Cause of idiopathic sudden sensorineural hearing loss: The stress response theory

Table 1 Proposed causes of idiopathic sudden sensorineural hearing loss during this decade

Main category	Subcategory	Significantly associated factors	NOT significantly associated factor	Ref.
Vascular impairment		MTHFR poly., homocysteine	FV poly., PT poly., AT, LAC, protein S, protein C	[1,2]
	Medical history	MTHFR poly., FV Leiden poly., folate, cardioV risk factors		[3]
	Medical history	Platelet GlyIa poly.	Platelet GlyIIIa poly., Framingham cardioV risk factors, FV Leiden poly., PT poly., history of cardioV events, brain stroke, antiphospholipid syndrome	[4,5]
		PAI-1 poly.		[6]
	Medical history	CFH poly. with DM	HT, lipid	[7]
	Medical history	Low FMD of the brachial artery	Low C-IMTl, LDL, cardioV risk factors	[8]
		Vertebrobasilar junction angulation		[9]
		High global oxidative stress index		[10]
			FV Leiden poly., PT poly.	[11]
	Medical history	SBP, personal/family history cardioV events	FV poly., PT poly., HT, DM, lipid, smoking, personal/family history or in the presence of thrombotic factors	[12]
		PKCH poly., MTHFR poly.		[13,14]
		Cho, LDL		[15]
		Cho, LDL, unsaturated fatty acid, coenzyme Q10, folate, homocysteine	MTHFR poly., FV poly., PT poly., antithrombin III, protein C and S, D-dimer, FG, activated protein C resistance	[16-18]
		MTHFR poly., FV Leiden poly., PT poly., platelet GlyIIIaA1/A2 poly., homocysteine, Cho, FG, folate		[19,20]
		MTHFR poly.	FV, PT, EPCR, PAI-1	[21]
	Medical history	ICAM-1, VCAM-1	Cho, triglyceride, FG, ESR, smoking, DM	[22]
		MTHFR poly. with MTR poly., MTR poly.	MTHFR poly. alone	[23]
		FV Leiden poly.	PT poly.	[24]
	Auto-immunity	Cho, homocysteine, PAI-1, anticardiolipin antibodies	FV Leiden poly., FII poly., antithrombin, protein C and S, lupus anticoagulant, lipoprotein(a)	[25]
		eNOS poly.		[26]
		FMD		[27]
		Whole blood viscosity, erythrocyte deformability index, activated clotting time, clot rate, PAI-1 antigen, factor VIII:C	Plasma viscosity, FG	[28]
	Auto-immunity	Antiendothelial cell antibody		[29,30]
Cytokine		IL-1B poly., TNF-β poly.		[31,32]
		TNF-α	IL-10, IL-12	[33]
		IL-6 poly.	IL-4R poly., IL-10 poly., TNF-α poly., TNFRSF1B poly., VEGF poly.	[34]
		IL-1A poly.	IL-1B poly.	[35]
	Vascular impairment		IL-6, IL-8, ICAM-1, VCAM-1, E-selectin, MCP-1, lipid, FG	[36]
		TNF-α, sCD40, sCD40L, T lymphocyte, CD40, cyclooxygenase 2, CD38 positive T or B lymphocyte	Monocyte, macrophage	[37]
Cellular stress		HSP70 poly.		[38]
			GPX1 poli., PON1 poli., PON2 poli., SOD2 poli.	[39]
			GST poly., CYP poly.	[40]
	Auto-immunity		Anti-HSP70 antibody, TNF-α, ESR, ANA, antiphospholipid antibody	[41]
	Auto-immunity	Anti-HSP70 antibody, anti-phospholipids antibody		[42]
		HSP70		[43]
			GST poly.	[44]
Infection		IgA to HSV1	IgG and IgM to CMV, VZV, HSV1, and HSV2. IgA to CMV, VZV, and HSV2	[45]
			Borrelia	[46]
			Herpes zoster	[47]
		Recent subclinical viral infection (cytomegalovirus, herpes simplex, Epstein-Barr virus), toxoplasmosis infections		[48]
			Enterovirus, cytomegalovirus, Epstein-Barr virus	[49]
Auto-immunity			Anti-double stranded DNA, RF, antiphospholipid IgG and M, antinuclear antibody, complements C3 and C4	[50]
		T cell responding to cochlin		[51]
Stress response theory		Neutrophil, NKCA, IL-6	TNF, hCRP	[52]
		Histological evidence of severe osmotic stress of the organ of Corti		[53]
Medical history		HIV		[54]
	Vascular impairment	SLE		[55]
	Vascular impairment	AMI		[56]
		Migrane with HT		[57]
	Vascular impairment	ED		[58]
	Vascular impairment	DM		[59]
		Chronic kidney disease with and without DM		[60]
		Allergy		[61]
		Male with OSA	Female with OSA	[62]
	Vascular impairment	CardioV risk factors, DM, Cho		[63]
		Family history of ISHL		[64]
	Vascular impairment	CerebroV stroke		[65]
Other aetiologies			Aquaporin 4 and 5 poly., estrogen receptor α poly.	[66]
		Round window membrane rupture		[67]
		Endolymphatic hydrops		[68]
			Eustachian tube dysfunction	[69]
		General anaesthesia		[70]
			Month, weather	[71]
		HLA-DQB1 and -DRB1		[72]
			Season, weather	[73]

Papers on human studies are categorized by the proposed etiologies. Papers that deduce possible etiologies from the effect of a treatment are excluded. For example, Kang et al[174] stated that the cause might be reactive oxygen metabolites produced by inner ear ischemia or inflammation, because high dose vitamin C was effective. Such papers are excluded from this table in order to save space, although they are noteworthy. AMI: Acute myocardial infarction; AT: Antithrombin; C-IMT: Carotid intima-media thickness; CardioV: Cardio vascular; CDL: CD ligand; CerebroV: Cerebrovascular; CFH: Complement factor H; Cho: Cholesterol; CMV: Cytomegalovirus; CYP: Cytochrome P450; DM: Diabetes mellitus; E-selectin: Endothelial selectin; ED: Erectile dysfunction; eNOS: Endothelial nitric oxide synthase; EPCR: Endothelial cell protein C receptor; ESR: Erythrocyte sedimentation rate; FG: Fibrinogen; FMD: Flow-mediated dilatation; FII: Factor II; FV: Factor V; Gly: Glycoprotein; GPX: Glutathione peroxidase; GST: Glutathione S-transferases; hCRP: High sensitivity C-reactive protein; HIV: Human immunodeficiency virus; HLA: Human leukocyte antigen; HSP: Heat shock protein; HSV: Herpes simplex virus; HT: Hypertension; ICAM-1: Intercellular adhesion molecule 1; IL: Interleukin; ISHL: Idiopathic sudden sensorineural hearing loss; LAC: Lupus anticoagulant; LDL: Low density lipoprotein; MCP-1: Monocyte chemoattractant protein 1; MTHFR: Methylene tetrahydrofolate reductase; MTR: Methionine synthase; NKCA: Natural killer cell activity; OSA: Obstructive sleep apnea; PAI-1: Plasminogen activator inhibitor-1; PKCH: Protein kinase C-Eta; poly.: Polymorphism; PON: Paraoxonase; PT: Prothrombin; RF: Rheumatoid factor; SBP: Systolic blood pressure; SLE: Systemic lupus erythematosus; sCD: Soluble cluster of differentiation; SOD: Superoxide dismutase; TNF: Tumor necrosis factor; TNFRSF1B: Tumor necrosis factor receptor superfamily 1b; VCAM-1: Vascular cell adhesion molecule 1; VEGF: Vascular endothelial growth factor; VZV: Varicella-zoster virus.

Table 2 Receptors of catecholamine in the cochlea

Location	Adrenergic receptor					Cholinergic receptor
	α1	α2	β1	β2	1β	M1	M2	M3	M5
IHC	○		○			○		○	○
OHC	○		○			○		○
Deiters’ cells			○	○		○	○	○	○
Hensen’s cells			○	○
Outer sulcus			○
Stria vascularis2				○
Strial marginal cell			○						○
Capillaries in the stria vascularis								○
Spiral ligament2			○	○		○	○	○	○
Rissener’s membrane					○
Spiral ganglion	○		○	○		○		○	○
Nerve fibers approaching HCs	○		○	○
Efferent fibers of the intraganglionic spiral bundle							○		○
Spiral modiolar artery	○	○
Endolymphatic sac				○

¹The specific receptor subtype, β1 or β2, was not determined;

²Note that the receptors were detected in tissues apart from blood vessels. IHC: Inner hair cell; OHC: Outer hair cell.

Table 3 Nuclear factor κ-light-chain-enhancer of activated B cells activation and associated cytokine expression in the lateral wall

Animal	Stressor	Time point	NF-κB		Other factors			Ref.
			Response	Location	Factor	Response	Location
CBA/CaJ mice	LPS, ip	24 h	Activation	Unilateral, II >> I, Lim.				[141]
	LPS, ip + dexamethasone, ip		No activation
	Anti-CD3, ip		Activation	I
	Taxol, ip		Activation	I
	100 dB SPL		Activation	Bilateral, I >> II, Lim.
CBA mice	117 dB SPL	4 h	Transcription	LW				[142]
		2-12 h1 (4 h)			iNOS	Transcription	LW
		0-12 h (6 h)			ICAM-1	Transcription	LW
		2-12 h (6 h)			VCAM-1	Transcription	LW
		14 h			ICAM-1	Expression	SV
		14 h			VCAM-1	Expression	SV
Swiss-Webster mice	Ag	7 d			Leukocytes	Expression2	SL3	[143]
	90 or 100 dB SPL	7 d				No expression
	90 or 100 dB SPL + Ag	7 d				No expression
	118 dB SPL	4 h	Activation	I, II, IV
		7 d	No activation		Leukocytes	Expression2	LW
					ICAM-1	Expression	II
	118 dB SPL + Ag	4 h	Activation	I, II, IV, HC, SC
		7 d	Activation	HC, SC	Leukocytes	Expression	LW4
			Activation		ICAM-1	Expression	II, III >> I4
C57/Bl6J mice	124 dB SPL	2 h	Activation	I, II, III, IV, SV	iNOS	Most of NF-κB activated cells		[144]
		72 h	Activation	I, II, III, IV, SV5	iNOS	Most of NF-κB activated cells5
Sprague-Dawley rats	Cisplatin, ip	24 h	Activation	I, II, III, IV, SV, OHC, Lim.	IL-1β	Expression	II, IV >> I, III, SMV	[145]
					IL-6	Expression	SMV
					TNF-α	Expression	I, II, III, IV, SV, Lim., SMV, HC
	Cisplatin + TNF-α inhibitor		No activation		IL-1β	No expression, no transcription
					IL-6	No expression, no transcription
					TNF-α	No expression, no transcription
Sprague-Dawley rats	124 dB SPL	3 h			IL-6	Expression	III, IV	[146]
		6 h				Expression	I, II, III, IV
		12 h				Expression	I, II, III, IV, SV, SG
		24 h				Expression	I, II, III, IV, SG6

¹The time in the parentheses is the time of the maximum up-regulation of a factor;

²The paper did not show whether it was significant or not in only the lateral wall, although it was significant in the total number of leukocytes in the modiolus, spiral limbus (Lim.), spiral ligament (SL), stria vascularis (SV), and the scala tympani. However, the number in the lateral wall showed a clear tendency of increase compared with controls;

³There were a small number of leukocytes in the spiral ligament;

⁴The leukocyte number and the intercellular adhesion molecule 1 (ICAM-1) expression intensity were significantly more than those of Ag alone and 118 dB noise alone in the total of modiolus, Lim., SL, SV, and the scala tympani;

⁵The intensity at 72 h was weaker than at 2 h;

⁶The intensity at 24 h was much weaker than at 12 h in the lateral wall. Some papers demonstrated nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activation in the lateral wall and cytokine expression. The systemic stressors that induce stress response of the lateral wall are shown in the column “Stressor”. Each paper used different methods and time points to observe the response. For example, the activation of NF-κB (Activation) (i.e., translocation of NF-κB from the cytoplasm into the nucleus), its transcriptional up-regulation (Transcription), and the protein expression (Expression) were analyzed. Some papers demonstrated which types of cells responded to stressors in the lateral wall, but some did not. Noise was band noise for 2 h in all experiments, and the intensities are shown in the table. I-IV, type I-IV fibrocytes in the lateral wall; II >> I, The NF-κB activation was much stronger in type II fibrocytes than type I fibrocytes; Ag, An adaptive inner ear immune response was created by sensitizing mice to the keyhole limpet hemocyanin. Then, the mice were sensitized systemically to the antigen in experimental conditions shown as Ag or + Ag in the table. iNOS: Inducible nitric oxide synthase; ip: Intraperitoneal injection; LPS: Lipopolysaccharide; LW: The transcriptional up-regulation or the protein expression was observed in the lateral wall: but the specific cell type was not determined; SC: Supporting cell; SMV: Spiral modiolar vein; VCAM-1: Vascular cell adhesion molecule 1; IL: Interleukin; TNF-α: Tumor necrosis factor α; HC: Hair cell; OHC: Outer hair cell.