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1.  Disrupted functional connectivity of the default mode network due to acute vestibular deficit 
NeuroImage : Clinical  2014;6:109-114.
Vestibular neuritis is defined as a sudden unilateral partial failure of the vestibular nerve that impairs the forwarding of vestibular information from the labyrinth. The patient suffers from vertigo, horizontal nystagmus and postural instability with a tendency toward ipsilesional falls. Although vestibular neuritis is a common disease, the central mechanisms to compensate for the loss of precise vestibular information remain poorly understood. It was hypothesized that symptoms following acute vestibular neuritis originate from difficulties in the processing of diverging sensory information between the responsible brain networks. Accordingly an altered resting activity was shown in multiple brain areas of the task-positive network. Because of the known balance between the task-positive and task-negative networks (default mode network; DMN) we hypothesize that also the DMN is involved.
Here, we employ functional magnetic resonance imaging (fMRI) in the resting state to investigate changes in the functional connectivity between the DMN and task-positive networks, in a longitudinal design combined with measurements of caloric function. We demonstrate an initially disturbed connectedness of the DMN after vestibular neuritis. We hypothesize that the disturbed connectivity between the default mode network and particular parts of the task-positive network might be related to a sustained utilization of processing capacity by diverging sensory information. The current results provide some insights into mechanisms of central compensation following an acute vestibular deficit and the importance of the DMN in this disease.
•fMRI connectivity analyses after vestibular neuritis in a longitudinal design•Initially disturbed connectedness between the DMN and task positive networks•Connectivity restoration after complete clinical recovery of patients
PMCID: PMC4215422  PMID: 25379422
fMRI; Resting state; Functional connectivity; Vestibular cortex; Vestibular deficit
2.  The effects of deefferentation without deafferentation on functional connectivity in patients with facial palsy 
NeuroImage : Clinical  2014;6:26-31.
Cerebral plasticity includes the adaptation of anatomical and functional connections between parts of the involved brain network. However, little is known about the network dynamics of these connectivity changes. This study investigates the impact of a pure deefferentation, without deafferentation or brain damage, on the functional connectivity of the brain. To investigate this issue, functional MRI was performed on 31 patients in the acute state of Bell's palsy (idiopathic peripheral facial nerve palsy). All of the patients performed a motor paradigm to identify seed regions involved in motor control. The functional connectivity of the resting state within this network of brain regions was compared to a healthy control group. We found decreased connectivity in patients, mainly in areas responsible for sensorimotor integration and supervision (SII, insula, thalamus and cerebellum). However, we did not find decreased connectivity in areas of the primary or secondary motor cortex. The decreased connectivity for the SII and the insula significantly correlated to the severity of the facial palsy. Our results indicate that a pure deefferentation leads the brain to adapt to the current compromised state during rest. The motor system did not make a major attempt to solve the sensorimotor discrepancy by modulating the motor program.
•fMRI resting state connectivity analyses after facial palsy•Decreased connectivity in areas of sensorimotor integration and supervision•Correlation of connectivity decreases and severity of the facial palsy•No connectivity changes in motor areas at rest•Results suggest and adaptation of the brain to a compromised state
PMCID: PMC4215462  PMID: 25379413
fMRI; Resting state; Facial palsy; Functional connectivity; Plasticity
3.  Prognostic impact of standard laboratory values on outcome in patients with sudden sensorineural hearing loss 
Aim of the present study was to evaluate prognostic factors, in particular standard laboratory parameters, for better outcome after idiopathic sudden sensorineural hearing loss (SSNHL).
Using a retrospective review, 173 patients were included presenting between 2006 and 2009 with unilateral SSNHL, ≥30 dB bone conduction in three succeeding frequencies between 0.125 to 8 kHz in pure tone audiometry (PTA), and a time interval between first symptoms and diagnostics ≤ 4 weeks. Hearing gain of <10 dB versus ≥10 dB in the affected ear in 6PTA values was the primary outcome criterion. Univariate and multivariate statistical tests were used to analyze predictors for better outcome.
The initial hearing loss was 50.6 ± 27.2 dB. The absolute hearing gain was 15.6 ± 20.1 dB. Eighty-one patients (47%) had a final hearing gain of ≥10 dB. Low-frequency hearing loss (p <0.0001); start of inpatient treatment <4 days after onset (p = 0.018); first SSNHL (versus recurrent SSNHL, p = 0.001); initial hearing loss ≥ 60 dB (p < 0.0001); an initial quick value lower than the reference values (p = 0.040); and a pretherapeutic hyperfibrinogenemia (p = 0.007) were significantly correlated to better outcome (≥10 dB absolute hearing gain). Multivariate analysis revealed that first SSNHL (p = 0.004), start of treatment <4 days after onset (p = 0.015), initial hearing loss ≥ 60 dB (p = 0.001), and hyperfibrinogenemia (p = 0.032) were independent prognostic factors for better hearing recovery.
Better hearing gain in patients with hyperfibrinogenemia might be explained by the rheological properties of the applied therapy and supports the hypothesis that SSNHL is caused in part by vascular factors.
PMCID: PMC4099099  PMID: 25028570
Serology; Blood value; Outcome; Prognostic marker; Hearing loss
4.  Quantitative Magnetic Resonance Imaging Volumetry of Facial Muscles in Healthy Patients with Facial Palsy 
Magnetic resonance imaging (MRI) has not yet been established systematically to detect structural muscular changes after facial nerve lesion. The purpose of this pilot study was to investigate quantitative assessment of MRI muscle volume data for facial muscles.
Ten healthy subjects and 5 patients with facial palsy were recruited. Using manual or semiautomatic segmentation of 3T MRI, volume measurements were performed for the frontal, procerus, risorius, corrugator supercilii, orbicularis oculi, nasalis, zygomaticus major, zygomaticus minor, levator labii superioris, orbicularis oris, depressor anguli oris, depressor labii inferioris, and mentalis, as well as for the masseter and temporalis as masticatory muscles for control.
All muscles except the frontal (identification in 4/10 volunteers), procerus (4/10), risorius (6/10), and zygomaticus minor (8/10) were identified in all volunteers. Sex or age effects were not seen (all P > 0.05). There was no facial asymmetry with exception of the zygomaticus major (larger on the left side; P = 0.012). The exploratory examination of 5 patients revealed considerably smaller muscle volumes on the palsy side 2 months after facial injury. One patient with chronic palsy showed substantial muscle volume decrease, which also occurred in another patient with incomplete chronic palsy restricted to the involved facial area. Facial nerve reconstruction led to mixed results of decreased but also increased muscle volumes on the palsy side compared with the healthy side.
First systematic quantitative MRI volume measures of 5 different clinical presentations of facial paralysis are provided.
PMCID: PMC4174245  PMID: 25289366
5.  3D-Ultrasonography for evaluation of facial muscles in patients with chronic facial palsy or defective healing: a pilot study 
While standardized methods are established to examine the pathway from motorcortex to the peripheral nerve in patients with facial palsy, a reliable method to evaluate the facial muscles in patients with long-term palsy for therapy planning is lacking.
A 3D ultrasonographic (US) acquisition system driven by a motorized linear mover combined with conventional US probe was used to acquire 3D data sets of several facial muscles on both sides of the face in a healthy subject and seven patients with different types of unilateral degenerative facial nerve lesions.
The US results were correlated to the duration of palsy and the electromyography results. Consistent 3D US based volumetry through bilateral comparison was feasible for parts of the frontalis muscle, orbicularis oculi muscle, depressor anguli oris muscle, depressor labii inferioris muscle, and mentalis muscle. With the exception of the frontal muscle, the facial muscles volumes were much smaller on the palsy side (minimum: 3% for the depressor labii inferior muscle) than on the healthy side in patients with severe facial nerve lesion. In contrast, the frontal muscles did not show a side difference. In the two patients with defective healing after spontaneous regeneration a decrease in muscle volume was not seen. Synkinesis and hyperkinesis was even more correlated to muscle hypertrophy on the palsy compared with the healthy side.
3D ultrasonography seems to be a promising tool for regional and quantitative evaluation of facial muscles in patients with facial palsy receiving a facial reconstructive surgery or conservative treatment.
PMCID: PMC4002923  PMID: 24782657
3D-Sonography; Facial musculature; Reconstructive surgery; Facial nerve; Facial palsy
6.  Clinical significance and diagnostic usefulness of serologic markers for improvement of outcome of tonsillectomy in adults with chronic tonsillitis 
The aim of the present study was to explore serological biomarkers which predict the outcome of tonsillectomy for chronic tonsillitis.
A case study in a University ENT department of 24 adult patients with chronic tonsillitis (CHT) in comparison to 24 patients with acute peritonsillar abscess (PTA) was performed. Blood samples for clinical routine hematological and serological parameters were assessed prior to surgery (T-1) and five days (T5) after tonsillectomy. Outcome 6 months later (T180) was documented using the Glasgow Benefit Inventory (GBI) and the Specific Benefits from Tonsillectomy Inventory (SBTI). Correlation analyses between CHT and PTA group as well as between the different time points within each group concerning the serological parameters and the outcome parameters were performed.
At T-1, patients in the CHT group presented with significantly higher lymphocytes counts (relative and absolute), basophils (relative and absolute) and eosinophils but less white-cells, monocytes, neutrophils (absolute and relative), alpha-1, alpha-2, beta globulins, immunoglobulin and lower C-reactive protein and procalcitonin values than patients in the PTA group (all p < 0.05, respectively). Within each group, different significant changes of the serum parameters (often in opposite direction) were observed between T-1 and T5. SBTI scores at T-1 were significantly lower in the CHT group. In contrast, most GBI scores at T180 were significantly higher in the CHT group. Between T-1 and T180 the SBTI scores improved in three quarters of the CHT patients but only in three fifths of the PTA patients. Higher eosinophil counts and immunoglobulin E levels at T-1 predicted higher GBI scores at T180 in the CHT group.
This pilot study showed a specific serological pattern for patients with chronic tonsillitis with a specific pattern of changes after tonsillectomy. But there is no established role for biomarkers currently used in clinical practice to predict the outcome of tonsillectomy for chronic tonsillitis.
PMCID: PMC3701599  PMID: 23816317
Serology; Outcome; Prognostic Marker; Peritonsillar Abscess; Chronic Tonsillitis
7.  Prognostication of recovery time after acute peripheral facial palsy: a prospective cohort study 
BMJ Open  2013;3(6):e003007.
Owing to a lack of prospective studies, our aim was to evaluate diagnostic factors, in particular, motor and non-motor function tests, for prognostication of recovery time in patients with acute facial palsy (AFP).
Prospective cohort study.
University hospital.
259 patients with AFP.
Clinical data, facial grading, electrophysiological motor function tests and other non-motor function tests were assessed for their contribution to recovery time.
The predominant origin of AFP was idiopathic (59%) and traumatic (21%). At baseline, the House-Brackmann scale (HB) was >III in 46% of patients. Follow-up time was 5.6±9.8 months with a complete recovery rate of 49%. The median recovery time was 3.5 months (95% CI 2.2 to 4.7 months). The following variables were associated with faster recovery: Interval between onset of AFP and treatment <6 days versus ≥6 days (median recovery time in months 2.1 vs 6.5; p<0.0001); HB ≤III vs >III (2.2 vs 4.6; p=0.001); no versus presence of pathological spontaneous activity in first electromyography (EMG; 2.8 vs probability of recovery <50%; p<0.0001); no versus voluntary activity in EMG (probability of recovery <50% vs 3.1; p<0.0001); normal versus pathological ipsilateral electroneurography (1.9 vs 6.5; p=0.008), normal versus pathological stapedius reflexes (1.6 vs 3.3; p=0.003).
Start of treatment and grading, but most importantly EMG evaluated for pathological spontaneous activity and the stapedius reflex test are powerful prognosticators for estimating the recovery time from AFP. These results need confirmation in larger datasets.
PMCID: PMC3669721  PMID: 23794548
8.  Phase I trial of split-dose induction docetaxel, cisplatin, and 5-fluorouracil (TPF) chemotherapy followed by curative surgery combined with postoperative radiotherapy in patients with locally advanced oral and oropharyngeal squamous cell cancer (TISOC-1) 
BMC Cancer  2012;12:483.
Induction chemotherapy (ICT) with docetaxel, cisplatin and fluorouracil (TPF) followed by radiotherapy is an effective treatment option for unresectable locally advanced head and neck cancer. This phase I study was designed to investigate the safety and tolerability of a split-dose TPF ICT regimen prior to surgery for locally advanced resectable oral and oropharyngeal cancer.
Patients received TPF split on two dosages on day 1 and 8 per cycle for one or three 3-week cycles prior to surgery and postoperative radiotherapy or radiochemotherapy. Docetaxel was escalated in two dose levels, 40 mg/m2 (DL 0) and 30 mg/m2 (DL −1), plus 40 mg/m2 cisplatin and 2000 mg/m2 fluorouracil per week using a 3 +3 dose escalation algorithm.
Eighteen patients were enrolled and were eligible for toxicity and response. A maximum tolerated dose of 30 mg/m2 docetaxel per week was reached. The most common grade 3+ adverse event was neutropenia during ICT in 10 patients. Surgery reached R0 resection in all cases. Nine patients (50%) showed complete pathologic regression.
A split-dose regime of TPF prior to surgery is feasible, tolerated and merits additional investigation in a phase II study with a dose of 30 mg/m docetaxel per week.
Trial registration number
NCT01108042 ( Identifier)
PMCID: PMC3485626  PMID: 23083061
Docetaxel; Cisplatin; 5-fluorouracil; Locally advanced oral cancer; Surgery; Radiotherapy
9.  Neoadjuvant Chemoradiation in Squamous Cell Carcinoma of the Maxillary Sinus: A 26-Year Experience 
Background. The aim of our study was to evaluate the effects of neoadjuvant platinum-based radiochemotherapy (RCT) in patients with maxillary sinus squamous cell carcinoma and to compare the results with other multimodality treatment concepts for advanced-stage maxillary sinus carcinoma in the literature. Methods. In total, 53 patients with squamous cell carcinoma of the maxillary sinus were reviewed retrospectively. All patients received a neoadjuvant RCT containing either cisplatin or carboplatin followed by radical surgery. Overall survival and locoregional control were plotted by Kaplan-Meier analysis. Prognostic factors were identified through univariate and multivariate analysis. Results. Five-year overall survival for all patients was 35%. Eleven patients achieved a complete response after radiochemotherapy. The complete response rate was significantly higher for patients treated with cisplatin (P = 0.028); however the 5-year overall survival rates did not differ significantly (P = 0.673) for patients treated with cisplatin (37%) and carboplatin (32%). Orbital invasion (P = 0.005) and complete response to radiochemotherapy (P = 0.021) had a significant impact on overall survival in univariate analysis. Conclusions. Neoadjuvant radiochemotherapy followed by radical surgery is an effective treatment for patients with advanced maxillary sinus squamous cell carcinoma. In terms of treatment response cisplatin seems to be more effective than carboplatin.
PMCID: PMC3465876  PMID: 23056940
10.  Modern concepts in facial nerve reconstruction 
Head & Face Medicine  2010;6:25.
Reconstructive surgery of the facial nerve is not daily routine for most head and neck surgeons. The published experience on strategies to ensure optimal functional results for the patients are based on small case series with a large variety of surgical techniques. On this background it is worthwhile to develop a standardized approach for diagnosis and treatment of patients asking for facial rehabilitation.
A standardized approach is feasible: Patients with chronic facial palsy first need an exact classification of the palsy's aetiology. A step-by-step clinical examination, if necessary MRI imaging and electromyographic examination allow a classification of the palsy's aetiology as well as the determination of the severity of the palsy and the functional deficits. Considering the patient's desire, age and life expectancy, an individual surgical concept is applicable using three main approaches: a) early extratemporal reconstruction, b) early reconstruction of proximal lesions if extratemporal reconstruction is not possible, c) late reconstruction or in cases of congenital palsy. Twelve to 24 months after the last step of surgical reconstruction a standardized evaluation of the therapeutic results is recommended to evaluate the necessity for adjuvant surgical procedures or other adjuvant procedures, e.g. botulinum toxin application. Up to now controlled trials on the value of physiotherapy and other adjuvant measures are missing to give recommendation for optimal application of adjuvant therapies.
PMCID: PMC2984557  PMID: 21040532
11.  Comparative proteomic analysis of normal and tumor stromal cells by tissue on chip based mass spectrometry (toc-MS) 
Diagnostic Pathology  2010;5:10.
In carcinoma tissues, genetic and metabolic changes not only occur at the tumor cell level, but also in the surrounding stroma. This carcinoma-reactive stromal tissue is heterogeneous and consists e.g. of non-epithelial cells such as fibroblasts or fibrocytes, inflammatory cells and vasculature-related cells, which promote carcinoma growth and progression of carcinomas. Nevertheless, there is just little knowledge about the proteomic changes from normal connective tissue to tumor stroma. In the present study, we acquired and analysed specific protein patterns of small stromal sections surrounding head and neck cell complexes in comparison to normal subepithelial connective tissue. To gain defined stromal areas we used laser-based tissue microdissection. Because these stromal areas are limited in size we established the highly sensitive 'tissue on chip based mass spectrometry' (toc-MS). Therefore, the dissected areas were directly transferred to chromatographic arrays and the proteomic profiles were subsequently analysed with mass spectrometry. At least 100 cells were needed for an adequate spectrum. The locating of differentially expressed proteins enables a precise separation of normal and tumor stroma. The newly described toc-MS technology allows an initial insight into proteomic differences between small numbers of exactly defined cells from normal and tumor stroma.
PMCID: PMC2826342  PMID: 20205871
12.  Schwann Cells Overexpressing FGF-2 Alone or Combined with Manual Stimulation Do Not Promote Functional Recovery after Facial Nerve Injury 
Purpose. To determine whether transplantation of Schwann cells (SCs) overexpressing different isoforms of fibroblast growth factor 2 (FGF-2) combined with manual stimulation (MS) of vibrissal muscles improves recovery after facial nerve transection in adult rat. Procedures. Transected facial nerves were entubulated with collagen alone or collagen plus naïve SCs or transfected SCs. Half of the rats received daily MS. Collateral branching was quantified from motoneuron counts after retrograde labeling from 3 facial nerve branches. Quality assessment of endplate reinnervation was combined with video-based vibrissal function analysis. Results. There was no difference in the extent of collateral axonal branching. The proportion of polyinnervated motor endplates for either naïve SCs or FGF-2 over-expressing SCs was identical. Postoperative MS also failed to improve recovery. Conclusions. Neither FGF-2 isoform changed the extent of collateral branching or polyinnervation of motor endplates; furthermore, this motoneuron response could not be overridden by MS.
PMCID: PMC2760319  PMID: 19830246
13.  Increased expression of ICAM-1, VCAM-1, MCP-1, and MIP-1α by spinal perivascular macrophages during experimental allergic encephalomyelitis in rats 
BMC Immunology  2002;3:11.
T-cells extravasation and CNS parenchyma infiltration during autoimmune neurodegenerative disease can be evoked by local antigen presenting cells. Studying the chemoattracting potential of spinal perivascular macrophages (SPM) during experimental allergic encephalomyelitis (EAE), we observed numerous infiltrates of densely-packed mononuclear cells. Apart from the poor spatial and optical resolution, no differentiation between the resident SPM (mabs ED1+, ED2+) and the just recruited monocytes/macrophages (mab ED1+) was possible.
This is why we labeled SPM by injections of different fluoresecent dyes into the lateral cerebral ventricle before induction of active EAE. Within an additional experimental set EAE was induced by an intraperitoneal injection of T-cells specifically sensitized to myelin basic protein (MBP) and engineered to express the green fluorescent protein (GFP). In both experiments we observed a strong activation of SPM (mabs OX6+, SILK6+, CD40+, CD80+, CD86+) which was accompanied by a consistently increased expression of ICAM-1, VCAM-1, and the chemokines MCP-1 and MIP-1α.
These observations indicate that SPM play a role in promoting lymphocyte extravasation.
PMCID: PMC126207  PMID: 12196270

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