[Show abstract][Hide abstract] ABSTRACT: Objective: To examine the epidemiology of referrals to a specialist neurotrauma clinic and explore and highlight implications for clinical practice and service development for persons with head injury/traumatic brain injury (HI/TBI). Design and methods: A retrospective population-based cohort study of all referrals to a specialist neurotrauma clinic over a 9-year period. Data from a specialist head injury database (which included all persons presenting to hospital with traumatic brain injury) were analysed. Results: In total, 1235 new patients of all ages, severities of injury, both admitted and non-admitted were referred. Referrals have increased due to successful integration with new service developments and resulting optimization of resources. Conclusions: Data gathered from the cohort gives increased understanding of the characteristics and numbers of patients requiring rehabilitation and adds to the evidence-base. Integration with new and complementary service developments has optimized the function/aims of the clinic and enhanced its role in terms of patient service and outcome and as a research resource. The model provides principles which may be applied to planning, organizing and providing follow-up/rehabilitation services for HI/TBI.
[Show abstract][Hide abstract] ABSTRACT: The extent of hemodynamic disturbances following subarachnoid hemorrhage (SAH) varies. We aim to determine the prognostic implications of unilateral and bilateral autoregulatory failure on delayed cerebral ischemia (DCI) and outcome.
[Show abstract][Hide abstract] ABSTRACT: In the healthy brain, small oscillations in intracranial pressure (ICP) occur synchronously with those in cerebral blood volume (CBV), cerebrovascular resistance, and consequently cerebral blood flow velocity (CBFV). Previous work has shown that the usual synchrony between ICP and CBFV is lost during intracranial hypertension. Moreover, a continuously computed measure of the ICP/CBFV association (Fix index) was a more sensitive predictor of outcome after traumatic brain injury (TBI) than a measure of autoregulation (Mx index). In the current study we computed Fix during ICP plateau waves, to observe its behavior during a defined period of cerebrovascular vasodilatation.
[Show abstract][Hide abstract] ABSTRACT: Cerebral vasospasm has traditionally been regarded as an important cause of delayed cerebral ischaemia (DCI) which occurs after aneurysmal subarachnoid haemorrhage, and often leads to cerebral infarction and poor neurological outcome. However, data from recent studies argue against a pure focus on vasospasm as the cause of delayed ischaemic complications. Findings that marked reduction in the incidence of vasospasm does not translate to a reduction in DCI, or better outcomes has intensified research into other possible mechanisms which may promote ischaemic complications. Early brain injury and cell death, blood-brain barrier disruption and initiation of an inflammatory cascade, microvascular spasm, microthrombosis, cortical spreading depolarisations and failure of cerebral autoregulation, have all been implicated in the pathophysiology of DCI. This review summarises the current knowledge about the mechanisms underlying the development of DCI. Furthermore, it aims to describe and categorise the known pharmacological treatment options with respect to the presumed mechanism of action and its role in DCI.
Journal of neurology, neurosurgery, and psychiatry. 05/2014;
[Show abstract][Hide abstract] ABSTRACT: AimIdiopathic intracranial hypertension (IIH) is prone to misdiagnosis. Our aim was to identify the reasons for this in children in our region referred for suspected IIH.Method
We reviewed the records of all children referred with symptoms and/or signs consistent with raised intracranial pressure (ICP) and normal magnetic resonance imaging of the brain to our tertiary neurology unit over 4 years. IIH was confirmed after expert ophthalmology including ultrasound/tomography and advanced cerebrospinal fluid (CSF) pressure studies.ResultsOf 15 children (six males, nine females; median age 12y, range 3–15y), six (five females, one male) were confirmed to have IIH. All weighed above the 91st centile and were over 10 years old. Four of the six had raised ICP secondary to other causes. Four had been misdiagnosed locally with papilloedema, three had drusen, and one had ‘crowded discs’. Two had raised CSF pressures on standard lumbar puncture, but 20-minute steady state and infusion studies were normal, with symptoms settling after therapy was withdrawn.InterpretationMisdiagnosis of IIH was frequent, but could be reduced by (1) expert ophthalmological fundoscopy, orbital ultrasound, and optical coherence tomography; (2) expert neuroradiology; and (3) assessment of steady state CSF pressure rather than standard opening pressure in centimetres of water.
Developmental Medicine & Child Neurology 05/2014; · 2.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The vascular wall tension (WT) of small cerebral vessels can be quantitatively estimated through the concept of critical closing pressure (CrCP), which denotes the lower limit of arterial blood pressure (ABP), below which small cerebral arterial vessels collapse and blood flow ceases. WT can be expressed as the difference between CrCP and intracranial pressure (ICP) and represent active vasomotor tone. In this study, we investigated the association of WT and CrCP with autoregulation and outcome of a large group of patients after traumatic brain injury (TBI).
We retrospectively analysed recordings of ABP, ICP and transcranial Doppler (TCD) blood flow velocity from 280 TBI patients (median age: 29 years; interquartile range: 20-43). CrCP and WT were calculated using the cerebrovascular impedance methodology. Autoregulation was assessed based on TCD-based indices, Mx and ARI.
Low values of WT were found to be associated with an impaired autoregulatory capacity, signified by its correlation to FV-based indices Mx (R = -0.138; p = 0.021) and ARI (R = 0.118; p = 0.048). No relationship could be established between CrCP and any of the autoregulatory indices. Neither CrCP nor WT was found to correlate with outcome.
Impaired autoregulation was found to be associated with a lower WT supporting the role of vasoparalysis in the loss of autoregulatory capacity. In contrast, no links between CrCP and autoregulation could be identified.
[Show abstract][Hide abstract] ABSTRACT: Infusion tests are important tools to assess cerebrospinal fluid (CSF)dynamics used in the preoperative selection of patients for shunt surgery, or to predict the scope of improvement from shunt revision. The aim of this study was to assess the repeatability of the key quantitative parameters describing CSF dynamics that are determined with infusion testing.
Eighteen patients in whom a constant infusion test was repeated within 102 days, without any intermediate surgical intervention, were studied. From each test baseline ICP, baseline pulse amplitude, outflow resistance, elastance coefficient and slope of the amplitude-pressure line were calculated and investigated with a regression and Bland-Altman analysis.
Significant correlations (P < 0.01) were found for the outflow resistance (R = 0.96), the elastance coefficient (R = 0.778) and the slope of the amplitude-pressure line (R = 0.876). The estimated 95% confidence level for outflow resistance was 3 mmHg/ml min. Likewise, the elastance coefficient lay within a range of 0.16/ml and the slope of the amplitude-pressure line within 0.25. The most inconsistent parameter found were baseline ICP (R = 0.272) and baseline pulse amplitude (R = 0.171).
The results of this study imply that the parameters resulting from an infusion study have to be considered within a range rather than as an absolute value.
[Show abstract][Hide abstract] ABSTRACT: Objectives: We studied possible link between cerebrospinal fluid (CSF) compensation and indices describing pulsatile inflow of cerebral arterial blood. Methods: A total of 50 infusion tests performed in patients with symptoms of normal pressure hydrocephalus (NPH) were examined retrospectively. Waveforms of CSF pressure, noninvasive arterial blood pressure (ABP), and transcranial Doppler (TCD) cerebral blood flow velocity (CBFV) were used to estimate relative changes in cerebral arterial compliance (Ca) and cerebrovascular resistance (CVR). Product of Ca and CVR, called cerebral arterial time constant (τ, unit: seconds), was calculated at the baseline and plateau phase of the test and compared with CSF compensatory parameters such as resistance to CSF outflow, elasticity, slope of amplitude-pressure line, and pulse amplitude of CSF pressure. Results: Neither of CSF compensatory parameters correlated with hemodynamic indices. However, the change in cerebral perfusion pressure (CPP) provoked change in τ (R = 0·33; P = 0·017) secondary to a change in CVR (R = 0·81; P < 0·0001). Changes in CVR and Ca had a reciprocal character (R = -0·64; P < 0·0001) with magnitude of variation in CVR (68%) prevailing over magnitude of changes in Ca (49%). Discussion: Hemodynamics of pulsatile inflow of cerebral arterial blood assessed by cerebral arterial time constant is not directly linked to dynamics of CSF circulation and pressure-volume compensation but is sensitive to changes in CPP during infusion test.
Neurological Research 03/2014; 36(3):255-61. · 1.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Traumatic brain injury (TBI) is the commonest cause of death and disability in those aged under 40 years. Interleukin-1 receptor antagonist (IL1ra) is an endogenous competitive antagonist at the interleukin-1 type-1 receptor (IL-1R). Antagonism at the IL-1R confers neuroprotection in several rodent models of neuronal injury (i.e., trauma, stroke and excitotoxicity). We describe a single center, phase II, open label, randomized-control study of recombinant human IL1ra (rhIL1ra, anakinra) in severe TBI, at a dose of 100 mg subcutaneously once a day for 5 days in 20 patients randomized 1:1. We provide safety data (primary outcome) in this pathology, utilize cerebral microdialysis to directly determine brain extracellular concentrations of IL1ra and 41 cytokines and chemokines, and use principal component analysis (PCA) to explore the resultant cerebral cytokine profile. Interleukin-1 receptor antagonist was safe, penetrated into plasma and the brain extracellular fluid. The PCA showed a separation in cytokine profiles after IL1ra administration. A candidate cytokine from this analysis, macrophage-derived chemoattractant, was significantly lower in the rhIL1ra-treated group. Our results provide promising data for rhIL1ra as a therapeutic candidate by showing safety, brain penetration and a modification of the neuroinflammatory response to TBI by a putative neuroprotective agent in humans for the first time.Journal of Cerebral Blood Flow & Metabolism advance online publication, 26 February 2014; doi:10.1038/jcbfm.2014.23.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 02/2014; · 5.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Object Based on continuous monitoring of the pressure reactivity index (PRx), the authors defined individualized intracranial pressure (ICP) thresholds by graphing the relationship between ICP and PRx. These investigators hypothesized that an "ICP dose" based on individually assessed ICP thresholds would correlate more closely with the 6-month outcome when compared with ICP doses derived by the recommended universal thresholds of 20 and 25 mm Hg. Methods This study was a retrospective analysis of prospectively collected data from 327 patients with severe traumatic brain injury. Results Individualized thresholds were visually identified from graphs of PRx versus ICP; PRx > 0.2 was the cutoff. Intracranial pressure doses were then computed as the cumulative area under the curve above the defined thresholds in graphing ICP versus time. The term "Dose 20" (D20) was used to refer to an ICP threshold of 20 mm Hg; the markers D25 and DPRx were calculated similarly. Separate logistic regression models were fit with death as the outcome and each dose as the predictor, both alone and adjusted for covariates. The discriminative ability of each dose for mortality was assessed by receiver operating characteristic AUC analysis in which 5-fold cross-validation was used. A clearly identifiable PRx-based threshold was possible in 224 patients (68%). The DPRx (AUC 0.81, 95% CI 0.74-0.87) was found to have the highest area under the curve (AUC) over both D20 (0.75, 95% CI 0.68-0.81) and D25 (0.77, 95% CI 0.70-0.83); in the cross-validation model, DPRx remained the best discriminator of mortality (DPRx: AUC 0.77 [95% CI 0.68-0.89]; D20: 0.72 [95% CI 0.66-0.81]; and D25: 0.65 [95% CI 0.56-0.73]). Conclusions The authors explored the importance of different ICP thresholds for outcome by calculating patient-specific ICP doses based on the continuous monitoring of cerebrovascular pressure reactivity. They found that these individualized doses of intracranial hypertension were stronger predictors of death than doses derived from the universal thresholds of 20 and 25 mm Hg. The PRx could offer a method that can be directed toward individualizing the ICP threshold.
Journal of Neurosurgery 02/2014; · 3.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Object The Cambridge Shunt Evaluation Laboratory was established 20 years ago. This paper summarizes the findings of that laboratory for the clinician. Methods Twenty-six models of valves have been tested long-term in the shunt laboratory according to the expanded International Organization for Standardization 7197 standard protocol. Results The majority of the valves had a nonphysiologically low hydrodynamic resistance (from 1.5 to 3 mm Hg/[ml/min]), which may result in overdrainage related to posture and during nocturnal cerebral vasogenic waves. A long distal catheter increases the resistance of these valves by 100%-200%. Drainage through valves without a siphon-preventing mechanism is very sensitive to body posture, which may result in grossly negative intracranial pressure. Siphon-preventing accessories offer a reasonable resistance to negative outlet pressure; however, accessories with membrane devices may be blocked by raised subcutaneous pressure. In adjustable valves, the settings may be changed by external magnetic fields of intensity above 40 mT (exceptions: ProGAV, Polaris, and Certas). Most of the magnetically adjustable valves produce large distortions on MRI studies. Conclusions The behavior of a valve revealed during testing is of relevance to the surgeon and may not be adequately described in the manufacturer's product information. The results of shunt testing are helpful in many circumstances, such as the initial choice of shunt and the evaluation of the shunt when its dysfunction is suspected.
Journal of Neurosurgery 01/2014; · 3.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Backround The extent of hemodynamic disturbances following subarachnoid hemorrhage (SAH) varies. We aim to determine the prognostic implications of unilateral and bilateral autoregulatory failure on delayed cerebral ische-mia (DCI) and outcome. Methods Ninety-eight patients with aneurysmal SAH were recruited. Autoregulation was assessed using systolic flow index—Sxa. Interhemispheric difference in autoreg-ulation was calculated to assess the spatial distribution and symmetry of autoregulatory changes. Assessment of interhemispheric difference in autoregulation in combina-tion with overall autoregulation was used to measure the extent of autoregulatory impairment. Patients were dichotomized by the presence of DCI and 3-month mRS. Results Higher flow velocity and worse autoregulation (p < 0.0000001, 95 % CI 10.7–21.3 and p = 0.00001, 95 % CI 0.03–0.07 for difference in FV and Sxa, respec-tively) were found ipsilateral to the ischemic hemisphere or location of aneurysm (if no ischemia detected). DCI group had a higher interhemispheric difference of autoregulation than non-DCI group (p = 0.035, 95 % CI 0.003–0.08). 16/18 patients with unfavorable outcome vs. 17/72 with favorable outcome had overall poor autoregulation with low interhemispheric differences (p = 0.0013, v 2). Uni-lateral autoregulatory failure was seen on a median day 3, bilateral on day 4, and vasospasm was detected on day 6. Conclusions Unilateral autoregulation failure was seen in patients who developed DCI (worse ipsilateral to the ischemic hemisphere). Bilateral autoregulation failure was seen more frequently in patients with unfavorable outcome. Analysis of the temporal profile showed unilateral dysau-toregulation as the primary event predisposing to DCI, which in selected cases led to bilateral failure and unfa-vorable outcomes.
[Show abstract][Hide abstract] ABSTRACT: Human brain chemistry is incompletely understood and better methodologies are needed. Traumatic brain injury (TBI) causes metabolic perturbations, one result of which includes increased brain lactate levels. Attention has largely focussed on glycolysis, whereby glucose is converted to pyruvate and lactate, and is proposed to act as an energy source by feeding into neurons' tricarboxylic acid (TCA) cycle, generating ATP. Also reportedly upregulated by TBI is the pentose phosphate pathway (PPP) that does not generate ATP but produces various molecules that are putatively neuroprotective, antioxidant and reparative, in addition to lactate among the end products. We have developed a novel combination of (13)C-labelled cerebral microdialysis both to deliver (13)C-labelled substrates into brains of TBI patients and recover the (13)C-labelled metabolites, with high-resolution (13)C NMR analysis of the microdialysates. This methodology has enabled us to achieve the first direct demonstration in humans that the brain can utilise lactate via the TCA cycle. We are currently using this methodology to make the first direct comparison of glycolysis and the PPP in human brain. In this article, we consider the application of (13)C-labelled cerebral microdialysis for studying brain energy metabolism in patients. We set this methodology within the context of metabolic pathways in the brain, and (13)C research modalities addressing them.
European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 12/2013; · 2.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Reducing cerebral perfusion pressure (CPP) below the lower limit of autoregulation (LLA) causes cerebral blood flow (CBF) to become pressure passive. Further reductions in CPP can cause cessation of CBF during diastole. We hypothesized that zero diastolic flow velocity (FV) occurs when diastolic blood pressure becomes less than the critical closing pressure (CrCP).
We retrospectively analyzed studies of 34 rabbits with CPP below the LLA, induced with pharmacologic sympathectomy (N = 23) or cerebrospinal fluid infusion (N = 11). Basilar artery blood FV and cortical Laser Doppler Flow (LDF) were monitored. CrCP was trended using a model of cerebrovascular impedance. The diastolic closing margin (DCM) was monitored as the difference between diastolic blood pressure and CrCP. LDF was recorded for DCM values greater than and less than zero.
Arterial hypotension caused a reduction of CrCP (p < 0.001), consistent with decreased wall tension (p < 0.001) and a drop in intracranial pressure (ICP; p = 0.004). Cerebrospinal infusion caused an increase of CrCP (p = 0.002) accounted for by increasing ICP (p < 0.001). The DCM was compromised by either arterial hypotension or intracranial hypertension (p < 0.001 for both). When the DCM reached zero, diastolic FV ceased for a short period during each heart cycle (R = 0.426, p < 0.001). CBF pressure passivity accelerated when DCM decreased below zero (from 1.51 ± 0.51 to 2.17 ± 1.17 % ΔLDF/ΔmmHg; mean ± SD; p = 0.010).
The disappearance of diastolic CBF below LLA can be explained by DCM reaching zero or negative values. Below this point the decrease in CBF accelerates with further decrements of CPP.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVES To image amyloid deposition in patients with traumatic brain injury (TBI) using carbon 11-labeled Pittsburgh Compound B ([11C]PiB) positron emission tomography (PET) and to validate these findings using tritium-labeled PiB ([3H]PiB) autoradiography and immunocytochemistry in autopsy-acquired tissue. DESIGN, SETTING, AND PARTICIPANTS In vivo PET at tertiary neuroscience referral center and ex vivo immunocytochemistry of autopsy-acquired brain tissue from a neuropathology archive. [11C]PiB PET was used to image amyloid deposition in 11 controls (median [range] age, 35 [24-60] years) and in 15 patients (median [range] age, 33 [21-50] years) between 1 and 361 days after a TBI. [3H]PiB autoradiography and immunocytochemistry for β-amyloid (Aβ) and β-amyloid precursor protein in brain tissue were obtained from separate cohorts of 16 patients (median [range] age, 46 [21-70] years) who died between 3 hours and 56 days after a TBI and 7 controls (median [range] age, 61 [29-71] years) who died of other causes. MAIN OUTCOMES AND MEASURES We quantified the [11C]PiB distribution volume ratio and standardized uptake value ratio in PET images. The distribution volume ratio and the standardized uptake value ratio were measured in cortical gray matter, white matter, and multiple cortical and white matter regions of interest, as well as in striatal and thalamic regions of interest. We examined [3H]PiB binding and Aβ and β-amyloid precursor protein immunocytochemistry in autopsy-acquired brain tissue. RESULTS Compared with the controls, the patients with TBI showed significantly increased [11C]PiB distribution volume ratios in cortical gray matter and the striatum (corrected P < .05 for both), but not in the thalamus or white matter. Increases in [11C]PiB distribution volume ratios in patients with TBI were seen across most cortical subregions, were replicated using comparisons of standardized uptake value ratios, and could not be accounted for by methodological confounders. Autoradiography revealed [3H]PiB binding in neocortical gray matter, in regions where amyloid deposition was demonstrated by immunocytochemistry; white matter showed Aβ and β-amyloid precursor protein by immunocytochemistry, but no [3H]PiB binding. No plaque-associated amyloid immunoreactivity or [3H]PiB binding was seen in cerebellar gray matter in autopsy-acquired tissue from either controls or patients with TBI, although 1 sample of cerebellar tissue from a patient with TBI showed amyloid angiopathy in meningeal vessels. CONCLUSIONS AND RELEVANCE [11C]PiB shows increased binding following TBI. The specificity of this binding is supported by neocortical [3H]PiB binding in regions of amyloid deposition in the postmortem tissue of patients with TBI. [11C]PiB PET could be valuable in imaging amyloid deposition following TBI.
[Show abstract][Hide abstract] ABSTRACT: To anticipate an increase in intra-cranial pressure (ICP), information about pressure-volume (p/v) compliance is required. ICP monitoring often fails at this task after head injury. Could a test that transiently shifts intra-cranial blood volume produce consistent information about the p/v relationship? Doppler flow velocities in the middle cerebral arteries (left: 80.8 ± 34.7 cm/s; right: 65.9 ± 28.0 cm/s) and ICP (16.4 ± 6.7 mm Hg) were measured in 29 patients with head injury, before and during moderate hypocapnia (4.4 ± 3.0 kPa). The ratio of vasomotor response to change in ICP differed between those with high (left: 14.8 ± 6.9, right: 14.4 ± 6.6 cm/s/kPa/mm Hg) and low (left: 1.8 ± 0.6, right: 2.2 ± 0.9 cm/s/kPa/mm g) intra-cranial compliance. Additionally, the ratio identified 12 patients deviating from the classic non-linear p/v curve (left: 5.7 ± 1.3, right: 5.8 ± 1.0 cm/s/kPa/mm Hg). They exhibited an almost proportional relationship between vasomotor and ICP responses (R = 0.69, p < 0.01). Results suggest that a test that combines the responses of two intra-cranial compartments may provide consistent information about intra-cranial p/v compliance, even if the parameters derived from ICP monitoring are inconclusive.
Ultrasound in medicine & biology 07/2013; · 2.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVES: To survey the attendance of patients presenting with a head injury (HI) at a UK emergency department (ED), identifying numbers, types of service and referral routes; to survey subsequent service use and to highlight the challenges in service planning and identifying which patients may potentially benefit from follow-up/rehabilitation input. DESIGN: A retrospective population-based case series study using multiple prospective and retrospective data sources. METHODS: Adults from the National Health Service (NHS) Cambridgeshire catchment area attending an ED over a 6-month period with a HI were identified from detailed ED reports, and any service use within the hospital after injury was tracked using a number of data sources. RESULTS: 1036 patients presented on 1081 occasions with a HI during the 6 months. Of the 1081 HIs, 979 (91%) were mild (Glasgow Coma Scale (GCS) score 13-15), 70 (6%) were moderate (GCS score 9-12), and 32 (3%) were severe (GCS score <9). A number of types of referral routes and systems were identified and analysed: 873 (81%) patients were discharged directly from ED, with four offered HI-specific follow-up. Of 208 admissions, 27 (2%) were to neurosurgical care, and 35 (3%) patients were offered HI-specific follow-up, 24 of these being in a specialist neurotrauma clinic. Follow-up started between 1 and 18 months after injury. At 24 months after injury, follow-up for 10 of these was still ongoing. CONCLUSIONS: These study findings highlight the difficulties in identifying patients who would benefit from follow-up, in particular after mild HI. Our study findings will form the basis of a long-term follow-up study.
Emergency Medicine Journal 06/2013; · 1.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A 47 year old man developed severe headaches after resection of an acoustic neuroma ipsilateral to non dominant venous drainage. CSF pressures were normal but imaging studies showed acquired, severe narrowing of the sigmoid sinus where it traversed the surgical defect. Stenting the sinus gave a lasting clinical improvement.
British Journal of Neurosurgery 05/2013; · 0.86 Impact Factor