Homozygous and compound heterozygous mutations in the ATP6V1B1 gene in patients with renal tubular acidosis and sensorineural hearing loss.

Distal renal tubular acidosis (dRTA) is characterized by the inability to excrete acid in the renal collecting ducts resulting in inappropriately alkaline urine and hyperchloremic (normal anion gap) metabolic acidosis in the context of a normal (or near-normal) glomerular filtration rate. Inborn dRTA can be due to autosomal dominant or recessive gene defects. Clinical symptoms vary from mild acidosis, incidental detection of kidney stones or renal tract calcification to severe findings such as failure to thrive, severe metabolic acidosis, and nephrocalcinosis. The majority of patients with recessive dRTA present with sensorineural hearing loss (SNHL). Few cases with abnormal widening of the vestibular aqueduct have been described with dRTA. Mutations in three different genes have been identified, namely SLC4A1, ATP6V1B1, and ATP6V0A4. Patients with mutations in the ATP6V1B1 proton pump subunit develop dRTA and in most of the cases sensorineural hearing loss early in childhood. We present two patients from two different and non-consanguineous families with dRTA and SNHL. Direct sequencing of the ATP6V1B1 gene revealed that one patient harbors two homozygous mutations and the other one is a compound heterozygous. To our knowledge, this is the first case in the literature describing homozygosity in the same dRTA gene on both alleles.

[The eye, vision and vertigo]. / Auge, Sehen und Schwindel.

Although ocular alterations alone rarely cause vertigo, the ophthalmologist can play an important role in the interdisciplinary context by testing visual function. Assessment of ocular motility is the most important individual examination in the diagnostic evaluation of vertigo. Methods that analyze specific visual functions, like the dynamic visual acuity test, may play an important role in the future. In addition to neuro-ophthalmologic disorders, ocular alterations are also receiving increasing attention. They are postulated to be a key element in the development of multifactorial age-related vertigo. However, further investigation is required to confirm this supposition and to define the influence of disturbances in specific visual qualities, e.g. visual acuity, visual field, binocular vision, anisometropia, multifocal correction, higher order aberrations and metamorphopsia.

Extraintestinal Crohn's disease mimicking autoimmune inner ear disease: a histopathological approach.

Patients with autoimmune inner ear disease develop rapidly progressive sensorineural hearing loss over a period of several weeks or months, often accompanied by vestibular loss. This disease can occur as a distinct clinical entity or in association with an underlying autoimmune disorder. Treatment comprises immunosuppression by corticosteroids, cytostatic drugs or tumor necrosis factor-α antagonists. We report histopathological and immunohistochemical findings of the inner ear of a patient with a granulomatous inner ear disease suffering from Crohn's disease that was nonresponsive to treatment and who underwent surgery for bilateral cochlear implants.

Otoconial loss or lack of otoconia - An overlooked or ignored diagnosis of balance deficits.

HYPOTHESIS: Lack of otoconia or otoconial loss may be the major reason for increasing imbalance with age, posttraumatic dizziness and residual dizziness as well as other so far unexplained imbalance affecting probably millions of people. BACKGROUND: It is written in every textbook that we need sensation of gravity for stable gait and stance, especially on two legs. Lack of otoconia is known to cause lifelong balance problems in animals. Loss of otoconia is happening in aging humans, like shown by increasing incidence of benign paroxysmal positional vertigo (BPPV) and in histological sections. While hundreds of papers have been published on BPPV, increasing imbalance with age and increasing falls, none has ever described the loss of otoconia as a major reason for this imbalance. Maybe this is due to the problems to proof this hypothesis in an individual patient. We will explain why otoconial loss may cause dizziness, postural and locomotor instability in patients with no other identifiable cause or in addition to other causes. Several reasons can cause otoconial loss and lead to the described symptoms. We will describe the symptoms and the tests which could in combination support the diagnosis. CONCLUSION: Our hypothesis argues for the new diagnosis in many patients with so far undiagnosed or incorrectly or incompletely diagnosed dizziness or imbalance.

Alexander's law in patients with acute vestibular tone asymmetry--evidence for multiple horizontal neural integrators.

Alexander's law (AL) states that the slow-phase velocity of spontaneous nystagmus of peripheral vestibular origin is dependent on horizontal gaze position, with greater velocity when gaze is directed in the fast-phase direction. AL is thought to be a compensatory reaction resulting from adaptive changes in the horizontal ocular motor neural integrator. Until now, only horizontal eye movements have been investigated with respect to AL. Because spontaneous nystagmus usually includes vertical and torsional components, we asked whether horizontal gaze changes would have an effect on the 3D drift of spontaneous nystagmus and, thus, on the vertical/torsional neural integrator. We hypothesized that AL reduces all nystagmus components proportionally. Moreover, we questioned the classical theory of a single bilaterally organized horizontal integrator and searched for nonlinearities of AL implying a network of multiple integrators. Using dual scleral search coils, we measured AL in 17 patients with spontaneous nystagmus. Patients followed a pulsed laser dot at eye level jumping in 5 degrees steps along the horizontal meridian between 25 degrees right and left in otherwise complete darkness. AL was observed in 15 of 17 patients. Whereas individual patients typically showed a change of 3D-drift direction at different horizontal eye positions, the average change in direction was not different from zero. The strength of AL (= rate of change of total velocity with gaze position) correlated with nystagmus slow-phase velocity (Spearman's rho = 0.5; p < 0.05) and, on average, did not change the 3D nystagmus drift direction. In general, eye velocity did not vary linearly with eye position. Rather, there was a stronger dependence of velocity on horizontal position when subjects looked in the slow-phase direction compared to the fast-phase direction. We conclude that the theory of a simple leak of a single horizontal neural integrator is not sufficient to explain all aspects of AL.

Vestibular and auditory deficits in Fabry disease and their response to enzyme replacement therapy.

Progressive hearing (pHL) and vestibular (pVL) loss are frequent deficits in Fabry disease (FD). Recently, enzyme replacement therapy (ERT) with human alpha-galactosidase A has become available. Here, we investigate the association between pHL and pVL in FD and their ERT responses. Pure tone audiometry (PTA) and head impulse testing (HIT) were administered at baseline in 47 patients (25 male, 18-60 y; 22 female, 17-74 y), of whom 24 also received caloric irrigation (CI). Of the 47 patients, 38 (24 male) were tested both before and during ERT (follow- up < or = 60 months). ERT consisted of agalsidase alfa infusions. At baseline, pHL was present in 88% of males and 86% of females. Over all tested frequencies (range: 0.5-6 kHz), pHL was significantly (two-way ANOVA: p < 0.05) greater at higher age and in males,with largest deficits at high frequencies. When assessed with HIT, 80% of males and 77% of females had pVL. pVL was significantly greater at higher age and in males. Tested with CI, 21% of males and 0% of females had pVL. No associations among individual semicircular canal (SCC) deficits, as tested by HIT, and hearing was observed in individual ears. After > or = 18 months of ERT, pVL was significantly smaller than at baseline (ANOVA for HIT: p < 0.01). In contrast, pHL remained unchanged by ERT over 60 months (p > 0.05). We conclude that pHL and pVL prevalences are similar in FD. To detect pVL, HIT is more sensitive than CI. We speculate that pHL and pVL emerge from lesions within the vestibulocochlear labyrinth, because no specific patterns of vestibulo-cochlear deficits were observed, as expected if lesions were more proximal along the inferior or superior branch of the vestibulo-cochlear nerve or labyrinthine artery. Finally, ERT stabilizes auditory and even improves vestibular function.

Compensatory saccades in head impulse testing influence the dynamic visual acuity of patients with unilateral peripheral vestibulopathy1.

BACKGROUND: Both the dynamic visual acuity (DVA) test and the video head-impulse test (vHIT) are fast and simple ways to assess peripheral vestibulopathy. After losing peripheral vestibular function, some patients show better DVA performance than others, suggesting good compensatory mechanisms. It seems possible that compensatory covert saccades could be responsible for improved DVA. OBJECTIVE: To investigate VOR gain and compensatory saccades with vHIT and compare them to the DVA of patients with unilateral peripheral vestibulopathy. METHODS: VOR gain deficit and compensatory saccades were measured with vHIT. VOR gain was calculated for each trial as mean eye velocity divided by mean head velocity during 4 samples between 24 ms - 40 ms after peak head acceleration. DVA was then assessed. VHIT was analyzed for percentage of covert saccades and for cumulative overt saccade amplitude. Twenty-four patients with unilateral vestibular deficit were included. A control group of 113 healthy subjects provided normal data. RESULTS: On the affected side, pathologic values for DVA (mean 0.83 logMAR±0.25 SD) and VOR gain (mean 0.16±0.13) were obtained, whereas the healthy side showed normal values (0.53 logMAR±0.15 for DVA and 0.89±0.18 for VOR gain). Yet, DVA performance on the affected side was significantly better in patients with higher covert saccade percentage (p = 0.012) and lower cumulative overt saccade amplitude (p < 0.001). CONCLUSION: Compensatory covert saccades seen in vHIT correlate with improved performance of DVA-testing in patients with unilateral peripheral vestibular loss. Hence, in addition to testing peripheral vestibulopathy, our results indicate a way for assessing rehabilitatory compensation in such patients by DVA in addition to vHIT.

Disinhibition of somatosensory and motor cortex in mitochondriopathy without myoclonus.

OBJECTIVE: To test electrophysiologically, if patients with mitochondriopathy but without evidence of myocloni have subclinical signs of disinhibition in motor and somatosensory cortices. METHODS: Two patients were studied and compared with age-matched control groups. RESULTS: In both patients, giant somatosensory evoked potentials after median nerve stimulation and a reduced intracortical inhibition tested by transcranial magnetic stimulation in a paired pulse paradigm indicated a dysfunction of inhibitory circuits in the motor as well as the somatosensory cortex. In addition, the somatosensory evoked 600 Hz activity recorded by magnetoencephalography was abolished. CONCLUSIONS: Patients with mitochondriopathy may suffer from a subclinical disturbance of inhibition in the sensorimotor cortex. The loss of 600 Hz activity indicates that these high-frequency oscillations could reflect the activity of inhibitory neurons in the somatosensory cortex.

Drug-induced nonconvulsive status epilepticus with low dose of tiagabine.

In placebo-controlled trials, the overall incidence of nonconvulsive status epilepticus was no higher in the tiagabine-treated group than in the placebo-group. Case reports of nonconvulsive status epilepticus under tiagabine suggested a specific role of dose levels, since in these patients symptoms occurred mostly at 40 mg/day or higher. We report a case of complex partial status epilepticus in a patient receiving a low dose of tiagabine and review all 11 case reports of nonconvulsive status epilepticus in patients on tiagabine, with regard to daily doses. Our analysis suggests an individual risk threshold of unknown aetiology.

Adaptation of the phase of the human linear vestibulo-ocular reflex (LVOR) and effects on the oculomotor neural integrator.

The phase of the translational linear VOR (LVOR) can be adaptively modified by exposure to a visual-vestibular mismatch. We extend here our earlier work on LVOR phase adaptation, and discuss the role of the oculomotor neural integrator. Ten subjects were oscillated laterally at 0.5 Hz, 0.3 g peak acceleration, while sitting upright on a linear sled. LVOR was assessed before and after adaptation with subjects tracking the remembered location of a target at 1 m in the dark. Phase and gain were measured by fitting sine waves to the desaccaded eye movements, and comparing sled and eye position. To adapt LVOR phase, the subject viewed a computer-generated stereoscopic visual display, at a virtual distance of 1 m, that moved so as to require either a phase lead or a phase lag of 53 deg. Adaptation lasted 20 min, during which subjects were oscillated at 0.5 Hz/0.3 g. Four of five subjects produced an adaptive change in the lag condition (range 4-45 deg), and each of five produced a change in the lead condition (range 19-56 deg), as requested. Changes in drift on eccentric gaze suggest that the oculomotor velocity-to-position integrator may be involved in the phase changes.

Detection and grading of endolymphatic hydrops in Menière disease using MR imaging.

BACKGROUND AND PURPOSE: Endolymphatic hydrops has been recognized as the underlying pathophysiology of Menière disease. We used 3T MR imaging to detect and grade endolymphatic hydrops in patients with Menière disease and to correlate MR imaging findings with the clinical severity. MATERIALS AND METHODS: MR images of the inner ear acquired by a 3D inversion recovery sequence 4 hours after intravenous contrast administration were retrospectively analyzed by 2 neuroradiologists blinded to the clinical presentation. Endolymphatic hydrops was classified as none, grade I, or grade II. Interobserver agreement was analyzed, and the presence of endolymphatic hydrops was correlated with the clinical diagnosis and the clinical Menière disease score. RESULTS: Of 53 patients, we identified endolymphatic hydrops in 90% on the clinically affected and in 22% on the clinically silent side. Interobserver agreement on detection and grading of endolymphatic hydrops was 0.97 for cochlear and 0.94 for vestibular hydrops. The average MR imaging grade of endolymphatic hydrops was 1.27 ± 0.66 for 55 clinically affected and 0.65 ± 0.58 for 10 clinically normal ears. The correlation between the presence of endolymphatic hydrops and Menière disease was 0.67. Endolymphatic hydrops was detected in 73% of ears with the clinical diagnosis of possible, 100% of probable, and 95% of definite Menière disease. CONCLUSIONS: MR imaging supports endolymphatic hydrops as a pathophysiologic hallmark of Menière disease. High interobserver agreement on the detection and grading of endolymphatic hydrops and the correlation of MR imaging findings with the clinical score recommend MR imaging as a reliable in vivo technique in patients with Menière disease. The significance of MR imaging detection of endolymphatic hydrops in an additional 22% of asymptomatic ears requires further study.

Quantitative analysis of benign paroxysmal positional vertigo fatigue under canalithiasis conditions.

In our daily life, small flows in the semicircular canals (SCCs) of the inner ear displace a sensory structure called the cupula which mediates the transduction of head angular velocities to afferent signals. We consider a dysfunction of the SCCs known as canalithiasis. Under this condition, small debris particles disturb the flow in the SCCs and can cause benign paroxysmal positional vertigo (BPPV), arguably the most common form of vertigo in humans. The diagnosis of BPPV is mainly based on the analysis of typical eye movements (positional nystagmus) following provocative head maneuvers that are known to lead to vertigo in BPPV patients. These eye movements are triggered by the vestibulo-ocular reflex, and their velocity provides an indirect measurement of the cupula displacement. An attenuation of the vertigo and the nystagmus is often observed when the provocative maneuver is repeated. This attenuation is known as BPPV fatigue. It was not quantitatively described so far, and the mechanisms causing it remain unknown. We quantify fatigue by eye velocity measurements and propose a fluid dynamic interpretation of our results based on a computational model for the fluid-particle dynamics of a SCC with canalithiasis. Our model suggests that the particles may not go back to their initial position after a first head maneuver such that a second head maneuver leads to different particle trajectories causing smaller cupula displacements.

Visual contribution to postural stability: Interaction between target fixation or tracking and static or dynamic large-field stimulus.

Stationary visual information has a stabilizing effect on posture, whereas moving visual information is destabilizing. We compared the influence of a stationary or moving fixation point to the influence of stationary or moving large-field stimulation, as well as the interaction between a fixation point and a large-field stimulus. We recorded body sway in 20 healthy subjects who were fixating a stationary or oscillating dot (vertical or horizontal motion, 1/3 Hz, +/-12 degrees amplitude, distance 96 cm). In addition, a large-field random dot pattern (extension: approximately 80 x 70 degrees) was stationary, moving or absent. Visual fixation of a stationary dot in darkness did not reduce antero-posterior (AP) sway compared to the situation in total darkness, but slightly reduced lateral sway at frequencies below 0.5 Hz. In contrast, fixating a stationary dot on a stationary large-field pattern reduced both AP and lateral body sway at all frequencies (0.1-2 Hz). Ocular tracking of the oscillating dot caused a peak in body sway at 1/3 Hz, i.e. the stimulus frequency, but there was no influence of large-field stimulus at this frequency. A stationary large-field pattern, however, reduced AP and lateral sway at frequencies between 0.1 and 2 Hz when subjects tracked a moving dot, compared to tracking in darkness. Our results demonstrate that a stationary large-field pattern has a stabilizing effect in all conditions, independent of whether the eyes are fixing on a stationary target or tracking a moving target.

Hearing loss in Fabry disease: data from the Fabry Outcome Survey.

Hearing loss is a common symptom in Fabry disease, but neither its natural course nor its aetiology has been defined precisely. The aim of this study was to provide a detailed epidemiological description of hearing impairment in patients in the Fabry Outcome Survey (FOS), which is the largest available database of Fabry patients. Questionnaires were completed by 566 Fabry patients, of whom 316 reported ear-related symptoms. Pure-tone audiograms from 86 patients, performed before starting enzyme replacement therapy, were analysed and compared with age- and sex-specific normal values (International Organization for Standardization, ISO 7029). When compared to an age-matched population (ISO 7029), 74% of patients had a threshold elevated above the 95th centile in at least one tested frequency. All frequencies were affected to a similar degree. However, only 14 patients (16%) were clinically affected by hearing impairment according to the age-independent World Health Organization (WHO) classification (mean threshold at 0.5, 1 and 2 kHz worse than 25 dB). Hearing loss was sensorineural in 63 patients (73%) of whom 7 patients (8%) had also a conductive component. One patient had a purely conductive hearing loss. Episodes of sudden hearing loss seemed to occur more frequently than in the general population. Men were affected earlier and more severely than women. Hearing in Fabry disease is significantly worse than in an age-matched general population but leads to clinically relevant hearing impairment in only 16% of cases. It resembles accelerated presbycusis with an additional Fabry-specific strial-type hearing loss.

Agalsidase alpha and hearing in Fabry disease: data from the Fabry Outcome Survey.

Fabry disease is an X-linked lysosomal storage disorder characterized by multi-organ dysfunction, including hearing loss - mainly sensorineural. The recent introduction of enzyme replacement therapy (ERT) has resulted in improvements in renal and cardiac function, pain and quality of life. One study has also suggested small improvements in high-frequency hearing. In this paper, we study the effect of ERT on hearing in patients in the Europe-wide database - the Fabry Outcome Survey (FOS). Twenty-six patients in FOS had pure-tone audiometry performed up to 6 months before starting ERT with agalsidase alpha and after a median of 12 months of treatment. We assessed changes in hearing thresholds, expressed as deviations from the 50th centile of the normal population (International Organization for Standardization ISO 7029) to correct for age-related non-specific hearing deterioration. Hearing did not change significantly in ears with normal hearing (less than 10 dB deviation from the 50th centile of ISO 7029) or those with severe hearing loss (more than 40 dB deviation from the 50th centile of ISO 7029) at baseline. In ears with a mild or moderate hearing loss at baseline, hearing thresholds, expressed as deviations from the normal 50th centile, improved significantly by 4-7 dB at most frequencies (P < 0.05). Agalsidase alpha stabilizes, and possibly improves, hearing in Fabry patients who have not already progressed to severe hearing loss. Further follow-up of these patients will determine the longer-term effects of ERT.

[Kirschner wire migration in the contralateral lung after osteosynthesis of a clavicular fracture]. / Kirschner-Draht-Migration in die kontralaterale Lunge nach Klavikulafraktur-Osteosynthese.

A 59-year-old patient was admitted complaining breathing-dependent pain in the lower right chest and increasing dyspnoea. Diminished breath sounds in the right lung and dullness in the lower right chest were found. Chest x-ray and complementary CT scan showed an intrapulmonary Kirschner wire and a large haematothorax but no pneumothorax. At 6 weeks before admission, the patient suffered a fracture of the medial left clavicle which was treated by closed reduction and percutaneous osteosynthesis with two Kirschner wires. The migrated K-wire and the haematoma were removed by video-assisted thoracoscopy without complications. Migration of Kirschner wires after clavicle fracture osteosynthesis is rare but dangerous. Migrations into the heart, lung, pulmonary vein or the cervical spinal cord have been recorded. Patients with K-wire osteosynthesis should be informed of the risk of wire migration and should undergo regular postoperative follow-ups including radiography every 2-4 weeks.

[Advantages of ENT-specialty-specific autopsy technique]. / Vorteile einer HNO-gebietsspezifischen Sektionstechnik.

At routinely performed autopsies as described by Hamperl in 1956, ENT-specific regions such as the naso- and mesopharynx usually remain untouched. However, in cases with pathological changes in these regions a topographical preparation is necessary. Moreover, there is great interest among ENT-surgeons for studying the pathology of this area and to practice endoscopic and microscopic operation techniques. In close cooperation with the pathologists at RWTH clinic, we re-examined and refined further an ENT-specific dissection technique that was first described by Gräff in 1932. It allows a complete en bloc resection of all ENT-relevant organs without disfiguring the body. It also provides an optimal anatomical overview and gives insight into interrelations of morphological findings (thus improving post-mortem diagnosis), as well as allows the possibility for practicing operative techniques apart from the corpse.

[Neuritis of the optic nerve after vaccinations against hepatitis A, hepatitis B and yellow fever]. / Optikusneuritis nach Impfung gegen Hepatitis A, B und Gelbfieber mit irreversiblem Visusverlust.

BACKGROUND: Vaccinations are preventive measures against serious infections. In relation to the number of vaccinations per year, the incidence of severe complications is extremely low. PATIENT: Two weeks after vaccinations against hepatitis A, hepatitis B and yellow fever in preparation for a trip to Africa a 21-year-old woman experienced an acute and irreversible loss of vision to 0,05 and nasal visual field defect in the left eye. Whereas vision acuity did not recover the scotoma disappeared within 6 weeks. Cerebrospinal fluid showed a lymphocytic pleocytosis. Oligoglonale bands were absent. Pathological parameters were not presented in the serum. The MRI showed a hyperintense thickening of optic nerve,as well as a hyperintense focus in right temporal side using the T(2)W-Sequence. CONCLUSION: Only few cases have been reported with neurological complications, such as encephalitis, following vaccinations each of the above mentioned. As no other causes for the inflammation were found, the optic nerve involvement must have been caused by the vaccination. Which of the three vaccinations caused encephalitis can not be classified.

Tracheobronchial foreign bodies. Experience at Red Cross Children's Hospital, 1985-1990.

Ninety-six children with suspected tracheobronchial foreign bodies were referred to the Department of Cardiothoracic Surgery at Red Cross War Memorial Children's Hospital, Cape Town, between February 1985 and February 1990. Foreign bodies were removed by rigid bronchoscopy from 63 patients, 79% of whom were under 5 years of age. The majority of patients (59%) presented more than 24 hours after aspiration of the foreign body, and this delay in definitive management was associated with an increased incidence of complications (P = 0.01). Complications occurred in 28 patients, and there was one fatality at bronchoscopy due to overwhelming aspiration of an unanticipated release of pus, following the removal of a chronically impacted foreign body. The complete classic diagnostic triad (sudden onset of coughing, wheezing and decreased air entry) was seldom present, and we recommend diagnostic bronchoscopy in children presenting with either a history of sudden choking or a witnessed aspiration of a foreign body, an unexplained acute wheeze or cough or a chronic pulmonary infection. This report also highlights the continued need for increased awareness on the part of both parents and medical practitioners of the need for early referral if a foreign body is suspected. Furthermore, public education is needed as regards the dangers of allowing young children to eat peanuts. Peanuts were the commonest foreign bodies removed.