Title: #More research is needed
Judged as uninformative by the British Medical Journal, the phrase “more research is needed” was banned from scientific articles in their issues. “More research is needed” is often the publishable version of we don’t know enough to draw definitive conclusions: I thought this title would aptly describe a column summarising recent research on Meniere’s disease (MD).
The journey begins with a study [A] by a Chinese group that investigated the electro-physiology behind the ototoxicity of Gentamicin (GM). We know that GM can be used to suppress vestibular cells (and the vertigo symptoms they produce) in subjects with intractable MD. But how?
Few studies in frogs have managed to show an effect of GM on calcium channels on the cell membrane, but, ultimately, the rule of thumb is: if a finding is not replicated in mammals, it may not apply to humans.
This study [A] used a guinea pig model (a mammal!) to shed light on how GM suppresses vestibular cells. Generally speaking, there are three main sites on the cell membrane that the GM can target: (1) the M2 mAChR, (2) the L-type Ca2+ channel, and (3) the BK channel. When these elements work fine, the cell can convey information to the brain, which can sometimes be noxious information that produces vertigos. The question this study poses is which site the GM actually uses. Via patch clamp technique - which allows measurement of tiny electrical activity near the membrane – it was possible to show that GM likely acts via L-type Ca2+ channel, which reduce the influx of calcium ions, thus blocking currents that propagate through BK channels. This is a first step towards a better understanding of GM’s active principles, which can in future lead to reduce its main potential side effect, hearing loss.
Study [B] by a group at John Hopkins, Baltimore – USA, looked into links between allergies and MD.
Let’s start with what they write last in their manuscript: “No known study to date has been published that examines the relationship between allergy and MD in the context of multivariate analysis”. That is to say, a connection between allergies and MD might exist, and might be used to improve the quality of life of MD sufferers; however, it might also just be a consequence of confounding factors – our apologies for taking your time!
Nonetheless, cross-sectional surveys have shown that the prevalence of a diagnosed allergy is about three times higher in MD subjects. Currently, there are several hypotheses that link allergic reactions to hydrops. Wheat has frequently been reported as food allergen, and isolated cases have been described where appropriate diets have resolved MD symptoms. Again, this is something that may have worked for some, but not for others. However, considering the relatively low risk to patients and low cost of the procedure, it is not unreasonable to include allergy avoidances plans for treatment of MD symptoms.
We recently had Dr Morrison give a beautiful talk at the past Meniere’s conference (the next one in October shouldn’t be missed!) and mentioning how endolymphatic sac decompression (ESD) is a safe and sometimes effective surgical technique. The review in [C] is a meta-analysis of nearly half a century worth of reports on ESD outcomes. Surely not every study included was methodically accurate, with confounding factors here and there, but in general the data suggests that sac decompression is effective at controlling vertigo in the short term (follow-up after 1 yr) and long term (>2 yr) in at least 75% of patients with intractable Meniere’s. The Mastoid shunt procedure was also quite effective, although the use of silastic sheets seemed to reduce slightly the long-term effect on vertigo control.
Also: I found the results from one (of the only two) fully-randomized studies included in the review very interesting, the study by Bretlau et al. (1989). In said study, about 70% of participants that had had ESC surgery experienced some relief, but so did the participants in the control group! Did MD subjects need ESD surgical intervention to alleviate their symptoms, or was it just as effective to have any intervention?
Next: if ESD has proven successful for intractable Meniere’s across studies that span the last few decades, a more recent study has shown that it might also be effective in preventing the Meniere’s from becoming bilateral. This is what Kitahara et al. tried to argue in a nice (yet non randomised) 5-year study [D]. In short, the group that received sac decompression was statistically less likely to develop bilateral MD. They speculate that this might be related to an overall reduction of plasma vasopressin levels following surgery. Other ways to reduce vasopressin levels is drinking plenty of water or avoiding bright light – which is often a treatment for Meniere’s anyway.
However, this study also showed that the ESD could prevent bilateral MD development only for subjects that already had “silent” endolymphatic hydrops in the contralateral ear, while it was non-effective for the group that did not have silent hydrops at first referral.
Of course, one question could be: how sensitive are our diagnostic tools when it comes to detect hydrops and/or silent hydrops? Not very, unfortunately, with sensitivities at approximately 60% for tests like those used in the study above (i.e., ECoG and G-test). Fortunately, there are more sophisticated techniques – e.g., high resolution MRI scanning with gadolinium and modified ABRs, that are quite promising (accuracies >90%). I will tell you more about these in future reviews.
Instead, let me conclude with study [E] that compared familial and sporadic MD (we also heard several good points about this from Dr Morrison). Two hundred and fifty Finnish sufferers of either sporadic or familial MD were scanned via questionnaires. It turned out that, while most symptoms were relatively quite similar across the two populations, a few others were not. First, familial MD subjects had more migraines, more severe hearing loss, and longer spells of vertigo. However, it is not clear why this should be the case – perhaps all symptoms are due to a common genetic abnormality? Second, a higher prevalence of autoimmune diseases was found in familial MD cases. This outcome, to some extent, could suggest that subjects with history of MD in their family may gain more benefit from steroid treatments. Finally, familial MD subjects reported onset of the disease about 5.6 yrs earlier than subjects with sporadic MD. It is possible, however, that the latter figure is due to the increased awareness of the condition in families that have history of MD, thus leading to earlier diagnoses.
That’s all for this first episode of More Research is Needed. Surely, we are still a long way from a complete understanding of Meniere's. After all, isn’t it true that MD teaches us the skill of patience ?
[A] Yu H. et al. (2014), “Gentamicin Blocks the ACh-Induced BK Current in Guinea Pig Type II Vestibular Hair Cells by Competing with Ca2+ at the L-Type Calcium Channel”, Int J Mol Sci (journal Impact Factor - IF 2.5)
[B] Weinreich, H.M., and Agrawal, Y. (2014), “The link between allergy and Meniere's disease”, Curr Opin Otolaryngol Head Neck Surg (IF 1.7)
[C] Sood, A.J. et al (2014), “Endolymphatic Sac Surgery for Meniere’s Disease: A Systematic Review and Meta-analysis”, J. Otol & Neurotol, (IF 2.0)
[D] Kitahara T. et al. (2014), “Does endolymphatic sac decompression surgery prevent bilateral development of unilateral Ménière disease?”, Laryngoscope (IF 2.0)
[E] Hietikko E. et al. (2014), “Higher prevalence of autoimmune diseases and longer spells of vertigo in patients affected with familial Meniere's disease -a clinical comparison of familial and sporadic Meniere's disease”, J Am Audiol, 2014 (IF 1.6)
SPiN Vol(Sept) 2014
Title: #Emerging diagnostic techniques
As promised in my previous post, this one will focus on emerging techniques to diagnose Meniere’s disease (MD). First, a general consideration we can all relate to: MD diagnoses are currently performed by exclusion. The diagnosis is often a line that connects two dots: a history of fluctuating hearing loss, and one or more documented vertigo attacks; in between, there are other symptoms such as aural fullness, dizziness or tinnitus. But before all the points are connected to lead towards a diagnosis of MD, other “measurable” diseases that can produce similar symptomatology, such as schwannomas or metabolic disorders, need to be excluded; this process is extremely time consuming and cause of distress.
Wouldn’t it be good to have an MD-sensitive test? Below I have summarised four recent studies that describe such a clinical tool.
The vestibular-evoked myogenic potential (VEMP) is an electrical activity that can be measured in response to acoustic stimuli, and is believed to be representative of the health status of the otoliths. Depending on electrode placement, one can measure cVEMPs (electrode on cervical muscle) or oVEMPs (extraocular muscle), which reflect saccule or utricule functions, respectively. VEMPs are not new, but it is a relatively recent application to use cVEMPs and eVEMPs to localize damages produced by the endolymphatic hydrops, often related to MD, and also to predict the amount of hearing loss that the subject might experience as the disease acerbates. Accuracy is not particularly high, but this might reflect a different sensitivity of the test for different types of MDs. It is probably conservative enough to say that including VEMPs in the battery of tests cannot hurt. For more on VEMPs, [A] would be an interesting reading.
Definitely very promising, but potentially also disappointing: Cochlear Hydrops Analysis Masking Procedures (CHAMPs). First described by Don et al. [B], the CHAMPs are auditory brain responses to masked click trains (sounds). By looking at a particular portion of the response, they noted that MD subject have a consistent pattern that allowed 100% sensitivity and specificity when differentiating them from control subjects. And this is the exciting and promising side. The other side of the coin is that recent studies have not been able to replicate Don et al.’s results – at least not with the incredibly high sensitivity and specificity. Pardon my repetitiveness, but more research is needed to further assess how reliable this diagnostic technique actually is.
Another promising diagnostic technique is described in [C] and termed Enhanced Vestibulo-Ocular Reflex (eVOR) to Electrical Vestibular Stimulation (EVS). One acronym at a time: the eVORs are automatic eye movements that stabilise images during head movements. The EVS is an electrical stimulation of the vestibular system that uses short galvanic currents with amplitudes in the order of tens of mA. When the vestibular systems are electrically stimulated via EVS, a phantom movement of the head is created that triggers the eVORs, i.e. the eyes will move accordingly. In [C], this mechanism was tested in MD and control subjects, with the hypothesis that the two groups would show different eVOR patterns. Indeed, all the 12 MD subjects reported abnormally high eVORs at high EVS, which could be regarded as an “unexpected” outcome at first: one would expect a damaged inner ear (in MD subjects) to produce smaller, not bigger signals than a healthy inner ear (control group). The authors’ interpretation is as follow: hydrostatic pressure build-up due to endolymphatic hydrops in MD subjects causes vestibular hair cell to be hypersensitive to the electrical stimulation, thus producing enhanced responses. However, the causative association between hydrops and MD still remains to be tested.
Another set of diagnostic techniques that rely on this association involves the use of high-resolution magnetic resonance imaging (MRI). MRI was initially used to exclude schwannomas or other retro-cochlear dysfunctions. Today, it is an excellent tool to quantify endolymphatic hydrops and observe potential abnormalities of the inner ear structure, and thus diagnose MD. While several other studies have compared different MRI imaging set ups (e.g., imaging sequence, contrast agent and delivery, etc.), in the study described in [D] one such technique (FYI, the “heavily T2-weighted FLAIR sequence with intratympanic gadolinum”) was used and compared against glycerol test and ECoG test in 20 subjects with definitive MD. Together, the glycerol and ECoG tests were positive 75% of the time (individually they were positive 55% and 60%, respectively). The high resolution 3T MRI, on the other hand, detected endolymphatic hydrops in nearly all of them (19/20). Admittedly, it is hard not to be positive about this technique, even though the absence of a control group in this study demands caution in interpreting the results (hopefully their MRI test would not be positive for the control group too??).
In sum, several promising approaches can lead to more accurate diagnoses of MD in the near future. Some techniques require refinements (e.g. VEMPs or eVOR), while others would benefit from further testing (e.g. CHAMPs or MRI), but this is all very encouraging. Writing this post made me so optimist that I almost forgot that, even with the best diagnostic tool at hand, we still have to answer the question of what to do next.
[A] Young Y-H. (2013), “Potential application of ocular and cervical vestibular-evoked myogenic potentials in Meniere's disease: A review”. The Laryngoscope (journal Impact Factor: 1.98)
[B] Don M. et al. (2005), “A Diagnostic Test for Ménière's Disease and Cochlear Hydrops: Impaired High-Pass Noise Masking of Auditory Brainstem Responses”. Otol Neurotol (IF 2.01)
[C] Aw S.T. et al, (2013), “Enhanced vestibulo-ocular reflex to electrical vestibular stimulation in Meniere's disease”. JARO (IF 2.95)
[D] Fukuoka et al. (2012), “Comparison of the diagnostic value of 3 T MRI after intratympanic injection of GBCA, electrocochleography, and the glycerol test in patients with Meniere’s disease”. Curr Otorhinolaryngol Rep (IF 2.27)