Demyelinating disease

Abstract

We conducted a study to determine whether vestibular nerves in patients with unilateral Meniere's disease whose symptoms are refractory to medical management exhibit neuropathologic changes. We also endeavored to determine whether retrocochlear abnormalities are primary or secondary factors in the disease process. To these ends, we obtained vestibular nerve segments from five patients during retrosigmoid (posterior fossa) neurectomy, immediately fixed them, and processed them for light and electron microscopy. We found that all five segments exhibited moderate to severe demyelination with axonal sparing. Moreover, we noted that reactive astrocytes produced an extensive proliferation of fibrous processes and that the microglia assumed a phagocytic role. We conclude that the possible etiologies of demyelination include viral and/or immune-mediated factors similar to those seen in other demyelinating diseases, such as multiple sclerosis and Guillain-Barre syndrome. Our findings suggest that some forms of Meniere 's disease that are refractory to traditional medical management might be the result of retrocochlear pathology that affects the neuroglial portion of the vestibular nerve.

Introduction

Meniere's disease is a debilitating inner ear disorder that is characterized by episodic vertigo, fluctuating progressive sensorineural hearing loss (SNHL), tinnitus, and aural fullness. (1) Both cochlear and vestibular forms of the disease have been recognized. (2) Possible etiologies include viral, allergic, genetic, vascular, and nutritional factors; altered glycoprotein metabolism; excessive endolymph production; immune-mediated factors; and combinations of any of the above. (3)

Many patients with Meniere's disease are responsive to traditional medical management with a diuretic, a low-salt diet, and/or a vestibular suppressant. Patients who do not respond to these therapies can be treated with alternate medications, including an oral steroid, a transtympanic steroid or gentamicin, or systemic methotrexate. (4) Surgery is reserved for patients who still do not respond; surgical procedures include endolymphatic sac decompression, vestibular neurectomy, or labyrinthectomy. The choice of procedure depends largely on the status of the patient's hearing.

Researchers have examined the excised portions of vestibular nerves obtained from patients with a variety of cochleovestibular disorders, including Meniere's disease, in several previous studies. Some of these authors have proposed that demyelination and axonal changes are underlying factors in the etiology of Meniere's disease. (5-10) However, others have regarded microscopic changes in the vestibular nerve as nonspecific, inconsistent, or insufficient to account for the reduced vestibular function, and, therefore, they consider these changes to be unrelated to symptoms and the disease process. (10-14)

In this article, we describe a study that we undertook to assess the type and extent of pathologic changes that occur in the vestibular nerve in patients with unilateral Meniere's disease whose symptoms are refractory to medical management. We also endeavored to determine whether these abnormalities are primary or secondary factors in the disease process.

Materials and methods

Our study group was made up of five patients--three women and two men, aged 39 to 76 years, all white--who underwent retrosigmoid vestibular neurectomy for the treatment of intractable Meniere's disease at the Medical College of Virginia Hospitals at Virginia Commonwealth University. The diagnosis of Meniere's disease had been made on the basis of symptoms of episodic vertigo of at least 20 minutes' duration, fluctuating hearing loss, tinnitus, and aural fullness. The diagnosis was supported by standard testing, including audiometry, electronystagmography, and electrocochleoraphy.

All patients had been unresponsive to medical management with traditional therapies, including a potassium-sparing diuretic, a low-salt diet, and/or a vestibular suppressant. All had also not responded to at least one course of a high-dose oral steroid (1 mg/kg/day) for 2 weeks. Findings on magnetic resonance imaging were normal in all patients. One patient underwent a Western blot test for antibody to the 68-kD inner ear protein, (15) and the result was negative. Another patient was diagnosed with concomitant ulcerative colitis.

Retrosigmoid vestibular neurectomy was performed on all patients, and a 2- to 3-mm segment of the vestibular nerve was removed from the cerebellopontine angle. Within 2 minutes of excision, the specimens were placed on pieces of Teflon-coated gauze and immersed in a fixative solution containing 4% paraformaldehyde and 0.5% purified glutaraldehyde in 0.1 M phosphate buffer (pH: 7.2). Specimens remained in the fixative solution for 12 to 18 hours at 4[degrees]C and then washed in phosphate buffer and trimmed to 1-mm segments. The segments were postfixed in 1% osmium tetroxide in 0.1 M phosphate buffer for 4 hours, washed in 0.05 M maleate buffer, and stained en bloc in 2% uranyl acetate in 0.05 M maleate buffer for 2 hours, all at 40 C with constant agitation. Segments were then dehydrated in methanol and propylene oxide and embedded in an epoxy resin. Semithin (1 to 2 pm) sections were cut with glass knives on an ultramicrotome and stained with toluidine blue and basic fuchsin for light microscopic examination with bright-field and differential interference contrast optics. Ultrathin (60 to 80 nm) sections were cut with a diamond knife on the ultramicrotome, collected on Formvar-coated single-slot grids, stained sequentially with 4% uranyl acetate and 1% lead citrate, and examined and photographed through an electron microscope.

Results

Light microscopic examination revealed a wide variation among the five vestibular nerves in the number, density, and size of myelinated axons. A characteristic feature of all nerves was the irregular appearance of the myelin (e.g., blebs and whorls) associated with medium- and large-diameter axons (figures 1, A, and 1, B). The number of axons that exhibited myelin abnormalities varied among the specimens. Smaller-diameter myelinated axons appeared to be unaffected. All five nerve segments also exhibited pale areas of fibrosis, in which the density of myelinated axons was reduced substantially (figure 1, C). In one specimen (taken from a 45-year-old woman), a large region of the vestibular nerve displayed extensive fibrosis that coexisted with numerous amyloid bodies (corpora amylacea) (figure 1, C). The extent of these abnormalities, however, did not appear to be correlated with the clinical symptoms because all five patients had a history of frequent and severe episodes of vertigo.

On electron microscopy, distinct abnormalities were observed in the myelination of axons with the vestibular nerves; the most common abnormalities were cleavage, splitting, and fragmentation of the myelin lamellae (figures 2, A, and 2, B). Many axons displayed concentric zones of inner pale and outer dark myelin (figure 2, A-C). Active demyelination was indicated by the association of fragmented myelinated axons with spongy phagocytes (figure 2, B). In some instances, attempted remyelination was suggested by the formation of a secondary thin myelin sheath around an axon that had abnormal myelin (figure 2, D). The possibility that these changes might be attributable to fixation artifact was minimized by the observation that apparently normal myelinated axons were present in the vicinity of the abnormal axons.

The pale areas of fibrosis that were observed on light microscopy corresponded to regions of active demyelination, as indicated by accumulations of myelin debris and the presence of large-diameter axons that were devoid of myelin sheaths (figure 3). A massive proliferation of fibrous astrocytic processes accompanied by reactive microglia (figure 4, A)--many of which displayed a phagocytic role (figure 4, B)--and amyloid bodies occupied regions of the nerves that were characterized by an absence of axons. Although a few immune-related cells were observed within the vasculature in the vicinity of the fibrotic regions, inflammatory cells generally were absent within the nerve matrix.

Discussion

Our most significant findings were (1) disruption and fragmentation of myelin, (2) demyelination with axon sparing, (3) phagocytosis of myelin debris and other degenerating elements by reactive microglia, and (4) proliferation of fibrous astrocytic processes. Authors of several previous studies attributed changes in the vestibular nerve (e.g., the difference in the number or density of abnormal myelinated axons compared with those of normal axons) as unrelated to any reduced vestibular function in most patients. (11-14) However, in some patients, degenerative changes in the vestibular nerve (including demyelination) have been regarded as causal factors in vestibular dysfunction. (7-11, 16-18) Although we cannot exclude the possibility of a primary process involving the peripheral vestibular neuroepithelial cells, our findings--particularly our finding of demyelination with axon sparing--are highly suggestive of an active primary demyelinating disease process that might be of immune-mediated origin. The use of cadaveric vestibular nerves as controls was felt to be inadequate because of the immediate postmortem neuronal changes.

Vertigo and SNHL are two common symptoms of Meniere's disease. SNHL has become recognized as a frequent manifestation of immune-mediated diseases. Both clinical and laboratory studies have demonstrated that inner ear structures can be affected either (1) indirectly by elevations of circulating serum immune complexes precipitated by generalized systemic disease or (2) directly by the presence of specific autoantibodies against sensorineural structures. (19-22) The incidence of immune-mediated Meniere's disease has been estimated to be between 10 and 50%, based on the presence of circulating immune factors and responsiveness to immunotherapy. (23,24) Lymphocyte transformation and lymphocyte migration inhibition indices are elevated in some patients with Meniere's disease who are responsive to steroid therapy. (24-27) However, a significant number of patients with Meniere's disease are unresponsive to steroid treatment, which suggests that a different mechanism such as retrocochlear involvement might be implicat ed in the pathogenesis of this disorder.

Certain demyelinating neurologic diseases, many of which have an immunologic basis, result in retro-cochlear hearing deficits as a result of the involvement of the vestibulocochlear nerve and/or the brainstem auditory pathways. Although sudden hearing loss is uncommon, it can be the initial symptom of multiple sclerosis (MS). (28-34) Both the 70-kDa and 27-kDa heat shock proteins have been isolated in MS lesions. These proteins might play a role not only in the protection and regeneration of axons, but also as additional targets of the immune response; they might also contribute to the progression of the disease process. (35) A significant percentage of patients with MS exhibit abnormal auditory brainstem responses. (36,37) Demyelination with axon sparing that is virtually indistinguishable from that observed in our study has been produced in experimental allergic encephalomyelitis (an animal model of MS) and correlated with prolonged latencies and inter-peak intervals of the auditory brainstem responses. (3 8) Progressive SNHL of retrocochlear origin has also been associated with peripheral neuropathy. (9,39) In addition, retrocochlear abnormalities, including degenerative axonal changes, have been observed in the vestibular nerves of some patients with Meniere's disease. (5-10,16,40,41) Observations have also been made of prolonged wave I latencies of auditory brainstem responses attributable to nerve conduction block that occurred as a result of demyelination in patients with Guillain-Barre syndrome. (42) Recent findings indicate that many patients with Meniere's disease have anti-sulfated glucuronyl glycolipid (SGGL) serum antibodies. Overall, SGGL antibodies are present in 64% of patients suspected of having immune-mediated SNHL, compared with only 7% of control subjects. (43) Furthermore, SGGLs are also present in the human vestibular labyrinth, endolymphatic sac, and vestibulocochlear nerve. (44)

Our findings suggest the possibility that primary vestibular neuropathy is present in some Meniere's disease patients who do not respond to traditional treatment with a diuretic, a low-salt diet, and/or a steroid. Immune-mediated processes should be considered in such cases, and patients might benefit from megadoses of an intravenous steroid for the management of autoimmune optic neuropathy, (45) optic neuritis, 4647 and MS. (48-50)

In conclusion, the findings of our study suggest that some forms of Meniere's disease that are refractory to traditional medical management might be the result of retrocochlear pathology that affects the neuroglial portion of the vestibular nerve. We found demyelination with axon sparing in our patients, which is indicative of a primary active disease process. Possible etiologies of the demyelination include viral and/or immune-mediated factors similar to those seen in other demyelinating diseases, such as MS and Guillain-Barre syndrome.

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From the Department of Otolaryngology--Head and Neck Surgery (Dr. Spencer, Dr. Sismanis, Dr. Kilpatrick, and Dr. Shaia) and the Department of Anatomy (Dr. Spencer), School of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond.

Reprint requests: Aristides Sismanis, MD, P.O. Box 980146, Richmond, VA 23298. Phone: (804) 828-3965; fax: (804) 828-5779; e-mail: Asismanis@aol.com

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