3.4. Comorbidities and associated conditions

← PREVIOUS: [[3.3. Environmental factors and triggers]] | NEXT: [[4. Pathophysiological Mechanisms]] → -------- ##### Summary >[!Summary] >- Many patients report chronic symptoms not attributable to orthostatic intolerance (functional gastrointestinal or bladder disorders, chronic headache, fibromyalgia, chronic fatigue, sleep disturbances, visceral symptoms & chronic pain disorders[[#^6]], functional motility disorders such as functional dyspepsia, gastric emptying disorders, irritable bowel syndrome and interstitial cystitis[[#^12]])[[#^1]][[#^13]], which cannot be mechanistacially explained by postural intolerance or excessive tachycardia[[#^11]] >- Many have been co-diagnosed with IBS (irritable bowel syndrome), some have hypermobile joints (joint hypermobility syndrome, a variant of Ehlers-Danlos Syndrome - where the onset POTS may be insidious and symptoms may develop over years beginning with teenage[[#^22]]) and some have abnormal sudomotor regulation[[#^19]] >- Some present with episodic flushing associated with surges in tachycardia and have co-existent mast cell activation[[#^20]] >- Patients with POTS who have chronic fatigue syndrome have higher laboratory markers of sympathetic activation than patients without chronic fatigue[[#^14]][[#^21]] >- EDS type III associated with sequence variations in tenascin X has been frequently associated with POTS[[#^15]][[#^29]] >- Chronic headache, including migraine, is a common comorbidity[[#^16]] and orthostatic headaches also occur[[#^17]] (the latter may be related to decreases in spinal venous pressure and volume of cerbrospinal fluid due to absolute or orthostatic hypovolemia[[#^26]]) >- Only a small subgroup of patients have a defined autonomic disorder[[#^3]] >- Cognitive and behavioral factors, somatic hypervigilance associated with anxiety, depression & behavioral amplification contribute to symptom chronicity[[#^2]][[#^4]] >- Physical deconditioning has an important role[[#^4]] >- ≤ 1/3 may develop secondary orthostatically triggered vasovagal syncope (reflex, neurally mediated)[[#^5]] >- hyperthyroidism or pheochromocytoma (catecholamine-secreting tumor) should be excluded in patients with excessive sympathetic responses (patients with hyperadrenergic POTS)[[#^7]] - laboratory studies should include determination of plasma and urinary metanephrine levels (if elevated imaging studies to detect pheochromocytoma)[[#^9]] >- Secondary hyperadrenergic POTS has also been associated with mast cell activation disorders[[#^8]] and may be also secondary to immune disorders associated with antibodies against components of the voltage-gated potassium channel complex (limbic encephalitis or Morvan syndrome)[[#^10]] >- it was proposed that CFS is part of the POTS spectrum[[#^28]] >- there is a higher than expected prevalence of joint hypermobility and chronic fatigue syndrome in patients with POTS[[#^32]] >- plethysmography may demonstrate splanchnic venous pooling in patients with IBS. The baroreflex response to reduced venous return (consequent to histamine or localized small molecule related vasodilation) can result in POTS[[#^33]] >------ >- 20 - 50% share diagnoses with CFS and EDS[[#^23]] >- Among all CFS patients 10 - 15% meet diagnostic POTS criteria (these patients are typically younger and have shorter disease duration)[[#^23]] >- In EDS, characteristic POTS symptoms can be found in ≤ 40% of patients (onset is typically not precipitated by viral infection)[[#^23]] >- 83% reported being diagnosed with another medical condition in addition to POTS[[#^24]] >- 7% reported having all three of the most common comorbidities (migraine headaches, IBS & EDS) > >| Commorbidity | Prevalence | >|:------------------------------------ |:---------- | >| Migraine headaches | 40%[[#^25]][[#^30]] ; 29.6%[[#^31]] | >| Irritable bowel syndrome (IBS)[[#^34]] | 30%[[#^25]] | >| Ehrlers-Danlos syndrome (EDS)) | 25%[[#^25]][[#^30]] | >| Chronic fatigue syndrome (CFS) | 21%[[#^25]][[#^30]] ; 17 - 23%[[#^27]] | >| Asthma | 20%[[#^25]] | >| Fibromyalgia | 20%[[#^25]][[#^30]] | >|Joint Hypermobility Syndrome[[#^34]] | 18.5%[[#^31]] | >| Raynaud's phenomena | 16%[[#^25]] | >| Iron deficiency anaemia | 16%[[#^25]] | >| Gastroparesis | 14%[[#^25]] | >| Vasovagal syncope | 13%[[#^25]] | >| Inappropriate sinus tachycardia | 11%[[#^25]] | >| Mast cell activation disorder | 9%[[#^25]][[#^30]] | >| Coronary artery disease | 7.4%[[#^31]] | >| Diabetes mellitus | 7.4%[[#^31]] | >| Hashimoto's thyroiditis (autoimmune) | 6%[[#^25]] | >| Mitochondrial cytopathy | 3.7%[[#^31]] | >| Coeliac disease (autoimmune) | 3%[[#^25]][[#^30]] | >| Sjögren's syndrome (autoimmune) | 3%[[#^25]] | >| Rheumatoid arthritis (autoimmune) | 2%[[#^25]] | >| Lupus (autoimmune) | 2%[[#^25]] | >| Other (autoimmune) | 4%[[#^25]] | -------- >_“Many patients with POTS also report symptoms not attributable to orthostatic intolerance, including those of functional gastrointestinal or bladder disorders, chronic headache, fibromyalgia, and sleep disturbances.”_ ([[Benarroch-2012]], [p. 1](zotero://open-pdf/library/items/WEZLT9QC?page=1&annotation=B79PCIA7))^1 >_“In many of these cases, cognitive and behavioral factors, somatic hypervigilance associated with anxiety, depression, and behavioral amplification contribute to symptom chronicity.”_ ([[Benarroch-2012]], [p. 1](zotero://open-pdf/library/items/WEZLT9QC?page=1&annotation=NZBC5SQV))^2 >_“Many patients with POTS present with multiple chronic symptoms that are not directly related to orthostatic stress, and only a small subgroup of patients with POTS have a defined autonomic disorder.”_ ([[Benarroch-2012]], [p. 1](zotero://open-pdf/library/items/WEZLT9QC?page=1&annotation=ITLEBJZN))^3 >_“Physical deconditioning and psychological factors have an important role in these patients.”_ ([[Benarroch-2012]], [p. 1](zotero://open-pdf/library/items/WEZLT9QC?page=1&annotation=MUD4UTDY))^4 >_“Up to one-third of patients may develop secondary orthostatically triggered vasovagal (reflex, neurally mediated) syncope.”_ ([[Benarroch-2012]], [p. 2](zotero://open-pdf/library/items/WEZLT9QC?page=2&annotation=3AKX8LYI))^5 >_“Many symptoms reported by patients with POTS, including visceral symptoms and chronic pain disorders, are not due to orthostatic intolerance and therefore are not, in the strict sense, part of the syndrome.”_ ([[Benarroch-2012]], [p. 2](zotero://open-pdf/library/items/WEZLT9QC?page=2&annotation=QL8QP8RE))^6 >_“Most patients with POTS and evidence of a sympathetic neuropathy restricted to the lower limbs have no identifiable cause of neuropathy; pheochromocytoma should be excluded in patients with excessive sympathetic responses.”_ ([[Benarroch-2012]], [p. 2](zotero://open-pdf/library/items/WEZLT9QC?page=2&annotation=D58YXX38))^7 >_“Secondary hyperadrenergic POTS has also been associated with mast cell activation disorders”_ ([[Benarroch-2012]], [p. 3](zotero://open-pdf/library/items/WEZLT9QC?page=3&annotation=BG8DWPEH))^8 >_“In patients with hyperadrenergic POTS, the possibility of hyperthyroidism or a catecholamine-secreting tumor, such as pheochromocytoma, should be considered. Laboratory studies should include determination of plasma and urinary metanephrine levels, and if they are elevated, imaging studies to detect pheochromocytoma may be necessary.”_ ([[Benarroch-2012]], [p. 3](zotero://open-pdf/library/items/WEZLT9QC?page=3&annotation=KCEB43XZ))^9 >_“Hyperadrenergic states may also be secondary to immune disorders associated with antibodies against components of the voltage-gated potassium channel complex in the setting of limbic encephalitis or Morvan syndrome”_ ([[Benarroch-2012]], [p. 3](zotero://open-pdf/library/items/WEZLT9QC?page=3&annotation=AM7KQ7FF))^10 >_“Many patients with POTS experience chronic symptoms that cannot be mechanistically explained by postural intolerance or excessive tachycardia. Many of these symptoms are also prevalent in patients without orthostatic intolerance; in these cases, excessive postural tachycardia is secondary to hypovolemia, prolonged bed rest, physical deconditioning, and anxiety, in various combinations.”_ ([[Benarroch-2012]], [p. 4](zotero://open-pdf/library/items/WEZLT9QC?page=4&annotation=RDPVMJ2R))^11 >_“These symptoms are similar to those typically reported by patients with functional motility disorders such as functional dyspepsia, gastric emptying disorders, irritable bowel syndrome, and interstitial cystitis, among others.”_ ([[Benarroch-2012]], [p. 4](zotero://open-pdf/library/items/WEZLT9QC?page=4&annotation=KC32YE5S))^12 >_“Chronic fatigue, fibromyalgia, and sleep disturbances [44] have been frequently associated with POTS.”_ ([[Benarroch-2012]], [p. 4](zotero://open-pdf/library/items/WEZLT9QC?page=4&annotation=5DSYZBSA))^13 >_“There is an overlap between chronic fatigue syndrome and POTS. Patients with POTS who have chronic fatigue syndrome have higher laboratory markers of sympathetic activation than patients without chronic fatigue.”_ ([[Benarroch-2012]], [p. 4](zotero://open-pdf/library/items/WEZLT9QC?page=4&annotation=NQUTBNZ9))^14 >_“EDS type III associated with sequence variations in tenascin X, has been frequently associated with POTS.”_ ([[Benarroch-2012]], [p. 4](zotero://open-pdf/library/items/WEZLT9QC?page=4&annotation=PIXWKPRY))^15 >_“Chronic headache, including migraine, is a common comorbidity in patients with POTS.”_ ([[Benarroch-2012]], [p. 4](zotero://open-pdf/library/items/WEZLT9QC?page=4&annotation=B7XB5PH8))^16 >_“Orthostatic headaches also occur in patients with POTS”_ ([[Benarroch-2012]], [p. 4](zotero://open-pdf/library/items/WEZLT9QC?page=4&annotation=74ALPRDZ))^17 >_“Functional neuroimaging studies also show that the connectivity among the amygdala, cingulate, and prefrontal cortex is affected in disorders such as anxiety and depression, which are common comorbid conditions in patients with symptoms associated with ([p. 5](zotero://open-pdf/library/items/WEZLT9QC?page=5&annotation=NYJVQYKU)) POTS, including those of visceral pain and dysmotility, chronic fatigue, fibromyalgia, and insomnia.”_ ([[Benarroch-2012]], [p. 6](zotero://open-pdf/library/items/WEZLT9QC?page=6&annotation=6KBILAMF))^18 >*“Many patients have been co-diagnosed with irritable bowel syndrome, some have hypermobile joints, and some have abnormal sudomotor regulation.” *([[Raj-2013]], [p. 2](zotero://open-pdf/library/items/CCJLQKRB?page=2&annotation=IW6HY8J4))^19 >*“Some patients with POTS present with episodic flushing associated with surges in tachycardia, and have co-existent mast cell activation.” *([[Raj-2013]], [p. 4](zotero://open-pdf/library/items/CCJLQKRB?page=4&annotation=4LXCXXIQ))^20 >*“Some authors have stressed an overlap between chronic fatigue syndrome and POTS. [20,21] A similar magnitude of increase in sympathetic tone at rest and during head-up tilt and impairment of baroreflex transfer was reported for patients with POTS and patients with chronic fatigue syndrome.” *([[Thieben-2007]], [p. 6](zotero://open-pdf/library/items/5WXWEQWX?page=6&annotation=P5V44TLM))^21 >*“In patients with joint hypermobility syndrome, a variant of Ehlers–Danlos Syndrome, the onset of POTS may be insidious and the symptoms may develop over years beginning with teenage [27].” *([[Fedorowski-2019]], [p. 3](zotero://open-pdf/library/items/BZ35QDLR?page=3&annotation=EPKWIBI7))^22 >*“a substantial proportion of POTS patients (20–50%) share diagnoses with chronic fatigue syndrome (CFS) and Ehlers–Danlos syndrome (EDS)[31, 33]. Among all CFS patients, around 10–15% meet diagnostic POTS criteria [58, 59]. These patients are typically younger and have shorter disease duration [59]. In EDS, characteristic POST symptoms can be found in up to 40% of patients and the onset is typically not precipitated by viral infection [60].” *([[Fedorowski-2019]], [p. 8](zotero://open-pdf/library/items/BZ35QDLR?page=8&annotation=R92QZ8JR))^23 >*“There were 3276 (83%) participants who reported being diagnosed by a physician with another medical condition in addition to POTS (Table 2). A number of co-morbid diagnoses were highly prevalent (≥20%). Only 290 (7%) of participants reported having all three of the most common comorbidities (migraine headaches, irritable bowel syndrome and Ehlers–Danlos syndrome)” *([[Shaw-2019]], [p. 3](zotero://open-pdf/library/items/48AJ3KVL?page=3&annotation=UHJQMN5A))^24 >![[Shaw-2019-4-x297-y62.png#invert_B| 400]] >([[Shaw-2019]], [p. 4](zotero://open-pdf/library/items/48AJ3KVL?page=4&annotation=3NEXIHXL))^25 >*“Many patients with POTS are diagnosed with migraine headaches. Orthostatic headaches may be related to decreases in spinal venous pressure and volume of cerebrospinal fluid due to an absolute or orthostatic hypovolemia” *([[Garland-2015]], [p. 3](zotero://open-pdf/library/items/CAWTWYLR?page=3&annotation=L5UJ45RI))^26 >*“Patients with POTS have a high prevalence of chronic fatigue (48-77%) and of CFS (17-23%)” *([[Garland-2015]], [p. 5](zotero://open-pdf/library/items/CAWTWYLR?page=5&annotation=S4KNMQ52))^27 >*“Okamoto et al. proposed that CFS is part of the POTS spectrum” *([[Garland-2015]], [p. 5](zotero://open-pdf/library/items/CAWTWYLR?page=5&annotation=B6FN7NVE))^28 >*“Wallman et al. ascertained the prevalence of EDS in their POTS population: 18% of POTS patients met criteria for EDS, compared to a 0.02% prevalence in the general population and 4% prevalence in their autonomic clinic patients without POTS [34]. Based on experience at his autonomic clinic, Professor Mathias reported that EDS type III is the most common disorder associated with POTS” *([[Garland-2015]], [p. 5](zotero://open-pdf/library/items/CAWTWYLR?page=5&annotation=8JAEXD4F))^29 >![[Zotero/Zotero Images/Raj-2022-3-x300-y313.png#invert_B| 400]] >([[Raj-2022]], [p. 3](zotero://open-pdf/library/items/YN8BG2FZ?page=3&annotation=8EEI2UAE))^30 >![[Zotero/Zotero Images/Kanjwal-2011-3-x61-y377.png]] >([[Kanjwal-2011]], [p. 3](zotero://open-pdf/library/items/R4GMHSS7?page=3&annotation=BT6QUA97))^31 >*“There is a higher than expected prevalence of joint hypermobility and chronic fatigue syndrome in patients with POTS.”* ([[Wells-2017]], [p. 1](zotero://open-pdf/library/items/HLELIN7I?page=1&annotation=SYXUBGSV))^32 >*“Although rarely performed, plethysmography may demonstrate splanchnic venous pooling in patients with IBS.8 The baroreflex response to reduced venous return (consequent to histamine or localized small molecule related vasodilation) can result in POTS. Nuclear medicine studies can demonstrate delayed gastric transit times, raising the possibility of an autonomic neuropathy; however, an increased awareness of symptoms (hypervigilance) may also explain some of the concurrence of IBS and POTS.9”* ([[Wells-2017]], [p. 2](zotero://open-pdf/library/items/HLELIN7I?page=2&annotation=UMBE99XB))^33 >![[Zotero/Zotero Images/Wells-2017-4-x50-y362.png]] >([[Wells-2017]], [p. 4](zotero://open-pdf/library/items/HLELIN7I?page=4&annotation=XUAQUZPB))^34