Laurence Dunn

Human neural stem cells in patients with chronic ischaemic stroke (PISCES): a phase 1, first-in-man study

BACKGROUND CTX0E03 is an immortalised human neural stem-cell line from which a drug product (CTX-DP) was developed for allogeneic therapy. Dose-dependent improvement in sensorimotor function in rats implanted with CTX-DP 4 weeks after middle cerebral artery occlusion stroke prompted investigation of the safety and tolerability of this treatment in stroke patients. METHODS We did an open-label, single-site, dose-escalation study. Men aged 60 years or older with stable disability (National Institutes of Health Stroke Scale [NIHSS] score ≥6 and modified Rankin Scale score 2-4) 6-60 months after ischaemic stroke were implanted with single doses of 2 million, 5 million, 10 million, or 20 million cells by stereotactic ipsilateral putamen injection. Clinical and brain imaging data were collected over 2 years. The primary endpoint was safety (adverse events and neurological change). This trial is registered with ClinicalTrials.gov, number NCT01151124. FINDINGS 13 men were recruited between September, 2010, and January, 2013, of whom 11 (mean age 69 years, range 60-82) received CTX-DP. Median NIHSS score before implantation was 7 (IQR 6-8) and the mean time from stroke was 29 (SD 14) months. Three men had subcortical infarcts only and seven had right-hemisphere infarcts. No immunological or cell-related adverse events were seen. Other adverse events were related to the procedure or comorbidities. Hyperintensity around the injection tracts on T2-weighted fluid-attenuation inversion recovery MRI was seen in five patients. At 2 years, improvement in NIHSS score ranged from 0 to 5 (median 2) points. INTERPRETATION Single intracerebral doses of CTX-DP up to 20 million cells induced no adverse events and were associated with improved neurological function. Our observations support further investigation of CTX-DP in stroke patients. FUNDING ReNeuron Limited.

NMDA receptor blockade fails to alter axonal injury in focal cerebral ischemia.

The ability of the NMDA receptor antagonist, MK-801, to protect myelinated axons after focal cerebral ischemia has been examined. Amyloid precursor protein (APP) immunocytochemistry was used to assess the anatomic extent of axonal injury, and conventional histopathology was used to assess the volume of ischemic damage to neuronal perikarya. The middle cerebral artery was permanently occluded in 16 cats. The cats were treated with either vehicle or MK-801 as a 0.5-mg/kg bolus at 15 minutes before middle cerebral artery occlusion, followed by an infusion of 0.14 mg/kg per hour. After 6 hours, the animals were killed and the brains processed for histology and immunocytochemistry. The volume of neuronal necrosis was determined from 16 preselected coronal levels of the brain. The circumscribed zones of APP accumulation in axons were mapped onto images at the same 16 coronal levels, and quantitative analysis was performed using a transparent counting grid, randomly placed over each image. The histologic appearance and anatomic location of axons with increased APP immunoreactivity was similar in animals treated with vehicle and MK-801. MK-801 failed to reduce the hemispheric APP score significantly. In vehicle-treated animals, there was a significant association between the volume of neuronal necrosis and the amount of APP immunoreactivity. MK-801 significantly reduced the slope of the association between the volume of neuronal necrosis and the amount of APP immunoreactivity compared with that observed in vehicle-treated animals. As a result, the ratio of hemispheric APP score and volume of neuronal necrosis was significantly increased with MK-801 treatment. The inability of NMDA receptor antagonists to protect axons may limit their functional efficacy in improving functional outcome after stroke.

The Camino Intracranial Pressure Sensor: Is it Optimal Technology? An Internal Audit with a Review of Current Intracranial Pressure Monitoring Technologies

OBJECTIVETo audit the reliability of the Camino intracranial pressure (ICP) sensor (Camino Laboratories, San Diego, CA) in our clinical practice as part of a continuing quality assurance program, and to assess its relative usefulness as compared with currently available ICP monitoring technologies that we reviewed. DESIGNProspective audit of ICP device reliability and function in 50 patients with head injuries. METHODSZero drift was recorded immediately after the ICP device was removed from the patient. Dynamic frequency response bench testing of each functioning catheter from 0 to 30 Hz and static calibration testing from 0 to 100 mm Hg during environmental temperature variation from 22 to 40°C were carried out. RESULTSZero drift (range, −13 to 22 mm Hg; median, −1 mm Hg) was recorded immediately after the devices were removed from patients. Seventeen (50%) of the devices tested for zero drift had absolute drifts of at least 3 mm Hg. There was no correlation between recorded zero drift and duration of monitoring (r = 0.154, P = 0.207). Five sensors (10% of those tested) failed during patient monitoring and were replaced. Static and dynamic calibration tests of the functioning sensors were within the manufacturer’s specifications. However, the sensitivity of the devices to environmental temperature remains a problem. CONCLUSIONThe Camino ICP sensor remains one of the most popular ICP monitoring devices for use in patients with traumatic brain injuries. However, our recent in-house assessment demonstrated the robustness of the device to be less than adequate during routine practice. In this study, more than 50% exhibited zero drift greater than 3 mm Hg, which is unacceptable in a catheter tip ICP monitoring device in which zero drift and calibration cannot be checked in vivo. A review of the literature revealed that other available ICP monitoring devices may prove to be more reliable and thus more appropriate for routine clinical measurement of ICP.

Anxiety and Depression after Spontaneous Subarachnoid Hemorrhage

OBJECTIVERelatively little attention has been paid to emotional outcome after subarachnoid hemorrhage (SAH). This study assessed levels of anxiety and depression among SAH survivors and related these to clinical indices. METHODSSeventy SAH patients from a consecutive series of neurosurgical admissions participated in semistructured assessments of functional outcome; 52 of the patients also returned standardized measures of emotional outcome. These data were compared with clinical indices collected during the initial hospital admission. RESULTSModerate to severe levels of anxiety were present in approximately 40% of patients 16 months after hemorrhage, with approximately 20% experiencing moderate to severe levels of depression. Although anxiety was more likely to be reported at interview by those with an SAH of Fisher Grade 4, the standardized measures of anxiety and depression were not associated with severity of hemorrhage or any other clinical variables. Both anxiety and depression were significantly associated with outcome indices such as return to work and engagement in social activities. CONCLUSIONAnxiety is a significant and lasting problem for approximately 40% of survivors of SAH. It is suggested that measures taken to prevent or treat such anxiety among survivors of SAH may serve to significantly improve functional outcome.

Secondary insults during the interhospital transfer of head-injured patients: an audit of transfers in the Mersey Region

To assess the incidence of secondary insults and unidentified extracranial injuries a prospective audit of 50 head-injury transfers to a regional neurosurgical unit using a standardized assessment proforma was undertaken. There was wide variability in the quality of transfers. Six per cent of the group were hypoxic on arrival and 15 per cent were hypotensive. In the patients with multiple injuries, 29 per cent had inadequately diagnosed or managed injuries when they arrived. A comparison of this cohort of patients with previous studies is presented. As a result of the audit a set of transfer and referral guidelines have been drawn up and, following distribution of the guidelines to our referring hospitals, a further cohort of patients will be audited.

The influence of apolipoprotein E genotype on outcome after spontaneous subarachnoid hemorrhage: a preliminary study

OBJECTIVE Possession of an apolipoprotein E (APOE)&egr;4 allele has been shown to be associated with a poor outcome after closed head injury and spontaneous intracerebral hemorrhage but not after ischemic stroke. This study assessed the influence of the APOE genotype on outcome in patients admitted to a neurosurgical unit with spontaneous subarachnoid hemorrhage. METHODS A total of 100 patients with spontaneous subarachnoid hemorrhage were studied. Four patients were excluded because the diagnosis of subarachnoid hemorrhage was not confirmed. The incidence of rehemorrhage and delayed ischemia and the outcome at 6 months were determined using the Glasgow Outcome Scale. APOE genotypes were determined by polymerase chain reaction and restriction enzyme digestion. RESULTS Allele frequencies in this patient group were 0.04 for &egr;2, 0.86 for &egr;3, and 0.1 for &egr;4. Of 96 patients, 72 had an aneurysmal hemorrhage and 1 had a hemorrhage from an arteriovenous malformation. In 14 patients, the results of angiography were negative, and in 9, no angiogram was performed. Of the 96 patients, 20 had one or more &egr;4 allele. Outcome at 6 months was no worse in patients with one or more &egr;4 allele than in those with no &egr;4 allele (odds ratio, 0.98; 95% confidence interval, 0.35–2.74). None of the 12 patients who experienced delayed ischemic deterioration had an &egr;4 allele. Of the 20 patients with an &egr;4 allele, 3 had a rehemorrhage, as compared with 6 of 76 patients without an &egr;4 allele. CONCLUSION There was underrepresentation of the &egr;4 allele in this group when compared with previously studied cases of subarachnoid hemorrhage with a fatal outcome and with the general population. This suggests that patients with the &egr;4 allele who have a subarachnoid hemorrhage are less likely to be admitted to a neurosurgical unit. This study does not support an association between possession of an &egr;4 allele and poor outcome in patients admitted to a neurosurgical unit with spontaneous subarachnoid hemorrhage, although the wide confidence interval does not preclude a clinically relevant association between APOE genotype and outcome. The findings indicate that an association between genotype and the development of delayed ischemic complications after subarachnoid hemorrhage may be possible.

Apolipoprotein E polymorphism and neuropsychological outcome following subarachnoid haemorrhage

Objectives– To investigate the association between APOE genotype and cognitive and emotional outcome following spontaneous subarachnoid haemorrhage (SAH).

Facial Nerve Repair and Regeneration: An Overview of Basic Principles for Neurosurgeons

Summary The facial nerve may be damaged by trauma, surgical manipulation, inflammation or neoplastic disease. Current techniques for repair and regeneration of the damaged nerve produce suboptimal results. This review outlines the current knowledge of experimental facial nerve regeneration in vitro and in vivo to provide an insight for neurosurgeons in clinical practice.

Initial experience of 3 Tesla versus conventional field strength magnetic resonance imaging of small functioning pituitary tumours

Background  Higher field strength magnetic resonance imaging (MRI) is becoming increasingly available and offers improved image quality; however, the clinical usefulness of this technique for the demonstration of surgically treatable functional pituitary adenomas has not been clearly established.

Multi-Centre Assessment of the Spiegelberg Compliance Monitor: Interim Results

Analyses of a multi-centre database of 71 patients at risk of raised ICP showed that in head injured patients (n = 19) and tumour patients (n = 13) clear inverse relationships of ICP vs compliance exist. SAH patients (n = 5) appear to exhibit a biphasic relationship between ICP and compliance, however greater numbers of patients need to be recruited to this group. Patients with hydrocephalus (n = 34) show an initial decrease in compliance while ICP is less than 20 mmHg, thereafter compliance does not show a dependence upon ICP. A power analysis confirmed that sufficient numbers of patients have been recruited in the hydrocephalus group and a ROC analysis determined that a mean compliance value of 0.809 (lower and upper 95% CL = 0.725 & 0.894 resp.) was a critical threshold for raised ICP greater than 10 mmHg. Preliminary time-series analyses of the ICP and compliance data is revealing evidence that the cumulative time compliance is in a low compliance state (< 0.5 ml/mmHg), as a proportion of total monitoring time, increases more rapidly than the cumulative time ICP is greater than 25 mmHg. Before trials testing compliance thresholds can be designed, we need to consider not just the absolute threshold, but the duration of time spent below threshold. A survey may be required to identify a consensus of what is the minimum duration of raised ICP above 25 mmHg needed to instigate treatment.