Jean-Philippe Guyot

APRIL secreted by neutrophils binds to heparan sulfate proteoglycans to create plasma cell niches in human mucosa

The bone marrow constitutes a favorable environment for long-lived antibody-secreting plasma cells, providing blood-circulating antibody. Plasma cells are also present in mucosa-associated lymphoid tissue (MALT) to mediate local frontline immunity, but how plasma cell survival there is regulated is not known. Here we report that a proliferation-inducing ligand (APRIL) promoted survival of human upper and lower MALT plasma cells by upregulating expression of the antiapoptotic proteins bcl-2, bcl-xL, and mcl-1. The in situ localization of APRIL was consistent with such a prosurvival role in MALT. In upper MALT, tonsillar epithelium produced APRIL. Upon infection, APRIL production increased considerably when APRIL-secreting neutrophils recruited from the blood infiltrated the crypt epithelium. Heparan sulfate proteoglycans (HSPGs) retained secreted APRIL in the subepithelium of the infected zone to create APRIL-rich niches, wherein IgG-producing plasma cells accumulated. In lower MALT, neutrophils were the unique source of APRIL, giving rise to similar niches for IgA-producing plasmocytes in villi of lamina propria. Furthermore, we found that mucosal humoral immunity in APRIL-deficient mice is less persistent than in WT mice. Hence, production of APRIL by inflammation-recruited neutrophils may create plasma cell niches in MALT to sustain a local antibody production.

Adaptation to Steady-State Electrical Stimulation of the Vestibular System in Humans

Objectives: Efforts are being made toward the development of a vestibular implant. If such a device is to mimic the physiology of the vestibular system, it must first be capable of restoring a baseline or “rest” activity in the vestibular pathways and then modulating it according to the direction and velocity of head movements. The aim of this study was to assess whether a human subject could adapt to continuous electrical stimulation of the vestibular system, and whether it was possible to elicit artificial smooth oscillatory eye movements via modulation of the stimulation. Methods: One bilaterally deaf patient with bilateral vestibular loss received a custom-modified Med-E1 cochlear implant in which one electrode was implanted in the vicinity of the left posterior ampullary nerve. This electrode was activated with biphasic pulse trains of 400-μs phase duration delivered at a repetition rate of 200 pulses per second. The resulting eye movements were recorded with 2-dimensional binocular video-oculography. Results: Successive “on-off” cycles of continuous electrical stimulation resulted in a progressively shorter duration of the nystagmic response. Once the adapted state was reached upon constant stimulation, amplitude or frequency modulations of electrical stimulation produced smooth oscillatory conjugated eye movements. Conclusions: Although this is a case study of one patient, the results suggest that humans can adapt to electrical stimulation of the vestibular system without too much discomfort. Once the subject is in the adapted state, the electrical stimulation can be modulated to artificially elicit smooth eye movements. Therefore, the major prerequisites for the feasibility of a vestibular implant for human use are fulfilled.

Eye movements in response to electrical stimulation of the lateral and superior ampullary nerves.

Objectives: Recently, we demonstrated that it was possible to elicit vertical eye movements in response to electrical stimulation of the posterior ampullary nerve. In order to develop a vestibular implant, a second site of stimulation is required to encode the horizontal movements. Methods: Three patients with disabling Menieres disease were included in the study. Before a labyrinthectomy via a standard transcanal approach was performed, their lateral and anterior ampullary nerves were surgically exposed under local anesthesia through a procedure we recently developed. The attic was opened, the incus and malleus head were removed, and a small well was drilled above the horizontal portion of the facial nerve canal to place an electrode. This electrode was used to deliver balanced biphasic trains of electrical pulses. Results: The electrical stimuli elicited mainly horizontal nystagmus without simultaneous stimulation of the facial nerve. Conclusions: It is possible to stimulate electrically the lateral and superior ampullary nerves without simultaneous stimulation of the facial nerve. Because the nerves run close to each other, electrical stimulation provoked eye movements that were not purely horizontal, but also had some vertical components. Nevertheless, this site can be used to encode horizontal movements, because central adaptation may correct unnatural afferent vestibular cues delivered by a prosthetic sensor. The range of stimulus intensities that produced a response was broad enough for us to envision the possibility of encoding eye movements of various speeds.

Eye movements in response to electric stimulation of the human posterior ampullary nerve.

Objectives: The concept of a vestibular implant to restore balance, similar to that of a cochlear implant to restore hearing in deaf patients, has been investigated in animal models. It remains to be shown, however, that electric stimulation of the human end organ or its vestibular nerve branches is capable of eliciting a nystagmic eye movement response. Methods: Three subjects were given electric stimulation of their posterior ampullary nerve, which was surgically exposed under local anesthesia, by a procedure developed by Gacek. The stimulus was a multiphasic, charge-balanced train of electric pulses. Results: In all subjects, a pulse repetition rate of 200 pulses per second produced a robust vertical nystagmus without any apparent change in the slow component velocity of the preexisting horizontal nystagmus. Conclusions: We have been able to replicate in humans a finding somewhat similar to that of Suzuki and Cohen in monkeys for electric stimulation of the posterior semicircular canal. The similarity is an eye movement with a large, predominant vertical component. The difference is that we saw no horizontal response component, and were not able to measure a torsional response, because we used 2-dimensional video methods. In addition, we found a robust nystagmus with slow component velocities that are large enough to compensate for vertical head movements. This is an essential step in demonstrating the feasibility of a vestibular prosthesis using electric stimulation.

Mental transformation abilities in patients with unilateral and bilateral vestibular loss

Vestibular information helps to establish a reliable gravitational frame of reference and contributes to the adequate perception of the location of one’s own body in space. This information is likely to be required in spatial cognitive tasks. Indeed, previous studies suggest that the processing of vestibular information is involved in mental transformation tasks in healthy participants. In this study, we investigate whether patients with bilateral or unilateral vestibular loss show impaired ability to mentally transform images of bodies and body parts compared to a healthy, age-matched control group. An egocentric and an object-based mental transformation task were used. Moreover, spatial perception was assessed using a computerized version of the subjective visual vertical and the rod and frame test. Participants with bilateral vestibular loss showed impaired performance in mental transformation, especially in egocentric mental transformation, compared to participants with unilateral vestibular lesions and the control group. Performance of participants with unilateral vestibular lesions and the control group are comparable, and no differences were found between right- and left-sided labyrinthectomized patients. A control task showed no differences between the three groups. The findings from this study substantiate that central vestibular processes are involved in imagined spatial body transformations; but interestingly, only participants with bilateral vestibular loss are affected, whereas unilateral vestibular loss does not lead to a decline in spatial imagery.

Short- and long-term results of stapedotomy and stapedectomy with a teflon-wire piston prosthesis.

We analyzed the results of 604 cases of primary stapes surgery performed between 1974 and 1997 with replacement of the stapes by a 0.6- or 0.8-mm Schuknecht Teflon-wire piston. At long-term follow-up (1 to 21 years; mean, 7 years), the residual air-bone gap was 10 dB or less in 79% of the cases. The hearing results and postoperative complications were comparable to those reported by authors who used the same evaluation criteria. Although the aim of the surgery was to perform a small stapedotomy with a narrow footplate perforation (0.8 mm), a large stapedotomy or a stapedectomy was performed in 134 cases (22.2%) because of surgical or anatomic conditions. Our results show that the larger footplate perforations allowed a better correction of the air-bone gap at the lower frequencies. The ears with larger perforations did not show a higher incidence of sensorineural hearing loss.

Artificial balance: restoration of the vestibulo-ocular reflex in humans with a prototype vestibular neuroprosthesis

The vestibular system plays a crucial role in the multisensory control of balance. When vestibular function is lost, essential tasks such as postural control, gaze stabilization, and spatial orientation are limited and the quality of life of patients is significantly impaired. Currently, there is no effective treatment for bilateral vestibular deficits. Research efforts both in animals and humans during the last decade set a solid background to the concept of using electrical stimulation to restore vestibular function. Still, the potential clinical benefit of a vestibular neuroprosthesis has to be demonstrated to pave the way for a translation into clinical trials. An important parameter for the assessment of vestibular function is the vestibulo-ocular reflex (VOR), the primary mechanism responsible for maintaining the perception of a stable visual environment while moving. Here we show that the VOR can be artificially restored in humans using motion-controlled, amplitude modulated electrical stimulation of the ampullary branches of the vestibular nerve. Three patients received a vestibular neuroprosthesis prototype, consisting of a modified cochlear implant providing vestibular electrodes. Significantly higher VOR responses were observed when the prototype was turned ON. Furthermore, VOR responses increased significantly as the intensity of the stimulation increased, reaching on average 79% of those measured in healthy volunteers in the same experimental conditions. These results constitute a fundamental milestone and allow us to envision for the first time clinically useful rehabilitation of patients with bilateral vestibular loss.

The Modified Ampullar Approach for Vestibular Implant Surgery: Feasibility and Its First Application in a Human with a Long-Term Vestibular Loss

Objective: To assess, for the first time in a human with a long-term vestibular loss, a modified approach to the ampullae and the feasibility of evoking a VOR by ampullar stimulation. Materials and methods: Peroperative stimulation of the ampullae, using the ampullar approach, was performed under full anesthesia during cochlear implantation in a 21-year-old female patient, who had experienced bilateral vestibular areflexia and sensorineural hearing loss for almost 20 years. Results: The modified ampullar approach was performed successfully with as minimally invasive surgery as possible. Ampullar stimulation evoked eye movements containing vectors congruent with the stimulated canal. As expected, the preliminary electrophysiological data were influenced by the general anesthesia, which resulted in current spread and reduced maximum amplitudes of eye movement. Nevertheless, they confirm the feasibility of ampullar stimulation. Conclusion: The modified ampullar approach provides safe access to the ampullae using as minimally invasive surgery as possible. For the first time in a human with long-term bilateral vestibular areflexia, it is shown that the VOR can be evoked by ampullar stimulation, even when there has been no vestibular function for almost 20 years. This approach should be considered in vestibular surgery, as it provides safe access to one of the most favorable stimulus locations for development of a vestibular implant.

Anatomic and Functional Long-Term Results of Canal Wall-Down Mastoidectomy

The objective of this study was to evaluate, over the long term, the anatomic and functional outcome of canal wall-down mastoidectomy performed for chronic otitis media with cholesteatoma and chronic otomastoiditis resistant to all conservative treatment. The study was made through a retrospective review of 338 cases of consecutive primary canal wall-down mastoidectomies performed between 1974 and 1998. Included were 259 cases with sufficient data. In all cases, functional reconstruction was performed at the same time as the mastoidectomy. Demographic and clinical data were collected from each file. From the clinical data, the surgical techniques, complications, the number of follow-up visits necessary to ensure cavity cleanliness, details of care provided over the period 1 to 24 years (mean, 7 years) after the operation, and audiometric data from admission and from the latest postoperative follow-up were retained. Canal wall-down mastoidectomies were followed up an average of 10 times during the first 6 months after operation, twice a year over the 6-year period following surgery, and less than twice a year beyond the 6-year period. Care was dispensed for meatal stenosis, scars, infections, polyps, and beads of cholesteatoma. Surgical revisions were performed because of residual or recurrent cholesteatoma in 6.1% of the cases, because of perforation of the tympanic membrane in 7.3% of the cases, and to improve hearing in 12.2% of the cases. At the last consultation, 1 to 24 years after surgery, cavities were found to be dry and self-cleaning in 95% of the cases, and still humid, with otorrhea, in 5% of the cases. Over the long term, the hearing threshold remained unchanged in 41.3% of the cases. It was improved after surgery by 10 to 19 dB in 15.4% of the cases, by 20 to 29 dB in 11.5% of the cases, and by more than 29 dB in 3.8% of the cases. The hearing threshold was thus improved or at least remained unchanged in 72.0% of cases. Hearing losses occurred in 28% of the cases: by 10 to 19 dB in 11.9%, by 20 to 29 dB in 6.5%, and by more than 29 dB in 9.2% of the cases. A sensorineural hearing loss of more than 60 dB at all frequencies occurred immediately after the operation in 2 cases (0.7%). There was 1 case of facial paralysis (0.3%). Four patients (1.5%) complained of persistent vertigo. Canal wall-down mastoidectomy is an adequate treatment for chronic otitis with cholesteatoma or chronic otomastoiditis. The anatomic and functional results are satisfactory, and the rate of complications is acceptably low. A tympanoplasty can be performed simultaneously. Thus, for the large majority of patients, only a single intervention is required; however, a small minority can benefit from a revision tympanoplasty. In order to obtain these results, both the patient and the surgeon should engage in a long-term follow-up.

Measurement of dynamic visual acuity in patients with vestibular areflexia

Abstract Conclusion: The test is simple and sensitive enough to separate normal subjects from patients suffering from a vestibular loss. There was also a good correlation between the objective results and the subjective complaint of oscillopsia. Objectives: Oscillopsia (i.e. blurred vision while walking) is often reported by patients suffering from vestibular loss. We developed a test to quantify oscillopsia. Methods: Visual acuity was determined in 16 normal subjects and in 8 patients suffering from a bilateral vestibular loss, at rest and while walking at increasing speed on a treadmill. Snellen optotypes were randomly projected on a screen and the visual acuity was determined with an adaptative staircase algorithm. Results: In normal subjects, the visual acuity did not decrease markedly during walking, but decreased significantly in patients with a vestibular loss.