Review of immunology

The inner ear demonstrates both cellular and humoral immunity. Most leukocytes enter the cochlea via the spiral modiolar vein. The innate immunity of the cochlea has been suggested to allow an adaptive local response to antigen challenge. Hashimoto and colleagues have suggested that the inner ear may be “primed” by lipopolysaccharides or other viral or bacterial antigens, resulting in the upregulation of interleukin (IL)-1C in the spiral ligament fibrocytes, permitting leukocytes to enter. Subsequently, in those having lymphocytes primed to react against inner-ear antigens, an initiated immune response may result in local inflammation. Altermatt and colleagues have suggested that the seat of immune activity in the inner ear appears to be the endolymphatic sac (ES) and duct. Immunoglobulin (Ig) G, IgM, IgA, and secretory components are found in the ES, and numerous plasma cells and macrophages reside in the perisaccular connective tissue.

Additionally, the labyrinth exhibits active components of allergic reactivity. Mast cells have been identified in the perisaccular connective tissue. Following sensitization, IgE-mediated degranulation of mast cells has resulted in eosinophilic infiltration of the peri connective tissue and, clinically, the production of endolymphatic hydrops.

The ES is capable of both processing antigen and producing its own local antibody response. Surgical destruction of the ES results in decreased antigen and antibody responses. The highly vascular subepithelial space of the ES contains numerous fenestrated blood vessels, with arterial branches of the posterior meningeal artery supplying the ES and duct. Although the labyrinth is protected by the blood-labyrinthine barrier, the posterior meningeal artery is fenestrated, offering a peripheral portal of circulation. Fenestrated vessels supplying organs involved in absorption (eg, kidney, choroid) are especially susceptible to damage by immune complex deposition.

Despite evidence of immune activity, only 30% of patients with MD show a true autoantibody response on Western blot assay to specific anticochlear antibody. Tests of abnormal cell-mediated immunity are either inconsistent or normal, even in patients with known causes of inner ear autoimmune dysfunction, including Cogan syndrome. Despite increased understanding of labyrinthine immunoreactivity, a reliable laboratory marker to “prove” autoimmune or allergic causation in patients with suspected inflammatory hearing loss has not yet been developed.

The first published report of MD believed to be provoked by an allergic reaction was in 1923. Both inhalant and food allergies have been linked with MD symptoms. Many of MD’s clinical characteristics suggest an underlying inflammatory, if not autoimmune, etiology, such as its propensity to wax and wane, with periods of remission. It is also bilateral in a significant number of cases.

There are different possible mechanisms by which an allergic reaction produces MD symptoms. First, the ES itself could be a target organ of the allergic reaction. The sac’s peripheral and fenestrated blood vessels could allow antigen entry, stimulating mast cell degranulation in the perisaccular connective tissue. The resulting inflammatory mediator release could affect the sac’s filtering capability, resulting in a toxic accumulation of metabolic products, and interfering with hair cell function. Also, the fenestrated blood vessels to the ES could be pharmacologically vulnerable to the effects of vasoactive mediators such as histamine, which are released in a distal allergic reaction. The unique blood supply of the interosseus ES would serve as a portal for these mediators to exert a direct pharmacologic effect. The potent vasodilating effects of histamine or other mediators could affect the resorptive capacity of the ES. Yan and colleagues have shown that Waldeyer ring in the nasopharynx is the anatomic site of T-cell homing to the ES. In systemically sensitized rodents, intranasal antigen stimulation with keyhole limpet hemocyanin (KLH) in Waldeyer ring resulted in an antigen-specific reaction in the ES and perilymphatic vessels, suggesting that viral or allergic antigen could be processed in the nasopharynx, with the resulting specific immune reaction occurring at the ES.

A second possible mechanism involves the production of a circulating immune complex, such as a food antigen, which is then deposited through the fenestrated blood vessels of the ES, producing inflammation. An increased incidence of circulating immune complexes in the serum has been described in both MD and allergic rhinitis. The inflammatory response resulting from the deposition of immune complexes along vascular basement membranes is the hallmark of an immune complex disease. Although the binding of the complexes to the cell membranes facilitates their phagocytosis, it also results in the release of tissue-damaging enzymes. This is believed to be the mechanism of unexplained sensorineural hearing loss in patients with Wegener granulomatosis, a prototype immune-complex–mediated disease. Upon examining the temporal bones of patients with Wegener granulomatosis and unexplained sensorineural hearing loss, the cochlea is found to be normal; the pathology occurs in the ES.

Alternatively, circulating immune complexes may be deposited in the stria, causing the normally intact blood-labyrinthine barrier to leak as a result of increased vascular permeability. In addition to disrupting normal ionic and fluid balance in the extracapillary spaces, this could facilitate the entry of autoantibodies into the inner ear.

A third possible mechanism is a viral antigen-allergic interaction. A predisposing viral upper respiratory infection in childhood (eg, mumps, herpes) antigenically stimulates Waldeyer ring, with subsequent T-cell homing to the ES, resulting in a chronic low-grade inflammation. This is not enough initially to result in hearing loss or vertigo, but it does produce mild impairment of ES absorption. Later in adult life, “something” in the system then stimulates excess fluid production. Several investigators have assumed that viral infections play a direct or indirect role in the etiology of MD. Gacek recently published temporal bone evidence of viral particles enclosed in transport vesicles in a patient with a history of MD. He also noted that antiviral treatment controlled vertigo in most patients with both MD and viral neuronitis.

Viruses are also capable of exacerbating allergic symptoms by several mechanisms. Both live and ultraviolet light–inactivated viruses have been shown to enhance histamine release, an effect believed to be mediated by interferon. Viruses can also damage epithelial surfaces, thereby enhancing antigen entry and increasing the responsiveness of target organs to histamine. It has long been noted that patients with poorly controlled allergy are more likely than nonallergic persons to develop upper and lower respiratory viral infections.

The herpes virus family would appear to be the most likely candidate for a viral stimulus. Patients with MD have elevations in serum antibody against herpes simplex and enterovirus. Additionally, Heat Shock Protein 70, an antibody frequently seen elevated in both MD and autoimmune inner ear disease (AIED), is often upregulated in viral infections.

Epidemiology of MD

In a survey performed of 734 patients with Ménière’s syndrome, the prevalence of skin test–confirmed concurrent allergic disease was 41%. Although the prevalence of allergic rhinitis is often quoted as 20% or more, the recent Allergies in America report, the largest survey to date regarding prevalence and disease burden of allergic rhinitis, found that physician-diagnosed allergic rhinitis in patients with rhinitic symptoms is 14%. Hence, the prevalence of physician-diagnosed allergy in American patients diagnosed with MD is almost 3 times that of the general population. In a more recent survey of patients with MD, Derebery and Berliner found that patients reported a 58% rate of allergy history and, again, a 41% rate of positive skin or in vitro test.

In his original description, Prosper Ménière’s suggested an association between migraine and MD. Since then, many investigators have noted paroxysmal headache independently occurring in many patients with MD. Radtke and colleagues published a well-designed prospective trial based on strict diagnostic criteria, which clearly established an increased lifetime prevalence of migraine in patients diagnosed with MD.

A recent study reported both an increased incidence of self-reported migraine and allergic rhinitis in patients with MD as compared with a control group of age- and sex-matched patients without MD attending an otolaryngology clinic. Sen and colleagues used a Web-based questionnaire to recruit 108 patients with MD, and a control group of 100 patients attending the otolaryngology clinic for other problems. The migraine prevalence in MD sufferers was 39.0% compared with 18.0% in the control group, whereas the prevalence of allergy in those with MD was 51.9%, compared with 23.0% in the control group. In the MD group, a history of allergy was significantly more prevalent in patients with migraine (71%) than in those without migraine (39%). There was no such link between allergy and migraine in the control group, with the combination of allergy and migraine 9 times more prevalent in the MD group.

The Sen and colleagues’ study is interesting because it suggests that in that large subset of patients with MD who also have migraine, the vast majority report an additional diagnosis of allergy. In reviewing their Web-based questionnaire, one weakness would be that the allergy history is obtained by simply asking the subjects whether they or family members suffer from any allergy, without confirmatory skin or in vitro testing. However, the fact that all patients—control group and patients with MD—were asked the same question and gave such differing responses adds credence to the supposition that there is a much higher incidence of allergy and migraine in patients with MD.

Although the list of “causes” for migraine is quite extensive, it has long been noted that allergic reactions were a common trigger in many sufferers. There are striking similarities among MD, allergy, and migraines concerning both symptom presentation and vascular changes. All 3 tend to recur cyclically, and sufferers are often able to note a cause and effect between a particular suspected “exposure” or event and the subsequent development of symptoms. The entities all show similar vascular changes as well: vasoconstriction, vasodilatation, and plasma extravasations, during the course of symptom production. Ibekwe and colleagues reported that there is an elevation in IgG containing immune complexes in the meningeal vessels of patients with migraine, as well as in the subepithelial layer of the endolymphatic sac in patients with MD. They hypothesized that there may be a common defective ion channel in both disease states, with the predominant expression in the inner ear and brain, resulting in a local increase in extracellular potassium and the production of symptoms.

Epidemiology of MD

In a survey performed of 734 patients with Ménière’s syndrome, the prevalence of skin test–confirmed concurrent allergic disease was 41%. Although the prevalence of allergic rhinitis is often quoted as 20% or more, the recent Allergies in America report, the largest survey to date regarding prevalence and disease burden of allergic rhinitis, found that physician-diagnosed allergic rhinitis in patients with rhinitic symptoms is 14%. Hence, the prevalence of physician-diagnosed allergy in American patients diagnosed with MD is almost 3 times that of the general population. In a more recent survey of patients with MD, Derebery and Berliner found that patients reported a 58% rate of allergy history and, again, a 41% rate of positive skin or in vitro test.

In his original description, Prosper Ménière’s suggested an association between migraine and MD. Since then, many investigators have noted paroxysmal headache independently occurring in many patients with MD. Radtke and colleagues published a well-designed prospective trial based on strict diagnostic criteria, which clearly established an increased lifetime prevalence of migraine in patients diagnosed with MD.

A recent study reported both an increased incidence of self-reported migraine and allergic rhinitis in patients with MD as compared with a control group of age- and sex-matched patients without MD attending an otolaryngology clinic. Sen and colleagues used a Web-based questionnaire to recruit 108 patients with MD, and a control group of 100 patients attending the otolaryngology clinic for other problems. The migraine prevalence in MD sufferers was 39.0% compared with 18.0% in the control group, whereas the prevalence of allergy in those with MD was 51.9%, compared with 23.0% in the control group. In the MD group, a history of allergy was significantly more prevalent in patients with migraine (71%) than in those without migraine (39%). There was no such link between allergy and migraine in the control group, with the combination of allergy and migraine 9 times more prevalent in the MD group.

The Sen and colleagues’ study is interesting because it suggests that in that large subset of patients with MD who also have migraine, the vast majority report an additional diagnosis of allergy. In reviewing their Web-based questionnaire, one weakness would be that the allergy history is obtained by simply asking the subjects whether they or family members suffer from any allergy, without confirmatory skin or in vitro testing. However, the fact that all patients—control group and patients with MD—were asked the same question and gave such differing responses adds credence to the supposition that there is a much higher incidence of allergy and migraine in patients with MD.

Although the list of “causes” for migraine is quite extensive, it has long been noted that allergic reactions were a common trigger in many sufferers. There are striking similarities among MD, allergy, and migraines concerning both symptom presentation and vascular changes. All 3 tend to recur cyclically, and sufferers are often able to note a cause and effect between a particular suspected “exposure” or event and the subsequent development of symptoms. The entities all show similar vascular changes as well: vasoconstriction, vasodilatation, and plasma extravasations, during the course of symptom production. Ibekwe and colleagues reported that there is an elevation in IgG containing immune complexes in the meningeal vessels of patients with migraine, as well as in the subepithelial layer of the endolymphatic sac in patients with MD. They hypothesized that there may be a common defective ion channel in both disease states, with the predominant expression in the inner ear and brain, resulting in a local increase in extracellular potassium and the production of symptoms.