An open angiography-based, dose rate escalation study on the effect of intravenous infusion of recombinant tissue plasminogen activator (rt-PA) on cerebral arterial recanalization in patients with acute focal cerebral ischemia was performed at 16 centers. Arterial occlusions consistent with acute ischemia in the carotid or vertebrobasilar territory in the absence of detectable intracerebral hemorrhage were prerequisites for treatment. After the 60-minute rt-PA infusion, arterial perfusion was assessed by repeat angiography and computed tomography scans were performed at 24 hours to assess hemorrhagic transformation. Of 139 patients with symptoms of focal ischemia, 80.6% (112) had complete occlusion of the primary vessel at a mean of 5.4 +/- 1.7 hours after symptom onset. No dose rate response of cerebral arterial recanalization was observed in 93 patients who completed the rt-PA infusion. Middle cerebral artery division (M2) and branch (M3) occlusions were more likely to undergo recanalization by 60 minutes than were internal carotid artery occlusions. Hemorrhagic infarction occurred in 20.2% and parenchymatous hematoma in 10.6% of patients over all dose rates, while neurological worsening accompanied hemorrhagic transformation (hemorrhagic infarction and parenchymatous hematoma) in 9.6% of patients. All findings were within prospective safety guidelines. No dose rate correlation with hemorrhagic infarction, parenchymatous hematoma, or both was seen. Hemorrhagic transformation occurred significantly more frequently in patients receiving treatment at least 6 hours after symptom onset. No relationship between hemorrhagic transformation and recanalization was observed. This study indicates that site of occlusion, time to recanalization, and time to treatment are important variables in acute stroke intervention with this agent.

Noise-induced hearing loss (NIHL) is a global health hazard with considerable pathophysiological and social consequences that has no effective treatment. In the heart, lung and other organs, cyclic guanosine monophosphate (cGMP) facilitates protective processes in response to traumatic events. We therefore analyzed NIHL in mice with a genetic deletion of the gene encoding cGMP-dependent protein kinase type I (Prkg1) and found a greater vulnerability to and markedly less recovery from NIHL in these mice as compared to mice without the deletion. Prkg1 was expressed in the sensory cells and neurons of the inner ear of wild-type mice, and its expression partly overlapped with the expression profile of cGMP-hydrolyzing phosphodiesterase 5 (Pde5). Treatment of rats and wild-type mice with the Pde5 inhibitor vardenafil almost completely prevented NIHL and caused a Prkg1-dependent upregulation of poly (ADP-ribose) in hair cells and the spiral ganglion, suggesting an endogenous protective cGMP-Prkg1 signaling pathway that culminates in the activation of poly (ADP-ribose) polymerase. These data suggest vardenafil or related drugs as possible candidates for the treatment of NIHL.

The exact neurophysiological basis of chronic tinnitus, which affects 10-15% of the population, remains unknown and is controversial at many levels. It is an open question whether phantom sound perception results from increased central neural gain or not, a crucial question for any future therapeutic intervention strategies for tinnitus.We performed a comprehensive study of mild hearing-impaired participants with and without tinnitus, excluding participants with co-occurrences of hyperacusis. A right-hemisphere correlation between tinnitus loudness and auditory perceptual difficulty was observed in the tinnitus group, independent of differences in hearing thresholds. This correlation was linked to reduced and delayed sound-induced suprathreshold auditory brain responses (ABR wave V) in the tinnitus group, suggesting subsided rather than exaggerated central neural responsiveness. When anatomically predefined auditory regions of interest were analysed for altered sound-evoked BOLD fMRI activity, it became evident that subcortical and cortical auditory regions and regions involved in sound detection (posterior insula, hippocampus), responded with reduced BOLD activity in the tinnitus group, emphasizing reduced, rather than increased, central neural gain. Regarding previous findings of evoked BOLD activity being linked to positive connectivities at rest, we additionally analysed r-fcMRI responses in anatomically predefined auditory regions and regions associated with sound detection. A profound reduction in positive interhemispheric connections of homologous auditory brain regions and a decline in the positive connectivities between lower auditory brainstem regions and regions involved in sound detection (hippocampus, posterior insula) were observed in the tinnitus group. The finding went hand-in-hand with the emotional (amygdala, anterior insula) and temporofrontal/stress-regulating regions (prefrontal cortex, inferior frontal gyrus) that were no longer positively connected with auditory cortex regions in the tinnitus group but were instead positively connected to lower-level auditory brainstem regions. Delayed sound processing, reduced sound-evoked BOLD fMRI activity and altered r-fcMRI in the auditory midbrain correlated in the tinnitus group and showed right hemisphere dominance as did tinnitus loudness and perceptual difficulty. The findings suggest that reduced central neural gain in the auditory stream may lead to phantom perception through a failure to energize attentional/stress-regulating networks for contextualization of auditory-specific information. Reduced auditory-specific information flow in tinnitus has until now escaped detection in humans, as low-level auditory brain regions were previously omitted from neuroimaging studies.Trial registration: German Clinical Trials Register DRKS0006332.

Background: Accumulating evidence suggests that tinnitus may occur despite normal auditory sensitivity, probably linked to partial degeneration of the cochlear nerve and damage of the inner hair cell (IHC) synapse. Damage to the IHC synapses and deafferentation may occur even after moderate noise exposure. For both salicylate- and noise-induced tinnitus, aberrant N-methyl-d-aspartate (NMDA) receptor activation and related auditory nerve excitation have been suggested as origin of cochlear tinnitus. Accordingly, NMDA receptor inhibition has been proposed as a pharmacologic approach for treatment of synaptopathic tinnitus. Methods: Round-window application of the NMDA receptor antagonist AM-101 (Esketamine hydrochloride gel; Auris Medical AG, Basel, Switzerland) was tested in an animal model of tinnitus induced by acute traumatic noise. The study included the quantification of IHC ribbon synapses as a correlate for deafferentation as well as the measurement of the auditory brainstem response (ABR) to close-threshold sensation level stimuli as an indication of sound-induced auditory nerve activity. Results: We have shown that AM-101 reduced the trauma-induced loss of IHC ribbons and counteracted the decline of ABR wave I amplitude generated in the cochlea/auditory nerve. Conclusion: Local round-window application of AM-101 may be a promising therapeutic intervention for the treatment of synaptopathic tinnitus.

The Tolosa-Hunt syndrome (THS), a steroid-responsive painful ophthalmoplegia secondary to idiopathic granulomatous inflammation, historically has been categorized as a diagnosis of exclusion because of its nonspecific radiologic presentation. Five patients who satisfied the anatomic and clinical criteria of this syndrome underwent highresolution CT of the orbital apex/cavernous sinus region. Two patients were diagnosed as having orbital apex pseudotumor, two as having cavernous sinus inflammation, and one as having a cavernous sinus epidermoid by the characteristic CT and clinical findings. Follow-up studies while the patients were asymptomatic demonstrated complete resolution of the CT abnormalities in four patients and clinical improvement in all five patients.Our data suggest that orbital apex pseudotumor and granulomatous inflammation of the cavernous sinus have similar clinical features and should be considered as part of the spectrum of THS. With the advent of high-resolution CT, THS may now be a diagnosis of inclusion. Symptomatic improvement after steroid therapy is an essential but not absolute proof of the syndrome, since lesions such as lymphomas may also respond to steroids. Resolution of the soft-tissue inflammation on CT is an additional criterion for diagnosis.The hallmark of the Tolosa-Hunt syndrome (THS) is a painful ophthalmoplegia that is steroid responsive. In 1954, Tolosa [1] reported a patient with left orbital pain , ipsilateral progressive visual loss , total left ophthalmoplegia, and hypesthesia over the first division of the trigeminal nerve. Cerebral angiography demonstrated narrowing of the intracavernous segment of the left internal carotid artery; at autopsy, a low-grade nonspecific granulomatous inflammation of the cavernou s sinus and adventitia of the carotid artery was identified . In 1961 , Hunt et al. [2] reported six cases of remittent unilateral retroorbital pain accompanied by extraocular palsies and occasional supraorbital numbness and blindness; these patients also improved promptly on corticosteroids . Since the radiologic findings of THS in the pre-CT era were often nonspecific and the symptom complex of painful ophthamoplegia could be clinically encountered in patients with other disorders (aneurysms , diabetes mellitus, periarteritis nodosa, parasellar neoplasm/infection , cavernous sinus thrombosis, and carotid cavernous fistula) , there has been a strong emphasis in the neurologic and ophthalmologic literature to categorize the THS as a diagnosis of exclusion . With the advent of high-reSOlution CT, lesions located in the orbital apex, superior orbital fissure, and cavernous sinus region that are directly responsible for the symptoms can now be imaged . As a result , we no longer believe that the THS is a diagnosis of exclusion . While the syndrome is often considered a benign, self-limiting entity, permanent damage to the involved cranial nerves can occur, making prompt diagnosis and steroid therapy mandatory. It is also important that the radiologist be aware of th...