The Journal of Laryngology and Otology June 1979. Vol. 93. pp. 545-561.
Metabolic investigations in Meniere's disease Preliminary findings By DAVID A. MOFFAT,* JOHN B. BOOTH, and ANDREW W. MORRISON,
THE aetiology of Meniere's disease remains an enigma. Since Prosper Meniere first described the disease in 1861, a large volume of literature has accumulated on the subject. Despite this, the cause of the endolymphatic hydrops first demonstrated by Hallpike and Cairns in 1938 has not been discovered, although many attractive theories have been proposed. These include hypo- and hyper-metabolic states as well as allergy and personality type. Both hypo- and hyper-glycaemia have been said to result in inner ear dysfunction. The relationship between sensorineural deafness and diabetes mellitus was first described over 100 years ago by Jordaof (1857). Since that time much has been written not only concerning hearing loss but also labyrinthine dysfunction (Jorgensen and Buch, 1961), although the reported incidence varies greatly. Diabetic angiopathy resulting in hypoxaemia was thought to produce temporary and then permanent structural damage to the neuroepithelium. Progressive sensorineural hearing loss, sudden deafness (Hegener, 1908) or Meniere's syndrome (Rott, 1946; Jorgensen, 1961) may result. Weille (1968) reported that 42 per cent of a series of 19 patients with Meniere's disease were suffering from reactive hypoglycaemia compared with 15 per cent of a control group. Many of his patients noted a decrease in auditory acuity before meals, with a post-prandial improvement. The hearing also improved after the administration of glucose in the glucose tolerance test. These findings can be related to the small glycogen store in nerve tissues which makes them highly dependent on the blood glucose level. Insulin sensitivity, perhaps related to adrenal insufficiency, could account for the hypoglycaemia (Tepperman, 1966). Descriptions of hypothyroidism with hearing loss are legion and date back to the 13th. Century. Both congenital and acquired hearing loss may be related to hypothyroidism and several syndromes have been described. Means (1948) noted that hearing loss and vertigo may be amongst the first signs of myxoedema and are reversible with treatment. The reversibility of the hearing loss was mentioned by Batsakis and Nishiyama (1962) and * Presented this paper to the Section of Otology at the Royal Society of Medicine in March 1978. t quoted by Taylor and Irwin (1978). 545 IB
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D. A. MOFFAT, J. B. BOOTH AND A. W. MORRISON
50 per cent of their patients improved after receiving thyroid extract. Poulsen (1966) observed that 40 per cent of his patients with classical myxoedema had a hearing loss and 66 per cent had vertigo. Histological studies of the acoustic and vestibular organs of patients with acquired myxoedema do not appear to have been reported but in endemic cretinism the hormonal dysfunction produces an increase in the ground substance content and hyaluronic acid and consequent expansion of connective tissue with ectatic changes in the semicircular canals and saccus endolymphaticus. Atrophy or deficient differentiation of the organ of Corti may occur with atrophic changes in the spiral ganglion. There is some evidence that hyperthyroidism may also produce a fluctuant hearing loss and vertigo (Permin and Poulsen, 1957). The relationship between hyperlipidaemia and inner ear dysfunction was noted as early as 1945 by Selfridge (quoted by Spencer, 1975). He suggested that Meniere's disease might depend on a disorder of the peripheral vascular system, (particularly the capillaries—Williams, 1952) and concluded that a lack of vitamin B complex might be responsible for a fatty liver, a high blood cholesterol level and a tendency towards vasospasm. Spencer (1973, 1975) has written extensively on hyperlipoproteinaemia in the aetiology of inner ear disease, proposing a correlation between the various metabolic abnormalities in Meniere's disease and hyperlipoproteinaemia since secondary causes of hyperlipoproteinaemia include myxoedema, nephrotic syndrome, diabetes, obesity and cigarette smoking. Patients with coronary artery disease may exhibit hyperglycaemia, glucose intolerance, exaggerated responses to glucose loading and hyperlipoproteinaemia and have a micro-angiopathy which may subside when the hyperlipidaemia is controlled. Related otological symptoms may resolve with the hyperlipidaemia. The possibility that allergic angioneurotic oedema might be one of the causes of endolymphatic hydrops was first considered by Quincke in 1893 (quoted by Shaver, 1975), but it was not until 1923 that Duke presented evidence for a specific allergic cause in Meniere's disease. Since that time further evidence has accumulated incriminating immediate hypersensitivity, where arteriolar spasm produces anoxia of the capillary loop and releases histamine which leads to dilatation and an increase in permeability (Williams, 1952). The subsequent increase in endolymph protein could produce hydrops, particularly in predisposed labyrinths where a degree of water imbalance already exists (Mygind and Dederding, 1938). Spasm of smooth muscle in branches of the internal auditory artery supplying the cristae and maculae will produce local anoxia and exacerbate the vertigo. Although atopy is thought to be common in these patients (Criep, 1939), it is the specific food allergies that have captured so much attention (Powers and House, 1969; Shaver, 1975). Clinically two types of food
METABOLIC INVESTIGATIONS IN MENIERE'S DISEASE
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allergy were identified by Rinkel et al. (1951)—fixed food sensitivity and cyclic food sensitivity. In fixed food hypersensitivity the same symptoms occur each time the food is eaten. The degree of sensitization is not altered by ingestion or prolonged elimination of food. The problem is more complex in cyclic food allergy where the elimination of the food leads to tolerance or adaptation whilst frequent ingestion results in greater sensitization. Diagnosis is often difficult, however, especially from the history, since the symptoms of food allergy are often vague and include flatulence, fluid retention, post-prandial fatigue, epigastric discomfort, headaches and nausea (Shaver, 1975). Many foodstuffs have been mentioned including dairy produce, wheat, corn, meat and vegetables but there seems to be little agreement on the most common offending foods. Sensitivity to chocolate is an interesting example because it can also cause migraine (Criepj 1939) and the association between Meniere's disease and migraine has been well documented (Atkinson, 1943; Golding-Wood, 1960; Hinchcliffe, 1967). In 1966 Klockhoffand Lindblom used glycerol dehydration to produce significant hearing threshold shifts in cases of Meniere's disease with fluctuating hearing loss. Glycerol, a trivalent alcohol (1,2,3 Propanetriol) given in high doses is not completely metabolised and is an osmotic diuretic, being excreted in the urine. It is possible that the osmotic effects of the glycerol reduced the endolymphatic hydrops and intra-labyrinthine pressure (Bosher and Warren, 1971). Klockhoff and Lindblom employed 1-5 g/kg body weight of glycerol, although more recently they have used 1-2 g/kg body weight and regarded a 10 dB improvement in three adjacent octave bands of the pure tone audiogram or a 12 per cent increase in the maximum discrimination score of the speech audiogram as being a significant improvement. Transtympanic Electrocochleography (ECochG) is now a well established technique for recording the electrical events occurring within the cochlea and VHIth nerve, in response to various sound stimuli. It may be employed to study the electrophysiological changes occurring in disease states. The compound VHIth nerve action potential/summating potential (AP/SP) waveform has been shown to be widened in cases of Meniere's disease (Gibson and Beagley, 1976). This widening has been found to be due to an enhanced SP or 'SP-like' component. The summating potential (SP) is a multicomponent response representing the sum of various nonlinearities occurring within the cochlea, the exact source being a matter of conjecture. The non-linearity producing an increased negative SP in endolymphatic hydrops may be due to displacement of the cochlear partition and thus asymmetry in the mechano-electric phenomena associated with the hair cell stimulation. The negative enhancement of the SP represents a DC shift in the baseline (Figure 1) and this is thought to be responsible for the widening of the AP/SP complex in Meniere's disease. At the London Hospital, patients suffering from Meniere's disease have
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D. A. MOFFAT, J. B. BOOTH AND A. W. MORRISON
A+B FIG. 1 Illustration of possible mechanism for enhanced negative SP in endolymphatic hydrops. A—DC shift in baseline of CM to upgoing clicks B—DC shift in baseline of CM to downgoing clicks A+B—DC shift in baseline alone displayed with CM subtracted.
recently been subjected to a series of investigations in an attempt to confirm or refute earlier work. The preliminary findings are presented. Patient Selection Twenty-seven patients were included in this initial study, 15 males and 12 females, with a mean age of 49-2 years (range 18-65 years). All patients were suffering from Meniere's disease, as defined by the Committee of Hearing and Equilibration of the American Academy of Ophthalmology and Otolaryngology (Alford, 1972). Full serological tests for syphilis, including the absorbed fluorescent treponemal antibody (FTA—ABS) and Treponema Pallidum haemagglutination (TPHA) tests were negative and tomograms of the internal auditory canals were normal. Audiometric findings indicated a recruiting hearing loss and the Hallpike-Fitzgerald caloric test usually revealed a variable degree of paresis. Sixteen patients (59 per cent) had all the classical manifestations of early Meniere's disease, including a fluctuating low frequency hearing loss. The disease was bilateral in four patients (15 per cent). Protocol for Metabolic Studies in Meniere's Disease Day 1 Patients were admitted in the afternoon and full clinical histories and examinations were carried out. They were given the Middlesex Hospital Questionnaire* and starved after supper from 9.00 p.m. Day 2 9.00 a.m.—Fasting blood was taken for glucose, cholesterol, triglycerides and thyroid stimulating hormone (TSH) estimations. 9.30 a.m.—A glucose tolerance test (GTT) was carried out. * Results to be published in a separate paper.
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549
Day 3 The patients were starved from midnight. 10.00 a.m.—Audiometric investigations including a pure tone audiogram, a speech audiogram, impedance studies and stapedial reflexes were then completed. —Blood and urine samples were obtained for preglycerol osmolality estimations. 11.00 a.m.—Baseline Transtympanic Electrocochleography (ECochG) was recorded. 11.30 a.m.—Oral glycerol 1-5 g/kg body weight was given to the patients. 11.30 a.m.—Continuous transtympanic electrocochleographic . to recordings were carried out, during glycerol dehydra1.30 p.m. tion. 1.30 p.m.—The audiometric investigations were repeated and blood and urine samples for post-glycerol osmolality estimations were collected. Method Prior to the glucose tolerance test patients were starved for 12 hours and had consumed a normal diet for 3 days before that. A standard 50 g glucose load was given and the blood and urine estimations were carried out over a 2\ hour period. Plasma glucose was determined, using an autoanalyser, by the glucose oxidase method. Patients were clinically assessed for thyroid dysfunction and also underwent an estimation of thyroid stimulating hormone (TSH). TSH levels were used because a rise is an early finding in the development of primary hypothyroidism (Mayberry et al. 1971) and may occur before the thyroxine level has fallen. The standard radioimmunoassay used was based on that described by Odell et al. (1965) using an MRC standard with a normal range in adults of 0-5, 6-10 being regarded as borderline in our laboratory. An assessment of serum cholesterol and triglycerides was carried out. Patients had previously eaten a normal diet and then fasted for 12 hours prior to the estimation. They had rested on a couch for at least 30 minutes and the blood was withdrawn without venous stasis. Normal values for our laboratory were:—Cholesterol—140-300 mg/100 ml (3-6-7-8 mmol/1) Triglycerides— 72-180 mg/100 ml (0-8-2-0 mmol/1) Evaluation of allergy both to common allergens and specific food allergens was by standard intradermal pin prick skin tests using allergens in glycero-saline (Table 1). A series of controls, matched for age and sex, were also tested. This test is a reliable method of assessing allergy and the IgE-mediated skin reaction consists of the classical urticarial type wheal.
550
D . A. MOFFAT, J. B. BOOTH AND A. W. MORRISON TABLE I INTRADERMAL PIN PRICK SKIN TESTS
Common Allergens
Specific Food Allergens
Control House dust mite Grass Pollen
Coffee Chocolate Milk (Cow) Mixed cheeses Egg yolk Egg white Maize grain Wheat grain Butter
=m1fdlyVpositive(lmmwheal)
Read as negative
++ = moderately positive (2mm wheal) +++ = strongly positive (3mm wheal) + + + + = very strongly positive (>3mm wheal)
Read as positive
+
In 21 of the 27 patients, continuous transtympanic electrocochleographic readings during glycerol dehydration were carried out, to study the electrophysiological changes occurring in the cochlea. Medelec-Amplaid Mk III evoked response audiometry (ERA) equipment was used. Adult patients were tested without sedation using the method of iontophoresis to anaesthetise the tympanic membrane (Ramsden et al., 1977). Patients were starved for 9 hours before the test. Prior to the electrocochleography, blood and urine samples were collected for osmolality estimations. A pure tone audiogram was recorded and then a speech audiogram using a Peters AP6 audiometer and Fry's phonetically balanced word lists (male voice). The electrodes were positioned with the patient lying comfortably in the supine position. A pre-glycerol recording was carefully made and particular attention paid to electrode contact and the consistency of the response. Iced lemon-flavoured glycerol 1-5 g/kg body weight was given to the patient orally via a pliable straw so that the fluid could be taken without moving the head position. The immediate post-glycerol response was then checked and the patients were monitored during the dehydration with full recordings to clicks and frequency-specific sine waves at one and two hours post-glycerol being made. In four patients the recordings were terminated at one hour because the patients were then uncomfortable. At the end of the test period the pure tone and speech audiograms were repeated and further blood and urine samples collected for post-glycerol osmolality estimations. Technical details of the electrocochleography and identification of the responses have been described in an earlier paper (Moffat et ah, 1978). In
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551
this series of patients the AP/SP complex and CM responses were noted throughout each recording. Changes in the SP during glycerol dehydration were observed more easily by using a subtraction technique whereby the SP was displayed largely uncontaminated by the AP (Moffat et ah, 1978). Some variation in the amplitude of the AP and CM (cochlear microphonic) occurred during the two-hour test period in some of the patients. This was possibly due to alteration in electrode contact. It was therefore felt that, under these circumstances, conclusions drawn from changes in the amplitude of the AP and SP should be guarded. However, the width and amplitude of the SP were easily assessed and, indeed, alteration of the SP was seen to modify the widened AP/SP complex considerably. In theory, accurate assessment of the negative SP may be obtained by measuring the amplitude in microvolts of the DC potential shift but this was found to be difficult practically even using the subtraction technique since there was always a small AP component within it. Since the widening of the AP/SP complex is proportional to the size of the SP, it was decided to measure changes in the width—W—of the SP in milliseconds (Fig. 2). Results The GTT results (Table II) were grouped according to the criteria of The British Diabetic Association (Fitzgerald and Keen, 1964). Normal AP/SP waveform (SP-shaded area)
Widened AP/SP waveform due to enhanced negative SP
W — width of AP/SP waveform in milli-seconds from onset of N i to point of return to baseline.
Ims
FIG.
2
552
D. A. MOFFAT, J. B. BOOTH AND A. W. MORRISON TABLE II RESULTS OF THE GLUCOSE TOLERANCE TESTS
27 Patients were tested 24 Patients had a normal GTT curve 0 Patients had a diabetic GTT curve 3 Patients (11 %) had a lag curve No patients had fasting hypoglycaemia (venous blood glucose of less than 40 mg/100 ml)
TABLE III RESULTS OF THE THYROID STIMULATING HORMONE ESTIMATIONS
27 Patients were tested 26 Patients had normal T.S.H. levels 1 Patient (3-7%) with high TSH level (68 Milli-units/litre) was clinically myxoedemic.
TABLE IV RESULTS OF SERUM CHOLESTEROL A N D TRIGLYCERIDES
15 male patients were tested 14 male patients had a normal lipid profile 1 male patient (6-6%) had primary hyperlipidaemia (W.H.O. Type II a) 12 female patients were tested 10 female patients had a normal lipid profile 1 female patient had hyperlipidaemia secondary to myxoedema (W.H.O. Type II b) 1 female patient (8%) had primary hyperlipidaemia (W.H.O. Type II b) None of the patients with primary hyperlipidaemia had abnormal GTT curves
TABLE V RESULTS OF PIN PRICK SKIN TESTS
Patient Reaction Negative 1 Positive 2 Positive 3 or more positive Total positive*
Control 20 5 1 1 7(26%)
Meniere's 22 2 2 1 5(18-5%)
* Barbee et al (1976) quote an incidence of 34 % of the general population with one or more positive allergens.
METABOLIC INVESTIGATIONS IN MENIERE'S DISEASE Allergen Reaction
Control
House dust mite Mixed grass pollens Coffee Chocolate Milk (Cow) Mixed cheeses Egg Yolk Egg White Maize grain Wheat grain Butter
3 5 0 0 0 1 0 0 0 1 1
3 2 2 0 0 1 0 0 0 0 0
11
8
Total
553
Meniere's
Results of the Glycerol Dehydration Tests and the Electrocochleographic Findings
In all patients included in the series, an increase in plasma osmolality of at least 10 mOsm/kg was noted. The mean change in plasma osmolality was 18-2 mOsm/kg (range 10-40 mOsm/kg). Patients were regarded as having had a significant change in the pure tone audiogram threshold (PTA) if it improved by 10 dB or greater at two or more audiometric frequencies. A significant change in the speech discrimination was taken as an improvement of 10 per cent or more in the maximum discrimination score. TABLE VI CHANGES IN PURE TONE THRESHOLD A N D SPEECH DISCRIMINATION FOLLOWING GLYCEROL DEHYDRATION
21 Patients were tested 1 Patient—significant change in PTA and speech discrimination 3 Patients—significant change in PTA alone 4 Patients—significant change in speech discrimination alone 13 Patients—no change in PTA or speech discrimination
= = = =
4- 8 % 14-3 % 19-0% 61-9%
Continuous transtympanic electrocochleographic recordings during the glycerol dehydration demonstrated a decrease in the negative SP (Figures 3, 4 and 5). TABLE VII TRANSTYMPANIC ELECTROCOCHLEOGRAPHY DURING GLYCEROL DEHYDRATION
'
21 Patients were tested 10 Patients—definite decrease ( > 1 ms) in width of AP/SP complex = 47- 6 % 4 Patients—possible decrease ( < lms) in width of AP/SP complex = 190% 7 Patients—no change in AP/SP complex = 33- 3 %
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D. A. MOFFAT, J. B. BOOTH AND A. W. MORRISON
I
HOUR POST GLYCEROL
Serum osmolaliiy 280mOsm/Kg PURE
TONE
290m'lOsm/Kg
AUDIOGRAM
SPEECH — NO
125
2SO
500 1000 2000 FREQUENCY (Hi)
CHANGE
4000
FIG.
3
Marked decrease in the negative SP observed one hour after the administration of glycerol. The shaded area in the pure tone audiogram represents the increase in threshold. (S=stimulus onset) TABLE VIH ELECTROCOCHLEOGRAPHY COMPARED WITH PURE TONE AND SPEECH AUDIOMETRY
8 Patients (38%) 10 Patients (47-6%)
showed a significant change in PTA and/or speech discrimination following glycerol dehydration showed a definite decrease in the width of the AP/SP complex following glycerol dehydration.
O
46
PRE GLYCEROL
I HOUR
I I O d B 2sine waves 2kHz HL
Subtraction
t
H
AP
S
Serum osmolality 290 mOs m/Kg
PURE
POST GLYCEROL
technique
TONE
305 mOsim / K g
AUDIOGRAM
_]• Ims
SPEECH — NO CHANGE
FREQUENCY (Hi)
FIG. 4 A smaller decrease in the negative SP following glycerol dehydration than in Figure 3, the change in the width of the SP being more noticeable than the change in the amplitude. PRE
GLYCEROL
SUBTRACTION — Clicks
I HOUR
POST
GLYCEROL
1-45 HOURS POST GLYCEROL
100 dB HL
Serum oimoljht/
FIG. 5 Progressive decrease in the negative SP up to 1.45 hours post-glycerol.
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D. A. MOFFAT, J. B. BOOTH AND A. W. MORRISON
Discussion and Conclusions
The unanswered question of whether Meniere's disease is a disease in its own right, or simply a symptom-complex, has puzzled and frustrated surgeons for many years. Mygind and Dederding (1932) stated tbat 'Meniere's disease is not a disease sui generis, but a typical reaction of a predisposed labyrinth to an almost infinite series of exo- and endo-genic influences, which have, however, this in common, that they express themselves through the vessels, especially the capillaries'. Many modern otologists concur with this view, believing that metabolic, allergic and psychosomatic factors can produce endolymphatic hydrops and, that when all of these entities have been discovered, Meniere's 'disease' will cease to exist. The vascular theory for the production of hydrops is used as a final common pathway for many of these metabolic states but proof for this is lacking and many basic questions pertaining to the normal physiology and pathophysiology remain to be answered. There were no diabetic GTT curves in this series compared with an incidence in the general population of 3 per cent. The 3 patients (11 per cent) aged 47, 58 and 60 respectively, who had lag curves, had 2-hour blood glucose levels of between 133-156 mg/100 ml. This is within the normal range since 20 per cent of patients over the age of 40 have 2-hour blood glucose levels in excess of 150 mg/100 ml (Williams, 1974). There was no fasting hypoglycaemia and no reactive hypoglycaemia, though to fully exclude the latter a 5-hour GTT is helpful (Powers, 1978). The incidence of reactive hypoglycaemia may be overestimated by some series in the literature, since 100 g of glucose has been used and this produces a higher incidence of reactive hypoglycaemia over 5 hours than is found with a standard 50 g load, though its significance is dubious (Marks, 1.974). The preliminary findings do not indicate an increased incidence of abnormal GTT curves compared with the general population. This is contrary to the findings of Shea and Kitabachi (1971) who quote an incidence of 57 per cent abnormal GTT curves in 70 Meniere's patients and Powers (1972) an incidence of 30 per cent (27 per cent hypoglycaemic, 3 per cent diabetic). The quoted incidence of hypothyroidism in patients of all ages in the general population varies considerably from series to series. Tunbridge et al. (1977) have quoted a figure of 0 08 per cent. One patient in this series was found to have hypothyroid levels of T.S.H. but the numbers are not great enough to conclude that there is an increased incidence of hypothyroidism in patients with Meniere's disease. Poulsen (1966) found that 12 per cent of Meniere's patients were hypothyroid. No patients in this group were clinically hyperthyroid or have developed clinical evidence of hyperthyroidism during a prolonged follow-up period. There was no increased incidence of byperlipidaemia in this group. Primary hyperlipidaemia was seen in 6-6 per cent of the male patieDts in this series which is considerably less than the 17 per cent in the local general population of men aged 20-69 years (Lewis et ah, 1974, North
METABOLIC INVESTIGATIONS IN MENIERE'S DISEASE
557
East London Survey). In the smaller female group 8 per cent had primary hyperlipidaemia which compares favourably with a figure of 8 per cent in the local general population aged 20-69 years. This in contrast to the findings of Spencer (1975), who found that 46-6 per cent of patients with symptoms of inner ear disease had hyperlipoproteinaemia but by no means all of his series had Meniere's syndrome and he was concerned with a different population. As far as allergy is concerned, considering both individual patient data and group data, the Meniere's group showed slightly less allergic phenomena than the control group. The only individual allergen which showed a marked difference between the two groups was coffee, to which 2 patients in the Meniere's group were positive compared with none in the control group. It should be noted, however, that only pin prick skin tests were carried out, since they are a reliable and sensitive method of assessing allergy. Bryans' modification of Black's cytotoxic food test (Bryan and Bryan, 1960), the serial dilution titration method of Rinkel (1963), the provocative skin food test of Lee et al. (1969) and the challenge feeding test (Rirtkel, 1934), were not utilised. Klockhoff and Lindblom's (1966) glycerol dehydration test was applied to twenty-one patients. The response to this test was measured by changes in the osmolality of the serum, the pure tone threshold of hearing, the maximum speech discrimination score and the width of the AP/SP (action potential/summating potential) complex. Using continuous transtympanic electrocochleographic recordings during glycerol dehydration, it was possible to demonstrate a marked decrease in the negative SP in many of the patients. It would seem possible that a decrease in the endolymphatic hydrops, secondary to glycerol dehydration, produces a movement of the basilar membrane towards the scala vestibuli, thus decreasing the asymmetry in the mechanoelectric phenomena associated with the hair cells. Alternatively, the effect of glycerol may decrease the endolymphatic potential primarily leading to a decreased negative SP. The fluctuant nature of the symptoms and signs, especially in the early stages of the disease, may be reflected in the differing (and sometimes normal) ECochG responses even before dehydration. At the present time the efficacy of conservative surgery for Meniere's disease is much debated. There is increasing evidence that surgical procedures on the endolymphatic sac can control the vertigo and stabilise or even improve the hearing threshold, but the mechanism is not clear and the selection of patients for this type of surgery is a practical problem. Shea (quoted by Klockhoff, 1975), suggested that a good response to glycerol dehydration was an indicator of a better prognosis in endolymphatic sac surgery. Morrison (1975) has shown, however, that saccus surgery is often beneficial, even in those patients without a fluctuating low tone hearing loss and showing a poor response to glycerol dehydration. Osmolality studies, it should be noted, were not carried out on all his
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patients in that series, therefore there was no proof that significant dehydration had always occurred. The intercorrelation between the measures used to assess the response to glycerol dehydration and their predictive value in respect of the course of Meniere's disease or of any therapeutic procedure adopted in its management will become apparent in the future. Further studies are in progress, particularly to assess their reliability and validity. Summary
The aetiology of Meniere's disease is unknown but in recent years many theories have been advanced to explain the observed pathological changes. These include abnormal metabolic states, allergy and personality type. In an attempt to throw more light on this and to confirm or refute the earlier work we studied twenty-seven (fifteen male:twelve female) patients with Meniere's disease who conformed to the criteria set out by the Committee of Hearing and Equilibration of the American Academy of Ophthalmology and Otolaryngology (Alford, 1972). In this series the incidence of abnormal metabolic states was no higher than that of a comparable group in the general population. There was no significant difference in response to pin prick skin tests compared with a control group. Klockhoff and Lindblom's (1966) glycerol dehydration test was applied to twenty-one patients. The response to this test was measured by changes in the osmolality of the serum, the pure tone threshold of hearing and the maximum speech discrimination score. Continuous transtympanic electrocochleographic recordings during glycerol dehydration were carried out and in 10 patients there was a definite decrease in the negative sununating potential. An electrophysiological explanation for this has been put forward and the possible use of this measurement in the diagnosis and management of Meniere's disease has been discussed. The intercorrelation between these measures and their predictive value will become apparent in the future. Acknowledgements
We would like to thank Mr. P. McKelvie for allowing us to test his patients who formed part of the series. We are indebted to Dr. B. J. Boucher for her advice on the metabolic aspects. We are grateful to Dr. D. T. D. Hughes and Dr. D. W. Empey for their help with the allergy tests and to Mrs. McDonnell for patiently testing a matched series of controls. REFERENCES ALFORD, B. R. (1972) Transactions American Academy of Ophthalmology and Otolaryngology 76, 1462. ATKINSON, M. (1943) Annals of Internal Medicine, 18, 797.
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BARBEE, R. A., LEBOWITZ, M. D., THOMPSON, H. C , and BURROWS, B. (1976) Annals ofInternal
Medicine, 84, 129. BATSAKIS, J., and NISMYAMA, R. (1962) Archives of Otolaryngology, 76, 401. BOSHER, S. K., and WARREN, R. L. (1971) Journal of Physiology, 212, 739. BRYAN, W. J. K., and BRYAN, M. P. (1960) Laryngoscope, 70, 810-824. CRIEP, L. H. (1939) The Pennsylvania Medical Journal, 43, 258. DUKE, W. W. (1923) Journal of the American Medical Association, 81, 2179. FITZGERALD, M. G., and KEEN, H. (1964) Lancet, 1, 1325.
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PERMIN, P. M., and POULSEN, H. (1957) Acta Otolaryngologica, 47, 220. POULSEN, H. (1966) Thyrotropic and Thyroid Hormone Control of the Inner Ear with Special Reference to Myxoedema and Meniere's Disease—in Hormones and Connective Tissue by G. Asboe-Hansen, Baltimore. Williams & Wilkins Co. p. 239. POWERS, W. H., and HOUSE, W. F. (1969) Laryngoscope, 79, 1330.
POWERS, W. H. (1972) Laryngoscope, 82, 1716. POWERS, W. H. (1973) Transactions American Academy of Ophthalmology and Otolaryngology, 77, 22. POWERS, W. H. (1978) Laryngoscope, 88, 122. RAMSDEN, R. T., GIBSON, W. P. R., and MOFFAT, D. A. (1977) Journal of Laryngology and
Otology, 91, 779. RINKEL, H. L. (1934) Southern Medical Journal, 27, 630-633. RTNKEL, H. J., RANDOLPH, T. J., and ZELLAR, M. (1951) Food Allergy, Springfield, IHionois, Charles C. Thomas Publishers. RINKEL, H. J. (1963) Archives of Otolaryngology, 77, 42-75. ROTT, H. F. (1946) InJoblin, The Treatment of Diabetes Mellitus, 10th. Edition (Philadelphia). SHAVER, E. F. (1975) Archives of Otolaryngology, 101, 96. SHEA, J. T., and KITABACHI, A. E. (1971) Journal of Tennessee Medical Association, 64, 862. SPENCER, J. T. (1973) Laryngoscope, 83, 639. SPENCER, J. T. (1975) Otolaryngologic Clinics of North America, 8, 483. TAYLOR, I. G., and IRWIN, J. (1978) Journal of Laryngology and Otology, 92, 99. TEPPERMAN, J. (1966) Metabolic and Endocrine Physiology, Year Book Medical Publishers Inc., Chicago. TUNBRIDGE, W. M. G., EVERED, D. C , HALL, R., APPLETON, D., BREWIS, M., CLARK, F.,
GRIMLEY EVANS, J., BIRD, T., SMITH, P. A., and YOUNG, E. (1977) Clinical Endocrinology, 7.
481^93. WEILLE, F. L. (1968) Archives of Otolaryngology, 87, 555.
560
D. A. MOFFAT, J. B. BOOTH AND A. W. MORRISON
WILLIAMS, H. L. (1952) Afeniere's Disease Edition 1, Springfield, Illinois, Charles C. Thomas. WILLIAMS, R. H. (1974) Textbook of Endocrinology 5th Edition, W. B. Saunders, Philadelphia, London, Toronto. Department of Otolaryngology, The London Hospital, Whitechapel, E.I.
A- 3
4-0 4-6 30. 2-3 30 2-8 2-0 3-5 40 20 5-1 40
30 30 80 10 2-6 4-5 3-4 3-5
1 hr. post glycerol
4-0 — 50 3-4 30
4-0 4-4 2-6 3-5 3-4 40 20
80 10 — 40 40 2-4
2-5
2 hrs. post glycerol
Patient's> initials are given merelyfor identification purposes. Change in PTA (pure tone audiogram) occurring a t two or more specific frequencies and measured in decibels. Change in speech discrimination is the percentage increase in the maximum discrimination score. AP/SP width refers to a measurement in milliseconds between the main descending and ascending limbs of the response at the level of the baseline (Figure 2).
40 50 3-6 20 6-5 46 3-5 4-7 60 50
3-25
40 6-5
25 10 15 15 18 10 40 15 10 13 15 20 25
DW CT SN VN ML EW LM CC BM PP CD JC MB nil nil nil nil nil 20 nil nil 10 nil nil nil 45
50 30 80 10 30 50 4-6 4-4
nil nil nil 24 nil 10 nil nil
10 nil ml nil nil 10 10 nil
15 12 15 18 40 15 12 25
IR DC AM MB AM PK DO EL
nil 30 nil nil nil nil nil nil nil nil 10 nil nil
Electrocochleography Width of AP/SP complex (ms) Pre-glycerol
Change in Speech discrimination (%)
Change in PTA (dB)
Change in Serum Osmolality mOsm/kg
Patient's Initials
APPENDIX
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Metabolic investigations in Meniere's disease Preliminary findings By DAVID A. MOFFAT,* JOHN B. BOOTH, and ANDREW W. MORRISON,
THE aetiology of Meniere's disease remains an enigma. Since Prosper Meniere first described the disease in 1861, a large volume of literature has accumulated on the subject. Despite this, the cause of the endolymphatic hydrops first demonstrated by Hallpike and Cairns in 1938 has not been discovered, although many attractive theories have been proposed. These include hypo- and hyper-metabolic states as well as allergy and personality type. Both hypo- and hyper-glycaemia have been said to result in inner ear dysfunction. The relationship between sensorineural deafness and diabetes mellitus was first described over 100 years ago by Jordaof (1857). Since that time much has been written not only concerning hearing loss but also labyrinthine dysfunction (Jorgensen and Buch, 1961), although the reported incidence varies greatly. Diabetic angiopathy resulting in hypoxaemia was thought to produce temporary and then permanent structural damage to the neuroepithelium. Progressive sensorineural hearing loss, sudden deafness (Hegener, 1908) or Meniere's syndrome (Rott, 1946; Jorgensen, 1961) may result. Weille (1968) reported that 42 per cent of a series of 19 patients with Meniere's disease were suffering from reactive hypoglycaemia compared with 15 per cent of a control group. Many of his patients noted a decrease in auditory acuity before meals, with a post-prandial improvement. The hearing also improved after the administration of glucose in the glucose tolerance test. These findings can be related to the small glycogen store in nerve tissues which makes them highly dependent on the blood glucose level. Insulin sensitivity, perhaps related to adrenal insufficiency, could account for the hypoglycaemia (Tepperman, 1966). Descriptions of hypothyroidism with hearing loss are legion and date back to the 13th. Century. Both congenital and acquired hearing loss may be related to hypothyroidism and several syndromes have been described. Means (1948) noted that hearing loss and vertigo may be amongst the first signs of myxoedema and are reversible with treatment. The reversibility of the hearing loss was mentioned by Batsakis and Nishiyama (1962) and * Presented this paper to the Section of Otology at the Royal Society of Medicine in March 1978. t quoted by Taylor and Irwin (1978). 545 IB
546
D. A. MOFFAT, J. B. BOOTH AND A. W. MORRISON
50 per cent of their patients improved after receiving thyroid extract. Poulsen (1966) observed that 40 per cent of his patients with classical myxoedema had a hearing loss and 66 per cent had vertigo. Histological studies of the acoustic and vestibular organs of patients with acquired myxoedema do not appear to have been reported but in endemic cretinism the hormonal dysfunction produces an increase in the ground substance content and hyaluronic acid and consequent expansion of connective tissue with ectatic changes in the semicircular canals and saccus endolymphaticus. Atrophy or deficient differentiation of the organ of Corti may occur with atrophic changes in the spiral ganglion. There is some evidence that hyperthyroidism may also produce a fluctuant hearing loss and vertigo (Permin and Poulsen, 1957). The relationship between hyperlipidaemia and inner ear dysfunction was noted as early as 1945 by Selfridge (quoted by Spencer, 1975). He suggested that Meniere's disease might depend on a disorder of the peripheral vascular system, (particularly the capillaries—Williams, 1952) and concluded that a lack of vitamin B complex might be responsible for a fatty liver, a high blood cholesterol level and a tendency towards vasospasm. Spencer (1973, 1975) has written extensively on hyperlipoproteinaemia in the aetiology of inner ear disease, proposing a correlation between the various metabolic abnormalities in Meniere's disease and hyperlipoproteinaemia since secondary causes of hyperlipoproteinaemia include myxoedema, nephrotic syndrome, diabetes, obesity and cigarette smoking. Patients with coronary artery disease may exhibit hyperglycaemia, glucose intolerance, exaggerated responses to glucose loading and hyperlipoproteinaemia and have a micro-angiopathy which may subside when the hyperlipidaemia is controlled. Related otological symptoms may resolve with the hyperlipidaemia. The possibility that allergic angioneurotic oedema might be one of the causes of endolymphatic hydrops was first considered by Quincke in 1893 (quoted by Shaver, 1975), but it was not until 1923 that Duke presented evidence for a specific allergic cause in Meniere's disease. Since that time further evidence has accumulated incriminating immediate hypersensitivity, where arteriolar spasm produces anoxia of the capillary loop and releases histamine which leads to dilatation and an increase in permeability (Williams, 1952). The subsequent increase in endolymph protein could produce hydrops, particularly in predisposed labyrinths where a degree of water imbalance already exists (Mygind and Dederding, 1938). Spasm of smooth muscle in branches of the internal auditory artery supplying the cristae and maculae will produce local anoxia and exacerbate the vertigo. Although atopy is thought to be common in these patients (Criep, 1939), it is the specific food allergies that have captured so much attention (Powers and House, 1969; Shaver, 1975). Clinically two types of food
METABOLIC INVESTIGATIONS IN MENIERE'S DISEASE
547
allergy were identified by Rinkel et al. (1951)—fixed food sensitivity and cyclic food sensitivity. In fixed food hypersensitivity the same symptoms occur each time the food is eaten. The degree of sensitization is not altered by ingestion or prolonged elimination of food. The problem is more complex in cyclic food allergy where the elimination of the food leads to tolerance or adaptation whilst frequent ingestion results in greater sensitization. Diagnosis is often difficult, however, especially from the history, since the symptoms of food allergy are often vague and include flatulence, fluid retention, post-prandial fatigue, epigastric discomfort, headaches and nausea (Shaver, 1975). Many foodstuffs have been mentioned including dairy produce, wheat, corn, meat and vegetables but there seems to be little agreement on the most common offending foods. Sensitivity to chocolate is an interesting example because it can also cause migraine (Criepj 1939) and the association between Meniere's disease and migraine has been well documented (Atkinson, 1943; Golding-Wood, 1960; Hinchcliffe, 1967). In 1966 Klockhoffand Lindblom used glycerol dehydration to produce significant hearing threshold shifts in cases of Meniere's disease with fluctuating hearing loss. Glycerol, a trivalent alcohol (1,2,3 Propanetriol) given in high doses is not completely metabolised and is an osmotic diuretic, being excreted in the urine. It is possible that the osmotic effects of the glycerol reduced the endolymphatic hydrops and intra-labyrinthine pressure (Bosher and Warren, 1971). Klockhoff and Lindblom employed 1-5 g/kg body weight of glycerol, although more recently they have used 1-2 g/kg body weight and regarded a 10 dB improvement in three adjacent octave bands of the pure tone audiogram or a 12 per cent increase in the maximum discrimination score of the speech audiogram as being a significant improvement. Transtympanic Electrocochleography (ECochG) is now a well established technique for recording the electrical events occurring within the cochlea and VHIth nerve, in response to various sound stimuli. It may be employed to study the electrophysiological changes occurring in disease states. The compound VHIth nerve action potential/summating potential (AP/SP) waveform has been shown to be widened in cases of Meniere's disease (Gibson and Beagley, 1976). This widening has been found to be due to an enhanced SP or 'SP-like' component. The summating potential (SP) is a multicomponent response representing the sum of various nonlinearities occurring within the cochlea, the exact source being a matter of conjecture. The non-linearity producing an increased negative SP in endolymphatic hydrops may be due to displacement of the cochlear partition and thus asymmetry in the mechano-electric phenomena associated with the hair cell stimulation. The negative enhancement of the SP represents a DC shift in the baseline (Figure 1) and this is thought to be responsible for the widening of the AP/SP complex in Meniere's disease. At the London Hospital, patients suffering from Meniere's disease have
548
D. A. MOFFAT, J. B. BOOTH AND A. W. MORRISON
A+B FIG. 1 Illustration of possible mechanism for enhanced negative SP in endolymphatic hydrops. A—DC shift in baseline of CM to upgoing clicks B—DC shift in baseline of CM to downgoing clicks A+B—DC shift in baseline alone displayed with CM subtracted.
recently been subjected to a series of investigations in an attempt to confirm or refute earlier work. The preliminary findings are presented. Patient Selection Twenty-seven patients were included in this initial study, 15 males and 12 females, with a mean age of 49-2 years (range 18-65 years). All patients were suffering from Meniere's disease, as defined by the Committee of Hearing and Equilibration of the American Academy of Ophthalmology and Otolaryngology (Alford, 1972). Full serological tests for syphilis, including the absorbed fluorescent treponemal antibody (FTA—ABS) and Treponema Pallidum haemagglutination (TPHA) tests were negative and tomograms of the internal auditory canals were normal. Audiometric findings indicated a recruiting hearing loss and the Hallpike-Fitzgerald caloric test usually revealed a variable degree of paresis. Sixteen patients (59 per cent) had all the classical manifestations of early Meniere's disease, including a fluctuating low frequency hearing loss. The disease was bilateral in four patients (15 per cent). Protocol for Metabolic Studies in Meniere's Disease Day 1 Patients were admitted in the afternoon and full clinical histories and examinations were carried out. They were given the Middlesex Hospital Questionnaire* and starved after supper from 9.00 p.m. Day 2 9.00 a.m.—Fasting blood was taken for glucose, cholesterol, triglycerides and thyroid stimulating hormone (TSH) estimations. 9.30 a.m.—A glucose tolerance test (GTT) was carried out. * Results to be published in a separate paper.
METABOLIC INVESTIGATIONS IN MENIERE'S DISEASE
549
Day 3 The patients were starved from midnight. 10.00 a.m.—Audiometric investigations including a pure tone audiogram, a speech audiogram, impedance studies and stapedial reflexes were then completed. —Blood and urine samples were obtained for preglycerol osmolality estimations. 11.00 a.m.—Baseline Transtympanic Electrocochleography (ECochG) was recorded. 11.30 a.m.—Oral glycerol 1-5 g/kg body weight was given to the patients. 11.30 a.m.—Continuous transtympanic electrocochleographic . to recordings were carried out, during glycerol dehydra1.30 p.m. tion. 1.30 p.m.—The audiometric investigations were repeated and blood and urine samples for post-glycerol osmolality estimations were collected. Method Prior to the glucose tolerance test patients were starved for 12 hours and had consumed a normal diet for 3 days before that. A standard 50 g glucose load was given and the blood and urine estimations were carried out over a 2\ hour period. Plasma glucose was determined, using an autoanalyser, by the glucose oxidase method. Patients were clinically assessed for thyroid dysfunction and also underwent an estimation of thyroid stimulating hormone (TSH). TSH levels were used because a rise is an early finding in the development of primary hypothyroidism (Mayberry et al. 1971) and may occur before the thyroxine level has fallen. The standard radioimmunoassay used was based on that described by Odell et al. (1965) using an MRC standard with a normal range in adults of 0-5, 6-10 being regarded as borderline in our laboratory. An assessment of serum cholesterol and triglycerides was carried out. Patients had previously eaten a normal diet and then fasted for 12 hours prior to the estimation. They had rested on a couch for at least 30 minutes and the blood was withdrawn without venous stasis. Normal values for our laboratory were:—Cholesterol—140-300 mg/100 ml (3-6-7-8 mmol/1) Triglycerides— 72-180 mg/100 ml (0-8-2-0 mmol/1) Evaluation of allergy both to common allergens and specific food allergens was by standard intradermal pin prick skin tests using allergens in glycero-saline (Table 1). A series of controls, matched for age and sex, were also tested. This test is a reliable method of assessing allergy and the IgE-mediated skin reaction consists of the classical urticarial type wheal.
550
D . A. MOFFAT, J. B. BOOTH AND A. W. MORRISON TABLE I INTRADERMAL PIN PRICK SKIN TESTS
Common Allergens
Specific Food Allergens
Control House dust mite Grass Pollen
Coffee Chocolate Milk (Cow) Mixed cheeses Egg yolk Egg white Maize grain Wheat grain Butter
=m1fdlyVpositive(lmmwheal)
Read as negative
++ = moderately positive (2mm wheal) +++ = strongly positive (3mm wheal) + + + + = very strongly positive (>3mm wheal)
Read as positive
+
In 21 of the 27 patients, continuous transtympanic electrocochleographic readings during glycerol dehydration were carried out, to study the electrophysiological changes occurring in the cochlea. Medelec-Amplaid Mk III evoked response audiometry (ERA) equipment was used. Adult patients were tested without sedation using the method of iontophoresis to anaesthetise the tympanic membrane (Ramsden et al., 1977). Patients were starved for 9 hours before the test. Prior to the electrocochleography, blood and urine samples were collected for osmolality estimations. A pure tone audiogram was recorded and then a speech audiogram using a Peters AP6 audiometer and Fry's phonetically balanced word lists (male voice). The electrodes were positioned with the patient lying comfortably in the supine position. A pre-glycerol recording was carefully made and particular attention paid to electrode contact and the consistency of the response. Iced lemon-flavoured glycerol 1-5 g/kg body weight was given to the patient orally via a pliable straw so that the fluid could be taken without moving the head position. The immediate post-glycerol response was then checked and the patients were monitored during the dehydration with full recordings to clicks and frequency-specific sine waves at one and two hours post-glycerol being made. In four patients the recordings were terminated at one hour because the patients were then uncomfortable. At the end of the test period the pure tone and speech audiograms were repeated and further blood and urine samples collected for post-glycerol osmolality estimations. Technical details of the electrocochleography and identification of the responses have been described in an earlier paper (Moffat et ah, 1978). In
METABOLIC INVESTIGATIONS IN MENIERE'S DISEASE
551
this series of patients the AP/SP complex and CM responses were noted throughout each recording. Changes in the SP during glycerol dehydration were observed more easily by using a subtraction technique whereby the SP was displayed largely uncontaminated by the AP (Moffat et ah, 1978). Some variation in the amplitude of the AP and CM (cochlear microphonic) occurred during the two-hour test period in some of the patients. This was possibly due to alteration in electrode contact. It was therefore felt that, under these circumstances, conclusions drawn from changes in the amplitude of the AP and SP should be guarded. However, the width and amplitude of the SP were easily assessed and, indeed, alteration of the SP was seen to modify the widened AP/SP complex considerably. In theory, accurate assessment of the negative SP may be obtained by measuring the amplitude in microvolts of the DC potential shift but this was found to be difficult practically even using the subtraction technique since there was always a small AP component within it. Since the widening of the AP/SP complex is proportional to the size of the SP, it was decided to measure changes in the width—W—of the SP in milliseconds (Fig. 2). Results The GTT results (Table II) were grouped according to the criteria of The British Diabetic Association (Fitzgerald and Keen, 1964). Normal AP/SP waveform (SP-shaded area)
Widened AP/SP waveform due to enhanced negative SP
W — width of AP/SP waveform in milli-seconds from onset of N i to point of return to baseline.
Ims
FIG.
2
552
D. A. MOFFAT, J. B. BOOTH AND A. W. MORRISON TABLE II RESULTS OF THE GLUCOSE TOLERANCE TESTS
27 Patients were tested 24 Patients had a normal GTT curve 0 Patients had a diabetic GTT curve 3 Patients (11 %) had a lag curve No patients had fasting hypoglycaemia (venous blood glucose of less than 40 mg/100 ml)
TABLE III RESULTS OF THE THYROID STIMULATING HORMONE ESTIMATIONS
27 Patients were tested 26 Patients had normal T.S.H. levels 1 Patient (3-7%) with high TSH level (68 Milli-units/litre) was clinically myxoedemic.
TABLE IV RESULTS OF SERUM CHOLESTEROL A N D TRIGLYCERIDES
15 male patients were tested 14 male patients had a normal lipid profile 1 male patient (6-6%) had primary hyperlipidaemia (W.H.O. Type II a) 12 female patients were tested 10 female patients had a normal lipid profile 1 female patient had hyperlipidaemia secondary to myxoedema (W.H.O. Type II b) 1 female patient (8%) had primary hyperlipidaemia (W.H.O. Type II b) None of the patients with primary hyperlipidaemia had abnormal GTT curves
TABLE V RESULTS OF PIN PRICK SKIN TESTS
Patient Reaction Negative 1 Positive 2 Positive 3 or more positive Total positive*
Control 20 5 1 1 7(26%)
Meniere's 22 2 2 1 5(18-5%)
* Barbee et al (1976) quote an incidence of 34 % of the general population with one or more positive allergens.
METABOLIC INVESTIGATIONS IN MENIERE'S DISEASE Allergen Reaction
Control
House dust mite Mixed grass pollens Coffee Chocolate Milk (Cow) Mixed cheeses Egg Yolk Egg White Maize grain Wheat grain Butter
3 5 0 0 0 1 0 0 0 1 1
3 2 2 0 0 1 0 0 0 0 0
11
8
Total
553
Meniere's
Results of the Glycerol Dehydration Tests and the Electrocochleographic Findings
In all patients included in the series, an increase in plasma osmolality of at least 10 mOsm/kg was noted. The mean change in plasma osmolality was 18-2 mOsm/kg (range 10-40 mOsm/kg). Patients were regarded as having had a significant change in the pure tone audiogram threshold (PTA) if it improved by 10 dB or greater at two or more audiometric frequencies. A significant change in the speech discrimination was taken as an improvement of 10 per cent or more in the maximum discrimination score. TABLE VI CHANGES IN PURE TONE THRESHOLD A N D SPEECH DISCRIMINATION FOLLOWING GLYCEROL DEHYDRATION
21 Patients were tested 1 Patient—significant change in PTA and speech discrimination 3 Patients—significant change in PTA alone 4 Patients—significant change in speech discrimination alone 13 Patients—no change in PTA or speech discrimination
= = = =
4- 8 % 14-3 % 19-0% 61-9%
Continuous transtympanic electrocochleographic recordings during the glycerol dehydration demonstrated a decrease in the negative SP (Figures 3, 4 and 5). TABLE VII TRANSTYMPANIC ELECTROCOCHLEOGRAPHY DURING GLYCEROL DEHYDRATION
'
21 Patients were tested 10 Patients—definite decrease ( > 1 ms) in width of AP/SP complex = 47- 6 % 4 Patients—possible decrease ( < lms) in width of AP/SP complex = 190% 7 Patients—no change in AP/SP complex = 33- 3 %
554
D. A. MOFFAT, J. B. BOOTH AND A. W. MORRISON
I
HOUR POST GLYCEROL
Serum osmolaliiy 280mOsm/Kg PURE
TONE
290m'lOsm/Kg
AUDIOGRAM
SPEECH — NO
125
2SO
500 1000 2000 FREQUENCY (Hi)
CHANGE
4000
FIG.
3
Marked decrease in the negative SP observed one hour after the administration of glycerol. The shaded area in the pure tone audiogram represents the increase in threshold. (S=stimulus onset) TABLE VIH ELECTROCOCHLEOGRAPHY COMPARED WITH PURE TONE AND SPEECH AUDIOMETRY
8 Patients (38%) 10 Patients (47-6%)
showed a significant change in PTA and/or speech discrimination following glycerol dehydration showed a definite decrease in the width of the AP/SP complex following glycerol dehydration.
O
46
PRE GLYCEROL
I HOUR
I I O d B 2sine waves 2kHz HL
Subtraction
t
H
AP
S
Serum osmolality 290 mOs m/Kg
PURE
POST GLYCEROL
technique
TONE
305 mOsim / K g
AUDIOGRAM
_]• Ims
SPEECH — NO CHANGE
FREQUENCY (Hi)
FIG. 4 A smaller decrease in the negative SP following glycerol dehydration than in Figure 3, the change in the width of the SP being more noticeable than the change in the amplitude. PRE
GLYCEROL
SUBTRACTION — Clicks
I HOUR
POST
GLYCEROL
1-45 HOURS POST GLYCEROL
100 dB HL
Serum oimoljht/
FIG. 5 Progressive decrease in the negative SP up to 1.45 hours post-glycerol.
556
D. A. MOFFAT, J. B. BOOTH AND A. W. MORRISON
Discussion and Conclusions
The unanswered question of whether Meniere's disease is a disease in its own right, or simply a symptom-complex, has puzzled and frustrated surgeons for many years. Mygind and Dederding (1932) stated tbat 'Meniere's disease is not a disease sui generis, but a typical reaction of a predisposed labyrinth to an almost infinite series of exo- and endo-genic influences, which have, however, this in common, that they express themselves through the vessels, especially the capillaries'. Many modern otologists concur with this view, believing that metabolic, allergic and psychosomatic factors can produce endolymphatic hydrops and, that when all of these entities have been discovered, Meniere's 'disease' will cease to exist. The vascular theory for the production of hydrops is used as a final common pathway for many of these metabolic states but proof for this is lacking and many basic questions pertaining to the normal physiology and pathophysiology remain to be answered. There were no diabetic GTT curves in this series compared with an incidence in the general population of 3 per cent. The 3 patients (11 per cent) aged 47, 58 and 60 respectively, who had lag curves, had 2-hour blood glucose levels of between 133-156 mg/100 ml. This is within the normal range since 20 per cent of patients over the age of 40 have 2-hour blood glucose levels in excess of 150 mg/100 ml (Williams, 1974). There was no fasting hypoglycaemia and no reactive hypoglycaemia, though to fully exclude the latter a 5-hour GTT is helpful (Powers, 1978). The incidence of reactive hypoglycaemia may be overestimated by some series in the literature, since 100 g of glucose has been used and this produces a higher incidence of reactive hypoglycaemia over 5 hours than is found with a standard 50 g load, though its significance is dubious (Marks, 1.974). The preliminary findings do not indicate an increased incidence of abnormal GTT curves compared with the general population. This is contrary to the findings of Shea and Kitabachi (1971) who quote an incidence of 57 per cent abnormal GTT curves in 70 Meniere's patients and Powers (1972) an incidence of 30 per cent (27 per cent hypoglycaemic, 3 per cent diabetic). The quoted incidence of hypothyroidism in patients of all ages in the general population varies considerably from series to series. Tunbridge et al. (1977) have quoted a figure of 0 08 per cent. One patient in this series was found to have hypothyroid levels of T.S.H. but the numbers are not great enough to conclude that there is an increased incidence of hypothyroidism in patients with Meniere's disease. Poulsen (1966) found that 12 per cent of Meniere's patients were hypothyroid. No patients in this group were clinically hyperthyroid or have developed clinical evidence of hyperthyroidism during a prolonged follow-up period. There was no increased incidence of byperlipidaemia in this group. Primary hyperlipidaemia was seen in 6-6 per cent of the male patieDts in this series which is considerably less than the 17 per cent in the local general population of men aged 20-69 years (Lewis et ah, 1974, North
METABOLIC INVESTIGATIONS IN MENIERE'S DISEASE
557
East London Survey). In the smaller female group 8 per cent had primary hyperlipidaemia which compares favourably with a figure of 8 per cent in the local general population aged 20-69 years. This in contrast to the findings of Spencer (1975), who found that 46-6 per cent of patients with symptoms of inner ear disease had hyperlipoproteinaemia but by no means all of his series had Meniere's syndrome and he was concerned with a different population. As far as allergy is concerned, considering both individual patient data and group data, the Meniere's group showed slightly less allergic phenomena than the control group. The only individual allergen which showed a marked difference between the two groups was coffee, to which 2 patients in the Meniere's group were positive compared with none in the control group. It should be noted, however, that only pin prick skin tests were carried out, since they are a reliable and sensitive method of assessing allergy. Bryans' modification of Black's cytotoxic food test (Bryan and Bryan, 1960), the serial dilution titration method of Rinkel (1963), the provocative skin food test of Lee et al. (1969) and the challenge feeding test (Rirtkel, 1934), were not utilised. Klockhoff and Lindblom's (1966) glycerol dehydration test was applied to twenty-one patients. The response to this test was measured by changes in the osmolality of the serum, the pure tone threshold of hearing, the maximum speech discrimination score and the width of the AP/SP (action potential/summating potential) complex. Using continuous transtympanic electrocochleographic recordings during glycerol dehydration, it was possible to demonstrate a marked decrease in the negative SP in many of the patients. It would seem possible that a decrease in the endolymphatic hydrops, secondary to glycerol dehydration, produces a movement of the basilar membrane towards the scala vestibuli, thus decreasing the asymmetry in the mechanoelectric phenomena associated with the hair cells. Alternatively, the effect of glycerol may decrease the endolymphatic potential primarily leading to a decreased negative SP. The fluctuant nature of the symptoms and signs, especially in the early stages of the disease, may be reflected in the differing (and sometimes normal) ECochG responses even before dehydration. At the present time the efficacy of conservative surgery for Meniere's disease is much debated. There is increasing evidence that surgical procedures on the endolymphatic sac can control the vertigo and stabilise or even improve the hearing threshold, but the mechanism is not clear and the selection of patients for this type of surgery is a practical problem. Shea (quoted by Klockhoff, 1975), suggested that a good response to glycerol dehydration was an indicator of a better prognosis in endolymphatic sac surgery. Morrison (1975) has shown, however, that saccus surgery is often beneficial, even in those patients without a fluctuating low tone hearing loss and showing a poor response to glycerol dehydration. Osmolality studies, it should be noted, were not carried out on all his
558
D. A. MOFFAT, J. B. BOOTH AND A. W. MORRISON
patients in that series, therefore there was no proof that significant dehydration had always occurred. The intercorrelation between the measures used to assess the response to glycerol dehydration and their predictive value in respect of the course of Meniere's disease or of any therapeutic procedure adopted in its management will become apparent in the future. Further studies are in progress, particularly to assess their reliability and validity. Summary
The aetiology of Meniere's disease is unknown but in recent years many theories have been advanced to explain the observed pathological changes. These include abnormal metabolic states, allergy and personality type. In an attempt to throw more light on this and to confirm or refute the earlier work we studied twenty-seven (fifteen male:twelve female) patients with Meniere's disease who conformed to the criteria set out by the Committee of Hearing and Equilibration of the American Academy of Ophthalmology and Otolaryngology (Alford, 1972). In this series the incidence of abnormal metabolic states was no higher than that of a comparable group in the general population. There was no significant difference in response to pin prick skin tests compared with a control group. Klockhoff and Lindblom's (1966) glycerol dehydration test was applied to twenty-one patients. The response to this test was measured by changes in the osmolality of the serum, the pure tone threshold of hearing and the maximum speech discrimination score. Continuous transtympanic electrocochleographic recordings during glycerol dehydration were carried out and in 10 patients there was a definite decrease in the negative sununating potential. An electrophysiological explanation for this has been put forward and the possible use of this measurement in the diagnosis and management of Meniere's disease has been discussed. The intercorrelation between these measures and their predictive value will become apparent in the future. Acknowledgements
We would like to thank Mr. P. McKelvie for allowing us to test his patients who formed part of the series. We are indebted to Dr. B. J. Boucher for her advice on the metabolic aspects. We are grateful to Dr. D. T. D. Hughes and Dr. D. W. Empey for their help with the allergy tests and to Mrs. McDonnell for patiently testing a matched series of controls. REFERENCES ALFORD, B. R. (1972) Transactions American Academy of Ophthalmology and Otolaryngology 76, 1462. ATKINSON, M. (1943) Annals of Internal Medicine, 18, 797.
METABOLIC INVESTIGATIONS IN MENIERE'S DISEASE
559
BARBEE, R. A., LEBOWITZ, M. D., THOMPSON, H. C , and BURROWS, B. (1976) Annals ofInternal
Medicine, 84, 129. BATSAKIS, J., and NISMYAMA, R. (1962) Archives of Otolaryngology, 76, 401. BOSHER, S. K., and WARREN, R. L. (1971) Journal of Physiology, 212, 739. BRYAN, W. J. K., and BRYAN, M. P. (1960) Laryngoscope, 70, 810-824. CRIEP, L. H. (1939) The Pennsylvania Medical Journal, 43, 258. DUKE, W. W. (1923) Journal of the American Medical Association, 81, 2179. FITZGERALD, M. G., and KEEN, H. (1964) Lancet, 1, 1325.
GIBSON, W. P. R., and BEAOLEY, H. A. (1976) Revue de Laryngologie, Otologie, Rhinologie 97, Supplement 53. GOLDING-WOOD, P. H. (1960) Journal of Laryngology and Otology, 74, 803. HALLPIKE, G. S., and CAIRNS, H. (1938) Journal of Laryngology and Otology, 53, 625. HEGENER, J. (1908) Zeitschrift Ohrenheilk, 55, 92. HINCHCLIFFE, R. (1967) Acta Otolaryngologica, 63, 384. JORGENSEN, M. B. (1961) Archives of Otolaryngology, 74, 373. JORGENSEN, M. B., and BUCH, N. H. (1961) Acta Otolaryngologica, 53, 350. KLOCKHOFF, I., and LINDBLOM, U. (1966) Acta Otolaryngologica, 61, 459. KLOCKHOFF, I. (1975) Otological Clinics of North America, Vol. 8, No. 2, 345. LEE, C. H., WILLIAMS, R. I., and BRINKLE, E. L. Jr. (1969) Archives of Otolaryngology, 90,87-94. LEWIS, B., WOOTTON, I. D. P., KRIKLER, D. M., FEBRUARY, A., CHAIT, A., OAKLEY, C. M.,
SIGURDSON, G., MAURER, B., and BIRKHEAD, J. (1974) Lancet, 1, 141.
MARKS, S. V. (1974) British Journal of Hospital Medicine, 731-743. MAYBERRY, W. E., GHARIB, H., BILSTAD, J. M., and SIZEMORE, G. W. (1971) Annals of Internal
Medicine, 74, 471-480. MEANS, T. H. (1948) Thyroid and its Diseases, 2nd Edition, Philadelphia, p. 231-234. MOFFAT, D. A., GIBSON, W. R. P., RAMSDEN, R. T., MORRISON, A. W., and BOOTH, J. B. (1978)
Acta Otolaryngologica, 85, 158. MORRISON, A. W. (1975) Endolymphatic Hydrops—in Management of Sensorineural Deafness, Chapter 5, 158. Butterworth & Co. Ltd. London. MYGIND, S. H., and DEDERDING, D. (1932) Acta Otolaryngologica, 17, 424. MYGIND, S. H., and DEDERDING, D. (1938) Annals of Otology, Rhinology and Laryngology, 47, 56. ODELL, W. D., WILBER, J. F., and PAUL, W. E. (1965) Metabolism, 14, 465-467.
PERMIN, P. M., and POULSEN, H. (1957) Acta Otolaryngologica, 47, 220. POULSEN, H. (1966) Thyrotropic and Thyroid Hormone Control of the Inner Ear with Special Reference to Myxoedema and Meniere's Disease—in Hormones and Connective Tissue by G. Asboe-Hansen, Baltimore. Williams & Wilkins Co. p. 239. POWERS, W. H., and HOUSE, W. F. (1969) Laryngoscope, 79, 1330.
POWERS, W. H. (1972) Laryngoscope, 82, 1716. POWERS, W. H. (1973) Transactions American Academy of Ophthalmology and Otolaryngology, 77, 22. POWERS, W. H. (1978) Laryngoscope, 88, 122. RAMSDEN, R. T., GIBSON, W. P. R., and MOFFAT, D. A. (1977) Journal of Laryngology and
Otology, 91, 779. RINKEL, H. L. (1934) Southern Medical Journal, 27, 630-633. RTNKEL, H. J., RANDOLPH, T. J., and ZELLAR, M. (1951) Food Allergy, Springfield, IHionois, Charles C. Thomas Publishers. RINKEL, H. J. (1963) Archives of Otolaryngology, 77, 42-75. ROTT, H. F. (1946) InJoblin, The Treatment of Diabetes Mellitus, 10th. Edition (Philadelphia). SHAVER, E. F. (1975) Archives of Otolaryngology, 101, 96. SHEA, J. T., and KITABACHI, A. E. (1971) Journal of Tennessee Medical Association, 64, 862. SPENCER, J. T. (1973) Laryngoscope, 83, 639. SPENCER, J. T. (1975) Otolaryngologic Clinics of North America, 8, 483. TAYLOR, I. G., and IRWIN, J. (1978) Journal of Laryngology and Otology, 92, 99. TEPPERMAN, J. (1966) Metabolic and Endocrine Physiology, Year Book Medical Publishers Inc., Chicago. TUNBRIDGE, W. M. G., EVERED, D. C , HALL, R., APPLETON, D., BREWIS, M., CLARK, F.,
GRIMLEY EVANS, J., BIRD, T., SMITH, P. A., and YOUNG, E. (1977) Clinical Endocrinology, 7.
481^93. WEILLE, F. L. (1968) Archives of Otolaryngology, 87, 555.
560
D. A. MOFFAT, J. B. BOOTH AND A. W. MORRISON
WILLIAMS, H. L. (1952) Afeniere's Disease Edition 1, Springfield, Illinois, Charles C. Thomas. WILLIAMS, R. H. (1974) Textbook of Endocrinology 5th Edition, W. B. Saunders, Philadelphia, London, Toronto. Department of Otolaryngology, The London Hospital, Whitechapel, E.I.
A- 3
4-0 4-6 30. 2-3 30 2-8 2-0 3-5 40 20 5-1 40
30 30 80 10 2-6 4-5 3-4 3-5
1 hr. post glycerol
4-0 — 50 3-4 30
4-0 4-4 2-6 3-5 3-4 40 20
80 10 — 40 40 2-4
2-5
2 hrs. post glycerol
Patient's> initials are given merelyfor identification purposes. Change in PTA (pure tone audiogram) occurring a t two or more specific frequencies and measured in decibels. Change in speech discrimination is the percentage increase in the maximum discrimination score. AP/SP width refers to a measurement in milliseconds between the main descending and ascending limbs of the response at the level of the baseline (Figure 2).
40 50 3-6 20 6-5 46 3-5 4-7 60 50
3-25
40 6-5
25 10 15 15 18 10 40 15 10 13 15 20 25
DW CT SN VN ML EW LM CC BM PP CD JC MB nil nil nil nil nil 20 nil nil 10 nil nil nil 45
50 30 80 10 30 50 4-6 4-4
nil nil nil 24 nil 10 nil nil
10 nil ml nil nil 10 10 nil
15 12 15 18 40 15 12 25
IR DC AM MB AM PK DO EL
nil 30 nil nil nil nil nil nil nil nil 10 nil nil
Electrocochleography Width of AP/SP complex (ms) Pre-glycerol
Change in Speech discrimination (%)
Change in PTA (dB)
Change in Serum Osmolality mOsm/kg
Patient's Initials
APPENDIX
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