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INTRODUCTION: Internal neurolysis (INL) is a surgical procedure where trigeminal nerve fibres are separated between the pons and porus trigeminus to relieve trigeminal neuralgia (TN). We report pain and functional outcomes to evaluate its safety and efficacy. MATERIALS AND METHODS: Prospective cohort of all patients undergoing retrosigmoid craniotomy and INL between 2015 and 2017 at University Hospital Southampton. Patients with type I (6) or type II (2) refractory TN and no clear neurovascular conflict were offered INL as an alternative to partial sensory rhizotomy. Barrow Pain Intensity Scale (BNI) and Brief Pain Inventory Facial scores (BPI-Facial) were assessed. Minimum follow-up was 2 years'. RESULTS: Eight patients (7F:1M) underwent INL. Two had MS. Pre-operatively, all had severe pain (BNI grade V) and the median BPI-Facial score was 115 (range 79-123).. There were no unexpected complications. On last follow-up, six (75%) had no pain (BNI grade I), while two (25%) had recurred (at 5 and 27 months). Median BPI-Facial score for all patients on the last follow-up was 20 (range 18-91) reflecting dramatically improved quality of life and activities. CONCLUSIONS: INL is a potentially safe and effective treatment for refractory TN. Long-term efficacy is unknown, but early results are promising.
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Radiocirurgia , Neuralgia do Trigêmeo , Humanos , Dor/cirurgia , Estudos Prospectivos , Qualidade de Vida , Radiocirurgia/métodos , Estudos Retrospectivos , Resultado do Tratamento , Nervo Trigêmeo/cirurgia , Neuralgia do Trigêmeo/cirurgia , Reino UnidoRESUMO
OBJECTIVE: Common surgical treatments for trigeminal neuralgia (TN) include microvascular decompression (MVD) and percutaneous procedures (glycerol rhizolysis; thermocoagulation; and balloon compression). Although the efficacy of each procedure has been documented, direct comparisons of their relative efficacies for TN are lacking. We aimed to directly compare long-term outcomes after first-time MVD with percutaneous surgery in primary (idiopathic and classical) TN and identify predictors of outcome. METHODS: We conducted a retrospective analysis of prospectively collected data on 185 patients undergoing MVD and 129 undergoing percutaneous surgery. Procedures were performed by one of two neurosurgeons in a single centre; an independent observer collected long-term follow-up data by interviews, using the same outcome measures for all procedures. RESULTS: MVD patients were younger than those undergoing percutaneous surgery (P <.001). MVD provided superior initial pain relief (P <.001): 87.0% had Barrow Neurological Institute class I or II pain scores after MVD compared with 67.2% after percutaneous surgery. The complication rate for percutaneous procedures was 35.7% and for MVDs was 24.9% (P =.04), including minor and transient complications. Kaplan-Meier analysis demonstrated that MVD provided longer pain relief than percutaneous procedures (P <.001); 25% of patients had recurrence at 96 months following MVD compared with 12 months after percutaneous surgery. Subgroup analysis showed that balloon compression provided more durable relief amongst percutaneous procedures. Multivariate analysis revealed that post-operative numbness and age were prognostic factors for percutaneous procedures (P =.03 and .01, respectively). CONCLUSIONS: MVD provides better initial pain relief and longer durability of relief than percutaneous surgery, although carrying a small risk of major complications. Amongst percutaneous procedures, balloon compression gave the most durable relief from pain. Older age and post-operative numbness were predictors of good outcome from percutaneous surgery. These results can help clinicians to counsel patients with primary TN on neurosurgical treatment selection for pain relief.
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Oclusão com Balão/efeitos adversos , Eletrocoagulação/efeitos adversos , Cirurgia de Descompressão Microvascular/efeitos adversos , Neuralgia do Trigêmeo/cirurgia , Adulto , Idoso , Humanos , Hipestesia/epidemiologia , Hipestesia/etiologia , Masculino , Pessoa de Meia-Idade , Dor/epidemiologia , Dor/etiologia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Neuralgia do Trigêmeo/terapiaRESUMO
BACKGROUND: Glycerol rhizolysis, thermocoagulation, and balloon compression are well established in the treatment of trigeminal neuralgia. OBJECTIVE: To compare the outcome profile of these 3 percutaneous procedures in a single centre over a long follow-up period. METHODS: Over 19 years, 393 procedures were performed on 210 trigeminal neuralgia patients. Patient records and telephone follow-up were used to determine demographic and operative details and surgical outcomes. The length of follow-up extended to over 17 years. RESULTS: The initial rates of complete pain relief with or without medication were 72% for glycerol, 80% for thermocoagulation, and 86% for balloon compression. Kaplan-Meier analysis of recurrence times showed that balloon compression provides significantly longer relief than the other 2 procedures. Complication rates for glycerol, thermocoagulation, and balloon compression were 30.3, 27.1, and 43.5%, respectively. Analysis of repeat procedures showed no difference in recurrence times for balloon compression or thermocoagulation compared with primary procedures, but repeat glycerol procedures gave shorter recurrence times. CONCLUSION: Balloon compression provides longer pain relief than glycerol and thermocoagulation. Although balloon compression is more likely to give numbness and complications, the complications are largely minor and transitory. Moreover, balloon compression following previous percutaneous procedures remains highly effective.
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Eletrocoagulação/métodos , Glicerol/administração & dosagem , Procedimentos Neurocirúrgicos/métodos , Medição da Dor/métodos , Neuralgia do Trigêmeo/diagnóstico , Neuralgia do Trigêmeo/terapia , Idoso , Feminino , Seguimentos , Humanos , Masculino , Medição da Dor/efeitos dos fármacos , Estudos Retrospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
KEY POINTS: The brain makes decisions by means of races between neural units representing alternative choices. In the present study, we record the eyemovements made in the Wheeless task, when a visual stimulus is followed after a short delay by another stimulus demanding a different response. The behaviour can be very precisely described as a race between three independent decision processes: one Go process for each of the responses, and a Stop process that tries to cancel the first, now erroneous, response. To explain the high success rate for cancellation that we observe, the onset time for the Stop process must be some 10-20 ms shorter than for Go. As well as extending our understanding of the dynamics of complex decision-making, this task provides a rapid, non-invasive method for quantifying disorders of higher neural function. ABSTRACT: The brain makes decisions by means of races between neural units representing alternative choices, and such models can predict behaviour in decision tasks in a precisely quantitative way. But what is less clear is how soon after the stimulus the race actually starts. In the present study, we re-visit a complex decision experiment: the Wheeless task, in which a saccadic stimulus is followed after a short delay by a second stimulus, with the subject sometimes making a saccade to the first, now inappropriate, stimulus, and sometimes going straight to the correct one. We demonstrate that a simple model with three accumulator units, two 'Go' and one 'Stop', can then account in detail for the individual responses made, as well as their timing. This complex decision-making behaviour is predicted directly for each individual subject by their performance in a simple step saccadic task, which identifies the two free parameters that are specific for each subject. By contrast to previous assumptions, we find that it is necessary for the onset time of the Stop unit to be shorter than for Go by 10-20 ms. This suggests a specifically fast mechanism for altering responses in situations where urgent action is needed to prevent an impending error.
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Desempenho Psicomotor/fisiologia , Tempo de Reação/fisiologia , Movimentos Sacádicos/fisiologia , Adulto , Feminino , Humanos , Masculino , Estimulação Luminosa , Adulto JovemRESUMO
In the anti-saccade task, a subject must make a saccadic eye movement in the opposite direction from a suddenly-presented visual target. This sets up a conflict between the natural tendency to make a pro-saccade towards the target and the required anti-saccade. Consequently there is a tendency to make errors, usually corrected by a second movement in the correct anti-saccade direction. In a previous paper, we showed that a very simple model, with racing LATER (Linear Approach to Threshold at Ergodic Rate) units for the pro- and anti-directions, and a stop unit that inhibits the impending error response, could account precisely for the detailed distributions of reaction times both for correct and error responses. However, the occurrence and timing of these final corrections have not been studied. We propose a novel mechanism: the decision race re-starts after an error. Here we describe measurements of all the responses in an anti-saccade task, including corrections, in a group of human volunteers, and show that the timing of the corrections themselves can be predicted by the same model with one additional assumption, that initiation of an incorrect pro-saccade also resets and initiates a corrective anti-saccade. No extra parameters are needed to predict this complex aspect of behaviour, adding weight to our proposal that we correct our mistakes by re-starting a neural decision race. The concept of re-starting a decision race is potentially exciting because it implies that neural processing of one decision can influence the next, and may be a fruitful way of understanding the complex behaviour underlying sequential decisions.
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Modelos Neurológicos , Movimentos Sacádicos/fisiologia , Feminino , Humanos , Masculino , Análise e Desempenho de Tarefas , Adulto JovemRESUMO
Glioblastoma is a devastating brain cancer for which effective treatments are required. Tumour-associated microglia and macrophages promote glioblastoma growth in an immune-suppressed microenvironment. Most recurrences occur at the invasive margin of the surrounding brain, yet the relationships between microglia/macrophage phenotypes, T cells and programmed death-ligand 1 (an immune checkpoint) across human glioblastoma regions are understudied. In this study, we performed a quantitative immunohistochemical analysis of 15 markers of microglia/macrophage phenotypes (including anti-inflammatory markers triggering receptor expressed on myeloid cells 2 and CD163, and the low-affinity-activating receptor CD32a), T cells, natural killer cells and programmed death-ligand 1, in 59 human IDH1-wild-type glioblastoma multi-regional samples (n = 177; 1 sample at tumour core, 2 samples at the margins: the infiltrating zone and leading edge). Assessment was made for the prognostic value of markers; the results were validated in an independent cohort. Microglia/macrophage motility and activation (Iba1, CD68), programmed death-ligand 1 and CD4+ T cells were reduced, and homeostatic microglia (P2RY12) were increased in the invasive margins compared with the tumour core. There were significant positive correlations between microglia/macrophage markers CD68 (phagocytic)/triggering receptor expressed on myeloid cells 2 (anti-inflammatory) and CD8+ T cells in the invasive margins but not in the tumour core (P < 0.01). Programmed death-ligand 1 expression was associated with microglia/macrophage markers (including anti-inflammatory) CD68, CD163, CD32a and triggering receptor expressed on myeloid cells 2, only in the leading edge of glioblastomas (P < 0.01). Similarly, there was a positive correlation between programmed death-ligand 1 expression and CD8+ T-cell infiltration in the leading edge (P < 0.001). There was no relationship between CD64 (a receptor for autoreactive T-cell responses) and CD8+/CD4+ T cells, or between the microglia/macrophage antigen presentation marker HLA-DR and microglial motility (Iba1) in the tumour margins. Natural killer cell infiltration (CD335+) correlated with CD8+ T cells and with CD68/CD163/triggering receptor expressed on myeloid cells 2 anti-inflammatory microglia/macrophages at the leading edge. In an independent large glioblastoma cohort with transcriptomic data, positive correlations between anti-inflammatory microglia/macrophage markers (triggering receptor expressed on myeloid cells 2, CD163 and CD32a) and CD4+/CD8+/programmed death-ligand 1 RNA expression were validated (P < 0.001). Finally, multivariate analysis showed that high triggering receptor expressed on myeloid cells 2, programmed death-ligand 1 and CD32a expression at the leading edge were significantly associated with poorer overall patient survival (hazard ratio = 2.05, 3.42 and 2.11, respectively), independent of clinical variables. In conclusion, anti-inflammatory microglia/macrophages, CD8+ T cells and programmed death-ligand 1 are correlated in the invasive margins of glioblastoma, consistent with immune-suppressive interactions. High triggering receptor expressed on myeloid cells 2, programmed death-ligand 1 and CD32a expression at the human glioblastoma leading edge are predictors of poorer overall survival. Given substantial interest in targeting microglia/macrophages, together with immune checkpoint inhibitors in cancer, these data have major clinical implications.
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Glioblastoma evolution is facilitated by intratumour heterogeneity, which poses a major hurdle to effective treatment. Evidence indicates a key role for oncogene amplification on extrachromosomal DNA (ecDNA) in accelerating tumour evolution and thus resistance to treatment, particularly in glioblastomas. Oncogenes contained within ecDNA can reach high copy numbers and expression levels, and their unequal segregation can result in more rapid copy number changes in response to therapy than is possible through natural selection of intrachromosomal genomic loci. Notably, targeted therapies inhibiting oncogenic pathways have failed to improve glioblastoma outcomes. In this Perspective, we outline reasons for this disappointing lack of clinical translation and present the emerging evidence implicating ecDNA as an important driver of tumour evolution. Furthermore, we suggest that through detection of ecDNA, patient selection for clinical trials of novel agents can be optimized to include those most likely to benefit based on current understanding of resistance mechanisms. We discuss the challenges to successful translation of this approach, including accurate detection of ecDNA in tumour tissue with novel technologies, development of faithful preclinical models for predicting the efficacy of novel agents in the presence of ecDNA oncogenes, and understanding the mechanisms of ecDNA formation during cancer evolution and how they could be attenuated therapeutically. Finally, we evaluate the feasibility of routine ecDNA characterization in the clinic and how this process could be integrated with other methods of molecular stratification to maximize the potential for clinical translation of precision medicines.
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Glioblastoma , Neoplasias , Humanos , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Oncogenes , Neoplasias/genética , Genômica/métodos , DNARESUMO
Hypomelanosis of Ito is a rare neurocutaneous syndrome characterized by presence of hypopigmented skin lesions arranged in whorls and streaks following the lines of Blaschko and are often accompanied by abnormalities of the central nervous system, skeletal system, eyes and teeth. Additional symptoms include deafness, hemihypertrophy, cardiac abnormalities, renal malformations, and abnormalities of the genitourinary tract.
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Hipopigmentação , Transtornos da Pigmentação , Humanos , Hipopigmentação/complicações , Hipopigmentação/etiologia , Transtornos da Pigmentação/complicações , Transtornos da Pigmentação/etiologiaRESUMO
Measurement of the stochastic distribution of reaction time or latency has become a popular technique that can potentially provide precise, quantitative information about the underlying neural decision mechanisms. However, this approach typically requires data from large numbers of individual trials, in order to enable reliable distinctions to be made between different models of decision. When data are not plentiful, an approximation to full distributional information can be provided by using a small number of quantiles instead of full distributions - often, just five are used. Although this can often be adequate when the proposed underlying model is a relatively simple one, we show here that, with more complex tasks, and correspondingly extended models, this kind of approximation can often be extremely misleading, and may hide important features of the underlying mechanisms that only full distributional analysis can reveal.
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Encéfalo/fisiologia , Tomada de Decisões/fisiologia , Neurônios/fisiologia , Tempo de Reação/fisiologia , Animais , Humanos , Modelos NeurológicosRESUMO
Response time, or latency, is increasingly being used to provide information about neural decision processes. LATER (Linear Approach to Threshold with Ergodic Rate) is a quasi-Bayesian model of decision-making, with the additional feature that it introduces a degree of gratuitous randomisation into the decision process. It has had some success in predicting latencies under various conditions, but has not specifically been applied to an equally important aspect of decision-making, namely errors: a complete model of decision-making should not only account for latency distributions of correct decisions but also of wrong ones. We therefore used a decision task that generates large numbers of errors: subjects are told to look at suddenly appearing targets of one colour, but not another. We found that subjects' faster responses are as likely to be correct as wrong, but eventually the latency distributions diverge, with errors becoming infrequent. It seems that colour information, arriving after a delay, results both in cancellation of the developing response to the mere existence of the target and in delayed initiation of the correct response. A simple model, using LATER units in a similar way to one that has previously successfully modelled countermanding, accurately predicts latency distributions and proportions of all responses, whether correct or incorrect, demonstrating that the LATER model can indeed account for errors as well as correct responses.
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Tomada de Decisões/fisiologia , Tempo de Reação/fisiologia , Movimentos Sacádicos/fisiologia , Feminino , Humanos , Masculino , Modelos Psicológicos , Testes Neuropsicológicos , Estimulação Luminosa , Desempenho Psicomotor/fisiologiaRESUMO
Oculomotor decision making can be investigated by a simple step task, where a person decides whether a target has jumped to the left or the right. More complex tasks include the countermanding task (look at the jumped target, except when a subsequent signal instructs you not to) and the Wheeless task (where the jumped target sometimes then quickly jumps to a new location). Different instantiations of the LATER (Linear Approach to Threshold with Ergodic Rate) model have been shown to explain the saccadic latency data arising from these tasks, despite it being almost inconceivable that completely separate decision-making mechanisms exist for each. However, these models have an identical construction with regards to predicting prosaccadic responses (all step task trials, and control trials in countermanding and Wheeless tasks, where no countermanding signal is given or when the target does not make a second jump). We measured saccadic latencies for 23 human observers each performing the three tasks, and modelled prosaccade latencies with LATER to see if model parameters were usefully preserved across tasks. We found no significant difference in reaction times and model parameters between the step and Wheeless tasks (mean 175 and 177â¯ms, respectively; standard deviation, SD 22 and 24â¯ms). In contrast, we identified prolonged latencies in the countermanding tasks (236â¯ms; SD 37â¯ms) explained by a slower rise and an elevated threshold of the decision making signal, suggesting elevated participant caution. Our findings support the idea that common machinery exists for oculomotor decision-making, which can be flexibly deployed depending upon task demands.
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Desempenho Psicomotor , Movimentos Sacádicos , Humanos , Estimulação Luminosa , Tempo de ReaçãoRESUMO
Human cancers harbor substantial genetic, epigenetic, and transcriptional changes, only some of which drive oncogenesis at certain times during cancer evolution. Identifying the cancer-driver alterations amongst the vast swathes of "passenger" changes still remains a major challenge. Transposon and CRISPR screens in vivo provide complementary methods for achieving this, and each platform has its own advantages. Here, we review recent major technological breakthroughs made with these two approaches and highlight future directions. We discuss how each genetic screening platform can provide unique insight into cancer evolution, including intra-tumoral heterogeneity, metastasis, and immune evasion, presenting transformative opportunities for targeted therapeutic intervention.
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Sistemas CRISPR-Cas , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Genes Neoplásicos , Neoplasias/genética , Animais , Carcinogênese/genética , Transformação Celular Neoplásica/genética , Elementos de DNA Transponíveis , Testes Genéticos , Humanos , Imunoterapia , Mutagênese , Metástase NeoplásicaRESUMO
BACKGROUND: Glioma is the most common intrinsic brain tumor and also occurs in the spinal cord. Activating EGFR mutations are common in IDH1 wild-type gliomas. However, the cooperative partners of EGFR driving gliomagenesis remain poorly understood. RESULTS: We explore EGFR-mutant glioma evolution in conditional mutant mice by whole-exome sequencing, transposon mutagenesis forward genetic screening, and transcriptomics. We show mutant EGFR is sufficient to initiate gliomagenesis in vivo, both in the brain and spinal cord. We identify significantly recurrent somatic alterations in these gliomas including mutant EGFR amplifications and Sub1, Trp53, and Tead2 loss-of-function mutations. Comprehensive functional characterization of 96 gliomas by genome-wide piggyBac insertional mutagenesis in vivo identifies 281 known and novel EGFR-cooperating driver genes, including Cdkn2a, Nf1, Spred1, and Nav3. Transcriptomics confirms transposon-mediated effects on expression of these genes. We validate the clinical relevance of new putative tumor suppressors by showing these are frequently altered in patients' gliomas, with prognostic implications. We discover shared and distinct driver mutations in brain and spinal gliomas and confirm in vivo differential tumor suppressive effects of Pten between these tumors. Functional validation with CRISPR-Cas9-induced mutations in novel genes Tead2, Spred1, and Nav3 demonstrates heightened EGFRvIII-glioma cell proliferation. Chemogenomic analysis of mutated glioma genes reveals potential drug targets, with several investigational drugs showing efficacy in vitro. CONCLUSION: Our work elucidates functional driver landscapes of EGFR-mutant gliomas, uncovering potential therapeutic strategies, and provides new tools for functional interrogation of gliomagenesis.
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Neoplasias do Sistema Nervoso Central/genética , Elementos de DNA Transponíveis , Receptores ErbB/genética , Genes erbB , Glioma/genética , Animais , Carcinogênese , Receptores ErbB/metabolismo , Instabilidade Genômica , Humanos , Camundongos Transgênicos , Terapia de Alvo Molecular , Mutagênese Insercional , Neoplasias Experimentais , Proteínas do Tecido Nervoso , Sequenciamento do ExomaRESUMO
An amendment to this paper has been published and can be accessed via the original article.
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The most common brain tumours, gliomas, have significant morbidity. Detailed biological and genetic understanding of these tumours is needed in order to devise effective, rational therapies. In an era generating unprecedented quantities of genomic sequencing data from human cancers, complementary methods of deciphering the underlying functional cancer genes and mechanisms are becoming even more important. Genetically engineered mouse models of gliomas have provided a platform for investigating the molecular underpinning of this complex disease, and new tools for such models are emerging that are enabling us to answer the most important questions in the field. Here, I discuss improvements to genome engineering technologies that have led to more faithful mouse models resembling human gliomas, including new cre/LoxP transgenic lines that allow more accurate cell targeting of genetic recombination, Sleeping Beauty and piggyBac transposons for the integration of transgenes and genetic screens, and CRISPR-cas9 for generating genetic knockout and functional screens. Applications of these technologies are providing novel insights into the functional genetic drivers of gliomagenesis, how these genes cooperate with one another, and the potential cells-of-origin of gliomas, knowledge of which is critical to the development of targeted treatments for patients in the clinic.
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BACKGROUND: Balloon compression (BC), thermocoagulation (TC), and glycerol rhizolysis (GR) are percutaneous surgical options for trigeminal neuralgia (TN). Whether the outcomes of these procedures in multiple sclerosis -related TN (MS-TN) are as effective as in idiopathic TN (ITN) is unknown. OBJECTIVE: To retrospectively compare pain relief, complications, and durability achieved by these 3 types of procedures in MS-TN and ITN. METHODS: Two hundred and four patients with typical TN were treated percutaneously: 33 had MS-TN (64 procedures) and 171 had ITN (329 procedures). All were performed by 1 of 2 neurosurgeons; interviews enabled long-term data to be gathered by an independent observer. RESULTS: MS-TN patients (53.1%) had Barrow Neurological Institute pain scores of I or II after a percutaneous procedure, compared with 59.3% in the ITN cohort; there was no difference in initial relief between the 2 groups overall (P = .52). There was a trend toward fewer complications in MS-TN compared with ITN (23.4% vs 33.7%, respectively; P = .058). Kaplan-Meier analysis demonstrated no difference in durability of relief in MS-TN (median 23.0 mo) compared with ITN overall (median 24.0 mo; P = .75). Subgroup analysis demonstrated longer relief from BC and TC compared with GR in MS-TN (P = .013). Multivariate analysis confirmed that although the presence of MS does not predict durability of outcome, postoperative numbness (P = .0046) and undergoing a repeat procedure (P = .037) were significant predictors. CONCLUSION: BC and TC are safe and effective in MS-TN. Postoperative numbness is the strongest prognostic factor in MS-TN.