Hyperbilirubinemia and Auditory Neuropathy/Auditory Dys-Synchrony: Interview with Frank Musiek, PhD
Douglas L. Beck, AuD, speaks with Dr. Musiek about the distinction and overlap of neuropathy/auditory dys-synchrony (AN/AD) and hyperbilirubinemia.
Academy: Hi, Frank. Thanks for your time today.
Musiek: Good morning, Doug. Nice to speak with you again.
Academy: Frank, I’d like to start by stating some of the basics about auditory neuropathy/auditory dys-synchrony (AN/AD) and hyperbilirubinemia just to make sure we’re all on the same page, and then ask you to comment on the two.
I guess the main audiologic attributes associated with AN/AD include hearing thresholds anywhere from normal to profound, absent or abnormal ABR, and typically present OAEs though there are exceptions. However, many authors have noted a lack of contralateral suppression for OAEs with AN/AD. Finally, AN/AD usually presents with poor word recognition scores, but not always. Is that about right?
Musiek: That’s correct. There can be considerable variability in the auditory findings as you have mentioned, which at times, makes things difficult to interpret. Let me state early on that I believe in AN as an entity, but its audiologic and anatomic understanding and classification needs further study and is open debate. In this brief discussion, let’s focus on only the term auditory neuropathy.
Academy: And recently, I read that perhaps up to 10 percent of all children with sensorineural hearing loss may have AN/AD?
Musiek: I read that, too. In my opinion, however, that’s over-estimated, even if one includes hyperbilirubinemia as a neuropathy, which I argue should not be the case.
Academy: Okay, glad I asked! And before moving on, I’ll just say a few words about hyperbilirubinemia. Hyperbilirubinemia is when there is too much bilirubin in the blood. When red blood cells break down, bilirubin is formed. Simply stated, it is generally processed by the liver, sent to the gut, and excreted. Sometimes because of immaturity or disease processes, the liver is compromised and it cannot rid itself of bilirubin. This causes a build up of the substance in the blood and tissues, e.g., hyperbilirubinemia. Bilirubin has pigment hence the yellowing of skin, eyes, etc. The key problem is that when there are high levels, bilirubin may get past the blood-brain barrier and damage nuclei in the central nervous system.
Further, bilirubin can interfere with ion exchange and nerve conduction and is in that respect, potentially neurotoxic. When neonates have highly elevated bilirubin, they may develop “kernicterus,” which is the end state of this pathology. Kernicterus/hyperbilirubinemia can actually stain the basal ganglia and nuclei of the brain including the auditory nuclei.
Musiek: That sounds about right, though I think it is generally free, unconjugated bilirubin that creates most of the problems, Doug.
Academy: Okay, so now that we’ve had a basic review, if you don’t mind, I’d like to jump right in and ask your thoughts as to the often-cited, but seldom discussed, relationship between auditory neuropathy/auditory dys-synchrony (AN/AD) and hyperbilirubinemia?
And if you don’t mind, let’s start with the 2003 article by Isabelle Rapin and Judy Gravel. I know Rapin and Gravel took issue with the term “auditory neuropathy” for a few reasons, such as “auditory neuropathy” implies a peripheral lesion, and so the term itself was likely anatomically incorrect, particularly if the site of lesion is the central auditory pathways or the brain stem, and they brought up other issues, too.
Musiek: Exactly. This is a subject that is very important and I think many people may have missed something here.
Therefore, I am happy to help clarify as best I can. In fact, Rapin and Gravel noted that hyperbilirubinemia is clearly a central disorder and when it impacts audition it impacts the central processes and has little to do with the auditory nerve. That’s the key take home point. The two can impact each other, they can co-exist, but they are absolutely of separate origin and one does not cause the other—unless there is retrograde degeneration from the cochlear nuclei to the auditory nerve.
Academy: And so auditory neuropathy in and of itself is actually a peripheral disorder?
Musiek: Yes, from at least one perspective. If you look in any medical or neurology textbook, neuropathy is defined as a peripheral nerve disorder—and as there is only one auditory nerve per ear, hence, the term “auditory neuropathy” implies dysfunction of the (peripheral) auditory nerve. If one defines this anatomically then it is clear AN means dysfunction and or pathology of only the auditory nerve. There could be an advantage to clarity by using an anatomical definition rather than defining it via test results which can be, as stated earlier, highly variable.
Academy: And separating AN/AD from hyperbilirubinemia is not a new concept, is it? Although people often toss the two together, but the essence of it is that one is a peripheral issue and the other is a central issue.
Musiek: Right. There’s nothing new here, there’s just history that’s been forgotten. AN/AD is a very rare peripheral disorder if you ascribe to AN being an auditory nerve disorder only—which is anatomically correct.
Going way back, in 1967, there was an important article in the literature by Raymond Carhart. He said that kernicterus (which you defined a few moments ago as essentially the pathological end-point of hyperbilirubinemia) is absolutely a central disorder, not a peripheral disorder. In 1976, William Dublin (a renowned auditory pathologist) wrote a monograph on the same topic and in 1986 he added a special issue of Archives of Otolaryngology saying essentially the same thing. Dublin showed that in cases of kernicterus, there was no observable cochlear damage, no inner or outer hair cell damage that they could find. However, he did demonstrate there was clear damage in the brainstem, vacuoles (areas of cell disappearance) primarily in the anterior ventral cochlear nucleus and often to spherical cells. However, there was little damage to the dorsal cochlear nucleus . Dublin and others also related that the damage was not only at the cochlear nucleus but other nuclei in the auditory pathway and brain. This is now well known (see Wennberg et al. 2006).
Academy: And why is the damage restricted to the brain, rather than the periphery?
Musiek: I can’t answer this entirely, but Rapin and Gravel emphasize the following and this may be a factor: the auditory nerve and the brain have two different types of myelin. The auditory nerve’s myelin is primarily from Schwann cells, whereas the brain’s myelin is oligodendritic myelin—and they are susceptible to different pathologies. Rapin clearly nailed this down and stated these are very different processes.
Hyperbilrubinemia is a disease of the central auditory nervous system, and AN is a disease of the peripheral auditory nervous system, including the auditory nerve.
Now, if there is enough damage to the cochlear nucleus (within the brain stem), there will be retrograde damage to the auditory nerve. Therefore, there could be damage to the auditory nerve but secondary damage.
So again, hyperbilirubinemia is not an auditory neuropathy as neuropathy is classically and anatomically defined. And importantly, she argued that when we use the term “auditory neuropathy” we should limit the discussion to disorders and disease of the auditory nerve, so as to be anatomically correct and that when the cochlear nucleus and more rostral structures are involved the term “central” should be used.
Academy: Makes perfect sense to me.
Musiek: Thanks. I would love to see us all use the same terms and definitions to describe these things—it would sure make it easier! We have gone from neuropathy to dysynchrony to spectrum disorder because there too many different disease processes and anatomical loci that we are trying to place under one roof.
Academy: Agreed. So again, the bottom line is auditory neuropathy/auditory dys-synchrony (AN/AD) and hyperbilirubinemia certainly can occur in-tandem, but they are not at all cause and effect.
Musiek: Well said. That is correct. By taking hyperbilirubinemia out of the AN mix, it may be a step that helps increase the consistency of audiologic findings, and be anatomically and medically correct.
Academy: Okay, thanks. Frank, it’s always a pleasure chatting with you, and thanks for your time and insight.
Musiek: My pleasure, Doug. Thanks for allowing me to address this issue.
For More Information, References, and Recommendations
Carhart R. (1967) Probable mechanisms underlying kernicteric hearing loss, Acta Otolaryngol. Supplement, 221.
Dublin W. (1976) Fundamentals of Sensorineural Auditory Pathology. Charles C. Thomas, Springfield, Ill.
Dublin, W. (1985) The cochlear nuclei pathology, Otolaryngol. Head and neck Surg. 93, 448-463.
Moller A., (2000) Hearing: Its Physiology and Pathophysiology, Academic Press, New York.
Rapin I, Gravel J. (2003) Auditory neuropathy physiologic and pathologic evidence calls for more diagnostic specificity, Int. J. Pedi. Otorhinolaryngol. 67, 707.
Wennberg R, Ahlfors C, Bhutani V, Johnson L, Shapiro S. (2006) Toward Understanding Kernicterus: A Challenge to Improve the Management of Jaundiced Newborns Pediatrics 117(2):474-485.
Frank Musiek, PhD, is the director auditory research at the NeuroAudiology Lab, Storrs University, Connecticut.
Douglas L. Beck, AuD, Board Certified in Audiology, is the Web content editor for the American Academy of Audiology.