With the Valsalva maneuver, the glottis is closed and the subject breathes against the closed glottis causing a forced expiration and increased intrathoracic pressure. Its mechanical effect directly from the high intrathoracic pressure increases blood pressure during phase I. During phase II, the high intrathoracic pressure reduces venous return to the heart resulting in decreasing cardiac output and dropping blood pressure (early phase II). The dropping blood pressure is sensed by the baroreceptors in the carotid sinus, the great vessel and the right atrium triggering baroreflex. The efferent pathways of baroreflex work through cardiovagal withdrawal and sympathetic activation to the heart and the blood vessels. Peripheral α-adrenergic activation on the vasculatures constrict peripheral vasculature. It is the main mechanism that recovers blood pressure during late phase II. Right upon discontinuation of the forced expiration, there is a transient drop in blood pressure due to mechanical effects because the intrathoracic pressure becomes relatively negative abruptly (phase III). Heart rate starts to rise initially by vagal withdrawal and later mainly by β-adrenergic sympathetic cardiac activation during phase II and III. When the forced expiration is stopped, a large volume of venous blood returning to the heart is pumped out by the heart at the increased rate. This leads to excessively increased cardiac output and rapidly increasing blood pressure, also known as blood pressure ‘overshooting’ during phase IV. Therefore, β-adrenergic sympathetic activation contributes to overshooting. Recovery of blood pressure during late phase II and blood pressure overshooting during phase IV are markers of normal sympathetic adrenergic function. The blood pressure overshooting triggers baroreflex activating cardiovagal tone and drops heart rate rapidly. A Valsalva ratio, a cardiovagal measure, is calculated from a maximal heart rate during phase IV and a following minimal heart rate ( Fig. 10.1C ). Patient’s Valsalva ratio is compared to age and sex-specific normative data.

The quantitative sudomotor axon reflex test (QSART) is a method to evaluate the post-ganglionic sympathetic cholinergic pathway. A dual-chamber capsule is placed tightly on the skin at four standardized areas of limbs, usually three on the lower extremity and one on the upper. Solution with acetylcholine in an outer chamber of the capsule has direct contact with the skin within the air-tight seal. Acetylcholine is penetrated into the skin by iontophoresis and stimulates unmyelinated C-fibers innervating the sweat glands. Neuronal excitation on the stimulated axons spreads to neighboring axons by axon-to-axon reflex summoning more sweat glands. The sweat amount is estimated based on relative changes in humidity in an inner chamber of the capsule. QSWEAT is a commercialized version of QSART. QSART is designed to detect a length-dependent small-fiber neuropathy. Abnormal QSART findings that do not have a distal-dominant pattern need cautious clinical interpretation.

Thermoregulatory sweat test (TST)

TST is another sweat test that provides topographical information on loss of sweating. A patient remains in a supine position in a sweat chamber where a room temperature is maintained high with control of humidity in order to induce sweating. Powder mixture is spread over the front side of patient’s body. Relatively low pH of sweating changes the color of indicator in the powder mixture, either alizarin red or iodine. TST can be helpful in determining presence of extra-intestinal autonomic dysfunction, localizing sudomotor problems, determining severity of autonomic failure, and following progression of disease . Fig. 10.2 shows various patterns of sweating abnormalities in patients with different gastrointestinal problems seen at our autonomic clinic.

Three representative cases of thermoregulatory sweat test (TST). Patients with gastrointestinal motility diseases may show various patterns of anhidrosis (loss of sweating) on the test depending on associated or underlying neurological disorders and their severity. A distal anhidrosis with Holmes-Adie syndrome, postural orthostatic tachycardia syndrome, and diarrhea-predominant irritable bowel syndrome (A). A regional anhidrosis with achalasia and positive anti-glutamic acid decarboxylase (anti-GAD) antibodies (B). A global anhidrosis with chronic gastroparesis and presumed autoimmune small-fiber neuropathy (C).

Skin biopsy

Skin biopsy is a pathological test for small-fiber neuropathies with relatively low risks to measure densities of mostly unmyelinated and thinly myelinated fibers in the epidermal layers of the skin. These fibers are mainly sensory nerve fibers. Bright-light immunohistochemistry protocol stains axons of the fibers with anti-protein gene product 9.5 antibody and makes them apparent under microscope as seen in Fig. 10.3 . Multiple sections from each skin sample are used to measure average intradermal nerve fiber densities . From the same samples of a skin biopsy, autonomic fibers innervating the sweat glands in the dermis can be evaluated and its methods for quantification have been improved by using computer software. New techniques reduce large variabilities originating from convoluted structure of the sweat glands . However, sweat gland nerve fiber density measurements through a skin biopsy have not been approved as a clinical diagnostic test for autonomic neuropathies yet although measurement of intraepidermal nerve fiber density is approved for clinical use. For research purpose, it is possible to assess autonomic innervation of other structures, such as blood vessels and arrector pili muscles, as well as to identify its neurochemical markers including tyrosine hydroxylase (sympathetic adrenergic fibers) and vasoactive intestinal peptide (sympathetic cholinergic fibers) .

Skin biopsy to measure intraepidermal nerve fibers. Bright-field immunohistochemistry of sections of punch skin biopsy samples with anti-protein gene product 9.5 antibody (PGP 9.5) staining reveals axons of unmyelinated and thin myelinated fibers. Sections from a lower thigh (A) and calf (B) of healthy subjects show intradermal nerve fibers branching up almost straight up to the skin surface (arrows) as well as dermal nerve bundles (triangles). In a section obtained from a lower thigh of patient with a small-fiber neuropathy, intradermal nerve fibers are visibly reduced (C). Intraepidermal nerve fiber density is measured from multiple sections of each biopsy site as described by Lauria et al .

Diabetic autonomic neuropathy

Diabetic gastroparesis is likely due to various mechanisms, including impaired modulation from extrinsic autonomic dysfunction. But studies have shown variable correlation between gastroparesis and autonomic cardiovascular neuropathy as measured by abnormal heart rate response of autonomic reflex tests. Diabetic gastroparesis is discussed separately in Chapter 18 .

Guillain-Barré syndrome (acute inflammatory demyelinating polyradiculopathy)

Various viral infections may result in segmental or diffuse autonomic dysfunction. The most common autonomic symptoms tend to be related to either cardiovascular, gastrointestinal or both. Guillain-Barré syndrome is an acute inflammatory peripheral neuropathy following an immunological stimulant, most commonly an infection. Patients usually present with ascending paralysis due to demyelination in the spinal roots and/or peripheral nerves. In severe cases causing debilitating weakness and respiratory failure, pronounced autonomic dysfunction is likely. Hemodynamic instability and sweating are common autonomic manifestations. Ileus was the most common autonomic symptom followed by hypertension, hypotension, fever, heart rate issues, and urinary retention in a retrospective study of 187 patients . Gastroparesis as a delayed complication has been reported . Another scenario is that of impaired gastrointestinal motility after an episode of acute gastroenteritis. The gastrointestinal impairment can affect the stomach, small intestine or colon in various combinations. Gastrointestinal motility disorders include achalasia, gastroparesis, intestinal pseudo-obstruction, colonic inertia and rarely megacolon. Typically, the patient has a history of low-grade fever, fatigue, myalgia, abdominal pain, vomiting or diarrhea that last for several days . As the acute systemic symptoms resolve over the subsequent 5 to 7 days, the patient has residual gastrointestinal difficulties that reflect dysmotility. There may be significant afferent visceral symptoms such as some degree of abdominal pain, nausea, sense of fullness and early satiety with or without vomiting and disrupted bowel control. Many antecedent infectious agents could produce such inflammatory process. Among bacterial causes, Campylobacter jejuni is the most commonly identified. Among viral causes, cytomegalovirus and Epstein-Barr virus are the most common pathogens. More severe forms of Guillain-Barré syndrome, such as acute motor axonal neuropathy or acute motor and sensory axonal neuropathy, are more likely to have Campylobacter jejuni infection as a precipitant . Other infectious agents that may produce post-infectious gastroparesis include enteroviruses, rotavirus and zoster . Zika virus infection has been reported to be associated with Guillain-Barré syndrome but related gastroparesis has not been reported. A small portion of patients reported diarrhea . Autonomic reflex tests often reveal a disruption in the parasympathetic and sympathetic neural controls in various combinations. In some cases, quantitative sweat test shows also impaired postganglionic sudomotor function indicating some degree of post-infectious autonomic neuropathy either in a distal dominant pattern or in a non-length dependent pattern . Guillain-Barré syndrome is a monophasic illness and most patients, particularly younger ones, recover more or less completely within 24 months. Some of these patients express low levels of antibodies such as ganglionic, potassium or calcium channel antibodies that indicate post-infectious autoimmune activation. Subsequent follow-up often shows normalization of these antibody levels along with gradual clinical improvement . Pathological studies in animal models and individual case reports have revealed various pathological findings that include partial loss of ganglion cells, neuronal intranuclear inclusions, neural degeneration and apoptosis, intestinal neuronal dysplasia or hyperplasia, mitochondrial changes, inflammatory changes, neurotransmitter depletion and interstitial cell pathology . In patients with mild gastric dysmotility, unexplained nausea and vomiting can develop despite normal intrinsic enteric innervation . These patients often receive a diagnosis of a functional gastrointestinal disorder. Several tests (discussed in the Chapter 11, Chapter 12, Chapter 13, Chapter 14, Chapter 15, Chapter 16 ) may assess gastric motility. Scintigraphy imaging is a practical initial method of evaluating these patients. If gastric dysmotility is present, treatment options include dietary modifications and pharmacotherapy. In more severe cases, total parenteral nutrition may be necessary. Protracted gastroparesis can lead to additional neurological issues related mainly to vitamins, coenzyme Q10 and carnitine deficiency, which can lead to persistent neuropathic deficits.

HIV (human immunodeficiency virus) autonomic neuropathy

Various authors have assessed autonomic symptoms by different questionnaire tools such as the survey of autonomic symptoms (SAS) and the autonomic symptom profile (ASP) . Gastroparesis symptoms (nausea, vomiting, or bloating) are common in HIV-positive patients with incidence of 37.5% . HIV patients with distal sensory neuropathy are more likely to have abnormal findings on autonomic reflex results. And autonomic symptoms are more common in this group with gastroparesis symptom (nausea, vomiting, or bloating after a small meal) seen in 24% in HIV patients with objective abnormalities in autonomic reflex . However, in a study of untreated HIV patients in Africa by Compostella et al. cardiovascular autonomic reflex were all normal or had only “borderline” response with no pathologically severe response although gastrointestinal dysfunction (bloated feeling of vomiting after a meal) was identified as frequently reported symptoms with orthostatic intolerance and secretomotor dysfunction . Solid gastric emptying is delayed in stronger association with advanced immunosuppression, weight loss and the presence of enteric infection. And autonomic reflex test does not have strong relation with delay in gastric emptying .

Autoimmune autonomic ganglionopathy (AAG)

Patients who developed severe symptomatic orthostatic hypotension and autonomic symptoms in other organs were reported as “pure pan-dysautonomia” a couple of decades ago . The authors speculated that it was a form of autonomic Guillain-Barré syndrome. Suarez and his colleagues reported 27 patients with idiopathic autonomic neuropathy . Vernino S et al reported autoantibodies targeting neuronal nicotinic acetylcholine receptors in the autonomic ganglia in patients with similar clinical features and have established a disease entity of autoimmune autonomic ganglionopathy . In the case series, the antibody was positive in 9% of patients with idiopathic gastrointestinal dysmotility. The condition can follow a prodromal viral illness or a surgical procedure. It seems to favor adults to elderly population, and there is a slight female predominance. While similar cases may occur in children, the incidence of antibodies is lower in pediatric group. AAG causes neurogenic orthostatic hypotension and multiple organ symptoms with increased titers of ganglionic acetylcholine receptor (gAChR) antibody. Autonomic failure, usually with higher titers of gAChR antibody, is characterized by cholinergic-dominant autonomic failure including sicca symptoms, poorly reactive or non-reactive pupils, loss of sweating, neurogenic bladders, intestinal motility problems . Affected men often report erectile dysfunction, with or without retrograde ejaculation. Pupillary reaction can be slowed, and the bedside examination may reveal partial tonic pupils (Adie’s pupil). The pupillary abnormalities and the sicca symptoms often contribute to visual blurring. Nineteen of 27 patients in the original report had gastrointestinal symptoms and half of 18 patients in a Mayo Clinic study reported symptoms of upper GI tract including early satiety, postprandial nausea and vomiting . The titers of gAChR antibody have weaker correlation with upper GI symptoms, while higher titers are associated with severe lower GI symptoms . But cholinergic autonomic failure assessed by autonomic reflex tests and composite autonomic symptom evaluation were more severe with higher titers, which is also linked to severity of neurogenic orthostatic hypotension . gAChR antibody can be detected in various conditions other than AAG and co-exists with other autoimmune antibodies. When it is detected in other conditions, titers tend to be low . Titers higher than 0.20 nmol/L have high specificity for AAG. gAChR antibody can be negative in up to 50% of patents presenting with typical clinical features , and a portion of the patients may become sero-positive on a repeated testing 6 to 12 months later (personal observations). AAG often has a subacute onset, reaching its peak of severity in autonomic symptoms within 6 weeks. A disproportionate involvement of the enteric nervous system favors AAG, and aids in the differential diagnosis . A lack of progression also differentiates AAG from neurodegenerative diseases with autonomic failure such as autonomic alpha-synucleinopathies. Recovery can be slow, and is incomplete in most cases.

Paraneoplastic and other autoimmune autonomic neuropathy

Hereditary amyloidosis neuropathy

Amyloid transthyretin (ATTR) amyloidosis is a systemic disease causing extracellular deposition of insoluble beta-structured fibrils and protein aggregates. ATTR amyloidosis can be of a hereditary form due to mutations in transthyretin gene or be a wild-type (wt-ATTR amyloidosis). Transthyretin (TTR) is a plasma transporter for thyroid hormones and retinol-binding protein and mainly synthesized in the liver. The transthyretin monomer has an approximate beta-structure after folding its structure. Four monomers make a tetramer with binding sites for thyroxine and retinol binding protein/vitamin A. Pathogenic mutations in TTR gene destabilize the TTR tetramers releasing abnormal monomers that aggregate as beta-structured fibrils, then amyloid deposits. In addition to pathological mutations, aging is also an important factor that decreases stability of TTR tetramers .

Gastrointestinal symptoms in hATTR amyloidosis have been studied in an international, multi-center, longitudinal study, the Transthyretin Amyloidosis Outcomes Survey (THAOS) . This study showed that gastrointestinal manifestations are common in hATTR amyloidosis and that unintentional weight loss is the most common symptom with early satiety as the second. mBMI (modified body mass index), an index for nutritional status obtained by multiplying body mass index with serum albumin, and an index for health-related quality of life are significantly associated with upper and lower gastrointestinal symptoms indicating presence of the symptoms has negative impacts on clinical outcomes although individual symptoms did not show such association. Gastrointestinal symptoms can be affected by multiple factors. With TTR mutations causing mainly cardiac problems such as the V122I, I68L, and L111M variants, gastrointestinal symptoms are not more frequent than in general population. Among non-cardiac dominant TTR mutations, the V30M variant has a higher prevalence of gastrointestinal symptoms than non-V30M variants. Early-onset type (onset <50 years) also increases risks of gastrointestinal symptoms. Not surprisingly, the longer duration of disease is, the more common gastrointestinal symptoms are. But each symptom has a different pattern. Early satiety is common as an early symptom and does not increase in frequency significantly during progression of the disease. Fecal incontinence is more frequent with a longer duration of disease. When considering an endoscopic biopsy, the upper GI tract (the stomach and duodenum) has higher amyloid deposits than lower GI tract. Sampling needs to be deep enough to include mucosal vessels because amyloid contents may not be seen in the mucosa .

Treatment of GI complications due to hATTR amyloidosis should focus on symptomatic managements addressing quality of life, malabsorption, and bacterial overgrowth. Treatments targeting the underlying pathology include stabilizers of TTR tetramers (tafamidis and diflunisal) and liver transplantation. Recently two agents that reduce hepatic production of TTR by RNA interference have been approved by the United States Food and Drug Administration. Both patisiran and inotersen were studied in hATTR amyloidosis with polyneuropathy in randomized, double-blinded, multicenter studies . Patients treated with either medication showed significant improvement in neuropathy-related indexes and quality of life measures. Autonomic dysfunctions were assessed in the study with patisiran only by using Composite Autonomic Symptom Score (COMPASS 31). COMPASS 31 is a scoring system using a questionnaire related to autonomic symptoms of multiple organ systems including gastrointestinal system. Patisiran did improve autonomic dysfunction in general but the study results did not provide information on symptoms of each organ system within COMPASS 31 .

Ehlers-Danlos syndrome

Ehlers Danlos syndrome (EDS) is a rather common condition that can be associated with gastric dysmotility. The prevalence of EDS is approximately 1:5000 . EDS has multiple subtypes . Hypermobile EDS is the most common subtype observed (71%), followed by classic EDS (11%), vascular EDS (7%) and other subtypes (10%) . Joint symptoms are the most common mode of presentation (60%). Gastrointestinal symptoms can be the presenting symptom in 9% of patients, increase over time and seem equally prevalent among all EDS subtypes. Diverse gastrointestinal symptoms including abdominal pain, nausea, constipation, heartburn, irritable bowel syndrome, vomiting, and diarrhea have been reported. In one large retrospective study , 56% of EDS patients (378/687 patients) had gastrointestinal symptoms, which were far more common in women. Esophagogastroduodenoscopy in 38% of the 378 patients revealed various abnormalities such as gastritis, hiatal hernia and reflux esophagitis. Gastric emptying in 76/378 patients was abnormal in 17 (22%): 8/17 had accelerated and 9/17 had delayed gastric emptying. Colonic transit time measured in 46/378 patients was abnormal in 28% (13/46): 9/13 had delayed and 4/13 had accelerated transit.

Gastric dysmotility in EDS has likely dual etiologies. Abnormal elasticity in the connective tissue of the gastrointestinal wall may disrupt the physiological motility by altering visceral compliance. A less common factor is the vascular component. Vascular studies reveal aneurysms in abdominal vessels in vascular EDS. Vascular anomalies may predispose to median arcuate ligament syndrome. But EDS is also associated with autonomic dysfunction, which contributes to some degree of segmental GI denervation. Some EDS patients have fibromyalgia; evaluation often finds small fiber neuropathy in these patients . This neuropathy contributes to various functional GI complaints by altering pain threshold, visceral sensitivity and gut motility.

Other rare genetic disorders associated with gastroparesis include mitochondrial neurogastrointestinal encephalopathy due to a mutation in the thymidine phosphorylase gene . Gastroparesis also occurs rarely in mitochondrial conditions secondary to mutation of the DNA polymerase gamma gene (POLG) . There are rare cases of sodium channel mutations causing small fiber neuropathy with gastroparesis .

Postural orthostatic tachycardia syndrome (POTS)

Patients with autonomic or small fiber neuropathy, including those with EDS and post-infectious syndrome, have a predisposition to orthostatic intolerance. This intolerance may take the form of orthostatic hypotension (early or delayed) or that of postural orthostatic tachycardia syndrome (POTS). POTS is a heterogeneous autonomic syndrome with exaggerated postural tachycardia and relevant symptoms of orthostatic intolerance. An exaggerated postural tachycardia is defined as a sustained increase in heart rate by at least 30 bpm (40 bpm for those at 19 or younger) without a significant drop in blood pressure (orthostatic hypotension) in 10 minutes after active or passive standing . Patients experience various symptoms of chronic orthostatic intolerance for more than 6 months resulting from reduced cerebral hypoperfusion (dizziness, lightheadedness, vision changes, near-fainting/fainting) and increased sympathetic activation (palpitations, shakiness, sweating, flushing, chest pain). POTS can be divided into three main types: neuropathic, central hyperadrenergic and deconditioning. But it is common that a patient with POTS may have overlapping clinical manifestations of different types. Additional factors include a relative deficit in blood volume , imbalance of the renin–angiotensin–aldosterone pathway , or autoantibodies targeting peripheral adrenergic receptors . Most patients report a history of preceding events, often infection, which raise possibilities of post-infectious or autoimmune process causing limited autonomic neuropathy (neuropathic POTS) or deconditioning due to acute illness. Patients tend to have various combinations of extra-cardiovascular symptoms including gastrointestinal, genitourinary, peripheral sensory, and pupilomotor complaints. Regardless of whether there is a preceding infection, gastrointestinal symptoms are commonly reported in POTS patients. A pooled data analysis from six studies showed that gastrointestinal symptoms have a prevalence of approximately 69% with nausea and abdominal pain as the most common . In a retrospective study, gastric emptying studies were abnormal in almost two-third cases of POTS and rapid gastric emptying was more common than delayed emptying , which is consistently observed in other studies . In the study, rapid gastric emptying was associated with physical deconditioning clinically determined by evaluating physicians based on level of reduced exercise capacity affecting normal daily activities. And delayed gastric emptying was more related with blood pressure drop at the first minute of a tilt-table test and sympathetic adrenergic dysfunction on autonomic reflex test . Pathogenesis of gastric dysmotility in POTS are likely multifactorial. As mentioned above, POTS is a heterogeneous condition of chronic orthostatic intolerance with multiple associated conditions including hypermobile Ehlers Danlos syndrome, small-fiber neuropathy, chronic fatigue syndrome, migraine, generalized pain, sleep disorders, and mast cell activation syndrome. Therefore, it is practically impossible to explain gastrointestinal symptoms in POTS patients with a single mechanism. A large portion of POTS patients are relatively young females with hypermobile Ehlers-Danlos Syndrome or hypermobility spectrum disorders. Patients with generalized hypermobile joints are more likely to have gastrointestinal motility findings and related symptoms compared to those without hypermobile joints. Its risk increases with the presence of POTS although there is no clear explanation. Mehr et al. hypothesized that the gastrointestinal system derived of sympathetic inhibitory innervation in neuropathic POTS is more likely to develop excessive and uncoordinated activities. The authors also suggested that uncoordinated or uncoupled neurovascular regulation in postprandial periods causes excessive blood pooling in splanchnic circulation and relevant postprandial symptoms in POTS patients . A small subset of patients with orthostatic intolerance revealed evidence of eosinophilic esophagitis or gastritis during GI investigations. A recent retrospective study found POTS prevalence of 1.25% in patients with eosinophilic gastrointestinal disorder, as compared to 0.17% in general population . There are animal models that suggest impaired enteric neuronal function in the presence of eosinophilic and neutrophil infiltrates . There is also a rare case report of pediatric patients with intestinal pseudo-obstruction, associated with eosinophilic infiltrate . On the other hand, the same models show little neurodegeneration even in the presence of significant eosinophilic infiltrates. Therefore, the exact mechanistic relation remains unknown.