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The evolutionary hypothesis of benign paroxysmal positional vertigo
Journal Pre-proofs The evolutionary hypothesis of benign paroxysmal positional vertigo Dong-Gyun Han, Dong-Jun Kim PII: DOI: Reference:
S0306-9877(19)31064-3 https://doi.org/10.1016/j.mehy.2019.109445 YMEHY 109445
To appear in:
Medical Hypotheses
Received Date: Accepted Date:
21 September 2019 17 October 2019
Please cite this article as: D-G. Han, D-J. Kim, The evolutionary hypothesis of benign paroxysmal positional vertigo, Medical Hypotheses (2019), doi: https://doi.org/10.1016/j.mehy.2019.109445
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier Ltd.
The evolutionary hypothesis of benign paroxysmal positional vertigo Dong-Gyun Han*, MD1, Dong-Jun Kim, NR2 1
Dr Han’s Neurology Clinic, 1661, Dongseo-daero, Dong-gu, Daejeon 34552, Republic of
Korea 2 ICU,
BAEKJE general hospital, 14, Simin-ro 294beon-gil, Nonsan-si, Chungcheongnam-do,
32980, Republic of Korea * Correspondence: Dong-Gyun Han, MD [email protected] Tel +82 42 710 7582 Fax +82 42 633 7583
Conflict of Interest The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Abstract
Human otoliths, primarily formed from salts of calcium and carbonate, are different from bones of the skeleton, which are composed of calcium phosphate. The echinoderms, which share the earliest common ancestor with us, began to protect the body by making an endoskeleton out of
calcium and carbon dioxide dissolved in the sea. In subsequent vertebrates, aerobic respiration supported strong muscle activity, but an occasional shortage of oxygen leaded to low pH due to the accumulation of lactate produced by anaerobic respiration, increasing the risk of melting bones composed of calcium carbonate. So, all vertebrates used calcium phosphate to increase bone strength, having a stronger ionic bonding than calcium carbonate. But otoliths, which are in the inner ear and thereby not connected to muscles, still use calcium carbonate. Benign paroxysmal positional vertigo (BPPV) is a disorder in which otoliths detached from the utricle enter the semicircular canals and cause a sense of rotation. Otoliths, the calcium carbonate ear bones retaining a long evolutionary history, can be easily broken at low pH. During sleep, shallow breathing produces mild respiratory acidosis and low pH in the blood. Since otoliths are corroded at low pH during nighttime, BPPV occurs frequently in the morning. In addition, diabetes mellitus or gout often decreases pH in the blood and increases the occurrence of BPPV.
Introduction The causes of detachment of otoliths in BPPV are largely unknown [1], but it is clear that BPPV has a high incidence in older ages and women in their 50s, and recent studies have found that calcium metabolism affects the formation of otoliths [2-4]. Calcium concentration in plasma is closely related to calcium concentration in the endolymph. Thus, in old ages, as calcium absorption in the intestine decreases, calcium concentration in the endolymph of the vestibular labyrinth also lessens to form defective otoliths [5, 6]. In addition, unlike long bones showing endochondral ossification, skulls formed by intramembranous ossification are
highly influenced by estrogen [7,8]. Consequently, estrogen may be involved in calcium metabolism of the otoliths of the inner ear. Saccules and utricles have a pattern of embedded otoliths in the fibrous mesh (otoconial membrane) [9], similar to the intramembranous ossification of the skull that is the structure of calcium salts in the preformed fibrous matrix [10]. Our bones are made of calcium phosphate. But, exceptionally otoliths are composed of calcium carbonate [9] and have a weaker ionic bonding than calcium phosphate. Thus, otoliths can easily fall off the otoconial membrane and cause BPPV when exposed to inflammation, infection or low pH. An evolutionary perspective on why otoliths are easy to fall off In evolutionary history, hearing is the last sense created by vertebrates on land. The sense of gravity, on the other hand, is the most primitive one that began with the hydromedusae before the divergence of Bilateria [11]. For sensing gravity efficiently, perhaps it would be better to use gravity-sensitive materials [12]. The composition of the seawater from which life originates is similar to the elements that make up its body fluid [13]. And seawater contains high levels of Ca2+ and HCO−3 [14]. Thus, crustaceans and echinoderms used gravitysensitive statolith in statocysts, which is made of Ca2+ and HCO−3 dissolved in the sea [12]. In addition to statolith, the echinoderms, one major group of the deuterostomes, which share the earliest common ancestor with us defended their body by creating first dermal bones made of calcium carbonate [15]. Echinoderms make dermal bones by depositing calcium carbonate around sensory cells derived from neural crest-like cells, secreting a mineralizing matrix [15]. In subsequent vertebrates, aerobic respiration supported strong muscle activity, but an occasional shortage of oxygen leaded to low pH due to the accumulation of lactate produced by anaerobic respiration, increasing the risk of melting bones composed of calcium carbonate. So, all vertebrates changed from calcium carbonate into calcium phosphate to increase bone
strength, which has a stronger ionic bonding than calcium carbonate [16]. However, exceptionally, otoliths, the ear stones with no muscle connectivity, still use calcium carbonate [17-21]. The otolith organs sensing gravity and linear acceleration differ in organic compounds of otoliths among species, but the minerals that form them are similar [17–21]. Otoliths are crystals of 95% calcium carbonate [22] and vary in size about 6 micrometers [23] in the shape of barrel, cylinder and aragonite [24,25]. Beginning at embryonic day 4 or 6 [26], otoliths grow, and at postnatal day 7, they are anchored to fibrous mesh (otoconial membrane) and do not regenerate for life [27]. Otoliths can be affected by low pH, just as limestones made of calcium carbonate readily dissolve in acidic rainwater. Calcium carbonate has a weaker ionic bonding than calcium phosphate. In other words, in situations of low pH, it is easy to melt. The acidity of the endolymph fluid is 7.38 pH in the saccule and 7.87 pH in the utricle, so if the pH becomes low, it is more likely that otoliths in the utricle melt [28]. In animal experiments or clinical studies, respiratory or metabolic acidosis may cause vertigo of vestibular origin [29]. Diabetes mellitus or hyperuricemia can sometimes lead to metabolic acidosis in the blood and result in low pH in the endolymphatic fluids, which will facilitate the breakdown of calcium carbonate otoliths [30,31]. Usually, the blood is subject to mild respiratory acidosis during nighttime, because the sensitivity of the chemoreceptor to carbon dioxide is somewhat diminished while we sleep [32,33]. During sleep, mild respiratory acidosis and low pH, even though not stronger than metabolic acidosis [34], are likely to result in the formation of defective otoliths through the active remodeling of otoliths of the inner ear. These defective otoliths are easily broken down, are rolled into the semicircular canals, and then cause vertigo when we wake up in the morning [35]. Otoliths that fall off the utricle enter the posterior semicircular canal in the most gravity-dependent position when lying down [36]. Also, since the otolith organs detect gravity or linear acceleration using the shearing force of the otoliths resting on top of the gelatinous matrix, it is possible that they
inherently fall off if we lie down for a long time or are forced to a certain position during dental procedures [1,37]. Calcium carbonate of otoliths is chemically dynamic compared to calcium phosphate of bone tissue. So, the formation and dissolution of otoliths are more rapid and dependent on calcium concentration in the endolymph. Calcium concentration in the endolymph plays the most important role in the formation of otoliths [38-40]. The endolymphatic fluid normally maintains a low calcium concentration of 20 μmol/L, and the free otoliths dissolve in about 20 hours. On the other hand, when the endolymphatic calcium concentration is 50-200 μmol/L, the otoliths are decomposed until about 100 to 130 hours [41]. If the calcium ions in the endolymph reach the saturation concentration, further formation of otoliths is difficult [40]. The causes of BPPV are largely unknown, but the remainders are associated with Ménière's disease, migraine, vestibular neuritis, a severe systemic disease, previous trauma, and history of otologic surgery [1]. Chronic and repetitive inflammation of the inner ear causes endolymphatic hydrops and abnormalities of ion channels [42], leading to increased calcium levels in the endolymphatic fluid. Ménière's disease is highly associated with abnormalities of ion channels, although it is not certain that abnormalities of ion channels are the cause or result of endolymphatic hydrops [43,44]. In particular, the induction of endolymphatic hydrops in experimental animals causes abnormalities of calcium channels and increases the concentration of calcium ions in the endolymph [45-47]. If the calcium saturation concentration in the endolymph is reached, no more otoliths is formed [40]. These results could be also seen in diseases that cause genetic abnormalities in the calcium channel, i.e. mutations in CACNA1A which encodes the P/Qtype voltage-gated calcium channel CaV2.1 (familial hemiplegic migraine type 1 and episodic ataxia type 2) [48,49]. Migraine is the primary brain dysfunction that shows a hyperexcitable cortex, which easily leads to cortical spreading depression (CSD). CSD increases extracellular presynaptic H+, K+, NO, Ca2+ and glutamate, and induces intracellular
calcium ion influx through postsynaptic NMDA receptor activation [48]. These substances also activate and sensitize meningeal trigeminovascular afferents which release CGRP, substance P and neurokinin A, and result in the neurogenic inflammation in meningeal blood vessels [50]. The same neurogenic inflammation occurs in the inner ear of patients with vestibular migraine [51, 52]. The endolymph is an unusual extracellular fluid with low Na+, high K+ and low Ca2+ concentration, similar to intracellular fluid [53]. If the Ca2+ concentration in the endolymph increases due to recurrent inflammation, thereby destroying the normal equilibrium between otolith formation and dissolution, defective otoliths will be formed [54] (Fig. 1). In other words, the likelihood of BPPV increases significantly. Conclusion The common pathophysiology of migraine caused by repetitive neurogenic inflammation in the trigeminovascular system and Ménière's disease due to infectious (virus and syphilis), autoimmune, genetic or traumatic causes is an abnormality of calcium regulation in the endolymph of the inner ear. Abnormal control of calcium metabolism in the endolymph in these diseases clearly increases the incidence of BPPV. In addition, a decrease in plasma calcium concentration could result in the formation of defective otoliths because more calcium resorption from otoliths occurs. The high incidence of BPPV in osteoporotic patients suggests that BPPV is closely related to calcium metabolism. Since otoliths, the calcium carbonate ear stones, are metabolically more active than bones composed of salts of calcium phosphate, they can be easily broken down by the diseases listed above. As the reason for susceptibility to BPPV, we inherited genes from the earliest common ancestor originated from the sea, which used calcium carbonate to make otoliths. References
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[20] Murayama E, Okuno A, Ohira T, Takagi Y, Nagasawa H. Molecular cloning and expression of an otolith matrix protein cDNA from the rainbow trout, Oncorhynchus mykiss. Comp Biochem Physiol B Biochem Mol Biol 2000;126(4):511-20. [21] Pisam M, Jammet C, Laurent D. First steps of otolith formation of the zebrafish: role of glycogen? Cell Tissue Res 2002;310(2):163-8. [22] S. E. Campana. Chemistry and composition of fish otoliths: pathways, mechanisms and applications Mar Ecol Prog Ser 1999;188:263-97. [23] Lim DJ. Otoconia in health and disease. A review. Ann Otol Rhinol Laryngol Suppl 1984;112:17-24. [24] Kido T, Takahashi M. Scanning electron microscopic study of amphibians otoconia. Auris Nasus Larynx 1997;24(2):125-30. [25] Oukda M, François M, Membre H, Bautz A, Dournon C. Crystallographic and chemical composition of otoconia in the salamander Pleurodeles waltl. Hear Res 1999;132(1-2):85-93. [26] Ballarino J, Howland HC, Skinner HC, Brothers EB, Bassett W. Studies of otoconia in the developing chick by polarized light microscopy. Am J Anat 1985;174(2):131-44. [27] Hughes I, Blasiole B, Huss D, Warchol ME, Rath NP, et al. Otopetrin 1 is required for otolith formation in the zebrafish Danio rerio. Dev Biol 2004;276(2):391-402. [28] Borelli G, Guibbolini ME, Mayer-Gostan N, Priouzeau F, De Pontual H, et al. Daily variations of endolymph composition: relationship with the otolith calcification process in trout. J Exp Biol 2003;206(Pt 15):2685-92.
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Conflict of Interest
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Acknowledgments I thank Sang-Hyeon Lee, Heue-Jung Park, Won-Hee Chung, Jung-Whoan Kim, Chun-Sik Kim, Sang-Cheol Park, Sook-Young Rho, Jae-Chun Bae, Seung-Hee Hong, Il-Joo Sun, PhilZa Cho for helpful discussions.
S0306-9877(19)31064-3 https://doi.org/10.1016/j.mehy.2019.109445 YMEHY 109445
To appear in:
Medical Hypotheses
Received Date: Accepted Date:
21 September 2019 17 October 2019
Please cite this article as: D-G. Han, D-J. Kim, The evolutionary hypothesis of benign paroxysmal positional vertigo, Medical Hypotheses (2019), doi: https://doi.org/10.1016/j.mehy.2019.109445
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier Ltd.
The evolutionary hypothesis of benign paroxysmal positional vertigo Dong-Gyun Han*, MD1, Dong-Jun Kim, NR2 1
Dr Han’s Neurology Clinic, 1661, Dongseo-daero, Dong-gu, Daejeon 34552, Republic of
Korea 2 ICU,
BAEKJE general hospital, 14, Simin-ro 294beon-gil, Nonsan-si, Chungcheongnam-do,
32980, Republic of Korea * Correspondence: Dong-Gyun Han, MD [email protected] Tel +82 42 710 7582 Fax +82 42 633 7583
Conflict of Interest The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Abstract
Human otoliths, primarily formed from salts of calcium and carbonate, are different from bones of the skeleton, which are composed of calcium phosphate. The echinoderms, which share the earliest common ancestor with us, began to protect the body by making an endoskeleton out of
calcium and carbon dioxide dissolved in the sea. In subsequent vertebrates, aerobic respiration supported strong muscle activity, but an occasional shortage of oxygen leaded to low pH due to the accumulation of lactate produced by anaerobic respiration, increasing the risk of melting bones composed of calcium carbonate. So, all vertebrates used calcium phosphate to increase bone strength, having a stronger ionic bonding than calcium carbonate. But otoliths, which are in the inner ear and thereby not connected to muscles, still use calcium carbonate. Benign paroxysmal positional vertigo (BPPV) is a disorder in which otoliths detached from the utricle enter the semicircular canals and cause a sense of rotation. Otoliths, the calcium carbonate ear bones retaining a long evolutionary history, can be easily broken at low pH. During sleep, shallow breathing produces mild respiratory acidosis and low pH in the blood. Since otoliths are corroded at low pH during nighttime, BPPV occurs frequently in the morning. In addition, diabetes mellitus or gout often decreases pH in the blood and increases the occurrence of BPPV.
Introduction The causes of detachment of otoliths in BPPV are largely unknown [1], but it is clear that BPPV has a high incidence in older ages and women in their 50s, and recent studies have found that calcium metabolism affects the formation of otoliths [2-4]. Calcium concentration in plasma is closely related to calcium concentration in the endolymph. Thus, in old ages, as calcium absorption in the intestine decreases, calcium concentration in the endolymph of the vestibular labyrinth also lessens to form defective otoliths [5, 6]. In addition, unlike long bones showing endochondral ossification, skulls formed by intramembranous ossification are
highly influenced by estrogen [7,8]. Consequently, estrogen may be involved in calcium metabolism of the otoliths of the inner ear. Saccules and utricles have a pattern of embedded otoliths in the fibrous mesh (otoconial membrane) [9], similar to the intramembranous ossification of the skull that is the structure of calcium salts in the preformed fibrous matrix [10]. Our bones are made of calcium phosphate. But, exceptionally otoliths are composed of calcium carbonate [9] and have a weaker ionic bonding than calcium phosphate. Thus, otoliths can easily fall off the otoconial membrane and cause BPPV when exposed to inflammation, infection or low pH. An evolutionary perspective on why otoliths are easy to fall off In evolutionary history, hearing is the last sense created by vertebrates on land. The sense of gravity, on the other hand, is the most primitive one that began with the hydromedusae before the divergence of Bilateria [11]. For sensing gravity efficiently, perhaps it would be better to use gravity-sensitive materials [12]. The composition of the seawater from which life originates is similar to the elements that make up its body fluid [13]. And seawater contains high levels of Ca2+ and HCO−3 [14]. Thus, crustaceans and echinoderms used gravitysensitive statolith in statocysts, which is made of Ca2+ and HCO−3 dissolved in the sea [12]. In addition to statolith, the echinoderms, one major group of the deuterostomes, which share the earliest common ancestor with us defended their body by creating first dermal bones made of calcium carbonate [15]. Echinoderms make dermal bones by depositing calcium carbonate around sensory cells derived from neural crest-like cells, secreting a mineralizing matrix [15]. In subsequent vertebrates, aerobic respiration supported strong muscle activity, but an occasional shortage of oxygen leaded to low pH due to the accumulation of lactate produced by anaerobic respiration, increasing the risk of melting bones composed of calcium carbonate. So, all vertebrates changed from calcium carbonate into calcium phosphate to increase bone
strength, which has a stronger ionic bonding than calcium carbonate [16]. However, exceptionally, otoliths, the ear stones with no muscle connectivity, still use calcium carbonate [17-21]. The otolith organs sensing gravity and linear acceleration differ in organic compounds of otoliths among species, but the minerals that form them are similar [17–21]. Otoliths are crystals of 95% calcium carbonate [22] and vary in size about 6 micrometers [23] in the shape of barrel, cylinder and aragonite [24,25]. Beginning at embryonic day 4 or 6 [26], otoliths grow, and at postnatal day 7, they are anchored to fibrous mesh (otoconial membrane) and do not regenerate for life [27]. Otoliths can be affected by low pH, just as limestones made of calcium carbonate readily dissolve in acidic rainwater. Calcium carbonate has a weaker ionic bonding than calcium phosphate. In other words, in situations of low pH, it is easy to melt. The acidity of the endolymph fluid is 7.38 pH in the saccule and 7.87 pH in the utricle, so if the pH becomes low, it is more likely that otoliths in the utricle melt [28]. In animal experiments or clinical studies, respiratory or metabolic acidosis may cause vertigo of vestibular origin [29]. Diabetes mellitus or hyperuricemia can sometimes lead to metabolic acidosis in the blood and result in low pH in the endolymphatic fluids, which will facilitate the breakdown of calcium carbonate otoliths [30,31]. Usually, the blood is subject to mild respiratory acidosis during nighttime, because the sensitivity of the chemoreceptor to carbon dioxide is somewhat diminished while we sleep [32,33]. During sleep, mild respiratory acidosis and low pH, even though not stronger than metabolic acidosis [34], are likely to result in the formation of defective otoliths through the active remodeling of otoliths of the inner ear. These defective otoliths are easily broken down, are rolled into the semicircular canals, and then cause vertigo when we wake up in the morning [35]. Otoliths that fall off the utricle enter the posterior semicircular canal in the most gravity-dependent position when lying down [36]. Also, since the otolith organs detect gravity or linear acceleration using the shearing force of the otoliths resting on top of the gelatinous matrix, it is possible that they
inherently fall off if we lie down for a long time or are forced to a certain position during dental procedures [1,37]. Calcium carbonate of otoliths is chemically dynamic compared to calcium phosphate of bone tissue. So, the formation and dissolution of otoliths are more rapid and dependent on calcium concentration in the endolymph. Calcium concentration in the endolymph plays the most important role in the formation of otoliths [38-40]. The endolymphatic fluid normally maintains a low calcium concentration of 20 μmol/L, and the free otoliths dissolve in about 20 hours. On the other hand, when the endolymphatic calcium concentration is 50-200 μmol/L, the otoliths are decomposed until about 100 to 130 hours [41]. If the calcium ions in the endolymph reach the saturation concentration, further formation of otoliths is difficult [40]. The causes of BPPV are largely unknown, but the remainders are associated with Ménière's disease, migraine, vestibular neuritis, a severe systemic disease, previous trauma, and history of otologic surgery [1]. Chronic and repetitive inflammation of the inner ear causes endolymphatic hydrops and abnormalities of ion channels [42], leading to increased calcium levels in the endolymphatic fluid. Ménière's disease is highly associated with abnormalities of ion channels, although it is not certain that abnormalities of ion channels are the cause or result of endolymphatic hydrops [43,44]. In particular, the induction of endolymphatic hydrops in experimental animals causes abnormalities of calcium channels and increases the concentration of calcium ions in the endolymph [45-47]. If the calcium saturation concentration in the endolymph is reached, no more otoliths is formed [40]. These results could be also seen in diseases that cause genetic abnormalities in the calcium channel, i.e. mutations in CACNA1A which encodes the P/Qtype voltage-gated calcium channel CaV2.1 (familial hemiplegic migraine type 1 and episodic ataxia type 2) [48,49]. Migraine is the primary brain dysfunction that shows a hyperexcitable cortex, which easily leads to cortical spreading depression (CSD). CSD increases extracellular presynaptic H+, K+, NO, Ca2+ and glutamate, and induces intracellular
calcium ion influx through postsynaptic NMDA receptor activation [48]. These substances also activate and sensitize meningeal trigeminovascular afferents which release CGRP, substance P and neurokinin A, and result in the neurogenic inflammation in meningeal blood vessels [50]. The same neurogenic inflammation occurs in the inner ear of patients with vestibular migraine [51, 52]. The endolymph is an unusual extracellular fluid with low Na+, high K+ and low Ca2+ concentration, similar to intracellular fluid [53]. If the Ca2+ concentration in the endolymph increases due to recurrent inflammation, thereby destroying the normal equilibrium between otolith formation and dissolution, defective otoliths will be formed [54] (Fig. 1). In other words, the likelihood of BPPV increases significantly. Conclusion The common pathophysiology of migraine caused by repetitive neurogenic inflammation in the trigeminovascular system and Ménière's disease due to infectious (virus and syphilis), autoimmune, genetic or traumatic causes is an abnormality of calcium regulation in the endolymph of the inner ear. Abnormal control of calcium metabolism in the endolymph in these diseases clearly increases the incidence of BPPV. In addition, a decrease in plasma calcium concentration could result in the formation of defective otoliths because more calcium resorption from otoliths occurs. The high incidence of BPPV in osteoporotic patients suggests that BPPV is closely related to calcium metabolism. Since otoliths, the calcium carbonate ear stones, are metabolically more active than bones composed of salts of calcium phosphate, they can be easily broken down by the diseases listed above. As the reason for susceptibility to BPPV, we inherited genes from the earliest common ancestor originated from the sea, which used calcium carbonate to make otoliths. References
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Conflict of Interest
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Acknowledgments I thank Sang-Hyeon Lee, Heue-Jung Park, Won-Hee Chung, Jung-Whoan Kim, Chun-Sik Kim, Sang-Cheol Park, Sook-Young Rho, Jae-Chun Bae, Seung-Hee Hong, Il-Joo Sun, PhilZa Cho for helpful discussions.