[Hearing classification in patients with vestibular schwannoma using German-language test procedures]. / Hörklassen bei Patienten mit Vestibularisschwannom bei Verwendung deutschsprachiger Testverfahren.

BACKGROUND: Hearing function in patients with vestibular schwannoma is often classified according to the Gardner and Robertson (1988) or the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS, 1995) systems. These classification systems are based on English-language test procedures, there is no German-language equivalent. The aim of the study was to investigate the influence of various target parameters on hearing classification and to derive a recommendation for the use of German-language test methods. MATERIALS AND METHODS: The rules for speech audiometry based on English-language test procedures were applied to German speech test materials. In 91 patients with vestibular schwannoma, pure tone hearing thresholds, speech recognition thresholds, and speech discrimination at different sound pressure levels were measured. The patients were categorized according to the Gardner and Robertson and AAO-HNS classifications. RESULTS: In both the Gardner-Robertson and the AAO-HNS classifications, the number of patients in the hearing classes with serviceable hearing function (measured as Pure Tone Average across three (3PTA) or four (4PTA) frequencies) was highest when using the 3PTA0,5;1;2 kHz condition, followed by 4PTA0,5;1;2;3 kHz, 4PTA0,5;1;2;4 kHz, and 4PTA0,5;1;2;"3"kHz. If maximum word recognition score (WRSmax) was used instead of word recognition 40 dB above the sensation level (WRS40SL), more patients were classified into the hearing classes with serviceable hearing function, irrespective of the mean pure tone hearing threshold. CONCLUSION: The Gardner-Robertson and AAO-HNS classifications can be used in German-speaking settings. The Freiburg monosyllabic test can be used to determine speech discrimination scores or maximum word recognition.

[Neuroprotective medication in vestibular schwannoma surgery]. / Medikamentöse Neuroprotektion in der Vestibularisschwannomchirurgie.

BACKGROUND: Except for glucocorticoids there is a lack of neuroprotective medication in neurosurgical interventions. OBJECTIVE: An overview of clinical trials investigating administration of the calcium antagonist nimodipine and hydroxyethyl starch (HES) in vestibular schwannoma (VS) surgery is given. Basic research is addressed and potential neuroprotective effect mechanisms are discussed, as are perspectives for application of the concept to other types of surgery with a risk postoperative impairment of nerve function. MATERIALS AND METHODS: A selective PubMed search was performed and all 10 clinical trials corresponding to the search criteria were included. RESULTS: Four trials with an intraoperative start of the medication showed a positive effect for the preservation of facial nerve function and hearing preservation. A pilot study showed superiority of prophylactic treatment over intraoperative application. There were no significant results in a prospective multicenter phase III trial. After 1 year, postoperative facial nerve preservation rates were excellent in both groups. However, the risk of hearing loss was twice as high in the control group. A combined analysis of the phase III trial with its pilot study showed significant results for better hearing preservation rates in the treatment group (probably by increasing the case load). CONCLUSION: Prophylactic nimodipine can be recommended in VS surgery in patients with good preoperative hearing. The effect mechanisms of nimodipine and modifications to prophylaxis should be clarified in basic research.

A-trains for intraoperative monitoring in patients with recurrent vestibular schwannoma.

BACKGROUND: Second surgery of recurrent vestibular schwannoma (VS) after previous surgery, stereotactic radiosurgery (SR) or fractionated radiotherapy (FR) carries an increased risk for deterioration of facial nerve function, e.g., due to adhesions, underlining the need for intraoperative monitoring. Facial "Atrain" EMG activity ("traintime") correlates with the degree of postoperative facial palsy. Studies investigating A-trains in VS patients with previous surgery, SR or FR are missing. We therefore investigated the value of A-train monitoring in patients undergoing second surgery for VS. METHOD: Intraoperative EMG data from patients who underwent second surgery for VS after previous surgery, SR and/or FR at our institution between 2006 and 2012 were retrospectively analyzed. Ten patients were selected (5 male): Seven had previous SR/RT and MS, three previous surgery only. Traintime values and distribution was compared to published thresholds and to 77 patients who underwent first surgery for VS during the same time period. RESULTS: A-trains were recorded early after opening of the dura, before facial nerve preparation. Mean traintime was 46.9 s (18.51 s ­ 80.82 s) in patients with previous SR/RT. In patients with previous MS only, traintime was 0.06 s, 0.99 s and 22.46 s. Compared to the literature, traintime was higher than expected in six patients (four with previous SR/RT, two without), respectively seven compared to the 77 patients with first surgery (5 SR/RT). Seven patients with previous SR/RT and none with previous surgery showed diffuse A-train distributions without significant percentages in single channels, compared to 60 of 77 patients with first surgery (p <0.02). CONCLUSIONS: Especially SR/RT, but also previous surgery seems to induce changes in the facial nerve leading to hyperexcitability and exceedingly high traintime values. Based on these findings, A-train monitoring in this specific patient group should be interpreted with caution.

Prophylactic intravenous nimodipine treatment in skull base surgery: pharmacokinetic aspects.

BACKGROUND: Nimodipine is primarily used in subarachnoid hemorrhage (SAH). Clinical trials revealed also a beneficial effect of prophylactic nimodipine treatment on cranial nerve functions following vestibular schwannoma surgery. OBJECTIVE: The unknown pharmacokinetics of prophylactically administered nimodipine were investigated. METHODS: Samples were taken from 27 patients with skull base lesions. Prophylactic intravenous nimodipine infusion was started 5.8-25.8 h (mean 17.9 h) before surgery. Nimodipine concentrations were determined in serum (intra- and postoperatively), cerebrospinal fluid (CSF) (intraoperatively), and tissue samples. RESULTS: Wide interindividual differences were observed. Mean concentrations for nimodipine were 46.9 ng/ml (SD: 6.4; min. 4.1 and max. 92.7 ng/ml) in intraoperative serum, 73.2 ng/ml (SD: 16.7; min. 6.6 and max. 253 ng/ml) in postoperative serum and 8.3 ng/ml (SD: 1.5; min. 1.0 und max. 29.7 ng/ml) in intraoperative CSF. The correlation between intra- and postoperative serum (p=0.004, r=0.560) and between intra-operative serum and CSF concentration (p=0.003, r=0.567) were statistically significant. Furthermore the correlation between intraoperative serum concentration and concentrations collected from vestibular nerves was high (r=0.711), but not statistically significant (p=0.178). CONCLUSIONS: Interindividually, continously administered intravenous nimodipine produces considerably variable serum levels. Controls of nimodipine serum concentrations may be useful to optimize nimodipine medication in skull base surgery and in the management of SAH. The serum nimodipine level is a useful marker for CSF and intracranial nerve tissue concentrations of nimodipine.

Nimodipine promotes regeneration of peripheral facial nerve function after traumatic injury following maxillofacial surgery: an off label pilot-study.

BACKGROUND: Animal tests, retro- and prospective clinical trials in neurosurgical departments have shown a beneficial effect of nimodipine on the preservation and recovery of facial and acoustic nerve function following vestibular schwannoma surgery. Encouraged by these positive results a pilot-study of nimodipine treatment in patients with a peripheral facial nerve (FN) paresis following maxillofacial surgery was performed. The rate and time of FN recovery were analysed and compared with the results in the literature. METHODS: Thirteen patients (n = 13) suffering from a moderate (1/13) up to a severe (12/13) peripheral FN paresis after maxillofacial surgery were treated with orally administered nimodipine. The anatomical main course of the FN was preserved in all patients with a 2nd to 3rd degree of Sunderland-injury (Sunderland, 1951). After no evidence of a spontaneous regeneration had shown, oral medication with nimodipine was started as an "off-label" use. RESULTS: An improvement of the FN function correlated to the start of the vasoactive medication and as a consequence a recovery of the FN function up to House-Brackmann (HB) grade I°-II° was observed in all the patients within a period of 2 months after the beginning of treatment (p = 0.00027). CONCLUSIONS: The clinical observations in these patients suggest a positive effect of nimodipine on the acceleration of peripheral FN regeneration after surgically caused trauma. The results of this pilot-study are very promising. A prospective study with a larger number of patients is planned to approve the beneficial effect of nimodipine on the peripheral FN in maxillofacial or otorhinolaryngological surgery.

Epidermoid tumor of the cerebellopontine angle presenting with selective sudden hearing loss. Intraoperative evidence of a pearl tumor infiltrating and compressing the cochlear nerve.

Epidermoid tumors of the cerebellopontine angle are associated with a variety of symptoms, usually attributed to compression and displacement of involved cranial nerves. The authors present a case of a large epidermoid tumor in the left cerebellopontine angle with sudden hearing loss and tinnitus. The intraoperative finding of migration of two tumor pearls into the cochlear nerve was the origin of the clinical sign. The patient improved remarkably after removal of the tumor. This case demonstrates the mechanism for selective hearing loss associated with the large cerebellopontine angle.

Practice in the perioperative prevention of deep vein thrombosis in german neurosurgical departments: is there a trend towards homogenization?

OBJECTIVE: There was no consensus on the most suitable perioperative prophylaxis of deep vein thrombosis (DVT) in neurosurgical patients. The aim of this work was to review the current practice and search for a standard protocol in the prophylaxis of DVT. METHODS AND MATERIAL: Questionnaires addressing the routine prophylaxis of perioperative DVT for 4 groups of neurosurgical procedures and the estimation of risks and benefits of perioperative heparin (unfractionated and/or low-molecular-weight) administration were sent to 130 neurosurgical departments in Germany. RESULTS: 103 of 130 questionnaires were returned and suitable for analysis. The use of heparin (unfractionated and/or low-molecular-weight) is common, with some variation depending on the type of operation (83.5-99%). In spinal procedures, heparin administration is commonly started early, i. e., between the preoperative and first postoperative day (90.3-97.1%). This differs in intracranial procedures. In most neurosurgical departments heparin administration is stopped at the day of discharge (69.6-77.4% depending on procedure). Enoxaparin is the most commonly used heparin. In spinal as well as in cranial procedures, thrombosis risk reduction is unanimously assumed to be lesser the later administration starts. The estimation of the risks related to heparin injection are considered to be higher in cranial than in spinal operation in the early postoperative period. Most departments use antithrombotic stockings (ATS) irrespective of the type of surgery. However, 11% never use ATS. CONCLUSIONS: In spinal surgery, a trend towards homogenization is observed with the early use of heparin. In intracranial procedures, practice is more heterogenous. The heterogeneity is due to the fact that the data available in the literature does not allow for the identification of an optimal protocol.

Does electrode placement influence quality of intraoperative monitoring in vestibular schwannoma surgery?

OBJECT: Continuous recording of electromyographic signals (EMG) is a standard method for intraoperative monitoring of facial nerve function in cerebello-pontine angle surgery. Subcutaneous needle electrodes in the facial muscles are used in different setups. The goal of this study was to compare two commonly used electrode setups concering sensitivity for pathological EMG activity. PATIENTS AND METHODS: A group of 10 patients undergoing vestibular schwannoma surgery were examined. Continuous EMG from facial muscles was recorded using needle electrodes in setups according to Kartush or Møller, with narrow or wide interelectrode distances, respectively. Quantity of pathological A-train activity and signal-to-noise ratios were compared between setups. RESULTS: A-train activity was seen in all patients. On average, 37% of A-train activity was seen in the Kartush setup alone, 4% in Møller setups alone and 59% in both setups synchronously (p<0.05; ratio of median train time--Kartush:Møller 3:2). The wide interelectrode distance of the Møller setup was found to be significantly more susceptible to artefacts, especially to low frequency and power line noise. Artefacts were the main reason for the Møller setup to fail detecting A-train activity. CONCLUSIONS: For continuous intraoperative monitoring of facial nerve function, narrow interelectrode distance should be used.

Increased dopaminergic neurotransmission in therapy-naïve asymptomatic HIV patients is not associated with adaptive changes at the dopaminergic synapses.

Central dopaminergic (DA) systems are affected during human immunodeficiency virus (HIV) infection. So far, it is believed that they degenerate with progression of HIV disease because deterioration of DA systems is evident in advanced stages of infection. In this manuscript we found that (a) DA levels are increased and DA turnover is decreased in CSF of therapy-naïve HIV patients in asymptomatic infection, (b) DA increase does not modulate the availability of DA transporters and D2-receptors, (c) DA correlates inversely with CD4+ numbers in blood. These findings show activation of central DA systems without development of adaptive responses at DA synapses in asymptomatic HIV infection. It is probable that DA deterioration in advanced stages of HIV infection may derive from increased DA availability in early infection, resulting in DA neurotoxicity. Our findings provide a clue to the synergism between DA medication or drugs of abuse and HIV infection to exacerbate and accelerate HIV neuropsychiatric disease, a central issue in the neurobiology of HIV.

Contrast enhancement and histopathological findings in vestibular schwannoma.

Changes of contrast uptake are considered to indicate the efficacy of therapy in irradiated vestibular schwannomas. We present a case of a large vestibular schwannoma with heterogeneous contrast uptake on MRI. Using neuronavigation, histological samples were obtained during surgery from an area with homogeneous contrast uptake and from a central tumor portion without contrast enhancement on MRI. Intraoperative investigation found no evidence of necrotic tumor, and histopathological examination revealed an active tumor in both sections, with no central necrosis. This finding illustrates the surgical experience that " necrotic tumor areas " on MRI may not be consistent with intraoperative findings. Lack of contrast uptake in previously irradiated schwannomas may not be indicative of effective radiotherapy.

Intraneural perineuriomas; a rare entity. Clinical, surgical and neuropathological details in the management of these lesions.

OBJECTIVE: Perineuriomas are rare benign peripheral nerve sheath tumors, which have only been included in the WHO classification system since 2000. They are divided into intraneural perineuriomas and soft tissue tumors. Intraneural perineuriomas were previously known as localized hypertrophic neuropathies. Because of their rarity there are only case reports in the literature. METHODS: Between 1992 and 2006 surgery was performed on four patients suffering from intraneural perineuriomas in our hospital. All patients were males, aged five, ten, twenty and twenty-nine years old. One of the tumors occurred in the ulnar nerve, one in the common peroneal part of the sciatic nerve and two of them in the radial nerve. In a retrospective study the clinical, electrophysiological and imaging data of the patients was analyzed. Two of these patients had previously been treated with decompression and neurolysis of the nerve for the suspicion of a nerve compression syndrome. Revisions were necessary following progressive neurological deterioration postoperatively. Explorations of the nerves showed nerve tumors. The tumors were resected and nerve grafting was performed. CONCLUSIONS: These tumors tend to affect the nerves of the upper extremities in children or young adults. The predominant symptom is a slow-progressive paralysis. Two of the four patients showed a partial improvement of their motor and sensorial nerve deficits in the long-term follow-up following complete tumor resection and interpositional autologous nerve grafts. No relapse could be observed. In cases of slow-progressive neurological deficits of a peripheral nerve in young patients the differential diagnosis should include the intraneural perineuriomas.

Neurosurgical management of previously coiled recurrent intracranial aneurysms.

OBJECTIVE: Endovascular treatment of cerebral aneurysms with detachable coils has proven to be a save and effective treatment. But long-term recurrence due to aneurysm regrowth or coil compaction has been reported in up to thirty percent of cases. Therefore a growing number of previously coiled aneurysms have to be retreated by coiling or, in some circumstances, by clipping. We present a consecutive series of ten patients who underwent surgical clipping for recurrent aneurysms after primary coil embolization. METHODS: During a 4-year period ten patients with intracranial aneurysms previously treated by coil embolization underwent surgery for clipping of recanalized aneurysms. All aneurysms were located in the anterior circulation (internal carotid artery [ICA], 2; middle cerebral artery [MCA], 3; anterior communicating artery [AcomA], 5). Clinical data and imaging studies of the patients were analyzed retrospectively. RESULTS: All recurrences were detected by routine control angiograms within a median period of 14 months after primary treatment. In three aneurysms treated for SAH dense arachnoid scarring around the aneurysm sac was noted. In four cases, coils were found intraoperatively to be extruding through the aneurysm sac into the subarachnoid space. Each aneurysm could be clipped without affecting the perfusion of the parent vessel. In one patient the aneurysm sac including the coil package was resected. In one patient one of the central anteromedial arteries was injured during dissection due to dense arachnoid scarring because of prior SAH. As a consequence infarction of the head of the caudate nucleus without neurological compromise was observed on follow-up CT scans. Another patient developed transient aphasia due to vasospasm in the early postoperative period with complete restitution. In the end all patients had an uneventful recovery. Removal of the coil package was not necessary in most cases. Clipping of the aneurysm neck was possible even in cases with coil dislocation into the parent vessel. CONCLUSION: Clipping of previously coiled aneurysms is a unique problem for vascular neurosurgeons. In most cases clipping is feasible. Clipping should still be considered as a definite treatment option in previously coiled recurrent aneurysms. Results in this small series were good.

Apoptosis inhibition in T cells triggers the expression of proinflammatory cytokines--implications for the CNS.

Stimulation of death receptors such as CD95 or TNF-R1 results in rapid onset of apoptosis. Here we show that inhibition of death receptor-induced apoptosis by the broad range caspase inhibitor ZVAD causes a switch from apoptotic to proinflammatory signaling. In previous studies we have reported that caspase inhibitors induce expression of various proinflammatory cytokines in CD95-stimulated primary T cells, such as TNF-alpha, IFN-gamma and GM-CSF. In this study we provide further evidence for the proinflammatory activity of CD95. Stimulation of CD95 by agonistic antibodies (7C11) resulted in expression of IL-2 in primary T cells, which was further enhanced when caspase activity was blocked by ZVAD. Moreover, CD95 triggered expression of IL-4 and IL-8 when caspase activity was inhibited, but not in the absence of ZVAD. Our findings are of significant importance for the CNS as changes in the cytokine pattern in the periphery affects the entry of various immune cells into the brain. Moreover, invading activated T cells can also directly influence the cytokine profile within the brain, triggering signaling cascades that eventually lead to neuronal cell death. The use of caspase inhibitors to prevent apoptotic cell death should be carefully evaluated in the management of systemic and CNS diseases.

Delayed facial nerve paresis following acoustic neuroma resection and postoperative vasoactive treatment.

OBJECT: Delayed facial nerve paresis is a well known clinical phenomenon following acoustic neuroma surgery, typically occurring early during the postoperative course. The clinical course of the delayed facial nerve paresis and intraoperative electromyographic (EMG) signals were evaluated in a subgroup of patients who underwent vasoactive treatment for preservation of hearing and developed secondary deterioration after termination of treatment. METHODS: Between 1990 and 2001 seven patients were identified who received vasoactive treatment for preservation of hearing and developed a delayed facial nerve paresis after termination of medication. Intraoperative facial nerve EMG activity was analyzed in six patients. RESULTS: All patients developed a delayed facial nerve paresis between 2-5 days following termination of a 10 day treatment consisting of HES and nimodipine. Medication was re-initiated and the facial nerve paresis improved in all patients. In two patients intraoperative EMG signals revealed "A-trains" waveform patterns, which are highly suggestive for an immediate postoperative facial nerve paresis, whereas in four patients no pathognomonic EMG patterns could be recorded. CONCLUSIONS: The delayed onset of a facial paresis following termination of vasoactive treatment points to a disturbed microcirculation of the nerve as the main pathophysiological feature. Two groups could be identified on the basis of intraoperative EMG activity. In one group with presence of "A-trains" medication apparently masked the onset of an immediate postoperative facial nerve deficit. Four patients without "A-trains" did not develop a typical delayed facial nerve paresis during vasoactive treatment, but thereafter. The time lag between termination of treatment and onset of a delayed palsy points to a protective effect due to improved microcirculation.

Dopamine deficits and regulation of the cAMP second messenger system in brains of simian immunodeficiency virus-infected rhesus monkeys.

The basal ganglia, structures rich in the neurotransmitter dopamine, are primarily affected during human immunodeficiency virus (HIV) infection. The authors measured levels of dopamine and its metabolites, homovanillic acid and 3,4-dihydroxyphenylacetic acid, in brains of uninfected and simian immunodeficiency virus (SIV)-infected rhesus monkeys during the asymptomatic stage of the infection. Moreover, the authors investigated changes in cyclic adenosine monophosphate (cAMP) and cAMP response element-binding protein (CREB), two factors involved in the signaling pathway of dopamine. The brain regions examined were the nucleus accumbens and the corpus amygdaloideum, which are limbic structures of the basal ganglia that are involved in the pathophysiology of psychiatric disorders and substance abuse. Dopamine content was reduced in both regions of SIV-infected monkeys compared to uninfected animals. Moreover, dopamine deficits were associated with a decrease in expression of total CREB. Intracellular concentrations of cAMP were decreased in nucleus accumbens and remained unchanged in corpus amygdaloideum of SIV-infected macaques. Changes in dopamine signaling were not related to pathology or viral load of the investigated animals. The results suggest that dopamine defects precede neurologic deficits and implicate dysfunction of the dopaminergic system in the etiopathogenesis of HIV dementia. Therefore, affective complications in HIV subjects should not be interpreted only as reactive psychological changes. The alterations in the mesolimbic dopaminergic system during asymptomatic stage of SIV infection implicate a biological background for psychiatric disorders in HIV infection.

Syncytium formation amplifies apoptotic signals: a new view on apoptosis in HIV infection in vitro.

Infection of CD4+ cells with HIV in vitro causes extensive cytopathology. The mechanism that underlies this process is unclear and conflicting data exist regarding whether cytotoxicity is due to necrosis or apoptosis. It was previously reported and is shown here that the coculture of HIV glycoprotein-expressing cells with CD4+ cells results in apoptosis within several hours. This study demonstrates that apoptosis did not occur in single cells and was mediated neither by CD4 nor by coreceptor signaling, indicating that apoptosis was not induced by intra- or intercellular glycoprotein-receptor interaction. Detection of apoptosis required cell-to-cell fusion and undetectable levels of apoptotic cell death were substantially amplified upon syncytium formation. Similar results were obtained with syncytium-forming cultures of measles virus glycoprotein-expressing cells. These findings indicate that the apoptotic cell death observed in cultures of HIV and other syncytium-forming viruses is primarily due to amplification of background apoptosis in the wake of cell-to-cell fusion.

Treatment of cells with detergent activates caspases and induces apoptotic cell death.

Due to their amphiphilic properties, detergents readily disrupt cellular membranes and cause rapid cytolysis. In this study we demonstrate that treatment of cells with sublytic concentrations of detergents such as Triton X-100, Nonidet P-40, n-octylglucoside and the bile salt sodium deoxycholate induce typical signs of apoptosis including DNA fragmentation and cleavage of poly(ADP-ribose) polymerase molecules. The detergent concentration required for apoptosis was below the critical micellar concentration. Induction of apoptosis was not restricted to human cells but similarly occurred in a variety of other vertebrate cell lines. Unstimulated peripheral blood mononuclear cells were susceptible to apoptosis induction by detergent suggesting that apoptosis in this circumstance is not mediated by CD95. Cell death was not due to influx of calcium from the medium. Apoptosis was blocked and cytolysis prevented by treatment with peptide inhibitors of caspases. These findings suggest a process of apoptosis that is initiated upon nonspecific alterations at the cell membrane level. Physiologic correlates of this process still have to be defined.

Influenza virus-induced NF-kappaB-dependent gene expression is mediated by overexpression of viral proteins and involves oxidative radicals and activation of IkappaB kinase.

Influenza A viruses are capable of inducing the expression of a variety of cytokine and proapoptotic genes in infected cells. The promoter regions of most of these genes harbor binding sites for the transcription factor NF-kappaB which is an important mediator of immune and inflammatory responses. Our present study is based on an observation that influenza A virus infection of cells stimulates transcriptional activation of the HIV-1 long terminal repeat (LTR) which harbors two regulatory NF-kappaB elements, and is aimed at identifying the molecular mechanisms involved in this process. We found that the expression of influenza virus hemagglutinin (HA), matrix protein (M), and nucleoprotein (NP), as single factors is sufficient to transcriptionally activate the HIV-1 LTR. This process is mediated by oxidative radicals because treatment of cells with pyrrolidine dithiocarbamate, a scavenger of such radicals, abolished the transactivating ability. Expression of different influenza proteins induces activation of NF-kappaB-dependent gene expression but not transcriptional activation of an AP-1/Ets-dependent promoter, indicating a selectivity for NF-kappaB transactivation. Furthermore, influenza protein expression induces activation of IkappaB kinase (IKK). Accordingly coexpression of a catalytically inactive mutant of IKK abolishes influenza protein induced activation of NF-kappaB as well as HIV-1 LTR-dependent reporter gene expression, suggesting that IKK is an important intermediate within this signaling process. Taken together, our results show that various influenza virus proteins act as viral transactivators to modulate transcriptional activity of kappaB-element harboring promoters such as the HIV-LTR.