Low-dose oral methotrexate management of patients with bilateral Meniere's disease.

Abstract

In this retrospective clinical trial, we evaluated the effectiveness of low-dose oral methotrexate in the management of bilateral Meniere's disease of immune-mediated origin. At our tertiary-care referral center, we evaluated ten men and eight women who had longstanding bilateral Meniere's disease that had been unresponsive to traditional conservative medical management. Sixteen of these patients had steroid-responsive bilateral Meniere's disease. Two patients had contraindications to steroids, but their clinical and laboratory evaluations were consistent with an immune-mediated process.

Patients were treated with 7.5 to 20 mg/week of oral methotrexate. The mean duration of treatment was 16.7 months (range: 8 to 35), with a mean followup of 2 years (range: 9 mo to 5 yr). Changes in clinical symptoms (vertigo, hearing loss, tinnitus, and aural fullness), audiometric changes, and side effects of therapy were evaluated.

Vertigo resolved in 14 patients (78%), was substantially alleviated in three patients (17%), and remained unchanged in one patient (6%). Hearing improved in five patients (28%) and stabilized in seven patients (39%). Tinnitus and aural fullness resolved or was relieved in 11 of 17 (65%) and 13 of 14 (93%) patients, respectively. Side effects were minimal and reversible.

We conclude that low-dose oral methotrexate is effective and safe for treating bilateral Meniere's disease of immune-mediated origin. In this study, methotrexate alleviated vertiginous symptoms and improved or stabilized hearing in most patients. Low-dose methotrexate can be considered for patients with immune-mediated bilateral Meniere's disease when long-term treatment is required or when a steroid or cyclophosphamide is contraindicated.

Introduction

Bilateral Meniere's disease is an uncommon entity that presents a management dilemma to the otologist. Conservative management of bilateral Meniere's disease includes a low-salt diet, diuretics, and vestibular suppressants. Patients in whom this treatment fails have few other options. Traditional surgical procedures for unilateral Meniere's disease are not applicable for patients with bilateral disease. Systemic streptomycin, although beneficial, is associated with a high incidence of ataxia and oscillopsia. [1-5] Oral steroids and/or cyclophosphamide are effective for a significant number of patients with immune-mediated bilateral Meniere's disease, but their side effects increase in incidence and severity with long-term use, and not all patients tolerate them. [6]

Methotrexate has been used effectively in the treatment of a broad spectrum of rheumatic diseases. [7-9] Low-dose methotrexate is the drug of choice in the long-term management of rheumatoid arthritis. [7] It has been reported that methotrexate is effective in treating cochleovestibular disorders of immune-mediated origin. [10,11]

In this study, we report our experience in managing bilateral Meniere's disease of immune-mediated origin with low doses of oral methotrexate.

Materials and methods

Patient selection and evaluation. This retrospective study evaluated the outcomes of 18 consecutively presenting patients with bilateral Meniere's disease of immunemediated etiology who were treated with methotrexate. All patients had a longstanding history of bilateral Meniere's disease that had failed to respond to a low-salt diet and diuretic therapy.

The diagnosis of steroid-responsive bilateral Meniere's disease was based on three criteria: 1) a history of episodic vertigo, bilateral fluctuating hearing loss, tinnitus, and aural fullness, 2) audiometric evidence of bilateral hearing loss (electronystagmography and electrocochleography were used in selected cases to support the clinical diagnosis), and 3) a diagnostic course of oral prednisone (1 mg/kg/day) for 2 to 4 weeks (prednisone test).

Sixteen patients had a positive prednisone test. A positive result was defined as 1) the elimination or marked alleviation of vertiginous symptoms, tinnitus, and aural fullness, 2) an improvement in pure-tone average (at 0.5, 1, 2, and 4 kHz) of more than 10 dB, and/or 3) a 15% increase in speech discrimination score. One patient with diabetes mellitus and another who had previously developed a rash while taking prednisone were started on methotrexate without a trial of steroids. Both of these patients had clinical histories and laboratory tests suggestive of an immune-mediated process.

Four patients had previously undergone surgery (two vestibular neurectomies, one endolymphatic sac drainage, and one labyrinthectomy) for incapacitating vertigo at other institutions. Two of these patients developed a profound hearing loss after surgery.

All patients underwent a metabolic workup, which consisted of a complete blood count with differential (CBC), a measurement of the erythrocyte sedimentation rate (ESR), a sequential multiple analysis of 20 serum chemical constituents, a fluorescent treponemal antibody absorption test, a determination of antinuclear antibody titers (ANA), a measurement of rheumatoid factor, and a urinalysis. A Western blot test for the detection of antibodies to inner ear antigens was obtained in eight patients. Liver enzyme levels and CBCs were monitored every 4 to 8 weeks during treatment.

Pure-tone average and speech discrimination were assessed every 2 to 3 months after the initiation of treatment. Followup audiologic evaluations were obtained every 6 to 12 months after the completion of treatment. Each patient's most recent audiogram was compared with his or her baseline audiogram.

Appropriate imaging studies (to rule out retrocochlear lesions) and baseline chest x-rays were obtained prior to the initiation of methotrexate.

Treatment. All patients were evaluated by a rheumatologist-immunologist prior to treatment, and they were followed at 4- to 8-week intervals throughout their treatment course. Our treatment protocol was identical to the regimen used to treat rheumatoid arthritis. [7] Oral methotrexate was started at a dose of 7.5 mg/week and was increased progressively to 12.5 to 15 mg/week. The minimum dose necessary to achieve optimum control of symptoms was used. The highest dose administered was 20 mg/week (two patients). All patients continued on a low-salt diet, a potassium-sparing diuretic (hydrochlorothiazide-triamterene), and 1 mg/day of folic acid to minimize complications such as stomatitis. [12] All patients were instructed to abstain from alcohol to decrease the risk of liver complications, and women of childbearing age were informed that methotrexate is a teratogen and can terminate pregnancy.

Control of symptoms. A minimum of 6 to 8 weeks of therapy is required to assess the response to methotrexate therapy. [11] All patients in this study received a minimum of 6 months' therapy. Vertigo was judged to be either resolved (completely absent), substantially improved (severity and frequency of attacks had decreased to the point that vertigo was no longer disabling), or unchanged. Hearing improvement after methotrexate therapy was defined as an increase of more than 10 dB in pure-tone average (at 0.5, 1, 2, and 4 kHz) and/or a 15% improvement in speech discrimination score. Tinnitus and aural fullness were recorded before, during, and after treatment and were reported as either resolved, improved, unchanged, or worse.

Results

The mean age of the 18 patients (10 men) in this study was 57 years (range: 36 to 77). The mean duration of symptoms prior to the initiation of methotrexate was 10 years (range: 1 to 45). The mean duration of methotrexate treatment was 16.7 months (range: 8 to 35), and-the mean followup was 2 years (range: 9 mo to 5 yr). Sixteen patients reported that vertigo was their most disabling symptom. The other two patients said that tinnitus and hearing loss were their main complaints, although both had occasional debilitating vertigo. Ten patients had other medical problems, including arthritis, diabetes, gout, idiopathic retinopathy, monoclonal gammopathy, and Reiter's syndrome (table 1). Significant metabolic test results included an elevated ESR (six patients), a positive ANA (four patients), a positive rheumatoid factor (two patients), and a positive Western blot test (four of the eight patients tested) (table 2).

The detailed data regarding the otologic and audiologic evaluations before and after methotrexate treatment are presented in table 3. Vertigo resolved in 14 patients (78%), was substantially controlled in three patients (17%), and remained unchanged in one patient (6%).

Hearing improved in five patients (28%), worsened in four (22%), and stabilized in seven (39%). The other two patients (11%) experienced improved hearing in one ear and poorer hearing in the other.

Of the 17 patients who had experienced tinnitus, the condition resolved in one (6%), was alleviated in 10 (59%), remained unchanged in five (29%), and worsened in one (6%). Tinnitus was not a significant complaint in one patient.

Of the 14 patients who had experienced aural fullness, the condition resolved in six patients (43%), was alleviated in seven (50%), and worsened in one (7%). It was not a significant complaint in four patients.

No patient developed any serious side effects throughout the course of treatment. The most common side effect was mild nausea on the day of treatment (table 4). Two patients developed severe nausea, which resolved when they were switched from oral administration to intramuscular injections. Other side effects included fatigue, diarrhea, hives, and mild alopecia, all of which were transient and did not interfere with the treatment or outcome.

Discussion

Immune-mediated processes have been implicated in the pathogenesis of Meniere's disease ever since McCabe first described autoimmune sensorineural hearing loss in his landmark paper in 1979. [13] Hughes et al reported that more than 50% of patients diagnosed with autoimmune sensorineural hearing loss had Meniere's syndrome. [14] Brookes identified elevated immune complexes in 54% of patients with Meniere's disease, compared with only 2.9% of controls. [15] The endolymphatic sac has been implicated as a site of immune-mediated pathologic changes in many cochleovestibular disorders. [16] According to another study, a deposition of immunoglobulin G was observed in 40% of endolymphatic sac specimens obtained during endolymphatic sac surgery from patients with Meniere's disease. [17]

Diagnosis. The diagnosis of immune-mediated Meniere's disease remains elusive. It is mainly based on the clinical presentation, laboratory testing, and response to steroids or other immunosuppressive agents. Bilateral symptoms, other associated systemic immune-mediated disorders, and a failure of conventional therapy should alert the otologist to a possible immune-mediated process. [18] The Western blot immunoassay for detecting antibodies to inner ear antigens and the lymphocyte transformation test have been reported to have a high degree of specificity in detecting immune-mediated otologic disorders. [10,11,19-21] However, neither of these useful tests is widely available or universally reimbursed by insurance carriers. Therefore, the diagnosis of immune-mediated otologic disease depends mainly on a high index of clinical suspicion and the alleviation of symptoms after a 2- to 4-week course of steroids or other immunosuppressive medications. [6,10,11,21,22]

Treatment. There is no universally accepted treatment for patients with bilateral Meniere's disease in whom traditional medical therapy with diuretics and a low-salt diet has failed. Most otologists agree that the traditional surgical approaches for the management of unilateral Meniere's disease, such as vestibular neurectomy and labyrinthectomy, are contraindicated in bilateral Meniere's s disease because of the risk of hearing loss, disequilibrium, and oscillopsia. [1,4] Endolymphatic sac decompression has been advocated for bilateral Meniere's disease and, although it is relatively safe, its long-term effectiveness is controversial. [23]

Nonsurgical treatments of bilateral Meniere's disease include aminoglycoside infusion into the middle ear, intramuscular streptomycin, and oral corticosteroids and/or cyclophosphamide (for disease of immune-mediated origin). Because of the risk of hearing loss, however, many otologists are reluctant to use an aminoglycoside in patients with bilateral disease. [4] Intratympanic gentamicin injection in the most active ear is an effective approach for managing vertigo when the most active ear can be identified. [24]

In 1948, Fowler reported the first documented use of streptomycin for the treatment of bilateral Meniere's disease, and this drug is still considered the treatment of choice. [3] Human and animal studies have shown that streptomycin is toxic to the crista of the semicircular canals and can produce a chemical ablation of the vestibular system and preserve hearing. [1] Side effects include perioral numbness and tingling, severe nausea, skin rash, and oscillopsia. [4] In 1980, Wilson and Schuknecht published the largest series of patients treated with ablative streptomycin therapy; they reported a complete resolution of vertigo in 19 of their 20 patients.[5] However, during treatment, all patients developed severe ataxia that did not resolve for 2 to 9 months. Wilson and Schuknecht reported that during 16 years of followup, three patients had persistent mild ataxia, four were unable to walk in the dark, and three had persistent oscillopsia. [5] In a meta-analysis published in 1990, Langman et al reviewed 12 stu dies documenting the outcomes of 107 patients who had been treated with ablative or titration streptomycin therapy. [1] Relief of vertigo was seen in 50 to 100% of patients who received ablative treatment and in 63 to 100% of patients who received titration therapy. Persistent disequilibrium, however, was noted in up to 64% of patients, regardless of whether they received ablative or titration therapy. Although streptomycin therapy is successful in controlling vertigo, it must be administered carefully to minimize associated morbidity.

Steroids and cyclophosphamide are the traditional medical treatments for immune-mediated cochleovestibular disorders, including bilateral Meniere's disease. Plasmapheresis has also been recommended, but it is expensive and not universally effective. [25] The duration of steroid or cyclophosphamide therapy should be individualized according to treatment response and drug tolerance. [26] Symptoms can recur when immunosuppressive treatment is discontinued early. The National Institutes of Health have recommended treating autoimmune vasculitis, such as Wegener' s granulomatosis and Cogan's syndrome, with immunosuppressive treatment for 1 year after the disappearance of active disease. [27,28] A similar duration of treatment has been suggested for immune-mediated otologic disorders. [29] Prolonged administration of steroids and/or cyclophosphamide has been associated with serious and sometimes life-threatening adverse reactions (table 5).

Side effects. In an effort to treat immune-mediated otologic disorders with a less toxic immunosuppressive agent that could be administered for a prolonged period, we began using low-dose oral methotrexate in 1991. This medication was found to be safe and effective. [10,11] Methotrexate has been widely used in the treatment of rheumatologic diseases, and it has revolutionized the treatment of rheumatoid arthritis. [7] Methotrexate is an antimetabolite that inhibits dihydrofolate reductase and interferes with DNA synthesis, repair, and replication. Despite its effectiveness, the mechanism of methotrexate action in chronic inflammation and immune-mediated disease remains unclear. [30,31] Weekly low-dose (7.5 to 25 mg) methotrexate has shown favorable results in adult and juvenile rheumatoid arthritis, corticosteroid-dependent asthma, inflammatory bowel disease, inflammatory myopathy, and inflammatory eye diseases. [9,32-35] In the past decade, methotrexate has replaced nonsteroidal antiinflammatory drugs as the treatment of choice for adult rheumatoid arthritis. [7] Long-term ([greater than]84 mo) prospective studies showed that the clinical response was sustained and the incidence of side effects was acceptable. [7,36]

Adverse reactions to methotrexate are completely different when it is taken at a low dose (7.5 to 25 mg/wk) than when it is taken in the high doses that are used in cancer chemotherapy (100 to 1,000 mg/[m.sup.2] body-surface area per cycle). [7] Nausea, anorexia, stomatitis, and diarrhea are the most common side effects, but dizziness, headache, mood alterations, and fatigue can also occur. Many of these adverse reactions can be diminished by supplemental folic acid therapy (1 mg/day). [7,12] Methotrexate is a teratogen that also induces abortion, so of course it should not be prescribed for pregnant women. [7] Low-dose methotrexate has exhibited no carcinogenic effect to date. [37] Serious complications include hepatotoxicity and cirrhosis. The risk of hepatotoxicity in rheumatoid arthritis has been estimated to be less than 1 per 1,000 cases after 5 years of treatment. [38] These risks are further minimized when small doses are used in a pulse fashion on a regular schedule. [7] Alcohol use, morbid obesity, glucose intolerance, and type 1 (insulin-dependent) diabetes are risk factors for hepatotoxicity. Rare complications of methotrexate therapy include nephrotoxicity, interstitial pneumonitis, hypersensitivity reactions, and reversible myelosuppres-sion. [39] Liver function tests should be monitored every 4 to 8 weeks while patients are on treatment, and drug doses should be adjusted accordingly. Routine liver biopsies are not necessary as long as liver function remains normal. [40] A prospective study of 230 rheumatoid arthritis patients found that only 8% discontinued treatment because of complications. [41]

The results of this study indicate that low-dose oral methotrexate is effective in the management of immune-mediated bilateral Meniere's disease. A minimum of 6 weeks of therapy is required before a response is seen. Vertigo resolved or was alleviated in 94% of our patients, and hearing improved or remained stable in 67%. In patients with significant tinnitus and aural fullness, these symptoms diminished or resolved in 65 and 93%, respectively. These results compare favorably with those seen with streptomycin, steroid, and cyclophosphamide treatment. Methotrexate was generally well tolerated by our patients, and side effects were mild and reversible. The use of methotrexate avoids the morbidity associated with streptomycin therapy and offers a viable alternative to steroids and/or cyclophosphamide, particularly when long-term treatment is required and/or when other immunosuppressant medications are contraindicated.

Although our results are encouraging, we acknowledge that this open clinical trial did not include a placebo control group. However, the possibility of spontaneous improvement in symptoms in patients with longstanding bilateral Meniere's disease is very unlikely. A prospective, randomized, multi-institutional study is needed to fully evaluate the efficacy of methotrexate and to compare it with other therapies for bilateral Meniere's disease.

In conclusion, the experience gained from this study suggests that 1) low-dose oral methotrexate is a safe and effective treatment for immune-mediated bilateral Meniere's disease, and provides good control of vertigo and stabilization of hearing in most patients, 2) methotrexate is generally well tolerated, with an acceptable incidence of side effects, and 3) methotrexate should be considered when long-term treatment is required or when steroids and/or cyclophosphamide are contraindicated.

From the Department of Otolaryngology--Head and Neck Surgery (Dr. Kilpatrick, Dr. Sismanis, and Dr. Spencer) and the Department of Internal Medicine (Rheumatology/Immunology) (Dr. Wise), Medical College of Virginia of Virginia Commonwealth University, Richmond.

Reprint requests: Aristides Sismanis, MD, Department of Otolaryngology--Head and Neck Surgery, P.O. Box 980146, Richmond, VA 23298.

References

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(4.) Graham MD. Bilateral Meniere's disease: Treatment with intramuscular titration streptomycin sulfate. Otolaryngol Clin North Am 1997;30:1097-100.

(5.) Wilson WR, Schuknecht HF. Update on the use of streptomycin therapy for Meniere's disease. Am J Otol 1980;2:108-11.

(6.) Harris JP, Darmstadt GL. Sensorineural hearing loss: Medical therapy. In: Gates G, ed. Current Therapy in Otolaryngology Head and Neck Surgery. Vol. 4. Philadelphia: B.C. Decker, 1990:50-6.

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(9.) Wilke WS. Methotrexate use in miscellaneous inflammatory diseases. Rheum Dis Clin North Am 1997;23:855-82.

(10.) Sismanis A, Thompson T, Willis HE. Methotrexate therapy for autoimmune hearing loss: A preliminary report. Laryngoscope 1994;104:932-4.

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(19.) Hughes GB, Moscicki R, Barna BP, San Martin JE. Laboratory diagnosis of immune inner ear disease. Am J Otol 1994;15:198-202.

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(23.) Larouere MJ, Kartush JM. Meniere's disease: Surgical therapy. In: Gates G, ed. Current Therapy in Otolaryngology Head and Neck Surgery. 6th ed. St. Louis: Mosby Year-Book, 1997:81-6.

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                 Associated medical disorders in the study
                                population
Arthritis              3
Diabetes mellitus      3
Gout                   1
Idiopathic retinopathy 1
Monoclonal gammopathy  1
Reiter's syndrome      1
                          Metabolic test results
Elevated erythrocyte                6/18 (33%)
sedimentation rate
Positive antinuclear antibody titer 4/18 (22%)
Positive rheumatoid factor test     2/18 (11%)
Positive Western blot test          4/8 (50%)
                     Effect of methotrexate treatment
                         on symptoms and hearing.
Patient         Symptoms
   #    Sex/Age Vertigo             Tinnitus              Aural fullness
                 Before    After     Before     After         Before
   1     F/36      +         -         B      [up arrow]        B
   2     M/57      +         -         B      [up arrow]        B
   3     F/62      +         -         R      [up arrow]        R
   4     M/75      +         -         B          []            B
   5     F/57      +         -         B          []            R
   6     M/43      +         -         B          -             B
   7     M/48      +         -         B      [up arrow]        B
   8     F/41      +         -         L      [up arrow]        L
   9     M/46      +         -        N/A        N/A           N/A
  10     M/56      +         -         L          []           N/A
  11     F/67      +         -         B      [up arrow]        B
  12     M/75      +     [up arrow]    B      [up arrow]        B
  13     M/40      +         []        B     [down arrow]       R
  14     F/51      +     [up arrow]    B          []           N/A
  15     F/47      +         -         B      [up arrow]        B
  16     F/74      +     [up arrow]    B          []           N/A
  17     M/77      +         -         B      [up arrow]        B
  18     M/75      +         -         B      [up arrow]        B
Patient              Audiologic results
   #                        PTA               SDS(%)
           After           Before       After Before   After
                           (R/L)               (R/L)
   1         -             58/70        37/54  72/80  100/100
   2         -             33/33        38/33  88/78   84/76
   3     [up arrow]        65/NR        45/NR  72/NR  100/NR
   4     [up arrow]        72/36        82/40 28/100  52/100
   5     [up arrow]        83/12        71/16 NR/100  65/100
   6         -             41/68        26/73 100/92  100/60
   7         -             51/60        57/56  76/88  88/100
   8         -             20/52        15/38 100/96  100/92
   9        N/A            51/NR        60/NR  83/NR   96/NR
  10        N/A            46/79        43/70  80/56   80/64
  11     [up arrow]        22/62        15/58 100/NR  100/12
  12     [up arrow]        78/81        78/88  72/72   56/52
  13    [down arrow]       36/32        62/66 100/100 100/100
  14        N/A            66/63        63/61  84/84   84/84
  15         -             37/52        33/55  96/92  100/88
  16        N/A            75/37        59/31  92/52  68/100
  17     [up arrow]        44/76        51/87  80/48   92/24
  18     [up arrow]        64/42        62/44  84/96   44/88
Key: PTA = pure-tone average, SDS = speech discrimination score,
M = male, F = female, B = bilateral, R = right ear, L = left ear,
NR = no response + = present, - = absent, [up arrow] = improvement
in symptoms or hearing,[[] REPRESENTS ARROW POINTING TO LEFT AND
RIGHT] = nochange in symptoms or hearing,[down arrow] = symptoms
grew worse during therapy.
                  Incidence of methotrexate side effects
                          in the study population
Nausea                         5 (3 mild,
                                  2 severe)
Transient fatigue              3
Diarrhea (on day of treatment) 1
Transient hives [*]            1
Mild alopeciat [+]             1
(*.)Resolved spontaneously and did not recur during therapy.
(+.)Transient and did not require discontinuing therapy.

Comparison of adverse reactions: Corticosteroids, cyclophosphamide, and low-dose methotrexate

Corticosteroids

Aseptic necrosis of femoral and humeral heads

Cataracts

Congestive heart failure

Cushingoid state

Fluid retention

Glaucoma

Hypertension

Increased intracranial pressure

Increased intraocular pressure

Insomnia

Manifestation of latent diabetes mellitus

Muscle weakness

Myopathy

Nervousness

Osteoporosis

Peptic ulcer perforation, hemorrhage

Pituitary, adrenocortical insufficiency

Potassium loss

Sodium retention

Cyclophosphamide

Alopecia, skin rash

Carcinogenesis (urinary bladder, myeloproliferative malignancies)

Hemorrhagic cystitis

Hemorrhagic myocarditis

Interstitial pulmonary fibrosis

Leukopenia

Nausea, vomiting

Sterility

Low-dose methotrexate

Alopecia

Anorexia

Dizziness

Fatigue

Hepatotoxicity, cirrhosis

Interstitial pneumonitis

Nausea, vomiting, diarrhea

Nephrotoxicity

Rash, pruritus, dermatitis

Reversible myelosuppression

Stomatitis

Thrombocytopenia