The Influence of Depression, Anxiety and Cognition on the Treatment Effects of Ginkgo biloba Extract EGb 761® in Patients with Tinnitus and Dementia: A Mediation Analysis.

BACKGROUND: Comorbid occurrence of tinnitus and emotional symptoms of anxiety and depression is highly prevalent. The Ginkgo biloba extract EGb 761® has been shown to be effective in reducing neuropsychiatric symptoms in patients with dementia and tinnitus. METHODS: We performed a mediation analysis to evaluate direct effects of EGb 761® on tinnitus severity, as well as indirect effects mediated by symptoms of depression and anxiety and by changed cognition. We pooled data from subsets of patients suffering from tinnitus that were enrolled in three double-blind, randomized, placebo-controlled clinical trials, which investigated the efficacy of EGb 761® (240 mg/day for 22-24 weeks) in dementia with concomitant neuropsychiatric symptoms. RESULTS: In total, 594 patients suffered from tinnitus (EGb 761®, 289; placebo, 305). Direct effects of EGb 761® on tinnitus severity (p < 0.001) in patients with mild to moderate dementia were found to represent about 60% of the total effect, whereas the indirect effects (p < 0.001) mediated by improvement of anxiety, depression and cognition represented about 40% of the total effect. CONCLUSIONS: EGb 761® could be considered as a supporting treatment for tinnitus in elderly patients suffering from dementia, with added benefit in those with symptoms of depression or anxiety.

Cerebral Venous Thrombosis with Migraine-Like Headache and the Trigeminovascular System.

Cerebral venous thrombosis- (CVT-) associated headache is considered a secondary headache, commonly presenting as intracranial hypertension headache in association with seizures and/or neurological signs. However, it can occasionally mimic migraine. We report a patient presenting with a migraine-like, CVT-related headache refractory to several medications but intravenous dihydroergotamine (DHE). The response to DHE, which is considered to be an antimigraine medication, in addition to the neurovascular nature of migraine, points out to a probable similarity between CVT-headache and migraine. Based on experimental studies, we discuss this similarity and hypothesize a trigeminovascular role in the genesis of CVT-associated headache.

The MDM4/MDM2-p53-IGF1 axis controls axonal regeneration, sprouting and functional recovery after CNS injury.

Regeneration of injured central nervous system axons is highly restricted, causing neurological impairment. To date, although the lack of intrinsic regenerative potential is well described, a key regulatory molecular mechanism for the enhancement of both axonal regrowth and functional recovery after central nervous system injury remains elusive. While ubiquitin ligases coordinate neuronal morphogenesis and connectivity during development as well as after axonal injury, their role specifically in axonal regeneration is unknown. Following a bioinformatics network analysis combining ubiquitin ligases with previously defined axonal regenerative proteins, we found a triad composed of the ubiquitin ligases MDM4, MDM2 and the transcription factor p53 (encoded by TP53) as a putative central signalling complex restricting the regeneration program. Indeed, conditional deletion of MDM4 or pharmacological inhibition of MDM2/p53 interaction in the eye and spinal cord promote axonal regeneration and sprouting of the optic nerve after crush and of supraspinal tracts after spinal cord injury. The double conditional deletion of MDM4-p53 as well as MDM2 inhibition in p53-deficient mice blocks this regenerative phenotype, showing its dependence upon p53. Genome-wide gene expression analysis from ex vivo fluorescence-activated cell sorting in MDM4-deficient retinal ganglion cells identifies the downstream target IGF1R, whose activity and expression was found to be required for the regeneration elicited by MDM4 deletion. Importantly, we demonstrate that pharmacological enhancement of the MDM2/p53-IGF1R axis enhances axonal sprouting as well as functional recovery after spinal cord injury. Thus, our results show MDM4-MDM2/p53-IGF1R as an original regulatory mechanism for CNS regeneration and offer novel targets to enhance neurological recovery.media-1vid110.1093/brain/awv125_video_abstractawv125_video_abstract.

PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system.

Axonal regenerative failure is a major cause of neurological impairment following central nervous system (CNS) but not peripheral nervous system (PNS) injury. Notably, PNS injury triggers a coordinated regenerative gene expression programme. However, the molecular link between retrograde signalling and the regulation of this gene expression programme that leads to the differential regenerative capacity remains elusive. Here we show through systematic epigenetic studies that the histone acetyltransferase p300/CBP-associated factor (PCAF) promotes acetylation of histone 3 Lys 9 at the promoters of established key regeneration-associated genes following a peripheral but not a central axonal injury. Furthermore, we find that extracellular signal-regulated kinase (ERK)-mediated retrograde signalling is required for PCAF-dependent regenerative gene reprogramming. Finally, PCAF is necessary for conditioning-dependent axonal regeneration and also singularly promotes regeneration after spinal cord injury. Thus, we find a specific epigenetic mechanism that regulates axonal regeneration of CNS axons, suggesting novel targets for clinical application.

Safe resection of arteriovenous malformations in eloquent motor areas aided by functional imaging and intraoperative monitoring.

BACKGROUND: Arteriovenous malformations (AVMs) proximal to motor cortical areas or motor projection systems are challenging to manage because of the risk of severe sensory and motor impairment. Surgical indication in these cases therefore remains controversial. OBJECTIVE: To propose a standardized approach for centrally situated AVMs based on functional imaging and intraoperative electrophysiological evaluation. METHODS: We conducted a retrospective analysis of 15 patients who underwent surgical treatment for AVMs in motor cortical areas or proximal to motor projections. Preoperative assessment included functional magnetic resonance and 3-dimensional tractography. Operations were performed under continuous electrophysiological monitoring aided by direct brain stimulation. We identified critical bloody supply to the motor areas by temporary occluding the feeding vessels under electrophysiological monitoring. Clinical outcome was evaluated with the modified Rankin Scale. RESULTS: Total resection was achieved in 12 cases, whereas electrophysiology limited total extirpation in 3 cases. A significant reduction of motor evoked potentials by up to 15% of the initial values was associated with good recovery of motor function; in contrast, the disappearance of potentials correlated with long-term impairment. The mean follow-up time was 13 months, and clinical assessments revealed overall functional improvement (P < .05). After surgery, 11 patients were asymptomatic or presented with only minor neurological deficits. CONCLUSION: Surgical resection of AVMs in eloquent motor areas can be considered a safe option for selected cases when performed in conjunction with a detailed functional assessment. Possible selection criteria for surgical treatment are discussed in light of the presented clinical data.

Transitional lumbosacral vertebrae and low back pain: diagnostic pitfalls and management of Bertolotti's syndrome.

OBJECTIVE: Bertolotti's syndrome is a spine disorder characterized by the occurrence of a congenital lumbar transverse mega-apophysis in a transitional vertebral body that usually articulates with the sacrum or the iliac bone. It has been considered a possible cause of low back pain. METHOD: We analyzed the cases of Bertolotti's syndrome that failed clinical treatment and reviewed the literature concerning this subject. RESULTS: Five patients in our series had severe low back pain due to the neo-articulation and two of them were successfully submitted to surgical resection of the transverse mega-apophysis. Taking into account the clinical and surgical experience acquired with these cases, we propose a diagnostic-therapeutic algorithm. CONCLUSION: There is still no consensus about the most appropriate therapy for Bertolotti's syndrome. In patients in whom the mega-apophysis itself may be the source of back pain, surgical resection may be a safe and effective procedure.

Transitional lumbosacral vertebrae and low back pain: diagnostic pitfalls and management of Bertolotti's syndrome / Dor lombar associada à vértebra de transição lombossacra: dificuldades no diagnóstico e manejo da síndrome de Bertolotti

OBJECTIVE: Bertolotti's syndrome is a spine disorder characterized by the occurrence of a congenital lumbar transverse mega-apophysis in a transitional vertebral body that usually articulates with the sacrum or the iliac bone. It has been considered a possible cause of low back pain. METHOD: We analyzed the cases of Bertolotti's syndrome that failed clinical treatment and reviewed the literature concerning this subject. RESULTS: Five patients in our series had severe low back pain due to the neo-articulation and two of them were successfully submitted to surgical resection of the transverse mega-apophysis. Taking into account the clinical and surgical experience acquired with these cases, we propose a diagnostic-therapeutic algorithm. CONCLUSION: There is still no consensus about the most appropriate therapy for Bertolotti's syndrome. In patients in whom the mega-apophysis itself may be the source of back pain, surgical resection may be a safe and effective procedure.

OBJETIVO: A síndrome de Bertolotti é uma desordem congênita da coluna vertebral caracterizada pela ocorrência de uma mega-apófise transversa lombar em uma vértebra de aspecto transicional, que geralmente se articula com o sacro ou com o osso ilíaco. Tal síndrome tem sido considerada possível causa de dor lombar. MÉTODO: Análise dos casos de síndrome de Bertolotti que apresentavam dor lombar sem melhora com tratamento conservador e revisão dos artigos publicados. RESULTADOS: Foram revisados cinco pacientes que não apresentaram melhora com o tratamento clínico, sendo que dois foram submetidos à ressecção cirúrgica da mega-apófise transversa. Considerando a experiência adquirida com estes casos, os autores propõem um algoritmo para diagnóstico e tratamento da Síndrome de Bertolotti. CONCLUSÃO: Ainda não há consenso sobre qual é a terapia mais apropriada para a Síndrome de Bertolotti. Em pacientes em que a mega-apófise parece ser a origem da lombalgia, a ressecção cirúrgica parece ser um procedimento seguro e efetivo.