MENIERE’S DISEASE — DO DIURETICS HAVE A ROLE IN THERAPY TODAY?

In the treatment of Meniere’s disease diuretics have lost the pride of place that it once enjoyed. Diuretics appear to have fallen out of favour of most contemporary neurotologists when it comes to choosing a drug for Meniere’s disease (MD), Betahistine is the first choice. However, in my clinical practice which is limited to Neurotology only I have had a very satisfactory experience with diuretics only in the management of Meniere’s disease and did not have much reason to choose betahistine over diuretics in most patients of recurrent Meniere’s disease. I am fully aware that this contradictscurrent consensus, and I am putting forward my views very hesitatingly more to clear my doubts and to be clarified on any irrationality that I may be having in my logic. This is one of the highest academic forums in Neurotology today and I would like to have my doubts cleared even if it stirs a hornet’s nest.

The logic in favour of BETAHISTINE in confirmed Meniere’s disease did not appear very convincing to me in spite of all the scientific propaganda and Cochrane reports telling us that the Betahistine is the drug of choice.

The Merriam-Webster Medical dictionary defines Hydrops as distension of a hollow organ with fluid. If Meniere’s disease is accepted as endolymphatichydrops the very definition implies that there is distension due to excessive fluid collection; if we accept this pathophysiology then the antidote for any oedema or fluid collection can be nothing other than agents that will drain out the fluid i.e., DIURETICS, and drugs that will reduce the secretion of fluids in the region.  However, the use of diuretics has not become the general accepted mode of treatment in endolymphatichydrops -Meniere’s disease.  Till the mid-80’s diuretics were found beneficial in MD but somehow the perceptions have changed and DIURETICS have now been dumped in favour of betahistine.

The Cochrane Database of Systematic Reviews of 2010 is used to sell the concept that Diuretics are not beneficial in Meniere’s disease. The article in question is a review article titled ‘Diuretics for Meniere’s disease or Syndrome (review)’by Burgess and Kundupublished in the Cochrane Collaboration 2010. The author’s conclusion in the review article is that there is insufficient good evidence of the beneficial effects of diuretics in Meniere’s disease as the studies were not of high quality due to inappropriate study design or absence of randomised placebo controlled trials; it does not say that diuretics do not work in Meniere’s disease.

My own experience as well as that of many others with diuretics has been very good and I have been using diureticsin patients with properly worked up Meniere’s disease(typical history, Glycerol test and EcochG +ve documentable SN deafness in all cases and n most cases some evidence of vestibular abnormality)over the last twenty five years. I have mainly used diuretics and carbonic anhydrase inhibitors as their use in endolymphatichydrops has appeared more rational and scientifically tenable to me. The logic of using diuretics that drain the fluid and drugs like carbonic anhydrase inhibitors that reduce secretion of fluid appears to be more direct and more convincing than the roundabout logic of betahistine increasing blood supply in the striavascularis and thereby reducing the excessive secretion of endolymph. Moreover the old study of Arrang et al published in the European Journal of Pharmacology shows that this function of the H1 receptors in enhancing blood flow works only at 100times the therapeutic dosage.

There are 3 ways a drug can an exert beneficial effects in Hydrops. First, by draining away the fluid, second by decreasing the generation of the fluid and lastly by changing the electrolyte composition in the inner ear. Diuretics do all of them. It is true that the hearing improvement/ decrease of tinnitus is not appreciable in long term use in most patients but it does not mean that diuretics do not have any effect. That diuretics induce dehydration and drainage of fluid from the inner ear which causes temporary benefit is evident in the Glycerol / furosemide dehydration test for diagnosis of Meniere’s disease. It is proof enough of the reversal of pathology caused by Diuretics even if not permanent. The hearing improvement is not permanent butthat  the improvement of vestibular symptoms with diuretics is long term has been shown in different studies some of which are detailed below.

Endolymphatichydrops is considered to be the principal histopathologic characteristic in temporal bones from patients with Meniere’s disease.ACETAZOLAMIDE is a Carbonic anhydrase inhibitor and it increases of osmolality in perilymph but not serum osmolality. Carbonic anhydrase inhibitors cause increased excretion of bicarbonate with accompanying sodium, potassium and water. Carbonic anhydrase inhibitors decrease the secretion of fluid and that is the basis of its use in Glaucoma which is a form of hydrops in the eye where excessive fluid (Aqueoushumour) is secreted in the anterior chamber of the eye.  A study by Heidechi and Kimura in ActaOtoaryngologica (1986) 101:43-52 titled ‘Effects of Diuretics in Endolymphatic‘ in which experimental endolymphatichydrops was induced in 77 albino guinea pigs by obliteration of endolymphatic sac and duct showed that 1 month of acetazolamide therapy suppressed the development of Endolymphatichydrops in the cochlea/ saccule/ utricle. It was also shown that significant dilatation does not take place in the semi-circular canals in most cases. This was a double blind placebo controlled study. It showed that when Acetazolamide was administered to these albino guinea pigs endolymphatichydrops did not reach the extent of distension shown in animal ears without acetazolamide treatment. Experiments like this prove the efficacy of DIURETICS in Meniere’s disease.

Some published reports of symptomatic improvements in patients with Meniere’s disease following acetazolamide administration:-

1. Corvera J. Carbonic anhydrase and internal ear. Ann OtolRhinolLaryngol1956; 65: 351-5.
2. Muftic MK. Acetazolamide in Meniere’s disease. Arch Otolaryngol1957; 65: 575-9.
3. Varga G, Miriszlai E, Szab6 LZ. Experiences with acetazolamide therapy applied in our clinic to patients suffering from Meniere’s disease for more than 8 years. J LaryngolOtol1966; 80: 250-69. 14

Animal experiments :-
4. H. Shinkawa and R. S. Kimura, Effect of Diuretics on EndolymphaticHydropsActaOtolaryngol (Stockh)1986; 101: 43-52

Some studies that have shown improvements with diuretics in Meniere’s disease are as follows:-

1967 Klockhoff + Lindblom – Htcz in DB trial – improvement in vertigo and deafness.
1974 Klockhoff + Lindblom – Chlorthalidone 7yr follow-up showed – improvement in 76% pts.
1986 Deelen + Huizing Triamterene + Hctz – improvement only in vertigo

Mechanism of action of diuretics as suggested in literature are:-

Carlberg + Farmer (1983)  suggested that – osmotic diuretics  like glycerol / furosemide cause rapid dehydration followed by decrease of inner ear pressure
Klockhoff + Lindblom (1967) suggested that – diuretics not only cause dehydration but possibly also have effects on labyrinthine electrolyte regulation
Deelan + Huizing (1986) – postulated that themechanism  by which Diazideincreases excretion of Sodiumbut decreases excretion of Pottasiumion transport mechanism in renal tubules and striavascularis of the inner ear is the same. The authors suggested that long term diuretics have an effect on the function of striavascularis and consequently on electrolyte regulation in inner ear.

Intratympanic Gadolinium enhanced MRI is the fool-proof test of endolymphatichydrops as we know today and possibly has more specificity than the electrocochleography test.  An IT Gadolinium enhanced MRI evidence of DIURETICS reversing endolymphatichydrops was published in ActaOto-Laryngologica, 2009; 129: 1326-1329 authored by Miyagawa et al. The paper titled‘Endolymphatichydrops and therapeutic effects are visualized in ‘atypical’ Meniere’s disease’  has shown endolymphatichydrops affecting the basal turn of the cochlea that could be completely reversed with osmotic diuretic-ISOSORBIDE for 350days with return of hearing to normalcy.

Conclusions:-

• Diuretics do have a positive role in therapy of Meniere’s disease that is evidence based, ethical and scientifically logical.
• Betahistine possibly also has a positive role in Meniere’s disease as evidenced by many studies but the mechanism of action is not as clear as that of Diuretics.
• Action of Betahistine may be at least partly due to its symptom relieving vestibular sedative effect and if so, long term use is not justifiable.
• More research needs to be taken up and the use of DIURETICS like ACETAZOLAMIDE/ FUROSEMIDE / HYDROCHLOROTHIAZIDE/ TRIAMTERENE / SPIRONOLACTONE  needs a re-think and re-acceptance for treatment of Meniere’s disease.