1.2. Key symptoms and clinical presentation

← PREVIOUS: [[1.1. Definition of POTS]] | NEXT: [[2. Diagnosis and Diagnostic Criteria]] → ------------- ##### Summary >[!Summary] >- proposed grouping: cardiovascular and noncardiovascular[[#^1]] ; orthostatic, nonorthostatic and diffuse associated symptoms[[#^5]] > >| CARDIOVASCULAR | REPORTED PREVALENCE | >|:------------------------------ |:------------------- | >| lightheadedness or dizziness | 78%[[#^5]] ; 95%[[#^21]] ; 99%[[#^35]] | >| disequilibrium | 75%[[#^21]] | >| tachycardia, palpitations | 97% (tachycardia)[[#^35]] ; 87% (palpitations)[[#^35]] ; 75%[[#^5]] (palpitations); 89%[[#^21]] ; 48.2% [[#^44]] | >| presyncope | 61%[[#^5]] ; 94%[[#^35]] ; 59.3% [[#^44]] | >| heat intolerance | 53%[[#^5]] ; 79%[[#^21]] ; 58%[[#^22]] | >| reduced exercise capacity | 53%[[#^5]] ; 81%[[#^21]] | >| sense of weakness | 50%[[#^5]] ; 94%[[#^21]] ; 83%[[#^35]] | >| sense of heaviness (e.g. legs) [[#^12]]| *N/S* | >| shortness of breath | 28%[[#^5]] ; 42%[[#^21]] ; 88%[[#^35]] | >| chest pain | 24%[[#^5]] ; 79%[[#^35]] | >| orthostatic hypertension | 18.5% [[#^44]] | >----------- >| GASTROINTESTINAL | REPORTED PREVALENCE | >|:------------------------- |:------------------- | >| nausea | 39%[[#^5]] ; 72%[[#^21]] ; 68%[[#^22]] ; 90%[[#^35]] ; 33% [[#^44]] | >|vomiting| 9%[[#^5]] ; 25%[[#^22]] | >| bloating | 24%[[#^5]] ; 72%[[#^22]] ; 79%[[#^35]] ; 33% [[#^44]] | >| diarrhea | 18%[[#^5]] ; 75%[[#^22]] ; 69%[[#^35]] ; 35% [[#^44]] | >| constipation | 15%[[#^5]] ; 50%[[#^22]] ; 71%[[#^35]] | >|abdominal pain| 15%[[#^5]] ; 62%[[#^22]] ; 83%[[#^35]] | >| early satiety |46%[[#^22]]| >|exacerbation by meals|24%[[#^5]] ; 42%[[#^21]]| >------------ >|NEUROLOGICAL (HEAD & BRAIN)) |REPORTED PREVALENCE| >|:--|:--| >|tremulousness or shakiness|38%[[#^5]] ; 80%[[#^21]] ; 78%[[#^35]] ; 67% [[#^44]]| >|brain fog (ex: difficulty concentrating, memory problems)|94% (concentration)[[#^35]] ; 87% (memory)[[#^35]] ; 96% [[#^51]]| >|headache | 94%[[#^35]]| >------------- >|NEUROLOGICAL (EYES & EARS) |REPORTED PREVALENCE| >|:--|:--| >|pupillary or visual symptoms (e.g. dry eyes, blurred or tunneled vision, light sensitivity/glare) |38% (dry eyes)[[#^21]] ; 3% (glare)[[#^5]] ; 53% (dry eyes)[[#^22]] ; 75% (blurred vision)[[#^35]] ; 60% (dry eyes)[[#^35]]| >|dry mouth|38%[[#^22]] ; 66%[[#^35]]| >|reduced salivation|12%[[#^22]]| >------------- >|NEUROLOGICAL (EXTREMITIES) |REPORTED PREVALENCE| >|:--|:--| >|foot or hand coldness|84% (foot coldness)[[#^35]] ; 82% (hand coldness)[[#^35]]| >|foot or hand numbness|58% (foot numbness)[[#^35]] ; 65% (hand numbness)[[#^35]]| >|foor or hand tingling| 67% (foot tingling)[[#^35]] ; 76% (hand tingling)[[#^35]]| >|pallor|71%[[#^22]]| >|redness[[#^43]]|61%[[#^22]]| >|sweating|30%[[#^22]]| >------------- >|SKIN |REPORTED PREVALENCE| >|:--|:--| >|skin flushing|69%[[#^35]]| >|hyperhidrosis|9%[[#^5]] ; 52% [[#^44]]| >|loss of sweating|5%[[#^5]]| >|clammy skin|70%[[#^21]]| >------------- >|BLADDER |REPORTED PREVALENCE| >|:--|:--| >|general bladder symptoms|9%[[#^5]]| >|frequent urination[[#^45]]|68%[[#^35]]| >------------- >|GENERALIZED ASSOCIATED |REPORTED PREVALENCE| >|:--|:--| >|exacerbation associated with menses|15%[[#^5]]| >|chronic fatigue|48%[[#^5]] ; 90%[[#^42]] ; 51.9% [[#^44]]| >|sleep disturbance[[#^42]]|32%[[#^5]]| >|migraine headache|28%[[#^5]] ; 46%[[#^23]]| >|myofascial pain|16%[[#^5]] ; 84%[[#^35]]| >|neuropathic type pain|2%[[#^5]]| >|anxiety|69%[[#^21]] ; 67% [[#^44]]| >- only a minority (≈ 30%) faint[[#^16]][[#^41]] ; 30-50%[[#^4]] ; 36%[[#^35]] ; 40.7% [[#^44]] >- patients typically present with a myriad of symptoms[[#^32]], which prevalence varies a lot[[#^3]] >- activities of daily living may greatly exacerbate symptoms causing significant limitations on functional capacity[[#^16]] ; additionally exacerbated by high ambient temperature[[#^12]][[#^25]], insufficient fluid intake[[#^25]], dehydration[[#^25]], physical strain[[#^12]][[#^25]], morning hours or fever[[#^25]], continued standing[[#^21]] >- acrocyanosis (dark red-blue discoloration of legs) not due to increased venous compliance, but may be caused by decrease in blood flow to skin (abnormal cutaneous nitric oxide activity)[[#^37]] >- patients with hyperadrenergic forms tend to have diarrhea rather than constipation[[#^46]] > ------------------- > **Brain fog** >- prevalent cognitive complaint similar to mental fatigue, with many triggers and modulators that may explain the symptom's physiology[[#^49]] >- brain fog may not be a problem with memory, but decreased attention and concentration[[#^26]][[#^39]] >- often worse with upright posture[[#^47]] >- defined as forgetfulness, difficulty thinking and focusing, and mental cloudiness or fatigue and is one of the most debilitating[[#^48]], disabling and prevalent symptoms in POTS[[#^66]] >- top ranked descriptors of brain fog were “forgetful” (91 %), “difficulty thinking” (89 %), “difficulty focusing” (88 %), “cloudy” (88 %), and “difficulty finding the right words or communicating” (88 %). The least commonly reported descriptors were “thoughts moving too quickly” (40 %), “detached” (60 %), “lost” (64 %), “sleepy” (69 %), and “annoying” (70 %)[[#^50]] >- 93% report daily frequency, 86% report that it fluctuates throughout the day. It affects schoolwork for 86%, work productivity for 80% and social activities for 67%[[#^51]] >- most frequent reported triggers of brain fog were physical fatigue (91 %), lack of sleep (90 %), prolonged standing (87 %), dehydration (86 %), and feeling faint (85%). While supine, physical fatigue triggered brain fog in 72 % of subjects, lack of sleep in 70%, dehydration in 60%, and feeling faint in 57%[[#^52]] >- 81% recommended lying down to improve brain fog[[#^53]])[[#^62]] >- for some it might not be relieved by recumbence, which is consistent with a carry-over effect from a physiological provocation, possibly explained by brain fog being triggered by excessive reductions in cerebral blood flow[[#^53]] >- brain fog can be triggered in the supine position as well[[#^53]][[#^54]][[#^59]][[#^60]][[#^61]] >- there is objective evidence of neurocognitive deficits in POTS individuals[[#^55]][[#^58]][[#^64]]: deficits in short-term memory and alertness, impaired selective attention and cognitive processing[[#^56]], impairment of attentional performance and reduction of executive function even during minimal orthostatic stress (sitting)[[#^57]] >- a significantly high proportion of POTS patients scored in a range consistent with clinical meaningful impairment for selective attention (ability to focus on competing informational cues). Mild impairment was also observed in cognitive processing speed (time to process information) and executive function (ability to plan, organize information, and adapt to changes)[[#^62]] >- data supports the hypothesis, that cognitive impairment in POTS is not a global problem caused by the disease itself, but a functional deficit induced by orthostatic stress, which might alter cerebral perfusion or central neurometabolic mechanisms[[#^57]]. However, since cognitive deficits were shown in the semi-recumbent position, when patients were asymptomatic and orthostatic tachycardia minimized, it nonetheless remains unclear if cognitive dysfunction in POTS definitely results from orthostatic stress, or is part of the disease[[#^65]] >- proposed pathophysiological mechanisms contributing to brain fog are: > 1. disturbances in cerebral blood flow and nitric oxide regulation[[#^68]] > 2. central norepinephrine dysregulation[[#^57]][[#^69]] > 3. structural and functional brain abnormalities (hyper-reactive bodily state in POTS may underlie disruption of emotional state by attenuating activity of the ventromedial prefrontal cortex[[#^70]] ; reduced gray matter volume in brain regions associated with autonomic control and emotional arousal and reduced white matter volume in primary somatosensory brain regions[[#^71]]) > 4. chronic fatigue[[#^72]] > 5. sleep disturbances[[#^73]][[#^76]] > ----------------- > **Sleep Disturbance** >- POTS patients have more sleep problems and excessive daytime sleepiness, as well as higher fatigue levels[[#^27]] >- there was a strong correlation between a reduced quality of life scores and sleep problems (over 50% of the variance of quality of life explained by the variance in sleep quality)[[#^27]][[#^40]] >- POTS patients have objective sleep deficits and lower HR variability during sleep suggesting lower parasympathetic tone and enhanced sympathetic tone. The primary sleep problem seems to be insomnia – both sleep onset and sleep maintenance insomnia[[#^74]] >- 32% have a diagnosed sleep disorder, most commonly insomnia[[#^75]] >- significant abnormalities in circadian rhythm or other sleep disorders[[#^77]] >- the sleep problems are thought to result from sympathetic or hypothalamic-pituitary axis activation to induce hyperarousal, or from comorbidities such as chronic pain[[#^78]] -------- ##### Groups >*“In general, the symptoms related to POTS may be divided for the didactic purpose into two main groups, cardiovascular and noncardiovascular.” *([[Fedorowski-2019]], [p. 4](zotero://open-pdf/library/items/BZ35QDLR?page=4&annotation=S9HSMRMM))^1 ##### Noncardiovascular symptoms >*“These symptoms are not directly related to the observed haemodynamic disorders” *([[Fedorowski-2019]], [p. 4](zotero://open-pdf/library/items/BZ35QDLR?page=4&annotation=ETKWTHRY))^2 >*“The most important features are of a general nature and include non-specific physical deconditioning, reduced exercise capacity, fatigue and weakness (Table 2). The most affected noncardiac areas are head and the nervous, respiratory, gastrointestinal and musculoskeletal systems. Some symptoms are a direct consequence of impaired autonomic regulation of basic homeostatic functions such as thermoregulation and peristalsis. The prevalence of different symptoms varies a lot, with some being more frequent, and other being less common” *([[Fedorowski-2019]], [p. 5](zotero://open-pdf/library/items/BZ35QDLR?page=5&annotation=S9FP3D38))^3 ##### Cardiovascular symptoms >*“This group of symptoms is related to an inadequate and exaggerated heart rate increase on standing, global postural haemodynamic instability, either hypertensive or hypotensive tendency, cerebral hypoperfusion, venous pooling, and disorders of vascular tone regulation in specific areas such as head, coronary arteries, skin, extremities [20, 32, 34, 35] (Table 2). Moreover, approximately 30–50% of all POTS patients faint [33, 35–37].” *([[Fedorowski-2019]], [p. 4](zotero://open-pdf/library/items/BZ35QDLR?page=4&annotation=8WZW2N5M))^4 ##### Symptoms >![[Low-2009-11-x72-y250.png#invert_B| 550]] >([[Low-2009]], [p. 11](zotero://open-pdf/library/items/I4WAD8AG?page=11&annotation=LVCU8FBG))^5 >_“The orthostatic tachycardia may be accompanied by symptoms of cerebral hypoperfusion and sympathetic hyperactivity that are relieved by recumbency.”_ ([[Benarroch-2012]], [p. 1](zotero://open-pdf/library/items/WEZLT9QC?page=1&annotation=XXM2X8NW))^6 >_“Symptoms of cerebral hypoperfusion include light-headedness, blurred vision, cognitive difficulties, and generalized weakness; symptoms of excessive sympathoexcitation include palpitations, chest pain, and tremulousness.”_ ([[Benarroch-2012]], [p. 1](zotero://open-pdf/library/items/WEZLT9QC?page=1&annotation=53ZH3EI3)^7 >_“The manifestations of POTS that reflect orthostatic intolerance (POTS in the strict sense) include those of cerebral hypoperfusion and reflex sympathetic activation”_ ([[Benarroch-2012]], [p. 2](zotero://open-pdf/library/items/WEZLT9QC?page=2&annotation=5PCPEZRZ))^8 >_“A percentage of patients with POTS experience visceral symptoms referred to the upper or lower gastrointestinal tract, bladder, and other organs. In a large series of adult patients with POTS, nausea was present in 39%, bloating in 24%, diarrhea in 18%, constipation in 15%, abdominal pain in 15%, and bladder symptoms in 9% of cases.”_ ([[Benarroch-2012]], [p. 4](zotero://open-pdf/library/items/WEZLT9QC?page=4&annotation=42IGWZPG))^9 >_“In a large series of adult patients with POTS, many reported chronic fatigue (48%), sleep disturbance (32%), and myofascial pain (16%).”_ ([[Benarroch-2012]], [p. 4](zotero://open-pdf/library/items/WEZLT9QC?page=4&annotation=99FLUMCD))^10 >*“Somatic hypervigilance and psychologic factors are involved in a significant proportion of patients.” *([[Low-2009]], [p. 1](zotero://open-pdf/library/items/I4WAD8AG?page=1&annotation=AVK5MI6H))^11 >*“The orthostatic symptoms consist of symptoms of reduced cerebral perfusion coupled with those of sympathetic activation. The most common symptoms are lightheadedness, palpitations, symptoms of presyncope, tremulousness, and weakness or heaviness (especially of the legs). These symptoms are commonly exacerbated by heat and exercise (Table 1). Other common symptoms are shortness of breath and chest pain. [11] The symptoms these patients experience differ from those of patients with orthostatic hypotension in that there are significant symptoms of sympathetic activation. [12] There may be an overrepresentation of migraine, sleep disorders, and fatigue, and fibromyalgia is sometimes associated.” *([[Low-2009]], [p. 2](zotero://open-pdf/library/items/I4WAD8AG?page=2&annotation=JJVKVMIG))^12 >*“Fatigue is commonly present. [11] Patients complain of poor exercise tolerance with physiological features including reduced stroke volume and reflex tachycardia typical of subjects who are deconditioned, such as in persons who have had prolonged bed rest. [15] Coupled with the poor exercise tolerance, an excessively long recovery cycle following exercise is often described. Additionally, patients typically note that they have low energy, even at rest. The sense of fatigue will sometimes occur in cycles and may last days or even weeks and then lift.” *([[Low-2009]], [p. 3](zotero://open-pdf/library/items/I4WAD8AG?page=3&annotation=IW38URBR))^13 >*“POTS patients have poor exercise tolerance, and deconditioning is often present, especially in patients with prominent fatigue and fibromyalgia type symptoms.” *([[Low-2009]], [p. 5](zotero://open-pdf/library/items/I4WAD8AG?page=5&annotation=N7EZ93NH))^14 >*“Symptoms often include both cardiac symptoms (rapid palpitations, lightheadedness, chest discomfort, and dyspnea) and non-cardiac symptoms (mental clouding [“brain fog”], headache, nausea, tremulousness, blurred or tunneled vision, poor sleep, exercise intolerance, and fatigue). Even activities of daily living, such as bathing or housework, may greatly exacerbate symptoms, with resultant fatigue. This can pose significant limitations on functional capacity. While pre-syncope and lightheadedness are common in these patients, only a minority (∼30%) actually faint. The chest pains are almost never due to coronary artery obstruction, but may be associated with electrocardiographic changes in the inferior leads, particularly when upright.” *([[Raj-2013]], [p. 2](zotero://open-pdf/library/items/CCJLQKRB?page=2&annotation=4EMSP97U))^16 >*“Patients with POTS often present with complaints of chronic fatigue, exercise intolerance, dizziness, diminished concentration, tremulousness, nausea, and recurrent syncope.” *([[Benrud-Larson-2002]], [p. 1](zotero://open-pdf/library/items/HUAS79XY?page=1&annotation=9Q3U5JM3))^17 >*“Although orthostatic intolerance is the hallmark of POTS, patients may experience other symptoms of autonomic dysfunction as well, including upper gastrointestinal (GI) tract symptoms, bowel and bladder dysfunction, and secretomotor dysfunction” *([[Benrud-Larson-2002]], [p. 1](zotero://open-pdf/library/items/HUAS79XY?page=1&annotation=IDGRCANP))^18 >*“Most patients had frequent, persistent, and at least moderately severe symptoms for less than 5 years. The following orthostatic symptoms occurred in more than 75% of subjects: light-headedness or dizziness, lower extremity or diffuse weakness, disequilibrium, tachycar- *([p. 1](zotero://open-pdf/library/items/X25GXI7E?page=1&annotation=WBC6Z4RF)) dia, and shakiness. Nonorthostatic symptoms included dry eyes or mouth, gastrointestinal complaints of bloating, early satiety, nausea, pain, and alternating diarrhea and constipation.” ([[Sandroni-1999]], [p. 1](zotero://open-pdf/library/items/X25GXI7E?page=1&annotation=TLM278SN))^19 >![[Sandroni-1999-2-x295-y316.png#invert_B| 450]] >([[Sandroni-1999]], [p. 2](zotero://open-pdf/library/items/X25GXI7E?page=2&annotation=DH9FLBZE))^20 >![[Sandroni-1999-3-x39-y328.png#invert_B| 450]] >([[Sandroni-1999]], [p. 3](zotero://open-pdf/library/items/X25GXI7E?page=3&annotation=7H5P73BQ))^21 >![[Sandroni-1999-3-x296-y355.png#invert_B| 450]] >([[Sandroni-1999]], [p. 3](zotero://open-pdf/library/items/X25GXI7E?page=3&annotation=X2QK9NI9))^22 >![[Sandroni-1999-4-x41-y293.png#invert_B| 450]] >([[Sandroni-1999]], [p. 4](zotero://open-pdf/library/items/X25GXI7E?page=4&annotation=YGD28UHR))^23 >*“The most common complaints are dizziness, weakness, rapid heartbeat and palpitation on standing. Moreover, patients often report physical deconditioning and reduced exercise capacity as well as headache, ‘brain fog’, dyspnoea, gastrointestinal disorders and musculoskeletal pain.” *([[Fedorowski-2019]], [p. 1](zotero://open-pdf/library/items/BZ35QDLR?page=1&annotation=5JZUWM9Y))^24 >*“Although the predominant and pathognomonic feature of POTS is chronic orthostatic intolerance, usually exacerbated by additional factors such as high ambient temperature, insufficient fluid intake, dehydration, physical strain, morning hours or fever, POTS patients typically present *([p. 3](zotero://open-pdf/library/items/BZ35QDLR?page=3&annotation=UQCWVPLU)) with a myriad of other symptoms [2, 20, 24, 30–32] (Table 2). The most common complaints in the initial presentation of POTS are dizziness, weakness, rapid heartbeat and palpitation on standing, headache, fatigue, abdominal pain and syncope” *([[Fedorowski-2019]], [p. 4](zotero://open-pdf/library/items/BZ35QDLR?page=4&annotation=ZID4MRWA))^25 >*“Many POTS patients complain of memory problems. In formal testing with the Inattention score from the Connors Adult ADHD Rating Scale, POTS patients scored significantly worse than did healthy control subjects 7. This suggests that the problem in POTS may not be with memory per se, but with diminished attention.”* ([[Raj-2013]], [p. 2](zotero://open-pdf/library/items/CCJLQKRB?page=2&annotation=XCG2MQWA))^26 >*“In addition to orthostatic intolerance and other autonomic features, such as sudomotor changes, patients commonly experience fatigue, abnormalities of sleep, and migraine headache” *([[Thieben-2007]], [p. 1](zotero://open-pdf/library/items/5WXWEQWX?page=1&annotation=U56N4BXM))^28 >![[Thieben-2007-4-x54-y386.png#invert_B| 500]] >([[Thieben-2007]], [p. 4](zotero://open-pdf/library/items/5WXWEQWX?page=4&annotation=S2RLY44Q))^29 >*“No statistically significant difference was found in the symptoms of patients with standing norepinephrine levels of 600 pg/mL or less compared with those with standing norepinephrine levels of more than 600 pg/mL (all P>.07), except for loss of sweating (P<.001) and hyperhidrosis (P=.03), which were more common in patients with higher norepinephrine levels.” *([[Thieben-2007]], [p. 5](zotero://open-pdf/library/items/5WXWEQWX?page=5&annotation=XBEGHPTG))^30 >*“Fatigue is often a major complaint of patients with POTS. Some patients have an extended period of exhaustion after a bout of symptoms. This period may last from hours to days. In some patients, overwhelming fatigue is a chronic and persistent symptom. These patients describe a low energy level” *([[Thieben-2007]], [p. 6](zotero://open-pdf/library/items/5WXWEQWX?page=6&annotation=9DLZCRVE))^31 >*“myriad of symptoms most commonly including lightheadedness (99%), tachycardia (97%), presyncope (94%), headache (94%) and difficulty concentrating (94%)” *([[Shaw-2019]], [p. 1](zotero://open-pdf/library/items/48AJ3KVL?page=1&annotation=RCS6J47S))^32 >*“The most common symptoms include lightheadedness (n = 3992; 99%), tachycardia (n = 3901; 97%), presyncope (n = 3789; 94%), headache (n = 3797; 94%) and difficulty concentrating (n = 3794; 94%). Of these symptoms, the triad of lightheadedness, tachycardia and presyncope was concomitantly present in 3677 (91%) of respondents. A pentad of all five symptoms was reported by 3331 (83%) of respondents.” *([[Shaw-2019]], [p. 5](zotero://open-pdf/library/items/48AJ3KVL?page=5&annotation=ZAAAAPD8))^33 >*“POTS is a chronic multisystem disorder involving a broader array of symptoms than the orthostatic tachycardia that defines it” *([[Shaw-2019]], [p. 7](zotero://open-pdf/library/items/48AJ3KVL?page=7&annotation=83MWDJZJ))^34 >![[Shaw-2019-7-x62-y78.png#invert_B| 400]] >([[Shaw-2019]], [p. 7](zotero://open-pdf/library/items/48AJ3KVL?page=7&annotation=8RY8YZJU))^35 >*“Orthostatic symptoms—Both cardiac symptoms, such as rapid palpitations, lightheadedness, chest discomfort, and dyspnea, and non-cardiac symptoms, such as mental clouding, headache, nausea, tremulousness, generalized weakness, and blurred or tunnel vision, are evident in POTS patients during upright posture” *([[Garland-2015]], [p. 3](zotero://open-pdf/library/items/CAWTWYLR?page=3&annotation=FMTQH4QF))^36 >*“A dark red-blue discoloration of the legs might occur with standing, extending from the feet to above the knees in ∼50% of patients with POTS. This acrocyanosis in POTS is not due to increased venous compliance [22;23] but may be caused by a decrease in blood flow to the skin, possibly related to abnormal cutaneous nitric oxide activity” *([[Garland-2015]], [p. 4](zotero://open-pdf/library/items/CAWTWYLR?page=4&annotation=97AWPR4E))^37 >*“In addition to orthostatic symptoms in POTS, patients experience non-specific signs and symptoms that seem unrelated to postural intolerance or excessive tachycardia [25]. These might or might not be associated with the autonomic nervous system and can also occur in individuals without POTS. Autonomic problems in POTS might include gastrointestinal complaints, such as abdominal pain, nausea and irritable bowel syndrome, as well as bladder symptoms and abnormal sudomotor regulation [19;26]. More generalized complaints in patients with POTS include hypermobile joints, exercise intolerance, migraine headaches, sleep disturbances, and fatigue” *([[Garland-2015]], [p. 4](zotero://open-pdf/library/items/CAWTWYLR?page=4&annotation=68S6NZFH))^38 >*“Only 30% or so of POTS patients actually experience syncope” *([[Garland-2015]], [p. 6](zotero://open-pdf/library/items/CAWTWYLR?page=6&annotation=PTXMGBDN))^41 >*“Headache and sleep disturbances are almost universal. Patients with POTS often have exercise intolerance, more than 90% have chronic fatigue and at least half meet criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)”* ([[Raj-2022]], [p. 2](zotero://open-pdf/library/items/YN8BG2FZ?page=2&annotation=JAUSJR4U))^42 >*“Nausea, bloating and functional bowel symptoms are common. Another common sign is peripheral acrocyanosis in the lower extremities when upright”* ([[Raj-2022]], [p. 2](zotero://open-pdf/library/items/YN8BG2FZ?page=2&annotation=PZ9RENWD))^43 >![[Benrud-Larson-2002-4-x50-y60.png#invert_B| 420]] >([[Benrud-Larson-2002]], [p. 4](zotero://open-pdf/library/items/HUAS79XY?page=4&annotation=MVMCWNNX)) #new ###### Hyperadrenergic POTS >![[Zotero/Zotero Images/Kanjwal-2011-3-x61-y377.png#invert_B| 350]] >([[Kanjwal-2011]], [p. 3](zotero://open-pdf/library/items/R4GMHSS7?page=3&annotation=BT6QUA97))^44 >*“Many will report a significant increase in urinary output after being upright for even a short period of time”* ([[Kanjwal-2011]], [p. 4](zotero://open-pdf/library/items/R4GMHSS7?page=4&annotation=P8EXGEM4))^45 >*“Patients with hyperadrenergic forms tend to have diarrhea rather than constipation”* ([[Kanjwal-2011]], [p. 4](zotero://open-pdf/library/items/R4GMHSS7?page=4&annotation=TXEJIM9W))^46 ##### Brain Fog >*“A particularly disabling symptom is “brain fog” or perceived cognitive impairment,19 which is often worse with upright posture.”* ([[Raj-2022]], [p. 2](zotero://open-pdf/library/items/YN8BG2FZ?page=2&annotation=FIALW6I9))^47 >*““Brain fog” is defined by POTS patients as forgetfulness, difficulty thinking and focusing, and mental cloudiness or fatigue and is one of the most debilitating POTS symptoms (Ross et al., 2013).”* ([[Miller-2018]], [p. 6](zotero://open-pdf/library/items/A3CIPE3G?page=6&annotation=4MSM2U7M))^48 >*“Although many patients with POTS complain of “memory problems” and “mental clouding”, these might actually represent decreased attention and concentration [27]. A comprehensive neuropsychological evaluation of 28 patients in a seated position found deficits in selective attention and cognitive processing, as well as impaired executive functioning. Memory function did not differ from healthy controls [29].”* ([[Garland-2015]], [p. 4](zotero://open-pdf/library/items/CAWTWYLR?page=4&annotation=U7HGD9LD))^39 >*“(1) brain fog is a prevalent cognitive complaint similar to mental fatigue, (2) there are many triggers and modulators of brain fog that may explain the symptom’s physiology, and (3) there are many treatment targets that may be effective for improving brain fog in POTS including some that are not typically recommended for POTS”* ([[Ross-2013]], [p. 4](zotero://open-pdf/library/items/5NBCV5L2?page=4&annotation=N5H52LXM))^49 >![[Zotero/Zotero Images/Ross-2013-14-x73-y379.png#invert_B| 500]] >([[Ross-2013]], [p. 14](zotero://open-pdf/library/items/5NBCV5L2?page=14&annotation=JA292ZSN)) > >*“the top ranked descriptors of brain fog were “forgetful” (91 %), “difficulty thinking” (89 %), “difficulty focusing” (88 %), “cloudy” (88 %), and “difficulty finding the right words or communicating” (88 %). The least commonly reported descriptors were “thoughts moving too quickly” (40 %), “detached” (60 %), “lost” (64 %), “sleepy” (69 %), and “annoying” (70 %)”* ([[Ross-2013]], [p. 3](zotero://open-pdf/library/items/5NBCV5L2?page=3&annotation=XKN57U68))^50 >![[Zotero/Zotero Images/Ross-2013-13-x72-y263.png#invert_B| 500]] >([[Ross-2013]], [p. 13](zotero://open-pdf/library/items/5NBCV5L2?page=13&annotation=2Z47YHPG))^51 >![[Zotero/Zotero Images/Ross-2013-10-x68-y313.png#invert_B| 700]] >([[Ross-2013]], [p. 10](zotero://open-pdf/library/items/5NBCV5L2?page=10&annotation=Z95PW5SB)) > >*“the most frequent reported triggers of brain fog were physical fatigue (91 %), lack of sleep (90 %), prolonged standing (87 %), dehydration (86 %), and feeling faint (85 %). While supine, physical fatigue triggered brain fog in 72 % of subjects, lack of sleep in 70 %, dehydration in 60 %, and feeling faint in 57 %”* ([[Ross-2013]], [p. 3](zotero://open-pdf/library/items/5NBCV5L2?page=3&annotation=XA547V8X))^52 >*“87 % of subjects reported prolonged standing to trigger their brain fog and 81 % recommended lying down to improve brain fog([p. 4](zotero://open-pdf/library/items/5NBCV5L2?page=4&annotation=QW2PBMZE)) [...] subjects did not agree that lying down relieved brain fog and felt that brain fog could be triggered in the supine position ([p. 4](zotero://open-pdf/library/items/5NBCV5L2?page=4&annotation=TUIL38CV)) [...} Our finding that brain fog can be triggered by upright posture but not relieved by recumbence is consistent with a carry-over effect from a physiological provocation. One possible explanation for this is that brain fog could be triggered by excessive reductions in cerebral blood flow that often occurs in POTS subjects when upright”* ([[Ross-2013]], [p. 4](zotero://open-pdf/library/items/5NBCV5L2?page=4&annotation=T7NYXC7A))^53 >*“Interestingly, brain fog has been reported to occur even in the supine position and may not be limited to upright posture.”* ([[Wells-2020]], [p. 2](zotero://open-pdf/library/items/AZH94A4I?page=2&annotation=WLKPHUKG))^54 >*“This study demonstrated objective evidence of neurocognitive deficits in POTS individuals but similar increment in CBF velocity parameters in response to visual stimuli in the PCA of both groups.”* ([[Wells-2020]], [p. 2](zotero://open-pdf/library/items/AZH94A4I?page=2&annotation=FUNSNPJ4))^55 >*“We found deficits in short-term memory and alertness in our POTS cohort. In contrast, others have shown impaired selective attention and cognitive processing but unaffected memory in POTS patients using different neuropsychological tests.13 This may be owing to the heterogenous nature of the condition and the many factors such as sleep disturbances, chronic fatigue, and medication use that may influence different facets of the cognitive status. These objective measures of cognitive dysfunction may in part explain the brain fog described by POTS patients even when recumbent, although the mechanisms remain unclear.”* ([[Wells-2020]], [p. 2](zotero://open-pdf/library/items/AZH94A4I?page=2&annotation=6JJNNPK5))^56 >![[Zotero/Zotero Images/Maier-2023-6-x38-y334.png]] >([[Maier-2023]], [p. 6](zotero://open-pdf/library/items/LQMXCPGX?page=6&annotation=PWGXIP4P)) > >*“The primary findings of this study were an impairment of attentional performance (TAP) during the seated position and a reduction of executive function (Stroop) while upright ([p. 5](zotero://open-pdf/library/items/LQMXCPGX?page=5&annotation=UQTF5AYM))in patients with PoTS compared with HCs.”* ([p. 6](zotero://open-pdf/library/items/LQMXCPGX?page=6&annotation=35B93A6S)) > >*“The results of the TAP in seated patients with PoTS compared with HCs provide further evidence that patients with PoTS show selective cognitive impairment of attentional performance, even during minimal orthostatic stress (sitting). This result is especially interesting in the context of the LPS as a measure of general cognitive ability, which showed no difference between patients with PoTS and HCs. Impaired attention in patients with PoTS was found in other studies in a seated position using Ruff 2 + 7 Speed Test [3], WAIS‑III digits forward [8], ADHD subscales [18] and CANTAB [41], and also while standing using CogState [8, 9] and TAP subtest for sustained attention [11].”* ([[Maier-2023]], [p. 6](zotero://open-pdf/library/items/LQMXCPGX?page=6&annotation=4BT8B75Q)) > >*“Patients scored worse than HCs for Stroop in the upright position and deteriorated from supine to the upright (upright and upright legs crossed) positions. In the supine position, where orthostatic stress is reduced to a minimum, no differences in cognitive tests were detected between PoTS and HCs. This validates the hypothesis that orthostatic stress itself impairs executive function in patients with PoTS. These findings are in line with results found in previous research: describing normal executive function in the supine position but an impairment during active standing [9] and in the seated position using Stroop and Trail Making Test B [3]”* ([p. 6](zotero://open-pdf/library/items/LQMXCPGX?page=6&annotation=8BRKQMA2)) > >*“In line with previous results [9], our results show a moderately positive correlation between impaired attention (TAP) and executive functioning (Stroop). There was a positive correlation between Stroop U and TAP in the HC group, but not in the PoTS group. As Stroop and TAP both require executive control [43], we would have expected the tests to correlate as seen in the HC group, if standing did not have any impact on executive control. On the other hand, for Stroop S (supine) we found a positive correlation with TAP in both the PoTS and the HC group. In recent research, “sustained ([p. 6](zotero://open-pdf/library/items/LQMXCPGX?page=6&annotation=BZGRZ9SY)) attention” was tested with the TAP in the supine position and at 60° head‑up tilt during, before, and after water ingestion. There was more cognitive impairment during head‑up tilt in patients with PoTS (more omissions in the TAP), which also indicates a decrease in working memory [11]. A positive effect on working memory was shown previously using intake of water to reduce orthostatic symptoms [11, 42]. It must be mentioned that in their study, cognitive performance was tested during passive tilt testing, whereas in our study, patients performed active standing, which pre‑activates the leg muscle pump as described above. Thus, all these data support the hypothesis that cognitive impairment in PoTS is not a global problem caused by the disease itself, but a functional deficit induced by orthostatic stress, which might alter cerebral perfusion or central neurometabolic mechanisms.”* ([p. 7](zotero://open-pdf/library/items/LQMXCPGX?page=7&annotation=BSN2FNGL)) > >*“in this study, one finding was that NE levels were elevated in both the supine and upright positions, similar to previous research [11], indicating an overactivity of the sympathetic nervous system in patients with PoTS compared with HCs. Moreover, there was a negative correlation between the degree of NE rise and Stroop performance while upright. In our study, we can exclude an effect of stress during the cognitive test on NE release because cognitive testing and NE testing were not performed at the same time, as recorded in another study [11]. An excessive NE rise in the PoTS group might negatively influence cognition, either by the central effects of NE itself or more profound symptoms during standing, as described previously [11]. In contrast, an association between plasma levels of NE and impaired cognition was not found, but their cognitive tests were performed in the seated position [3]. In our sample, TAP median values, which were also tested in a seated position, did not correlate with NE responses.”* ([[Maier-2023]], [p. 8](zotero://open-pdf/library/items/LQMXCPGX?page=8&annotation=REXEWR9Z))^57 >![[Zotero/Zotero Images/Raj-2018-23-x70-y326.png]] >([[Raj-2018]], [p. 23](zotero://open-pdf/library/items/IYRK4T6C?page=23&annotation=MDGCWYHK))^58 >*“In addition to orthostatic symptoms, many POTS patients report incapacitating cognitive dysfunction or “brain fog” even while lying down or seated. Consistent with these subjective reports, there is accruing objective evidence of specific cognitive difficulties in POTS, with studies showing mild to moderate cognitive impairment using standardized neuropsychological assessment batteries.”* ([[Raj-2018]], [p. 1](zotero://open-pdf/library/items/IYRK4T6C?page=1&annotation=6U5EBRXM))^59 >*“An initial study by Raj et al. provided evidence that seated adult POTS patients exhibit significant inattention when compared with healthy subjects using the Connors Adult Attention Deficit Hyperactivity Disorder (ADHD) Rating Scale long form.17 Compared with ADHD patients, the impaired attention in POTS was less severe, developed later in life, and was not associated with significant hyperactivity suggesting a distinct cognitive phenotype”* ([[Raj-2018]], [p. 7](zotero://open-pdf/library/items/IYRK4T6C?page=7&annotation=LQCHJUDG))^60 >*“Another study by Anderson et al. similarly showed impaired focused attention in seated adult POTS patients using the Wechsler Adult Intelligence Scale III (WAIS-III).6 This study also examined for acute changes in cognitive function in POTS in response to orthostatic stress using the CogState computerized test battery. In the semi-recumbent position, there were no differences in psychomotor function, attention, information processing, or shortterm memory between POTS patients and matched healthy subjects. During 60° HUTT however, POTS patients exhibited increased response times during tasks of attention and ([p. 7](zotero://open-pdf/library/items/IYRK4T6C?page=7&annotation=F4YH2VTI)) information processing.”* ([[Raj-2018]], [p. 8](zotero://open-pdf/library/items/IYRK4T6C?page=8&annotation=7M3NSMCZ))^61 >*“While the average cognitive test scores were within normal limits, a significantly higher proportion of POTS patients scored in a range consistent with clinically meaningful impairment for selective attention (ability to focus on competing informational cues). Mild impairment was also observed in cognitive processing speed (time to process information) and executive function (ability to plan, organize information, and adapt to changes) in POTS”* ([[Raj-2018]], [p. 8](zotero://open-pdf/library/items/IYRK4T6C?page=8&annotation=XUL4B533))^62 >*“While no differences were observed while supine, POTS/CFS patients had impaired accuracy and longer response times during n-back testing when tilted to greater than 45° angles.”* ([[Raj-2018]], [p. 8](zotero://open-pdf/library/items/IYRK4T6C?page=8&annotation=XGBC3PTX))^63 >*“studies have shown selective impairment of measures of cognitive function in POTS including attention, cognitive processing speed, memory function, and executive function”* ([[Raj-2018]], [p. 8](zotero://open-pdf/library/items/IYRK4T6C?page=8&annotation=UFRC8HAA))^64 >*“While often attributed as an orthostatic symptom, many POTS patients report cognitive dysfunction in the supine and seated positions.14 Furthermore, cognitive deficits were shown in the semi-recumbent position, when patients were asymptomatic and orthostatic tachycardia minimized.10 Thus, it remains unclear if cognitive dysfunction in POTS results from orthostatic stress, or is part of the disease.”* ([[Raj-2018]], [p. 8](zotero://open-pdf/library/items/IYRK4T6C?page=8&annotation=S9YXHV7S))^65 >*“Brain fog is reported as one of the most disabling and prevalent symptoms in POTS.”* ([[Raj-2018]], [p. 11](zotero://open-pdf/library/items/IYRK4T6C?page=11&annotation=QYHT63V9))^66 ###### Brainfog Pathophysiology >*“Several pathophysiological mechanisms have been proposed that could contribute to impaired psychological and cognitive function in POTS, all with limited to no supporting evidence.”* ([[Raj-2018]], [p. 9](zotero://open-pdf/library/items/IYRK4T6C?page=9&annotation=FSFWK2LU))^67 ###### Disturbances in cerebral blood flow and nitric oxide regulation >*“An increased oscillatory pattern of cerebral blood flow has been described in patients with POTS during head-up tilt that has been demonstrated to be associated with marked reduction in cognitive performance and functional hyperemia.58,59 Further, downregulation of nitric oxide receptor sites may explain the impaired nitric oxide-related cerebral vasodilation and blunted cerebral blood flow velocity following administration of sodium nitroprusside while supine and during upright tilt.60”* ([[Wells-2017]], [p. 7](zotero://open-pdf/library/items/HLELIN7I?page=7&annotation=RGAP3HN4))^68 ###### Central Norepinephrine Dysregulation >*“Centrally acting norepinephrine transporter inhibitors, which increase synaptic levels of norepinephrine, improve attention and memory but can mimic clinical features of POTS.”* ([[Raj-2018]], [p. 9](zotero://open-pdf/library/items/IYRK4T6C?page=9&annotation=HN34726B))^69 ###### Structural and Functional Brain Abnormalities >*“Compared with controls, POTS patients had accentuated and prolonged cardiac acceleration in orienting response, as well as enhanced deactivation of the ventromedial prefrontal cortex, in response to external stimuli. The authors suggest that a hyper-reactive bodily state in POTS may underlie disruption of emotional state by attenuating activity of the ventromedial prefrontal cortex.”* ([[Raj-2018]], [p. 9](zotero://open-pdf/library/items/IYRK4T6C?page=9&annotation=M9RA7HKA))^70 >*“The authors found reduced gray matter volume in the left anterior insula, right middle frontal gyrus, and right cingulate gyrus in POTS patients compared with healthy subjects, brain regions associated with autonomic control and emotional arousal. They also observed reduced white matter volume in primary somatosensory brain regions in POTS. Importantly, left insula volume negatively correlated with trait anxiety (measured by State-Trait Anxiety Inventory) and depression (measured by Beck Depression Inventory-II) scores in POTS patients.”* ([[Raj-2018]], [p. 9](zotero://open-pdf/library/items/IYRK4T6C?page=9&annotation=XECXV7ZN))^71 ###### Chronic Fatigue >*“POTS patients with higher fatigue reported greater severity and frequency of cognitive impairment and reduced efficacy of therapies to improve cognitive symptoms.”* ([[Raj-2018]], [p. 10](zotero://open-pdf/library/items/IYRK4T6C?page=10&annotation=YXQIFSGX))^72 ###### Sleep Disturbances >*“Sleep plays a critical role in attention, learning, memory, and cognitive processing.33 POTS patients report nocturnal sleep disruption, sleep-related symptoms (e.g. daytime sleepiness, fatigue), longer sleep onset latency, and sleep disorders (e.g. insomnia, sleep apnea).”* ([[Raj-2018]], [p. 10](zotero://open-pdf/library/items/IYRK4T6C?page=10&annotation=97VC9V6V))^73 >*“How sleep efficiency affects cognition in POTS patients is unknown but, we can postulate that sleep quality is a major contributor to brain fog in POTS”* ([[Ross-2013]], [p. 5](zotero://open-pdf/library/items/5NBCV5L2?page=5&annotation=EXMVU68U))^76 ##### Sleep Disturbance >*“POTS patients commonly complain of fatigue, unrefreshing sleep, and daytime sleepiness. When formally assessed using a Fatigue Visual Analogue Scale, the Medical Outcomes Study Sleep Survey, and the Epworth Sleepiness Scale (respectively), POTS patients had more sleep problems (Sleep Problems Index: 58±18 vs. 20±13; P <0.0001) and excessive daytime sleepiness (10.2±5.7 vs. 6.2±3.2; P<0.0001) compared with healthy controls 8. POTS patients also had higher fatigue levels (7.5±2.0 vs. 2.8±2.5; P<0.0001). We 8 and others 9 have documented low health related quality of life in patients with POTS. Using the SF-36, Benrud-Larssen et al. 9 reported that physical and mental composite scores for POTS patients were comparable to patients with congestive heart failure. It is noteworthy that of the 8 domains specifically addressed by the SF-36, the only one in which POTS patients did not fare worse than the control group was in mental health 9. The subjects in the aforementioned sleep study each also completed the RAND-36, a validated general health-related quality of life tool. There was a strong correlation between the RAND-36 physical health composite scores and the Sleep Problems Index (R2=0.53; P<0.0001), with over 50% of the variance in physical health explained by the variance in sleep quality 8.”* ([[Raj-2013]], [p. 3](zotero://open-pdf/library/items/CCJLQKRB?page=3&annotation=BUYNWJ4J))^27 >*“POTS patients have low sleep quality which is associated with low quality of life (Bagai et al., 2011). POTS patients also have objective sleep deficits and lower heart rate variability during sleep suggesting lower parasympathetic tone and enhanced sympathetic tone (Mallien et al., 2014). The primary sleep problem seems to be insomnia – both sleep onset and sleep maintenance insomnia, and not other problems such as sleep apnea”* ([[Miller-2018]], [p. 6](zotero://open-pdf/library/items/A3CIPE3G?page=6&annotation=5Z5IW2FE))^74 >*“POTS patients describe poorer sleep quality, more daytime sleepiness, greater fatigue, and substandard quality of life compared to healthy subjects [5]. These reports are consistent with a reduction in sleep efficiency determined by actigraphy” *([[Garland-2015]], [p. 5](zotero://open-pdf/library/items/CAWTWYLR?page=5&annotation=M4GIV2DI))^40 >*“32 % of subjects reported having a diagnosed sleep disorder, most commonly insomnia, sleep apnea, or restless leg syndrome”* ([[Ross-2013]], [p. 5](zotero://open-pdf/library/items/5NBCV5L2?page=5&annotation=5IYR72BU))^75 >*“The timing and number of hours spent sleeping may identify significant abnormalities in circadian rhythm or other sleep disorders.”* ([[Wells-2017]], [p. 4](zotero://open-pdf/library/items/HLELIN7I?page=4&annotation=CLN4MJRJ))^77 >*“These sleep problems are thought to result from sympathetic or hypothalamic-pituitary axis activation to induce hyperarousal, or from comorbidities such as chronic pain.”* ([[Raj-2018]], [p. 10](zotero://open-pdf/library/items/IYRK4T6C?page=10&annotation=KIPDDNY6))^78 -------- Tags: #symptoms