Amazing progress has been made in providing useful hearing to hearing-impaired individuals using cochlear implants, but challenges remain. One such challenge is understanding the effects of partial degeneration of the auditory nerve, the target of cochlear implant stimulation. Here we review studies from our human and animal laboratories aimed at characterizing the health of the implanted cochlea and the auditory nerve. We use the data on cochlear and neural health to guide rehabilitation strategies. The data also motivate the development of tissue-engineering procedures to preserve or build a healthy cochlea and improve performance obtained by cochlear implant recipients or eventually replace the need for a cochlear implant.

Partial loss and subsequent recovery of cochlear implant function in the first few weeks following cochlear implant surgery has been observed in previous studies using psychophysical detection thresholds. In the current study, we explored this putative manifestation of insertion trauma using objective functional measures: electrically-evoked compound action potential (ECAP) amplitude-growth functions (ECAP amplitude as a function of stimulus level). In guinea pigs implanted in a hearing ear with good post-implant hearing and good spiral ganglion neuron (SGN) survival, consistent patterns of ECAP functions were observed. The slopes of ECAP growth functions were moderately steep on the day of implant insertion, decreased to low levels over the first few days after implantation and then increased slowly over several weeks to reach a relatively stable level. In parallel, ECAP thresholds increased over time after implantation and then recovered, although more quickly, to a relatively stable low level as did thresholds for eliciting a facial twitch. Similar results were obtained in animals deafened but treated with an adenovirus with a neurotrophin gene insert that resulted in good SGN preservation. In contrast, in animals implanted in deaf ears that had relatively poor SGN survival, ECAP slopes reached low levels within a few days after implantation and remained low. These results are consistent with the idea that steep ECAP growth functions require a healthy population of auditory nerve fibers and that cochlear implant insertion trauma can temporarily impair the function of a healthy SGN population.

In humans with cochlear implants, functional measures show considerable variation from one stimulation site to another along the electrode array. Our research has demonstrated that (1) the across-site patterns of the functional data are stable over time but differ across subjects; and (2) the across-site patterns are measure specific. These observations are consistent with the hypotheses that implant performance at a given stimulation site is dependent on specific conditions near the site, and that the various functional measures do not all depend on the same conditions. However, we lack direct evidence as to the specific conditions leading to the site-specific differences in performance in humans. Studies in our guinea pig laboratory and elsewhere have demonstrated highly significant correlations between psychophysical or electrophysiological measures of implant function and anatomical measures of cochlear health. Furthermore, the correlated anatomical features differ across functional measures. Finally, some functional measures that are correlated with anatomical measures of cochlear health in animals are predictive of speech recognition ability in human implant users. The data support efforts to preserve and/or restore the health of the implanted cochlea. [This work was supported by NIH/NIDCD grants R01 DC010786, R01 DC010412, and P30 DC05188, and a contract from MED-EL.]

Anaphylaxis is a sudden onset, immediate reaction that implies a risk of death. Think of a “rule of 2s” for anaphylaxis, which implies that reactions usually begin within 2 minutes to 2 hours after injection, infusion, ingestion, contact, or inhalation. Fatalities can be from asphyxiation from laryngeal or oropharyngeal swelling, collapse from hypotensive shock, cardiac arrest, or acute severe bronchoconstriction that causes respiratory failure and arrest. When there is activation of mast cells and basophils in anaphylaxis, chemical mediators are detectable. The preformed mediators from mast cells include histamine, tryptase, carboxypeptidase A, and proteoglycans (heparin, chondroitin sulfates). Newly synthesized mediators include prostaglandin D2, leukotriene D4, and platelet activating factor. Crucial actions of the mediators include an abrupt increase in vascular permeability, vascular smooth muscle relaxation, and bronchial smooth muscle contraction. Anaphylaxis can be classified into immunologic, nonimmunologic, or idiopathic based on the associated mechanism. For example, immunologic causes of anaphylaxis are those mediated by immunoglobulin E (IgE) antibodies acting through the FcεR I (foods, insect venom, 32 β-lactam antibiotics), whereas non-IgE immunologic anaphylaxis is mediated without the presence of anti-allergen IgE antibodies or via FcεRI activation (radiographic contrast material). Nonimmunologic anaphylaxis involves mast cell mediator release such as occurs with exercise or with cold temperature exposure, or from medications such as opioids or vancomycin. Idiopathic anaphylaxis involves mast cell activation (acutely elevated urine histamine or serum tryptase) and activated lymphocytes. Because anaphylaxis is a medical emergency, the drug of choice is epinephrine, not H1 antihistamines or H2 receptor antagonists.

Hypersensitivity pneumonitis (HP), also referred to as extrinsic allergic alveolitis, is characterized by non‐immunoglobulin E mediated inflammation of the parenchyma, alveoli, and terminal airways of the lung initiated by inhaled antigens in a susceptible host. Etiologic agents of HP are either organic high-molecular-weight compounds (e.g., bacteria, fungi, amoebae, plant and animal proteins) or inorganic low-molecular-weight haptens (e.g., isocyanates) and drugs (including amiodarone, nitrofurantoin, and minocycline). Six significant predictors have been identified that provide approximately 95% diagnostic accuracy. These six predictors are (1) exposure to a known offending allergen, (2) positive precipitating antibodies to the offending antigen, (3) recurrent episodes of symptoms, (4) inspiratory crackles on lung auscultation, (5) symptoms that occur 4‐8 hours after exposure, and (6) weight loss. HP is staged into acute, subacute, and chronic. In the acute stage, after direct exposure to the antigen, there are fever, chills, nonproductive cough, dyspnea, malaise, and myalgias, all of which resemble influenza. However, if obtained, a chest radiograph demonstrates nodular infiltrates, and pulmonary function testing is restrictive (unless the cause is avian, in which case, obstruction or obstruction with restriction is present). In the chronic stage, fever and chills are absent, but weight loss can occur. The immunologic response includes activated macrophages and CD8+ cytotoxic lymphocytes, and bronchoalveolar lavage fluid reveals marked lymphocytosis with a ratio of CD4+ to CD8+ cells of <1. Activated macrophages have increased expression of CD80/CD86, and T cells have increased expression of its counter-ligand, CD28, evidence for heightened antigen presentation.