Measurement of Intraspinal Pressure After Spinal Cord Injury: Technical Note from the Injured Spinal Cord Pressure Evaluation Study.

Intracranial pressure (ICP) is routinely measured in patients with severe traumatic brain injury (TBI). We describe a novel technique that allowed us to monitor intraspinal pressure (ISP) at the injury site in 14 patients who had severe acute traumatic spinal cord injury (TSCI), analogous to monitoring ICP after brain injury. A Codman probe was inserted subdurally to measure the pressure of the injured spinal cord compressed against the surrounding dura. Our key finding is that it is feasible and safe to monitor ISP for up to a week in patients after TSCI, starting within 72 h of the injury. With practice, probe insertion and calibration take less than 10 min. The ISP signal characteristics after TSCI were similar to the ICP signal characteristics recorded after TBI. Importantly, there were no associated complications. Future studies are required to determine whether reducing ISP improves neurological outcome after severe TSCI.

Waveform Analysis of Intraspinal Pressure After Traumatic Spinal Cord Injury: An Observational Study (O-64).

Following a traumatic brain injury (TBI), intracranial pressure (ICP) increases, often resulting in secondary brain insults. After a spinal cord injury, here the cord may be swollen, leading to a local increase in intraspinal pressure (ISP). We hypothesised that waveform analysis methodology similar to that used for ICP after TBI may be applicable for the monitoring of patients with spinal cord injury.An initial cohort of 10 patients with spinal cord injury, as presented by the first author at a meeting in Cambridge in May 2012, were included in this observational study. The whole group (18 patients) was recently presented in the context of clinically oriented findings (Werndle et al., Crit Care Med, 42(3):646-655, 2014, PMID: 24231762). Mean pressure, pulse and respiratory waveform were analysed along slow vasogenic waves.Slow, respiratory and pulse components of ISP were characterised in the time and frequency domains. Mean ISP was 22.5 ± 5.1, mean pulse amplitude 1.57 ± 0.97, mean respiratory amplitude 0.65 ± 0.45 and mean magnitude of slow waves (a 20-s to 3-min period) was 3.97 ± 3.1 (all in millimetres of mercury). With increasing mean ISP, the pulse amplitude increased in all cases. This suggests that the ISP signal is of a similar character to ICP recorded after TBI. Therefore, the methods of ICP analysis can be helpful in ISP analysis.

Opportunities and dangers for neurosurgery in the current NHS.

The NHS is entering a third decade of administrative turbulence and cost pressures and many view the new NHS structure and systems as complex and confusing. Health and social care budgets are being merged in some geographical areas and large efficiency savings are needed by 2020. There are risks that lie ahead for neurosurgery and our patients if the specialty becomes further fragmented and opportunities for positive change are missed. One of the new care models proposed in the NHS five year plan is specialist care provided across multiple hospital sites by a single overarching specialist trust, mirroring ophthalmology where the Moorfields trust provides specialist eye services in over 20 locations in London and the South East. This model lends itself to adoption by neurosurgery and has the potential to increase standards, efficiency, training and research.

Intraspinal pressure and spinal cord perfusion pressure after spinal cord injury: an observational study.

OBJECT: In contrast to intracranial pressure (ICP) in traumatic brain injury (TBI), intraspinal pressure (ISP) after traumatic spinal cord injury (TSCI) has not received the same attention in terms of waveform analysis. Based on a recently introduced technique for continuous monitoring of ISP, here the morphological characteristics of ISP are observationally described. It was hypothesized that the waveform analysis method used to assess ICP could be similarly applied to ISP. METHODS: Data included continuous recordings of ISP and arterial blood pressure (ABP) in 18 patients with severe TSCI. RESULTS: The morphology of the ISP pulse waveform resembled the ICP waveform shape and was composed of 3 peaks representing percussion, tidal, and dicrotic waves. Spectral analysis demonstrated the presence of slow, respiratory, and pulse waves at different frequencies. The pulse amplitude of ISP was proportional to the mean ISP, suggesting a similar exponential pressure-volume relationship as in the intracerebral space. The interaction between the slow waves of ISP and ABP is capable of characterizing the spinal autoregulatory capacity. CONCLUSIONS: This preliminary observational study confirms morphological and spectral similarities between ISP in TSCI and ICP. Therefore, the known methods used for ICP waveform analysis could be transferred to ISP analysis and, upon verification, potentially used for monitoring TSCI patients.

Brain tumor classification using the diffusion tensor image segmentation (D-SEG) technique.

BACKGROUND: There is an increasing demand for noninvasive brain tumor biomarkers to guide surgery and subsequent oncotherapy. We present a novel whole-brain diffusion tensor imaging (DTI) segmentation (D-SEG) to delineate tumor volumes of interest (VOIs) for subsequent classification of tumor type. D-SEG uses isotropic (p) and anisotropic (q) components of the diffusion tensor to segment regions with similar diffusion characteristics. METHODS: DTI scans were acquired from 95 patients with low- and high-grade glioma, metastases, and meningioma and from 29 healthy subjects. D-SEG uses k-means clustering of the 2D (p,q) space to generate segments with different isotropic and anisotropic diffusion characteristics. RESULTS: Our results are visualized using a novel RGB color scheme incorporating p, q and T2-weighted information within each segment. The volumetric contribution of each segment to gray matter, white matter, and cerebrospinal fluid spaces was used to generate healthy tissue D-SEG spectra. Tumor VOIs were extracted using a semiautomated flood-filling technique and D-SEG spectra were computed within the VOI. Classification of tumor type using D-SEG spectra was performed using support vector machines. D-SEG was computationally fast and stable and delineated regions of healthy tissue from tumor and edema. D-SEG spectra were consistent for each tumor type, with constituent diffusion characteristics potentially reflecting regional differences in tissue microstructure. Support vector machines classified tumor type with an overall accuracy of 94.7%, providing better classification than previously reported. CONCLUSIONS: D-SEG presents a user-friendly, semiautomated biomarker that may provide a valuable adjunct in noninvasive brain tumor diagnosis and treatment planning.

Monitoring of spinal cord perfusion pressure in acute spinal cord injury: initial findings of the injured spinal cord pressure evaluation study*.

OBJECTIVES: To develop a technique for continuously monitoring intraspinal pressure at the injury site (intraspinal pressure) after traumatic spinal cord injury. DESIGN: A pressure probe was placed subdurally at the injury site in 18 patients who had isolated severe traumatic spinal cord injury (American Spinal Injuries Association grades A-C). Intraspinal pressure monitoring started within 72 hours of the injury and continued for up to a week. In four patients, additional probes were inserted to simultaneously monitor subdural pressure below the injury and extradural pressure. Blood pressure was recorded from a radial artery catheter kept at the same horizontal level as the injured segment of the spinal cord. We determined the effect of various maneuvers on spinal cord perfusion pressure and spinal cord function and assessed using a limb motor score and motor-evoked potentials. SETTING: Neurosurgery and neuro-ICU covering a 3 million population in London. SUBJECTS: Patients with severe traumatic spinal cord injury. Control subjects without spinal cord injury (to monitor spinal cerebrospinal fluid signal and motor evoked potentials). INTERVENTIONS: Insertion of subdural spinal pressure probe. MEASUREMENTS AND MAIN RESULTS: There were no procedure-related complications. Intraspinal pressure at the injury site was higher than subdural pressure below the injury or extradural pressure. Average intraspinal pressure from the 18 patients with traumatic spinal cord injury was significantly higher than average intraspinal pressure from 12 subjects without traumatic spinal cord injury. Change in arterial PCO2, change in sevoflurane dose, and mannitol administration had no significant effect on intraspinal pressure or spinal cord perfusion pressure. Increase in inotrope dose significantly increased spinal cord perfusion pressure. Bony realignment and laminectomy did not effectively lower intraspinal pressure. Laminectomy was potentially detrimental by exposing the swollen spinal cord to compression forces applied to the skin. By intervening to increase spinal cord perfusion pressure, we could increase the amplitude of motor-evoked potentials recorded from below or just above the injury level in nine of nine patients with traumatic spinal cord injury. In two of two patients with American Spinal Injuries Association grade C traumatic spinal cord injury, higher spinal cord perfusion pressure correlated with increased limb motor score. CONCLUSIONS: Our findings provide proof-of-principle that subdural intraspinal pressure at the injury site can be measured safely after traumatic spinal cord injury.

Glioblastoma blood flow measured with stable xenon CT indicates tumor necrosis, vascularity, and brain invasion.

Tumor vasculature is a promising therapeutic target in glioblastoma. Imaging tumor blood flow may help assess the efficacy of anti-angiogenic treatments. We determined the clinical usefulness of stable xenon CT performed preoperatively in patients with glioblastoma. This is a prospective cohort study. We determined absolute tumor blood flow before surgery in 38 patients with glioblastoma using stable xenon CT. We also histologically examined tumor specimens obtained from surgery and quantified their vascularity (by CD31 and CD105 immunostain), necrosis (by hematoxylin and eosin stain), and the presence of neuronal processes (by neurofilament immunostain). According to the xenon CT blood flow map, there are 3 types of glioblastoma. Type I glioblastomas have unimodal high blood flow histograms; histologically there is little necrosis and vascular proliferation. Type II glioblastomas have unimodal low blood flow histograms; histologically there is prominent necrosis and vascular proliferation. We propose that in type II glioblastoma, the abnormal vessels induced by hypoxia are inefficient at promoting blood flow. Type III glioblastomas have multimodal blood flow histograms. Histologically there is significant neuronal tissue within the tumor. Patients with type III glioblastomas were more likely to develop a post-surgical deficit, consistent with the inclusion of normal tissue within the tumor. Preoperative measurement of absolute blood flow with stable xenon CT in patients with glioblastoma predicts key biological features of the tumor and may aid surgical planning.

Neutrophil protease inhibition reduces neuromyelitis optica-immunoglobulin G-induced damage in mouse brain.

OBJECTIVE: Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system associated with pathogenic autoantibodies against the astrocyte water channel protein aquaporin-4 (AQP4). The presence of neutrophils is a characteristic feature in NMO lesions in humans. Neutrophils are not generally found in multiple sclerosis lesions. We evaluated the role of neutrophils in a mouse NMO model. METHODS: NMO lesions were produced in mice by intracerebral injection of immunoglobulin G (IgG) isolated from NMO patient serum and human complement. We previously reported that this mouse model produces the characteristic histological features of NMO, including perivascular complement activation, inflammatory cell infiltration, and loss of myelin, AQP4, and glial fibrillary acidic protein. Lesions are absent when AQP4 null mice are used or when IgG from non-NMO patients is injected. RESULTS: We found remarkably reduced neuroinflammation, myelin loss, and AQP4 loss in brains of neutropenic mice at 24 hours and 7 days, and increased severity of NMO lesions in mice made neutrophilic by granulocyte colony stimulating factor. NMO lesions were greatly reduced by intracerebral administration of the neutrophil protease inhibitors Sivelestat and cathepsin G inhibitor I or by intraperitoneal injection of Sivelestat alone. Immunostaining of human NMO lesions for neutrophil elastase revealed many degranulating perivascular neutrophils, with no equivalent perivascular neutrophils in human multiple sclerosis lesions. INTERPRETATION: Our data implicate a central role of neutrophils in the pathogenesis of early NMO lesions and suggest the potential utility of neutrophil protease inhibitors such as Sivelestat in NMO therapy.

T cell deficiency does not reduce lesions in mice produced by intracerebral injection of NMO-IgG and complement.

We reported recently that intracerebral administration of NMO-IgG with human complement produces neuromyelitis optica (NMO) lesions in mice. We examined the role of T cells in the formation of NMO lesions by comparing brain histopathology in wildtype and nude mice. Brains were co-injected with IgG from NMO patients and human complement. At 24h and 5days, wildtype vs. nude mouse brains had comparable inflammation (CD45 immunoreactivity), loss of myelin (Luxol Fast Blue staining) and loss of AQP4 immunoreactivity. We conclude that T cells are not required for the formation of NMO lesions in this mouse model.

Dangers of bone graft substitutes: lessons from using GeneX.

BACKGROUND: Bone graft substitutes are widely used in spinal surgery. Here, serious complications associated with the bone graft substitute GeneX are presented. GeneX contains tri-calcium phosphate and calcium sulphate. METHODS: GeneX was used in three patients who had spinal decompression and fusion. Mice were also injected with GeneX, demineralised bone matrix (DBX) or saline subcutaneously. After 24 h the extent of tissue damage and inflammation in tissue sections was quantified. To understand the licensing process for bone graft substitutes, the U.S. Food and Drug Administration (FDA) and the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) websites were accessed. RESULTS: All patients developed sterile pus in soft tissues adjacent to the GeneX followed by skin breakdown in two and pharyngeal perforation in one. In mice, GeneX produced moderate or severe skin damage compared with no or mild skin damage after DBX (p<0.05) or saline (p<0.05) injection. GeneX caused more inflammation in mouse dermis (1704±193 leucocytes/mm2, mean ± SE) than DBX (537 ± 266, p<0.01) or saline (136 ± 19, p<0.01). The FDA and MHRA classify bone graft substitutes as medical devices. In contrast with drugs, medical devices do not need to undergo clinical safety tests before obtaining FDA 510(k) clearance for use in patients. CONCLUSION: GeneX may cause soft tissue inflammation and destruction and should not be placed next to thin walled structures, such as skin or pharynx, because it may erode through these tissues. Bone graft substitutes should undergo mandatory detailed safety testing prior to approval. This could be achieved by reclassifying them as drugs.

Diffusion tensor imaging discriminates between glioblastoma and cerebral metastases in vivo.

In a prospective study, patients with a radiologically proven brain tumour underwent diffusion tensor imaging (DTI) prior to definitive diagnosis and treatment. Twenty-eight patients with a histologically proven glioblastoma or metastasis were included in the study. Following the definition of regions of interest, DTI metrics [mean diffusivity (MD) and fractional anisotropy (FA)] were calculated for the tumour volume and the surrounding region of peritumoral oedema. These metrics were then subjected to logistic regression to investigate their ability to discriminate between glioblastomas and cerebral metastases. A cross-validation was performed to investigate the ability of the model to predict tumour. The logistic regression analysis correctly distinguished glioblastoma in 15 of 16 cases (93.8%) and metastasis in 11 of 12 cases (91.7%). Cross-validation resulted in the model correctly predicting 14 of 16 (87.5%) glioblastomas and 10 of 12 (83.3%) metastases studied. MD was significantly higher (p = 0.02) and FA was significantly lower (p = 0.04) within the oedema surrounding metastases than within the oedema around glioblastomas. MD was significantly higher (p = 0.02) within the tumour volume of the glioblastomas. Our results demonstrate that, when DTI metrics from the tumour volume and surrounding peritumoral oedema are studied in combination, glioblastoma can be reliably discriminated from cerebral metastases.

Serum angiogenic profile of patients with glioblastoma identifies distinct tumor subtypes and shows that TIMP-1 is a prognostic factor.

Angiogenesis plays a key role in glioblastoma biology and antiangiogenic agents are under clinical investigation with promising results. However, the angiogenic profiles of patients with glioblastoma and their clinical significance are not well understood. Here we characterize the serum angiogenic profile of patients with glioblastoma, and examine the prognostic significance of individual angiogenic factors. Serum samples from 36 patients with glioblastoma were collected on admission and simultaneously assayed for 48 angiogenic factors using protein microarrays. The data were analyzed using hierarchical cluster analysis. Vessel morphology was assessed histologically after immunostaining for the pan-endothelial marker CD31. Tumor samples were also immunostained for tissue inhibitor of metalloproteinase-1 (TIMP-1). Cluster analysis of the serum angiogenic profiles revealed 2 distinct subtypes of glioblastoma. The 2 subtypes had markedly different tumor microvessel densities. A low serum level of TIMP-1 was associated with significantly longer survival independent of patient age, performance status, or treatment. The serum angiogenic profile in patients with glioblastoma mirrors tumor biology and has prognostic value. Our data suggest the serum TIMP-1 level as an independent predictor of survival.

Combined use of neuroradiology and 1H-MR spectroscopy may provide an intervention limiting diagnosis of glioblastoma multiforme.

PURPOSE: To evaluate the accuracy of (1)H-MR spectroscopy ((1)H-MRS) as an intervention limiting diagnostic tool for glioblastoma multiforme. GBM is the most common and aggressive primary brain tumor, with mean survival under a year. Oncological practice currently requires histopathological diagnosis before radiotherapy. MATERIALS AND METHODS: Eighty-nine patients had clinical computed tomography (CT) and MR imaging and 1.5T SV SE (1)H-MRS with PRESS localization for neuroradiological diagnosis and tumor classification with spectroscopic and automated pattern recognition analysis (TE 30 ms, TR 2000 ms, spectral width 2500 Hz and 2048 data points, 128-256 signal averages were acquired, depending on voxel size (8 cm(3) to 4 cm(3)). Eighteen patients from a cohort of 89 underwent stereotactic biopsy. RESULTS: The 18 stereotactic biopsies revealed 14 GBM, 2 grade II astrocytomas, 1 lymphoma, and 1 anaplastic astrocytoma. All 14 biopsied GBMs were diagnosed as GBM by a protocol combining an individual radiologist and an automated spectral pattern recognition program. CONCLUSION: In patients undergoing stereotactic biopsy combined neuroradiological and spectroscopic evaluation diagnoses GBM with accuracy that could replace the need for biopsy. We do not advocate the replacement of biopsy in all patients; instead our data suggest a specific intervention limiting role for the use of (1)H-MRS in brain tumor diagnosis.

Patient safety and image transfer between referring hospitals and neuroscience centres: could we do better?

INTRODUCTION: District general hospital scanners have historically been linked to regional neuroscience units for specialist opinions on scans and to make decisions on transfer of patients requiring neurosurgical management. The implementation of digital picture archiving and communication systems (PACS) in all hospitals in the UK has disrupted these dedicated links and technical and information governance issues have delayed reprovision of electronic transfer of images for rapid expert decision making in this group of patients. We studied improvement in image transfer to acute neurosurgery units over a 4-year period. METHODS: Four-year sequential review of national provision of image transfer facilities into neurosurgery units; observational study of delays associated with image transfer modalities in one representative tertiary referral centre. RESULTS: During the 4 years of study, all hospitals nationally have implemented digital PACS systems for image viewing. Remote image viewing facilities have gradually changed with dedicated image links being replaced by remote PACS access. However, a minority of referrals (12%) still require images to be physically transferred between hospitals using couriers for CD-ROMs. The detailed study within our own unit shows that this adds a mean delay of 5.8 h to decision making. CONCLUSIONS: Image transfer in neuroscience has been neglected following the shift to PACS servers. The recommendations of the 2004 Neuroscience Critical Care Report are unmet and patient safety is being threatened by a continued failure to implement a coordinated solution to this problem.

Implementation of the European Working Time Directive in neurosurgery reduces continuity of care and training opportunities.

BACKGROUND: Implementation of the European Working Time Directive (EWTD) raises questions about reduced surgical training opportunities and lost continuity of patient care. We studied the effect that the EWTD has had in these areas for residents in the neurosurgical unit at St. George's Hospital, London, UK. METHODS: Case notes for 50 emergency and 50 elective operative admissions were randomly selected before and after implementation of an EWTD compliant resident roster (total, 200 episodes). Each was objectively scored for continuity of care from the operating surgeon. Rosters from 3 months before and after implementation were compared to assess training opportunities available. RESULTS: A significant reduction was observed in continuity of emergency care following introduction of the EWTD compliant roster (P < 0.009). The same proportion of residents consented and operated on elective cases; however, a significant reduction in continuity of postoperative care was observed (P < 0.0001). Resident training opportunities were substantially affected with reduced involvement in outpatient (72% vs. 60%) and operating sessions (79% vs. 63%) with their nominated consultant. CONCLUSIONS: The EWTD has had a marked adverse impact on continuity of care for neurosurgical patients at St. George's Hospital. Residents' training opportunities were reduced.

Ex-vivo HRMAS of adult brain tumours: metabolite quantification and assignment of tumour biomarkers.

BACKGROUND: High-resolution magic angle spinning (HRMAS) NMR spectroscopy allows detailed metabolic analysis of whole biopsy samples for investigating tumour biology and tumour classification. Accurate biochemical assignment of small molecule metabolites that are "NMR visible" will improve our interpretation of HRMAS data and the translation of NMR tumour biomarkers to in-vivo studies. RESULTS: 1D and 2D 1H HRMAS NMR was used to determine that 29 small molecule metabolites, along with 8 macromolecule signals, account for the majority of the HRMAS spectrum of the main types of brain tumour (astrocytoma grade II, grade III gliomas, glioblastomas, metastases, meningiomas and also lymphomas). Differences in concentration of 20 of these metabolites were statistically significant between these brain tumour types. During the course of an extended 2D data acquisition the HRMAS technique itself affects sample analysis: glycine, glutathione and glycerophosphocholine all showed small concentration changes; analysis of the sample after HRMAS indicated structural damage that may affect subsequent histopathological analysis. CONCLUSIONS: A number of small molecule metabolites have been identified as potential biomarkers of tumour type that may enable development of more selective in-vivo 1H NMR acquisition methods for diagnosis and prognosis of brain tumours.

The clinical value of early postoperative MRI after lumbar spine surgery.

INTRODUCTION: MRI scanning has historically been considered difficult to interpret in the early period following lumbar spine surgery, and hence of limited value. We investigate the hypothesis that MRI scanning within 6 weeks of lumbar spine surgery cannot accurately diagnose neural compression in symptomatic patients, and define the utility of postoperative MRI in this context. METHODS: A series of 32 consecutive patients had early postoperative MRI following lumbar discectomy or laminectomy for continued, worsening or new symptoms of neural compression. The neuroradiologists' reports were evaluated for the reported presence of neural compression and confidence level (low, medium, high). These MRI findings were then compared to the patients' subsequent course and findings of any surgery performed. RESULTS: Twenty of 29 scans (69%) were confidently predictive of the correct treatment pathway (reoperation with positive finding or conservative treatment with a good outcome) whereas 3/3 (100%) patients who had conservative management despite the MRI confidently suggesting compression had poor outcome. The MRI is highly likely to influence management: 11/14 (79%) patients with scans suggesting neural compression had revision surgery and 18/18 (100%) patients with no neural compression on MRI were managed conservatively. CONCLUSIONS: Our data suggest that early MRI scanning after lumbar laminectomy or discectomy accurately detects neural compression at the surgery site in patients with continued or worsening symptoms.

Correlations between in vivo (1)H MRS and ex vivo (1)H HRMAS metabolite measurements in adult human gliomas.

PURPOSE: To assess how accurately ex vivo high-resolution magic angle spinning (HRMAS) proton magnetic resonance spectroscopy ((1)H MRS) from small biopsy tissues relate to in vivo (1)H MRS (from larger tumor volumes) in human astrocytomas. MATERIALS AND METHODS: In vivo (PRESS, TE = 30 msec) and ex vivo (presaturation) (1)H spectra of 17 human astrocytomas (4 grade II, 1 grade III and 12 glioblastomas) were quantified using LCModel. Concentrations of 11 metabolites and 2 lipid/macromolecules were retrospectively compared, with histogram analysis of the in vivo MRI data used to evaluate tumor heterogeneity. RESULTS: For homogeneous-appearing tumors, significant correlations were found between in vivo and ex vivo (1)H MRS concentrations of those metabolites known to be metabolically stable in postmortem tissues (eg, creatine, myo-inositol, total cholines, and the approximately 1.3 and 0.9 ppm lipids). Anaerobic glycolysis during biopsy surgical removal depletes the tissue of glucose, increasing alanine and lactate, and resulted in no correlation between these in vivo and ex vivo metabolite concentrations. CONCLUSION: Within defined limitations, ex vivo astrocytoma biopsy HRMAS (1)H spectra have similar metabolic profiles to that obtained in vivo and therefore detailed ex vivo characterization of glioma biopsies can directly relate to the original tumor.

Intra-cerebral injection of neuromyelitis optica immunoglobulin G and human complement produces neuromyelitis optica lesions in mice.

Neuromyelitis optica is an inflammatory demyelinating disease of the central nervous system associated with autoantibodies against the glial water channel protein aquaporin-4. It has recently been reported that immunoglobulin from neuromyelitis optica patients injected peripherally does not cause lesions in naive rats, but only when pre-existing central nervous system inflammation is present. Here, we investigated whether immunoglobulin G from aquaporin-4-autoantibody-positive neuromyelitis optica patients has the potential to damage the central nervous system either alone or in the presence of human complement. Immunoglobulin G from neuromyelitis optica patients did not activate mouse complement and was not pathogenic when injected into mouse brain. However, co-injection of immunoglobulin G from neuromyelitis optica patients with human complement produced neuromyelitis optica-like lesions in mice. Within 12 h of co-injecting immunoglobulin G from neuromyelitis optica patients and human complement, there was a striking loss of aquaporin-4 expression, glial cell oedema, myelin breakdown and axonal injury, but little intra-parenchymal inflammation. At 7 days, there was extensive inflammatory cell infiltration, perivascular deposition of activated complement components, extensive demyelination, loss of aquaporin-4 expression, loss of reactive astrocytes and neuronal cell death. In behavioural studies, mice injected with immunoglobulin G from neuromyelitis optica patients and human complement into the right hemisphere preferentially turned to the right at 7 days. No brain inflammation, demyelination or right-turning behaviour was seen in wild-type mice that received immunoglobulin G from non-neuromyelitis optica patients with human complement, or in aquaporin-4-null mice that received immunoglobulin G from neuromyelitis optica patients with human complement. We conclude that co-injection of immunoglobulin G from neuromyelitis optica patients with human complement reproduces the key histological features of neuromyelitis optica and that aquaporin-4 is necessary and sufficient for immunoglobulin G from neuromyelitis optica patients to exert its effect. In our mouse model, immunoglobulin G from neuromyelitis optica patients does not require pre-existing central nervous system inflammation to produce lesions.