ReNeuron Limited.

R aised intracranial pressure (ICP) is a common problem in neurosurgical and neurological practice. It can arise as a consequence of intracranial mass lesions, disorders of cerebrospinal fluid (CSF) circulation, and more diffuse intracranial pathological processes. Its development may be acute or chronic. There are well established methods for the measurement, continuous monitoring, and treatment of raised ICP. Evidence from prospective randomised controlled clinical trials that monitoring and treatment of raised ICP per se improves outcome is currently lacking for many conditions. c PATHOPHYSIOLOGYThe normal range of ICP varies with age (table 1) though values in the paediatric population are not well established. Thresholds for initiating treatment for intracranial hypertension vary according to aetiology and within single conditions there is debate about the appropriate upper limit of normal. For example, various authors have suggested thresholds of 15, 20, and 25 mm Hg for the initiation of treatment for raised ICP in patients with head injury. Table 2 lists some common causes of raised ICP. Volume-pressure relationsThe relation between volume and pressure within the cranium is non-linear ( fig 1). The Monro-Kellie hypothesis states that the sum of the intracranial volumes of blood, brain, CSF, and other components (for example, tumour, haematoma) is constant. The skull is considered as an enclosed and inelastic container. An increase in the volume of any one of the intracranial contents must be offset by a decrease in one or more of the others or be associated with a rise in ICP. Intracranial blood (especially in the venous compartment) and CSF are the two components whose volume can adapt most easily to accommodate an increase in the volume of intracranial contents. Once these compensatory mechanisms are exhausted, further increases in volume result in large rises in ICP. Compliance (the change in volume for a given change in pressure) provides an index of compensatory reserve, with low values suggesting a diminished reserve. ICP waveformAlthough continuous ventricular pressure monitoring in humans had been reported earlier, Lundberg first classified ventricular pressure fluctuations in humans in 1960 (fig 2). c A waves or plateau waves-These comprise a steep rise in ICP from near normal values to 50 mm Hg or more, persisting for 5-20 minutes and then falling sharply. These waves are always pathological and indicate greatly reduced compliance. They are frequently accompanied by neurological deterioration. c B waves-These rhythmic oscillations occur every 1-2 minutes. ICP rises in a crescendo manner to levels 20-30 mm Hg higher than baseline and then falls abruptly. These waves were originally always associated with Cheyne-Stokes respiration. However, they also occur in ventilated patients and are probably related to changes in cerebrovascular tone and cerebral blood volume. B waves are also indicative of failing intracranial compensation. c C waves-These oscillations occur with a frequency of 4-8 per minute...

BackgroundHuman neural stem cell implantation may offer improved recovery from stroke. We investigated the feasibility of intracerebral implantation of the allogeneic human neural stem cell line CTX0E03 in the subacute—chronic recovery phase of stroke and potential measures of therapeutic response in a multicentre study.MethodsWe undertook a prospective, multicentre, single-arm, open-label study in adults aged >40 years with significant upper limb motor deficits 2–13 months after ischaemic stroke. 20 million cells were implanted by stereotaxic injection to the putamen ipsilateral to the cerebral infarct. The primary outcome was improvement by 2 or more points on the Action Research Arm Test (ARAT) subtest 2 at 3 months after implantation.FindingsTwenty-three patients underwent cell implantation at eight UK hospitals a median of 7 months after stroke. One of 23 participants improved by the prespecified ARAT subtest level at 3 months, and three participants at 6 and 12 months. Improvement in ARAT was seen only in those with residual upper limb movement at baseline. Transient procedural adverse effects were seen, but no cell-related adverse events occurred up to 12 months of follow-up. Two deaths were unrelated to trial procedures.InterpretationAdministration of human neural stem cells by intracerebral implantation is feasible in a multicentre study. Improvements in upper limb function occurred at 3, 6 and 12 months, but not in those with absent upper limb movement at baseline, suggesting a possible target population for future controlled trials.FundingReNeuron, Innovate UK (application no 32074-222145).Trial registration numberEudraCT Number: 2012-003482-18

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