[Prevalence of peripheral vestibular diseases in children in Germany]. / Prävalenz peripher-vestibulärer Erkrankungen bei Kindern in Deutschland.

INTRODUCTION: Dizziness is a common complaint among patients; however, a lack of valid data concerning age and gender distribution of dizziness disorders among children under the age of 15 years can preclude effective diagnosis and treatment. The goal of this study was to describe the prevalence and gender distribution of three classical peripheral vestibular disorders; benign paroxysmal positional vertigo (BPPV), vestibular neuritis (VN), and Menière's disease (MD) as well as unspecific dizziness (UV) in children between 0 and 15 years of age, using state sponsored health insurance data. METHODS: A population-based epidemiological survey based on confirmed International Classification of Diseases (ICD) 10 codes of all persons aged 0-15 years in a national population was performed. Outcome measures were age and gender distribution and prevalence of BPPV, VN, and MD in this population. RESULTS: Dizziness diagnosed as being of peripheral vestibular origin was found in 1414 patients. The prevalence of peripheral vestibular disorders was found to be 15.16 per 100,000 individuals. The BPPV was coded most frequently with a prevalence of 10.21 per 100,000 individuals, followed by VN with a prevalence of 3.5 per 100,000 and MD at 1.54 per 100,000. CONCLUSION: Peripheral vestibular disorders can occur in childhood and the prevalence increases with age. In childhood, girls and boys are similarly affected. Peripheral vestibular disorders should be taken into consideration when a young child presents with vertigo or dizziness and are even more important when a child presents with unclear symptoms, as very young children might not be able to adequately verbalize dizziness and vertigo. For that reason peripheral vestibular disorders in childhood are probably underdiagnosed.

Selected ENT symptoms in functional disorders of the upper cervical spine and temporomandibular joints.

This paper discusses otorhinolaryngological symptoms associated with functional disorders of the upper cervical spine. Hints aimed to avoid misdiagnoses of cross-organ otorhinolaryngological symptoms as phobic or psychogenic disorders are presented. Clinically relevant neuroanatomical convergence of the upper cervical spine (occiput to C3) is fundamental for the interpretation of functional otorhinolaryngological symptoms. Based thereon, evidence for the most common cervical differential diagnoses of dizziness, tinnitus, dysphagia, and craniomandibular dysfunction is presented separately. The corresponding therapeutic options and their contraindications are discussed in the concluding chapter. The importance of interdisciplinary cooperation in related fields is emphasized.

Diabetes-induced microvascular complications at the level of the spinal cord: a contributing factor in diabetic neuropathic pain.

KEY POINTS: Diabetes is thought to induce neuropathic pain through activation of dorsal horn sensory neurons in the spinal cord. Here we explore the impact of hyperglycaemia on the blood supply supporting the spinal cord and chronic pain development. In streptozotocin-induced diabetic rats, neuropathic pain is accompanied by a decline in microvascular integrity in the dorsal horn. Hyperglycaemia-induced degeneration of the endothelium in the dorsal horn was associated with a loss in vascular endothelial growth factor (VEGF)-A165 b expression. VEGF-A165 b treatment prevented diabetic neuropathic pain and degeneration of the endothelium in the spinal cord. Using an endothelial-specific VEGFR2 knockout transgenic mouse model, the loss of endothelial VEGFR2 signalling led to a decline in vascular integrity in the dorsal horn and the development of hyperalgesia in VEGFR2 knockout mice. This highlights that vascular degeneration in the spinal cord could be a previously unidentified factor in the development of diabetic neuropathic pain. ABSTRACT: Abnormalities of neurovascular interactions within the CNS of diabetic patients is associated with the onset of many neurological disease states. However, to date, the link between the neurovascular network within the spinal cord and regulation of nociception has not been investigated despite neuropathic pain being common in diabetes. We hypothesised that hyperglycaemia-induced endothelial degeneration in the spinal cord, due to suppression of vascular endothelial growth factor (VEGF)-A/VEGFR2 signalling, induces diabetic neuropathic pain. Nociceptive pain behaviour was investigated in a chemically induced model of type 1 diabetes (streptozotocin induced, insulin supplemented; either vehicle or VEGF-A165 b treated) and an inducible endothelial knockdown of VEGFR2 (tamoxifen induced). Diabetic animals developed mechanical allodynia and heat hyperalgesia. This was associated with a reduction in the number of blood vessels and reduction in Evans blue extravasation in the lumbar spinal cord of diabetic animals versus age-matched controls. Endothelial markers occludin, CD31 and VE-cadherin were downregulated in the spinal cord of the diabetic group versus controls, and there was a concurrent reduction of VEGF-A165 b expression. In diabetic animals, VEGF-A165 b treatment (biweekly i.p., 20 ng g-1 ) restored normal Evans blue extravasation and prevented vascular degeneration, diabetes-induced central neuron activation and neuropathic pain. Inducible knockdown of VEGFR2 (tamoxifen treated Tie2CreERT2 -vegfr2flfl mice) led to a reduction in blood vessel network volume in the lumbar spinal cord and development of heat hyperalgesia. These findings indicate that hyperglycaemia leads to a reduction in the VEGF-A/VEGFR2 signalling cascade, resulting in endothelial dysfunction in the spinal cord, which could be an undiscovered contributing factor to diabetic neuropathic pain.

[Selected otorhinolaryngological symptoms in functional disorders of the upper cervical spine and temporomandibular joints]. / Ausgewählte HNO-Symptome bei funktionellen Störungen der oberen Halswirbelsäule und der Kiefergelenke.

This paper discusses otorhinolaryngological symptoms associated with functional disorders of the upper cervical spine. Hints aimed to avoid misdiagnoses of cross-organ otorhinolaryngological symptoms as phobic or psychogenic disorders are presented. Clinically relevant neuroanatomical convergence of the upper cervical spine (occiput to C3) is fundamental for the interpretation of functional otorhinolaryngological symptoms. Based thereon, evidence for the most common cervical differential diagnoses of dizziness, tinnitus, dysphagia, and craniomandibular dysfunction is presented separately. The corresponding therapeutic options and their contraindications are discussed in the concluding chapter. The importance of interdisciplinary cooperation in related fields is emphasized.

[Pilot study: Determination of the subjective trunk vertical in upright head position]. / Pilotstudie: Bestimmung der subjektiven Rumpfvertikalen in lotrechter Kopfposition.

BACKGROUND: Consensus has been established that the subjective vertical (SV) is a result of multimodal sensory integration. In order to be able to calculate the vestibulocervical sensory competence for the SV, the isolated subjective trunk vertical axis (STV) was measured under conditions of vertical head fixation. MATERIALS AND METHODS: Young, healthy volunteers (n = 49) were compared to older, healthy volunteers (n = 50) on a three-dimensionally deflectable (tilt, torsion, pitch) trunk excursion chair in which the volunteer's head remains in an upright position. Another young, healthy group was divided into a placebo (n = 27) and a monophasic cervical transcutaneous electrical nerve stimulation (C-TENS; n = 22) group to examine verticality perception. RESULTS: In the STV after trunk pitch, age was a significant variable (p = 0.021). The older, healthy group of subjects missed the physical vertical by an average of 1.8° more than the younger group. Only the placebo group showed an average improvement in STV of 4.3° after torsion. CONCLUSION: Apart from the macular organs the vestibulocervical sensory afference is involved in finding the trunk vertical. A difference in age to the disadvantage of the older healthy subjects was observed, as well as a lack of learning success after applied C­TENS. The presented pilot study was able to confirm that a correct vertical trunk sensation is caused by vestibulocervical sensory afference in upright head position.

[Current aspects of ototoxicity. Ototoxic substances and their effects]. / Aktuelle Aspekte zur Ototoxizität : Ototoxische Substanzen und deren Effekte.

Ototoxicity describes reversible or irreversible disorders of inner ear functions due to the influence of chemical, biological, or physical substances. Ototoxicity should be kept in mind during differential diagnosis of hearing loss, tinnitus, dizziness, and vertigo. In clinical practice, drug-induced ototoxic effects play a major role. The otorhinolaryngologist should also be involved in interdisciplinary cooperation, e.g., during treatment with antineoplastic chemotherapeutic agents with potential ototoxic side effects. In clinical practice, multimedication and interactions between different agents can complicate precise correlation in individual cases. Recent studies also show that noncellular components, such as otoconia, are extremely sensitive to chemical attacks.

[Current aspects of ototoxicity : Local ototoxic effects, diagnosis, prevention, and treatment]. / Aktuelle Aspekte zur Ototoxizität : Lokale ototoxische Wirkungen, Diagnostik, Prävention und Therapie.

The otorhinolaryngologist is often involved in an interdisciplinary approach to diagnose ototoxic side effects. Under certain conditions, chemical agents-particularly drugs-can have ototoxic effects. This is not only true for systemic administration, but also for local application (e.g., transdermal and transtympanal). Identifying and avoiding ototoxicity is still a challenge in clinical practice. The audiological monitoring of patients receiving potentially cochleotoxic drugs is now standardized. For diagnosis of suspected vestibulotoxic effects, the video head impulse test and vestibular evoked myogenic potentials seem to be suitable procedures for objective assessment. The early detection of such ototoxic effects has important implications for the prevention of hearing and balance disorders. Recent studies show that intratympanic delivery of medications might play an important role in the limitation of ototoxically induced hearing loss. In peripheral vestibulopathies with episodic vertigo, which strongly affect quality of life, ototoxic effects can be used for therapeutic purposes.

[Frequency-specific analysis of the hVOR Prior of Cochlear Implant Operation]. / Frequenzspezifische Untersuchung des hVOR im Vorfeld einer CI-Operation.

Dizziness is one of the most common postoperative complications after a cochlear-implant (CI) surgery. With our prospective, matched-paired controlled study, we could demonstrate that patients with distinctive sensorineural hearing loss--even without any complaints of dizziness--already have a reduced horizontal vestibular-ocular-reflex (hVOR). Compared to controls, CI patients presented with a significantly reduced gain. 9 out of 17 CI patients showed physiological results in rotatory testing and video head thrust testing. One patient presented with pathological results in both tests. Remarkably, there were 2 patients who presented with pathological head impulse testing but normal values in rotatory testing and 5 patients who showed normal gains in video head impulse testing but abnormal rotatory tests. These findings clearly show the importance of a differentiated, frequency-dependent pre-operative vestibular assessment including rotatory testing and video-head impulse testing. Additionally, only an accurate pre-operative vestibular testing allows evaluating possible post-operative dizziness related complications and should be documented precisely, also for forensic reasons. This is the key to differentiate post-operative dizziness from an pre-operatively existing vestibular disorder that possibly might not be clinically apparent by the time of testing.

Regulation of alternative VEGF-A mRNA splicing is a therapeutic target for analgesia.

Vascular endothelial growth factor-A (VEGF-A) is best known as a key regulator of the formation of new blood vessels. Neutralization of VEGF-A with anti-VEGF therapy e.g. bevacizumab, can be painful, and this is hypothesized to result from a loss of VEGF-A-mediated neuroprotection. The multiple vegf-a gene products consist of two alternatively spliced families, typified by VEGF-A165a and VEGF-A165b (both contain 165 amino acids), both of which are neuroprotective. Under pathological conditions, such as in inflammation and cancer, the pro-angiogenic VEGF-A165a is upregulated and predominates over the VEGF-A165b isoform. We show here that in rats and mice VEGF-A165a and VEGF-A165b have opposing effects on pain, and that blocking the proximal splicing event - leading to the preferential expression of VEGF-A165b over VEGF165a - prevents pain in vivo. VEGF-A165a sensitizes peripheral nociceptive neurons through actions on VEGFR2 and a TRPV1-dependent mechanism, thus enhancing nociceptive signaling. VEGF-A165b blocks the effect of VEGF-A165a. After nerve injury, the endogenous balance of VEGF-A isoforms switches to greater expression of VEGF-Axxxa compared to VEGF-Axxxb, through an SRPK1-dependent pre-mRNA splicing mechanism. Pharmacological inhibition of SRPK1 after traumatic nerve injury selectively reduced VEGF-Axxxa expression and reversed associated neuropathic pain. Exogenous VEGF-A165b also ameliorated neuropathic pain. We conclude that the relative levels of alternatively spliced VEGF-A isoforms are critical for pain modulation under both normal conditions and in sensory neuropathy. Altering VEGF-Axxxa/VEGF-Axxxb balance by targeting alternative RNA splicing may be a new analgesic strategy.

Spinal cord vascular degeneration impairs duloxetine penetration.

Introduction: Chronic pain is a prevalent physically debilitating health-related morbidity. Frontline analgesics are inadequate, providing only partial pain relief in only a proportion of the patient cohort. Here, we explore whether alterations in spinal cord vascular perfusion are a factor in reducing the analgesic capability of the noradrenaline reuptake inhibitor, duloxetine. Method: An established rodent model of spinal cord vascular degeneration was used. Endothelial-specific vascular endothelial growth factor receptor 2 knockout mouse was induced via hydroxytamoxifen administered via intrathecal injection. Duloxetine was administered via intraperitoneal injection, and nociceptive behavioural testing was performed in both WT and VEGFR2KO mice. LC-MS/MS was performed to explore the accumulation of duloxetine in the spinal cord in WT and VEGFR2KO mice. Results: Spinal cord vascular degeneration leads to heat hypersensitivity and a decline in capillary perfusion. The integrity of noradrenergic projections (dopa - hydroxylase labelled) in the dorsal horn remained unaltered in WT and VEGFR2KO mice. There was an association between dorsal horn blood flow with the abundance of accumulated duloxetine in the spinal cord and analgesic capacity. In VEGFR2KO mice, the abundance of duloxetine in the lumbar spinal cord was reduced and was correlated with reduced anti-nociceptive capability of duloxetine. Discussion: Here, we show that an impaired vascular network in the spinal cord impairs the anti-nociceptive action of duloxetine. This highlights that the spinal cord vascular network is crucial to maintaining the efficacy of analgesics to provide pain relief.

Vestibular testing in children - The suppression head impulse (SHIMP) test.

INTRODUCTION: The incidence of vestibular disorders and vertigo during childhood is increasing and pediatric clinicians have become more sensitive to children's balance disorders; thus, there is a need for appropriate detection test procedures for peripheral vestibular hypofunction. In order to ensure a reliable diagnosis and minimize misdiagnosis, a standardized clinical procedure via careful history and clinical examination is recommended. However, children, especially, are often unable to verbalize "vertigo" in a concrete manner, which often necessitates a consultation with a pediatrician holding nonspecific symptoms. The so-called suppression of the head impulse test (SHIMPs) represents a modification of the video head impulse test (HIMP) and is used for a more sensitive assessment of residual vestibular functions. In adults, SHIMPs are already an established diagnostic method. Nevertheless, to date, nothing is known about the applicability and standard values in childhood. MATERIAL AND METHODS: In this monocentric, prospective study, we investigated whether SHIMPs enable a sensitive functional analysis of the vestibular system in healthy children of different ages. For this purpose, SHIMPs were performed in 40 children aged 3-18 years. RESULTS: In this study, we demonstrated that SHIMPs can be easily performed in children (3-18 years). It is vital that the test be appropriately explained for children to ensure sufficient test tolerance and compliance. CONCLUSION: SHIMPs are a helpful supplement to clinically established vestibular tests such as the HIMP in pediatric vestibular balance disorder diagnostics and can be integrated into the clinical routine, especially in children who have minimal verbal abilities or understanding of the instructions for HIMP. Similar to the HIMP, SHIMPs are characterized by a short test duration and a high tolerance.

Cancer Chemotherapy in Early Life Significantly Alters the Maturation of Pain Processing.

Advances in pediatric cancer treatment have led to a ten year survival rate greater than 75%. Platinum-based chemotherapies (e.g. cisplatin) induce peripheral sensory neuropathy in adult and pediatric cancer patients. The period from birth through to adulthood represents a period of maturation within nociceptive systems. Here we investigated how cisplatin impacts upon postnatal maturation of nociceptive systems. Neonatal Wistar rats (Postnatal day (P) 7) were injected (i.p.) daily with either vehicle (PBS) or cisplatin (1mg/kg) for five consecutive days. Neither group developed mechanical or thermal hypersensitivity immediately during or after treatment. At P22 the cisplatin group developed mechanical (P < 0.05) and thermal (P < 0.0001) hypersensitivity versus vehicle group. Total DRG or dorsal horn neuronal number did not differ at P45, however there was an increase in intraepidermal nerve fiber density in cisplatin-treated animals at this age. The percentage of IB4+ve, CGRP+ve and NF200+ve DRG neurons was not different between groups at P45. There was an increase in TrkA+ve DRG neurons in the cisplatin group at P45, in addition to increased TrkA, NF200 and vGLUT2 immunoreactivity in the lumbar dorsal horn versus controls. These data highlight the impact pediatric cancer chemotherapy has upon the maturation of pain pathways and later life pain experience.

Identification of mechano-sensitive C fibre sensitization and contribution to nerve injury-induced mechanical hyperalgesia.

BACKGROUND: C fibre hyperexcitability is fundamental to chronic pain development in humans and rodents; therefore, peripheral sensory neuronal sensitization plays a role in the development of mechanical hyperalgesia. However, the axonal properties and underlying mechanisms that are associated to these chronic pain states still require investigation. METHODS: Teased fibre electrophysiology of the saphenous nerve was used to identify C fibres in naïve and nerve-injured rats. C fibres were identified using electrical stimulation which further provided conduction velocity slowing profiles. From these nerve filaments evoked responses to mechanical stimuli were recorded. Vehicle or galanin were applied directly to the saphenous nerve trunk prior to stimulation. RESULTS: Increased levels of mechanically evoked activity in mechano-sensitive C fibres was associated to reduced conduction failure, enhanced conduction velocity latency recovery and reduced conduction velocity slowing. Mechanical hyperalgesia developed in nerve-injured animals in which mechano-sensitive C fibres demonstrated increased mechanically evoked responses and reduced rate of adaptation. Mechano-sensitive C fibres in nerve-injured animals had reduced levels of conduction velocity slowing, enhanced rate of conduction velocity recovery and reduced firing frequency failure versus naïve animals; all hallmarks of enhanced sensory neuronal excitability. Directly applying the antinociceptive agent galanin to the saphenous nerve trunk in naive animals led to increased conduction failure, reduced latency recovery rate and increased levels of conduction velocity slowing. DISCUSSION: Nerve injury-induced enhanced neural responses to mechanical stimulation are associated to defined parameters setout by conduction velocity slowing, mediated via axonal processing. Application of galanin inhibits axonal excitability.

Optimization of multiplexed bead-based cytokine immunoassays for rat serum and brain tissue.

The ability to simultaneously quantify multiple signaling molecule protein levels from microscopic neural tissue samples would be of great benefit to deciphering how they affect brain function. This follows from evidence that indicates signaling molecules can be pleiotropic and can have complex interactive behavior that is regionally and cellularly heterogeneous. Multiplexed examination of tissue proteins has been exceedingly difficult because of the absence of available techniques. This void now has been removed by the commercial availability of bead-based immunoassays for targeted proteins that allow analyses of up to 100 (6-150 kDa) proteins from as little as 12 microl. Thus far used only for sera (human and mouse) and culture media, we demonstrate here that sensitive (as low as 2 pg/ml), wide-ranging (up to 2-32 000 pg/ml), accurate (8% intra-assay covariance) and reliable (4-7% inter-assay covariance) measurements can be made of nine exemplary cytokines (e.g., IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-10, GM-CSF, IFN-gamma, TNF-alpha) simultaneously not only from rat serum but, for the first time, also brain tissue. Furthermore, we describe animal handling procedures that minimize stress as determined by serum glucocorticoid levels since they can influence cytokine expression.

[Dizziness from the viewpoint of otorhinolaryngology]. / Gleichgewichtsstörungen aus HNO-ärztlicher Sicht.

Dizziness is a common symptom in daily clinical practice. Dizziness and vertigo affect the quality of life as they are associated with the risk of falls leading to limited ability of independent locomotion and thus to a reduction in social contact. The source of problems with dizziness is localized in the area of visual, somatosensory and vestibular sense inputs. The ear nose and throat (ENT) specialist is involved in an interdisciplinary context to elucidate and treat peripheral vestibular disorders. The subjective symptoms of dizziness have to be clarified by taking a careful patient history. By means of objective tests (cVEMP, oVEMP, video-head impulse test) the ENT specialist is able to selectively analyze the function of the five vestibular receptors; therefore, a topological assignment in peripheral vestibulopathy is possible. The exact diagnosis is a prerequisite for a specific therapy and many diseases can be evidence-based, safe and effectively treated.

Endogenous analgesic action of the pontospinal noradrenergic system spatially restricts and temporally delays the progression of neuropathic pain following tibial nerve injury.

Pontospinal noradrenergic neurons form part of an endogenous analgesic system that suppresses acute pain, but there is conflicting evidence about its role in neuropathic pain. We investigated the chronology of descending noradrenergic control during the development of a neuropathic pain phenotype in rats following tibial nerve transection (TNT). A lumbar intrathecal cannula was implanted at the time of nerve injury allowing administration of selective α-adrenoceptor (α-AR) antagonists to sequentially assay their effects upon the expression of allodynia and hyperalgesia. Following TNT animals progressively developed mechanical and cold allodynia (by day 10) and subsequently heat hypersensitivity (day 17). Blockade of α2-AR with intrathecal yohimbine (30 µg) revealed earlier ipsilateral sensitization of all modalities while prazosin (30 µg, α1-AR) was without effect. Established allodynia (by day 21) was partly reversed by the re-uptake inhibitor reboxetine (5 µg, i.t.) but yohimbine no longer had any sensitising effect. This loss of effect coincided with a reduction in the descending noradrenergic innervation of the ipsilateral lumbar dorsal horn. Yohimbine reversibly unmasked contralateral hindlimb allodynia and hyperalgesia of all modalities and increased dorsal horn c-fos expression to an innocuous brush stimulus. Contralateral thermal hyperalgesia was also reversibly uncovered by yohimbine administration in a contact heat ramp paradigm in anaesthetised TNT rats. Following TNT there is an engagement of inhibitory α2-AR-mediated noradrenergic tone which completely masks contralateral and transiently suppresses the development of ipsilateral sensitization. This endogenous analgesic system plays a key role in shaping the spatial and temporal expression of the neuropathic pain phenotype after nerve injury.

Intraoperative cone beam computed tomography in the management of facial fractures.

Computed tomography is currently the standard in preoperative evaluation of facial fractures, but cone beam computed tomography (CBCT) or digital volume tomography (DVT) offers potential advantages. Intraoperative imaging may facilitate adequate fracture reduction, optimising fracture repair. The aim of this article is to demonstrate the potential benefits of a new mobile CBCT system in a series of patients with complex facial fractures. Intraoperative imaging was performed with the xCAT ENT portable CBCT system. Images were provided in three planes and in a three-dimensional reconstruction. This system was used for intraoperative imaging of 46 consecutive facial trauma patients. The impact of intraoperative CBCT on the management of these cases is described and two select cases are presented to illustrate the potential benefits of this technique. Intraoperative CBCT was successfully performed in all patients and has led to immediate consequences in 12 (26%) cases. In 5 cases, fracture reduction turned out to be insufficient and was further optimized and in 5 other cases the titanium implant (orbital mesh) was not placed in the optimal position and the position was corrected. Bony fragments were detected and removed in 2 cases. Intraoperative imaging provides a number of advantages over post-therapeutic imaging in the management of facial fractures.