MEDICAL REPORTS

Meniere’s and hydropic inner ear disease

Meniere’s disease (MD) is a degenerative inner ear syndrome without a cure and defined by 3 major symptoms: episodic vertigo, tinnitus and sensorineural hearing loss with low and medium frequencies. It is a multifactorial, complex condition with great clinical heterogeneity and large differences in response to therapy. It is rare in children and manifests itself most often in midlife and has long been, but loosely associated with anxiety, depression and other psychological disturbances and personality disorders. Variations such as extreme vertigo or tinnitus types have been reported.

MD often clusters with immune disorders and is explained by an over accumulation of endolymph with increased pressure in the cochlear duct and outpouching in scala media (endolymphatic hydrops), which damages the organ of Corti. With limited or no access, the condition can be a diagnostic challenge with little by way of specific biomarkers, although endolymphatic hydrops can be visualised with MRI. However, with the inner ear having a unique immune response to protect irreplaceable hair cells, any spill over into blood for analysis post splenic phase can confuse the clinical picture. Decades of study and thousands of reports have implicated different pathways including immune complex deposits from circulating immune complexes in basement membranes from an antibody type Th2 response, molecular mimicry, complement activation, receptor dysfunction and neurological inflammation.This illness is currently identified via “diagnosis by exclusion” in which the condition is distinguished from others with overlapping symptoms by a process of elimination as it can also share symptoms with other disorders. There are many therapeutic options for MD, but none is considered effective by the scientific community.

Hydropic Inner Ear Disease:

Endolymphatic hydrops can be attributed to clinical variants with different mechanisms such as autoimmunity, auto-inflammation, aberrant response to viruses, diet, drugs and lifestyle factors with many other variables. Anatomical variation in morphology and the endolymphatic sac function is also a factor. The vast majority of cases are sporadic, although familial aggregation is now recognised. Experimental work under Prof Bill Gibson at Sydney University showed the long standing theory that inner ear membranes ‘rupture’ to cause symptoms is no longer tenable. Endolymphatic hydrops is an active process and a hydropic fistula between the compartmentalised pars inferior and pars superior with ionic imbalances and systemic impacts between compartments is regarded as the modern approach. This is born out by the astonishing fact that sensorineural hearing can be preserved after surgical removal of the semicircular canals. With inner ears being high metabolic consumers of ATP, homeostatic endolymphatic regulation is tightly controlled and calcium composition of vestibular endolymph is not the same as the cochlea, otherwise calcium carbonate would have trouble forming and maintaining otoconia. Studies show hypoxia, damaged stria vascularis and spiral ganglion and altered immune and stress response in MD. Hydrops is thus both a clinical marker and a mechanism of action. 

Gene Function in Hydropic Inner Ear Disease:

MD is largely sporadic, but a number of genes have been described in autosomal dominant families. Detailed phenotyping and cluster analyses have found several clinical predictors for different subgroups of patients, which indicate different mechanisms, including genetic and immune factors. Many mechanisms have been found to be involved in MD. For example, a pro-inflammatory immune response mediated by IL-1β, TNFα and IL-6, suggesting an auto-inflammatory process in some and an endophenotype found in 18% of patients with autoimmune MD defined by an NFκB-mediated inflammation in the carriers of the single nucleotide variant rs4947296. MD, hearing loss and tinnitus gene studies share a few common gene variations that map to structures in the inner ear and neuronal pathways. 

Other groups have found genetically diverse pathways where different systems involve discrete HLA classes and haplotypes. Yet others have uncovered gene determining redox and pentose phosphate pathways with other enzymopathies, meaning a log jam, a speeding up or slowing down to create inner ear dysfunction due to abnormal coding for particular proteins, notably when challenged with environmental insults and infectious antigen. The idea there is a single MD gene is thus not evident. What emerges from machine analysis of large datasets and bioinformatics processing is that MD manifests in people with a diverse set of subtle, but benign gene variations that, in and of themselves, do not cause endolymphatic hydrops. It is the discrete combinations in different ethnicities that predispose certain individuals to symptoms, and usually only under certain conditions or insults such as virus recrudesce. Thus endolymphatic hydrops is a common end point where acidification of endolymph can alter the immune response, endocochlea potential and hair cell function and manifest as the defining symptoms.  

Empowering Treatment with Genetic Data and Machine Analysis:

The Otogenex MD report is unique as it funnels decades of international study and data to one pipeline, and uses algorithms to compare the genetic sequence of an individual with MD symptoms to that known in the current literature for personalised, targeted treatments and better long term health outcomes. This breakthrough understanding of inner ear and genetic impacts using computer analysis has potential to guide treatment paths to halt or slow the usual degenerative process in MD, reduce or eliminate vertigo attacks and preserve existing hearing in preference to destructive surgery or inevitable assisted hearing technologies. Gene tests can form the foundation screen for diet and lifestyle modifications, serve as a catalyst for further tests or a referral on to another medical specialty with foundational information for further tests. Gene based reports have the potential to monitor patients more often, whilst preserving hearing and balance function for longer, with less intrusive treatments and greater long term patient-doctor relationships.

In time, pioneering gene therapies and treatments now in the pipeline can be assisted by genetic analysis and screening, with the potential of hearing restoration for some forms of MD. For some recent scientific papers on MD, go here. For comment on machine assisted diagnostics go here and on personalised, precision treatments in otolaryngology, go here and here.