Occipital nerve stimulation for drug-resistant chronic cluster headache: a prospective pilot study

BACKGROUND: Drug-resistant chronic cluster headache (drCCH) is a devastating disorder for which various destructive procedures have been tried unsuccessfully. Occipital nerve stimulation (ONS) is a new, safe strategy for intractable headaches. We undertook a prospective pilot trial of ONS in drCCH to assess clinical efficacy and pain perception. METHODS: Eight patients with drCCH had a suboccipital neurostimulator implanted on the side of the headache and were asked to record details of frequency, intensity, and symptomatic treatment for their attacks in a diary before and after continuous ONS. To detect changes in cephalic and extracephalic pain processing we measured electrical and pressure pain thresholds and the nociceptive blink reflex. FINDINGS: Two patients were pain free after a follow-up of 16 and 22 months; one of them still had occasional autonomic attacks. Three patients had around a 90% reduction in attack frequency. Two patients, one of whom had had the implant for only 3 months, had improvement of around 40%. Mean follow-up was 15.1 months (SD 9.5, range 3-22). Intensity of attacks tends to decrease earlier than frequency during ONS and, on average, is improved by 50% in remaining attacks. All but one patient were able to substantially reduce their preventive drug treatment. Interruption of ONS by switching off the stimulator or because of an empty battery was followed within days by recurrence and increase of attacks in all improved patients. ONS did not significantly modify pain thresholds. The amplitude of the nociceptive blink reflex increased with longer durations of ONS. There were no serious adverse events. INTERPRETATION: ONS could be an efficient treatment for drCCH and could be safer than deep hypothalamic stimulation. The delay of 2 months or more between implantation and significant clinical improvement suggests that the procedure acts via slow neuromodulatory processes at the level of upper brain stem or diencephalic centres.     

The good use of plasma. A critical analysis of five international guidelines

Background

The clinical use of fresh-frozen plasma (FFP) is progressively increasing both nationally and internationally, despite the fact that many studies have shown the weaknesses of the indications for its use. Guidelines on the good use of plasma have, therefore, been adopted in various countries. The aim of the present study was to analyse some of the existing guidelines on the good use of plasma, applying a scientifically validated method, as a preliminary step in the implementation of Regional guidelines.

Methods

A bibliographic search (1990–2006) was conducted in databases, websites, and the archives of scientific societies. Relevant articles were recovered in full. The selected guidelines were evaluated using the AGREE instrument, which assesses the completeness and structural quality of the guidelines and, in some aspects, the contents of the recommendations. The project, co-ordinated by the Regional Centre for Co-ordination and Compensation (CRCC) and carried out by four Services of Immunohaematology and Transfusion (SIT) in Umbria, was funded by the Region of Umbria and approved by the four health care institutions involved.

Results

The bibliographic search yielded 3067 abstracts of which 239 were considered relevant. The analysis of these led to the recovery of 11 guidelines, among which five were selected: those from the British Committee for Standards in Haematology, the Agence Française de Securité Sanitaire de Produits de Sante, the Canadian Members of the Expert Working Group, the American Society of Anesthesiologists Task Force on Blood Component Therapy and the National Health and Medical Research Council (NHMRC)/Australasian Society of Blood Transfusion.

Conclusions

None of the guidelines analysed obtained a score higher than 50% in all the domains of the AGREE score. There was no evidence of a tendency to improvement over time in the guidelines analysed. Objective evaluation of the guidelines analysed could provide the starting point for the subsequent production of similar documents.     

Common and unique neuro-functional basis of induction, visualization, and spatial relationships as cognitive components of fluid intelligence

Neuroimaging research of fluid intelligence (Gf) has mainly focused on the neural basis of abilities explaining performance on cognitive tasks. However, the neuro-functional basis of clearly defined theoretical cognitive components underlying Gf remains unclear. Induction, visualization, and spatial relationships have the highest relevance for Gf (Carroll, 1993). Here we report a functional magnetic resonance imaging (fMRI) study exploring the neural correlates of these abilities characterized by their unidimensionality and matched for task-difficulty, as evidenced by a psychometric calibration study. Twenty-two healthy young adult females, recruited from a large sample of 300 participants, with either below- or above-average Gf abilities underwent fMRI scanning during Gf task performance. The results reveal that these tasks activate a shared frontoparietal network. Specific activations were also observed, in particular for induction and visualization. The key findings suggest that Gf comprises distinguishable cognitive abilities, but the Gf construct is associated with a common network.     

Translation of drug effects from experimental models of neuropathic pain and analgesia to humans

Neuropathic pain research remains a challenging undertaking owing to: (i) the lack of understanding about the underlying disease processes; and (ii) poor predictive validity of the current models of evoked pain used for the screening of novel compounds. Common consensus is that experimental models replicate symptoms (i.e. have face validity but no construct validity). Another issue that requires attention is the sensitivity of endpoints to discriminate drug effects that are relevant to the disease in humans. In this paper we provide an overview of the pre-clinical models that can be used in conjunction with a model-based approach to facilitate the prediction of drug effects in humans. Our review strongly suggests that evidence of the concentration-effect relationship is necessary for translational purposes.     

Differences in the sensitivity of behavioural measures of pain to the selectivity of cyclo‐oxygenase inhibitors

Objectives: Freund's complete adjuvant (FCA) is an animal model of inflammatory pain commonly used in the screening of COX‐inhibitors. However, there is little understanding of how behavioural measures of the anti‐inflammatory effect in the FCA model correlate to differences in mechanism of action and whether such endpoints equally reflect drug activity in humans. In the current investigation we evaluate the time course of the analgesic effect for different endpoints after treatment with drugs with varying degrees of selectivity for COX‐1 and COX‐2. We also assess prostaglandin (PGE₂) and thromboxane (TXB₂) inhibition to establish the correlation between behavioural measures and the degree of selectivity for COX‐1 and COX‐2. Methods: Sprague–Dawley rats were treated with FCA by intra‐plantar injection. On post‐inoculation day (PID) 7, rats received a single oral dose of naproxen, diclofenac, ketorolac or rofecoxib. Drug treatment continued until PID 21. A control group received placebo only. Behavioural endpoints for inflammatory pain and blood samples for biomarkers were obtained at various time points before and after dosing to characterise the time course of drug effect and disease progression. Results: COX‐inhibitors showed no effect on the dynamic plantar test. In contrast, full analgesia was observed after drug administration for weight bearing capacity (WBC) and paw pressure (PP), with varying duration of the effect for each of the endpoints. No tolerance to drug effect was observed up to 14 days of chronic treatment. Rofecoxib showed an increase in baseline pain threshold values after chronic treatment, which may be related to its pharmacokinetic characteristics. Conclusions: Changes in paw pressure threshold seem to best reflect the anti‐hyperalgesic properties of COX‐inhibitors with enough sensitivity to enable estimation of the dose‐exposure‐response curve.     

Metabolic shift in liver: Correlation between perfusion temperature and hypoxia inducible factor-1α

AIM: To study at what temperature the oxygen carried by the perfusate meets liver requirements in a model of organ perfusion. METHODS: in this study, we correlated hypoxia induciblefactor(Hi F)-1α expression to the perfusion temperature and the hepatic oxygen uptake in a model of isolated perfused rat liver. Livers from Wistar rats were perfused for 6 h with an oxygenated medium at 10, 20, 30 and 37 ℃. Oxygen uptake was measured by an oxygen probe; lactate dehydrogenase activity, lactate release and glycogen were measured spectrophotometrically; bile flow was gravitationally determined; p H of the perfusate was also evaluated; Hi F-1α m RNA and protein expression were analyzed by real time-polymerase chain reaction and ELi SA, respectively. RESULTS: Livers perfused at 10 and 20 ℃ showed no difference in lactate dehydrogenase release after 6 h of perfusion(0.96 ± 0.23 vs 0.93 ± 0.09 m U/min per g) and had lower hepatic damage as compared to 30 and 37 ℃(5.63 ± 0.76 vs 527.69 ± 45.27 m U/min per g, respectively, P s 0.01). After 6 h, tissue ATP was significantly higher in livers perfused at 10 and 20 ℃than in livers perfused at 30 and 37 ℃(0.89 ± 0.06 and 1.16 ± 0.05 vs 0.57 ± 0.09 and 0.33 ± 0.08 nmol/mg, respectively, P s 0.01). No sign of hypoxia was observed at 10 and 20 ℃, as highlighted by low lactate release respect to livers perfused at 30 and 37 ℃(121.4 ± 12.6 and 146.3 ± 7.3 vs 281.8 ± 45.3 and 1094.5 ± 71.7 nmol/m L, respectively, P s 0.02), and low relative Hi F-1α m RNA(0.40 ± 0.08 and 0.20 ± 0.03 vs 0.60 ± 0.20 and 1.47 ± 0.30, respectively, P s 0.05) and protein(3.72 ± 0.16 and 3.65 ± 0.06 vs 4.43 ± 0.41 and 6.44 ± 0.82, respectively, P s 0.05) expression.CONCLUSION: Livers perfused at 10 and 20 ℃ show no sign of liver injury or anaerobiosis, in contrast to livers perfused at 30 and 37 ℃.     

Evaluation of treatment response in depression studies using a Bayesian parametric cure rate model

Efficacy trials with antidepressant drugs often fail to show significant treatment effect even though efficacious treatments are investigated. This failure can, amongst other factors, be attributed to the lack of sensitivity of the statistical method as well as of the endpoints to pharmacological activity. For regulatory purposes the most widely used efficacy endpoint is still the mean change in HAM-D score at the end of the study, despite evidence from literature showing that the HAM-D scale might not be a sensitive tool to assess drug effect and that changes from baseline at the end of treatment may not reflect the extent of response. In the current study, we evaluate the prospect of applying a Bayesian parametric cure rate model (CRM) to analyse antidepressant effect in efficacy trials with paroxetine. The model is based on a survival approach, which allows for a fraction of surviving patients indefinitely after completion of treatment. Data was extracted from GlaxoSmithKline's clinical databases. Response was defined as a 50% change from baseline HAM-D at any assessment time after start of therapy. Survival times were described by a log-normal distribution and drug effect was parameterised as a covariate on the fraction of non-responders. The model was able to fit the data from different studies accurately and results show that response to treatment does not lag for two weeks, as is mythically believed. In conclusion, we demonstrate how parameterisation of a survival model can be used to characterise treatment response in depression trials. The method contrasts with the long-established snapshot on changes from baseline, as it incorporates the time course of response throughout treatment.