Proceedings British Neurosurgery ResearchGroup Research ...stimulation of ET receptors or vascular...

J'ournal ofNeurology, Neurosurgery, and Psychiatry 1996;61:545-554

Proceedings of the joint meeting of the British NeurosurgeryResearch Group and the Research Society of NeurologicalSurgeons (USA), the Copthorne Hotel, Newcastle-upon-Tyne23-26 May 1996

INTRACRANIAL NEOPLASMS OCCURRING INTHE FIRST YEAR OF LIFE: CLINICAL FEATURES,MANAGEMENT, AND OUTCOME

PJ Kane, K Phipps, WFJ Harkness, RDHayward. The Hospital for Sick Children,Great Ormond Street, London, UK

Intracranial neoplasms are uncommon inthe first year of life. The traditional view isthat the results of treatment in this agegroup are poor. The presenting features,clinical management, and functional out-come have been reviewed for 49 children,aged less than one year, who were treatedfor brain tumours at Great Ormond Streetduring the period 1982-93.The cohort (26 girls and 23 boys) repre-

sents 7-5% of all children with braintumours referred to the unit in the sameperiod. Increasing head size was the mostcommon presenting symptom and macro-crania (with features of raised intracranialpressure) was the most common sign. Fortysix children underwent one or more opera-tions. Twenty two children received radio-therapy and/or chemotherapy. In most casesthree or more specialties were involved inclinical management. Twenty nine childrensurvived two years after diagnosis and 19survived more than five years. Twelve chil-dren receive mainstream education.The management of brain tumours in

infants requires a multidisciplinary approachand places significant demands on resources.In view of the infrequency of these tumoursit is proposed that the treatment of thesechildren is centralised in designated units toallow efficient use of resources and allowtreatment protocols to be developed.

RADICAL SURGERY IN THE TREATMENT OFLOW GRADE GLIOMAS

KS O'Neill, ND Kitchen, PR Wilkins, HTMarsh. Atkinson Morley's Hospital,London, UK

The natural history of low grade gliomas isuncertain. Factors known to correlate withsurvival include age, gross total removal, andlack of major preoperative and postoperativedeficit.The aim was to develop a standardised

surgical technique providing maximaltumour resection with minimal surgicalmorbidity which will improve long termrecurrence rate and survival.A series of 51 patients with a mean age of

35 admitted with a clinical and radiologicaldiagnosis of low grade glioma since 1989were studied.

Brain MRI and awake craniotomy withfunctional mapping was combined with astandardised technique of systematically

sampling the resection margins with multi-ple peroperative smear biopsies. If a micro-scopic tumour was present, further resectionand biopsy was undertaken until clear. Toconfirm sensitivity of smear cytology and tovalidate the technique half of each biopsywas sent for smear and half for histologicalconfirmation.

Preoperative baseline was compared withthree month, six month, then ongoing yearlyassessments incorporating MRI, clinical andepileptic status, psychometry, AMH, andGlasgow outcome scales.

Average follow up was 22-2 months. Allbut one patient presented with epilepsy and70% remain fit free since surgery. There hasbeen no surgical mortality and minimalmorbidity with only four new mild perma-nent neurological deficits. Of the 51patients, 43 were confinned low gradetumours on histology. Of those 22 had"total resection" on marginal biopsies andonly one has recurred with malignantchange. Histological confirmation of smearbiopsy has been performed on seven patientsso far. In five low grade astrocytomas, bothsmear and histology correlated, but in twooligodendrogliomas tumour was seen on his-tology which was not detected on smear.

This technique is logistically simple andsafe. Histological results suggest the tech-nique is valid for low grade astrocytomas butnot oligodendrogliomas and reasons for thiswere discussed. Despite this, results areencouraging, and long term follow up willhopefully show a low recurrence rate andincreased survival.

CHARACTERISATION OF ENDOTHELINRECEPTORS IN HUMAN BRAIN TUMOURS

SP Harland, RE Kuc, JD Pickard, APDavenport. University Department ofNeurosurgery, Addenbrooke's Hospital,Cambridge, UK

Endothelin (ET) immunoreactivity, produc-tion, and specific receptors have been identi-fied in the human brain. ET is implicated inthe pathogenesis of post SAH vasospasm bystimulation of ET receptors or vascularsmooth muscle cells. ET increases mitogen-esis in glial cells in culture and thus has beenimplicated as a growth factor in cerebralneoplasia. ET receptor subtypes in normalhuman cerebral cortex (CC), glioblastomamultiforme (GBM), and meningiomas(MG) were characterised using subtypeselective radioligands ([1251]-PD151242(ETA) and [1251]-BQ3020 (ETB)). In satura-tion binding assays PD15124 bound withhigh affinity to a single population of ETreceptors in CC (n = 5; KD= 1-07 (0-14)nM; Bm, = 25 06 (3 4) fmol/mg protein);GBM (n = 5; KD = 1-62 (0 20) nM; B,,y =

147-04 (62-8) fmol/mg protein) and MGs (n= 5; KD = 2-65 (0 33) nM; Bm, = 364-8(74 2) fmol/mg protein). BQ3020 alsobound with high affinity to a single popula-tion of ET receptors in CC (n = 5; KD =0-84 (0 2) nM; B,.,. = 232-7 (38-2) fmol/mgprotein); GBM (n = 5; KD = 1-38 (0-28)nM; Bm,. = 234-0 (153-6) fmol/mg protein)and MGs (n = 5; K1 = 0-21 (0-06) nM; Bmax= 64-0 (25-8) fmol/mg protein). Auto-radiography revealed a high concentration ofETA receptors within the pial and intra-parenchymal vessels and meninges overlyingCC. Grey and white matter were diffuselyETB positive. GBM had a strongly vascularpattern of ETA distribution. ETA receptorswere dense and homogeneous in MGs. Incompetition experiments the orally activenon-peptide antagonist PD156707 had highaffinity and selectivity for the ETA receptor.Selective ETA receptor manipulation mayhave potential benefits in vascular diseaseand neoplasia without producing detrimen-tal effects on ETB positive brainparenchyma.

AN INVESTIGATION INTO THE EXPRESSION OFCD44 INVASION RELATED ANTIGEN IN GLIALTUMOURS AND ITS POSSIBLE ROLE INGUIDING RESECTION

KS O'Neill, KK Martin, AP King, PRWilkins, HT Marsh, GJ Pilkington, BA Bell.Atkinson Morley's Hospital and Institute ofPsychiatry, London, UK

CD44 is a major receptor for hyaluronicacid enabling cell binding and motilitywithin the extracellular matrix. Evidenceshows an upregulation on certain neoplasticcells and suggests a key role in tumour inva-sion. The differential expression of CD44 inresection smears of glial tumours was inves-tigated in relation to the proliferatingtumour mass, the invading tumour margin,and adjacent brain. Characterisation of inva-sion marker expression in both low and highgrades may help to utilise this information todetermine the patterns, extent, and limits ofinvasion. This is of particular importance tothe treatment of low grade gliomas, forwhich there is increasing clinical evidencethat radical excision reduces recurrence rateand may have considerable survival benefit.At craniotomy samples are taken from the

tumour mass, macroscopic margin, andouter band of surrounding brain. Theseareas are confirmed with peroperative diag-nostic smear cytology. Each sample under-goes smear and cell culture for laterimmunocytological analysis of tumour andinvasion related antigens.

So far 12 patients have been analysed forhigh grade astrocytomas and eight low gradegliomas, three of which were oligoden-

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drogliomas. The pattern of expression wassimilar for all tumour types. Little or noexpression of CD44 was seen within thetumour bulk but an increase in expressionwas seen in the margins and also outer banddespite this area being confirmed in somelow grades as tumour free. This pattern ofCD44 expression suggests an absence inproliferating cells in the tumour mass and anupregulation at the margins supporting itsrole in invasion. However its presence in theouter band may simply reflect that the trueouter limits of the tumour had not beenreached or represent an upregulation of thereceptor on both neoplastic cells and reac-tive glia. The significance of this remains tobe established and studies on future patientsand specific molecular splice variants ofCD44 are planned.

NITRIC OXIDE SYNTHASE ACTIVITY IN HUMAN

GLIOBIAS'I'OMA: A HISTOCHEMICAL STUDY

GR Swaroop, JW Ironside, IR Whittle.Department of Clinical Neurosciences,Western General Hospital, Edinburgh, UK

In the CNS regulation of vascular tone andblood flow, neuronal signalling, and immunemechanisms are mediated by NO. Nitricoxide synthase (NOS), the enzyme for syn-thesis of NO, exists as inducible (iNOS) andconstitutive (cNOS) forms. As glioblastomaare composed of dedifferentiated astrocytes,neoplastic endothelial cells, and infiltratingmacrophages this study was undertaken todetermine whether they express NOS.

Frozen tissue from 19 human glioblas-toma were studied. NADPH diaphorase his-tochemistry was performed on 20 p sections.Adjacent 5 p sections were stained withhaematoxylin and eosin. Formation of a pur-plish formazan deposit was taken as positive.Under light microscopy intensity, locality,relation to specific tumour cells, and vesselswere assessed and compared with normalbrain.

All the tumours showed parenchymal pos-itivity. The pattern varied between tumoursand different tumour regions. Necrotic areasshowed no NOS activity. Vascular endothe-lium showed the most consistent pattern. Inall the endothelium was stained denser com-pared to tumour parenchyma and normalvasculature. Endothelial proliferation in par-ticular showed positivity. This study hasdemonstrated that human glioblastomaexpress NOS. The staining is more pro-nounced in the neoplastic cells and bloodvessels of glioblastoma than normal brain.This suggests that NO may regulate the nor-mal resting tone of arterioles, hence tumourblood flow.

MODIFIED VIRAL THERAPY FOR MALIGNAN'I'GLIOMAS: IN VITRO ASSESSMENT OF ICP 34-5MU'I'AN' INDICA'I'ES A POTENTIALLYEFFECTIVE CLINICAL THERAPY

GS Cruikshanks, EA McKie, AR MacLean,AD Lewis, R Rampling, SM Brown.Departments of Neurosurgery and Neuro-Virology, Institute of Neurological Sciences,Southern General Hospital, Glasgow, UK

Conventional therapy for high grade glialbrain tumours involves maximal resectionand radiation. Even with the addition ofadjuvant chemotherapy the median survivalstill approximates to one year. There is a

clear need for alternative therapies whichaddress both the focal and diffuse nature ofthese heterogeneous tumours. One approachis to use viruses as tumoricidal agents intheir own right.The potential therapeutic use of the her-

pes simplex virus (HSV) mutant 1716 hasbeen evaluated. The mutant is deleted in theRL1 gene and fails to produce the virulencefactor ICP 34 5.

1716 replication was analysed in bothestablished human glioma cell lines, and inprimary cell cultures derived from humantumour biopsy material. In most cultures,virus replication occurred and consequentialcell death resulted. In most cell lines whichwere non-permissive for mutant replication,premature shut off of cell protein synthesiswas induced in response to lack of expres-sion of ICP 34-5.

Hence RL1 negative mutants have theadvantage of providing a double hit phe-nomenon whereby cell death could occur byeither pathway. Moreover, 1716 by virtue ofits selectivity to replicate within a tumourcell has the potential to immediately delivera "suicide" gene product to the requiredsite, and facilitate a new and possibly effec-tive tumour therapy.

I'HENYLBUTYRATE AS A NOVEL'HERAPEUlTICCOMPOUND FOR THE TREATMENT OFMALIGNANT GLIOMA: FROM LABORA'I'ORYBENCH TO PATIENT BEDSIDE

HH Engelhard, HA Duncan, RJ Homer.Neurosurgery, Northwestern University,Suite 500, 233 E Erie, Chicago I1, USA

Sodium phenylbutyrate (SPB) is a phenyl-fatty acid which induces a differentiationresponse in many malignant cell lines. Inthese studies, the effect of SPB was investi-gated in cultured rat and human gliomacells, primary human glioblastoma (GBM)explants and in an animal tumour model.Clinical trials of SPB for the treatment ofpatients with GBM have now been started.Cells were analysed to assess the effect ofSPB on proliferation, cell cycle distribution,morphology, migration, invasiveness, apoto-sis, and c-mnyc and urokinase expression.Techniques included light and immunofluo-rescence microscopy, flow cytometry,scratch and Matrigel assays, DNA elec-trophoresis, and northern blot analysis.

Results showed that SPB treatmentdecreased cell counts and %S phase cells ina dose dependent fashion. For Ul 18MGcells, counts were 100 (21)%, 54 (7)%, 43(13)%, and 27 (7)% for 72 hours of treat-ment with 0, 2, 4, and 8 mM SPB, respec-tively. Primary GBM explant cells hadcounts of 100 (5)%, 71 (7)%, 51 (3)%, and42 (4)%. For C6 cells, %S phase was 32(3)%, 27 (1)%, 18 (2)%, and 14 (3)%,respectively. Treatment with SPB causedthe extrusion of long cytoplasmic processes,similar to those of differentiated astrocytes,and inhibition of cellular migration, but didnot cause apotosis. SPB caused down mod-ulation c-myc and urokinase expression by20-75% depending on cell type and dura-tion of treatment. Rats tolerated SPB infu-sion without discernable toxicity at clinicallyrelevant doses. SPB is available in an oralformulation for patient use. For all thesereasons, SPB continues to be an extremelypromising novel agent for use in patientswith malignant glioma.

DIFFERENTIAL. EFFECT'S OF COMBINATIONS OFCAMPTOTHECIN DERIVATIVE.S ANI) E'T'OPOSIDEON GLIOBLASTOMA AND) COLON CARCINOMA

RA Fenstermaker, GJ Castglia, MJCiesielski. Department of Neurosurgery,SUNY at Buffalo School of Medicine andBiomedical Sciences, and Roswell ParkCancer Institute, Buffalo, New York, USA

The limited success of standard chemother-apy for malignant gliomas suggests the needto identify combinations of agents with syn-ergistic activity against gliomas. Topois-omerases (topo) are nuclear enzymes thatrelieve the torsional constraint of DNAimposed during replication and transcrip-tion. Because these two nuclear factorsexhibit related actions, the possibility of syn-ergistic cytotoxicity between the two classesof topoisomerase inhibitors was evaluated.Combinations of topo I inhibitors 9-aminocamptothecin (9-AC) or topotecan(TPT) and a topo II inhibitor etoposide(VP- 16) were tested for synergistic cytotoxi-city in glioblastoma cell lines (U87, U1 18,U138, U373, SW1088, SW1783) and acolon carcinoma cell line (HT-29) usingsuforhodamine B (SRB) assays. IC9,s for 9-AC ranged from 7nM-1 11,uM, and TPTIC.ws ranged from 32nM-0-568pM. Cellsexposed to VP-16 had IC591s from1 48-13 6pM. When the two types of topoinhibitors were combined, the IC9,s werereduced up to fivefold. The combinationindex (CI) for drug interaction was signifi-cantly less than 1-0 (P < 005) for allglioblastoma cells indicating synergy. Incolon carcinoma, the CIs of the combinedagents were both equal to 1-0 indicatingadditivity. A differential effect on DNA frag-mentation was also apparent with mildantagonism in colon carcinoma and synergyin glioblastoma. In glioblastoma but notcolon carcinoma, subcytotoxic doses of 9-AC led to enhanced cytotoxicity of VP-16and vice versa. These findings suggest a tis-sue specific pattern to topo I and topo IIinhibitor interaction producing synergisticcytotoxicity in glioblastoma cells.

INFL,UENCE OF DOMINANT HEMISPHERICLOCALISA'I'ION ON TUMOUR ASSOCIATEDLANGUAGE DYSFUNC'I'ION

AM Thompson, R Taylor, R Sellar, IRWhittle. Department of Clinical Neuro-sciences, Western General Hospital, CreweRoad, Edinburgh, UK

Current knowledge regarding patterns oflanguage localisation in the dominant hemi-sphere has been derived from stroke studies.Classically a lesion in the territory of thethird frontal gyrus will result in a non-fluentor Broca's dysphasia whereas Wemicke'sdysphasia will follow damage to the superiortemporal gyrus. In this study the relationbetween the location of solitary tumours inthe dominant hemisphere and patterns oflanguage disorders was studied to evaluatethe hypothesis that tumour induced impair-ments of language do not conform with thepatterns of localisation in stroke. Patientswith a solitary dominant hemispherictumour were assessed using the Westernaphasia battery and Boston naming testbefore biopsy or resection. All patients wereon steroids (mean 9-3 mg/day). Tumourswere identified on either axial CT or MRI.Tumour location was assigned to one or

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more of six regions of the dominant hemi-sphere by placing a specially designed braintemplate over each scan. Statistical analysisto determine relations between languagescores and tumour location was carried outusing the Pearson r with Bonferroni correc-tion.

Sixty patients were studied. There werehighly significant correlations (P < 0 001)between the presence of tumour in Broca'sarea and (a) expressive language deficits; (b)anomia; and (c) impaired comprehension oflanguage. Several specific language abnor-malities were also found in patients withtumours in the temporal pole. There was nosignificant association between any featureof language dysfunction and tumours in theregion of Wernicke's area.

These results confirm the original hypoth-esis: Broca's dysphasia is not typically asso-ciated with impaired comprehension;anomia is not restricted to lesions in Broca'sarea; and damage to Wemicke's area usuallyresults in specific patterns of language dys-function whereas lesions in the temporalpole do not. The reason for these findingsand the use of templates was discussed.

SHOULD ENDOLYMPHATIC SAC TUMOURS BECONSIDERED PART OF THE VON-HIPPEL-LINDAU COMPLEX?

RE Tibbs Jr, AP Bowles Jr. Neurosurgery,University of Mississippi Medical Centre,2500 North State St, Jackson, Mississippi,USA

A patient with an endolymphatic sac tumourand van Hippel-Lindau disease is reported.An exhaustive literature review yielded onlyseven other reported cases. A summary oftheir characteristics was given. Endo-lymphatic sac tumours are rare and havebeen recently identified as a source of neo-plasia. Von Hippel-Lindau (vHL) disease ischaracterised by numerous cystic and solidneoplasms. The vHL tumour suppressorgene has been identified, and, with it, othershave been able to show similar geneticmutation in some of the tumours associatedwith vHL disease. A similar mutation in theendolymphatic sac tumour occurred in thispatient and it is proposed that this tumourshould be included in the range of neo-plasms associated with vHL disease.

HEAD INJURY PREDICTION REVISITED

IR Chambers, L Treadwell, A McNay, ADMendelow. Regional Medical PhysicsDepartment and Department of Surgery(Neurosurgery), University of NewcastleUpon Tyne, UK

In 1989 the Northern Regional HealthAuthority created a multidisciplinary headinjury audit team. Its aim was to investigatethe practice of head injury management andto make recommendations as to how itcould be improved. To predict the likeli-hood of an adverse outcome a database of1143 admissions to Newcastle GeneralHospital (NGH) during 1987, 1988, and1990 was analysed and a very simple modelfor outcome prediction based upon fourmain prognostic indicators (verbal orienta-tion, pupillary reaction, motor response, andage) was developed (table).

Between January 1992 and June 1995there was a further total of 2591 admissions

Modelfor prediction ofoutcome after head injury (favourable = GR/MD)% Favourable outcome on discharge

Group 1987; 88; 90 1992-5

1 Verbally oriented 99-4 98-12 Not verbally oriented 96-3 81-1

Age under 40Good motor responseEqual and reacting pupils

3 Not verbally oriented 89-4 60-2Age 40 or overGood motor responsePupils equal and reacting

4 Not verbally oriented 72-7 70 4Good motor responsePupils not equal and reacting

5 Not verbally oriented 55-1 63-3Not a good motor responsePupils equal and reacting

6 Not verbally oriented 27-9 28 8Not a good motor responsePupils not equal and reacting

GR = Good recovery; MD = moderate disability.

to NGH. Of these 2569 had the relevantdata to recalculate the outcome predictionmodel.The prediction model calculated on the

original data was confirmed by the analysisof the later data. Whereas the model is sim-ple it provides a useful tool to identify thosecases which may benefit from further audit.

ANATOMY OF DELAY IN PATIENTSUNDERGOING CRANIOTOMY FOR ACUTETRAUMATIC INTRACRANIAL HAEMATOMA

K Seex, F McNeil, G Teasdale. Departmentof Neurosurgery, Southern GeneralHospital, Glasgow, UK

Delay in evacuation of traumatic intracranialhaematoma (TIH) can adversely affect out-come. To identify where delays occur and toinvestigate whether the site of CT-localhospital or neurosurgical unit (NSU)-affects the time to surgery, data on 50consecutive patients arriving at the neuro-surgical intensive care unit between March94 and February 95 was prospectively col-lected. Clinical information, time to acci-dent and emergency, NSU, CT, theatre,incision and any delays, elective or other-wise, were recorded.

There were 44 male and six femalepatients with a mean age of 40 years (range1-67). 45/50 (90%) patients arrived at theNSU in coma or sedated and ventilated.21/50 (42%) had local hospital CT. 29/50(58%) had scans at the NSU. The corre-sponding median times from arrival at thelocal hospital to arrival at the NSU were 260and 183 minutes and the median times fromarrival at the NSU until incision were 100and 1 10 minutes respectively.

In "static" patients, waiting for local hos-pital CT introduces substantial delay.Within the NSU there is minimal delay inobtaining CT but opportunities exist toaccelerate theatre arrangements.

EFFECTS OF A SIMPLE PATIENT SPECIFICREMINDER ON IMPLEMENTATION OFGUIDELINES ON HEAD INJURY IN ACCIDENTAND EMERGENCY DEPARTMENTS

S Bergin, AD Mendelow, R Thomson.Directorate of Professional Advice andPublic Health, Tees Health/Department ofEpidemiology and Public Health, NewcastleUniversity, UK

Head injury is a cause of preventable morbid-ity and mortality. Guidelines on selection forskull radiography (SXR) and admission havebeen developed. A controlled study in threeaccident and emergency departments evalu-ated the impact of patient specific reminders(guidelines attached to the medical record).Appropriateness of SXR and admission wasassessed from the medical record (n = 2539).Significant changes over time in the recordingof signs and symptoms occurred in controland intervention departments. However,there was no change in the apparent appro-priateness of SXR or admission decisionsover time or following intervention. Therewas no significant difference in the propor-tion of cases managed appropriately, at eachsite, before and after implementation of theguidelines (for SXR: before 69-0-70-5%,after 666-70-9%; for admission: before91-7-94-8%, after 93-0-95 0%). This patientspecific reminder had no apparent effect onthe implementation of these guidelines inaccident and emergency departments. Nonethe less, since the introduction of the guide-lines, regional referral of intracranialhaematomas has more than doubled.

SAFETY OF EXTENDED ADMINISTRATION TOHEAD INJURED PATIENTS OF APTIGANEL HCL(CERESTAT5), A NON-COMPETITIVE NMDAANTAGONIST

G Teasdale, A Wagstaff, on behalf of the1102-005 (CERESTAT5) Studies Group.Institute of Neurological Sciences, Glasgow,UK

Aptiganel HCI (CERESTAT', CambridgeNeuroScience) shows powerful neuroprotec-tion experimentally and is unique as the onlynon-competitive NMDA antagonist beingdeveloped for clinical use in traumatic braininjury. The safety of neuroprotective dosagesgiven over clinically relevant durations hasbeen investigated. Severely head injuredpatients (GCS < 8) were studied in sevencentres in Scotland and the United Stateswithin 12 hours of injury. Initially patientswere randomly allocated either to placebo (n= 9) or Aptiganel (n = 24) given over periodsincreasing from 12 to 72 hours; 14 furtherpatients received Aptiganel in a 72 hour openstudy. Pharmacokinetic studies showed thatplasma concentrations of Aptiganel of 30ng/ml were achieved and maintained (threetimes the neuroprotective level experimen-tally). One patient received an inadvertent

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overdose and developed seizures; otherwisethere were no unexpected treatment relatedadverse effects. Mean blood pressure,intracranial pressure, and cerebral perfusionpressure did not differ between patients ran-domised to placebo or Aptiganel but ICPvariability was less in the latter group.Amongst randomised patients one out of ninereceiving placebo and four out of 24 receivingAptiganel died. Overall mortality at twomonths was 35%, death in each case beingattributed to severity of injury. We concludethat Aptiganel HCI can be given safely, at aclinically relevant dosage (15 mg bolus plus 3mg per hour) for 72 hours and that the effi-cacy of this regimen should be studied in adefinitive phase III trial.

IS HYPNOTRAEMIA IN ACU'I'E HEAD INJURY ASIGNIFI(CAN'T SECOND)ARY INSULT?

W Poon, Y Lolin, K Goh, V Yeung, XL Zhu,J Hsaing, C Cockram. Neurosurgical Unit,Prince of Wales Hospital, The ChineseUniversity of Hong Kong

The aim of this study was to determine theincidence and pathophysiology of hypona-traemia (plasma sodium, pNa < 134 mmol/l)after acute head injury, and to correlate thiswith the outcome. Head injured patientsrequiring intensive care management werestudied prospectively, with daily sampling ofplasma/urine for biochemistry and theirderived parameters, central venous pressure(CVP) recording, plasma atrial natriureticpeptide (ANP), and antidiuretic hormone(ADH) measurements.

Thirty consecutive patients were studied.Eleven patients (37%) had at least oneepisode of severe hyponatraemia (pNa < 125mmol/l) during the first week of admission,and eight (27%) had mild hyponatraemia(pNa 125-134 mmol/l). Of these 19 patientswith hyponatraemia, 11 (58%) had cerebralsalt wasting (CSW) associated with a raisedplasma ANP (92-8 (26-8) v 48-3 (31 2)pg/ml, P < 0-05) but not ADH concentra-tions (8-9 (4-1) v 6-5 (3 2) pg/ml), whereaseight patients had the syndrome of inappro-priate secretion of ADH (SIADH). Severehyponatraemia was associated with a higherincidence of unfavourable outcome (8/11(72%) v mild hyponatraemia 1/8 (13%) vnormal 3/11 (27%); df = 2, x2= 8-2, P =0-02).

Severe hyponatraemia (pNa < 125mmol/l) in acute neurotrauma was a definitesecondary insult resulting in poorer outcome.Accurate diagnosis and immediate treatmentwere therefore essential to prevent furtherbrain damage.

PLASMA SUBS'I'T'F'U'l' DIASPIRIN CROSS LINKEDHAEMOGLOBIN (DCLHB) REDUCES RAISEDINTRACRANIAI, PRESSURE IN A RODENT MODELOF IMPACT ACCELERATION HEAD INJURY

I Piper, M Souter, P Andrews, M Garrioch.Department of Clinical Neurosciences,Western General Hospital, UK

Diaspirin cross linked haemoglobin(DCLHb) is a new oxygen carrying plasmasubstitute with vasoconstrictive propertiesmediated by high affinity binding of nitricoxide by the haem moiety. The aim of thisstudy was to assess, using a rodent model ofhead injury, the effects of DCLHb on cere-

bral blood flow (CBF) and raised intracranialpressure (ICP).Ten anaesthetised, paralysed, and venti-

lated Sprague-Dawley rats were randomlyallocated to either treatment (DCLHb 400mg/Kg IV) or placebo (plasma protein sub-stitute 4-5% IV) groups. After a 450 g x 2m weight drop injury, all animals underwenta 30 minute period of bilateral carotid liga-tion in combination with a phlebotomyinduced period of hypotension (blood pres-sure (BP) 40-50 mm Hg). After reperfusion,DCLHb or the placebo agents were infusedand the animals then instrumented for mea-surement of intraventricular ICP and CBFin the region of sensorimotor cortex usingthe hydrogen clearance technique. BP, ICP,CPP (BP-ICP), and CBF were measured atfour hours after injury in all animals afterwhich animals were given a terminal anaes-thetic.

Analyses showed that DCLHb signifi-cantly reduced ICP (13 (6) -. 3 (3) mmHg, P = 0-01), increased CPP (64 (25) -+102 (19) mm Hg, p = 0 024) and increasedCBF (22 (6) -+ 30 (7) ml/100 g/min, p =0-022). Neuropathological studies are inprogress to determine if these beneficialeffects of DCLHb on the pathophysiologyafter head injury translate into neuroprotec-tlon.

GIUIAMATE EXCITOTOXICIlY ISPOlENTIATEl) BY NON-LETHAL HYPOXIA INORGANO'I'YPIC HIPPOCAMPAL SLICE CULIURES

AK Pringle, C Gascoigne, LE Sundstrom, Flannotti. Clinical Neurological Sciences,University of Southampton, SouthamptonGeneral Hospital, Southampton, UK

Antagonists of glutamate receptors signifi-cantly reduce ischaemic neuronal damage.However, the concentration of extracellularglutamate in the ischaemic brain is not suffi-cient to induce neuronal damage in acuteslices of neuronal tissue. Glutamate toxicityin ischaemia must therefore result from acombination of factors. The neurotoxicity ofsimultaneous exposure of cultured hip-pocampal slices to low levels of glutamateand hypoxia has been investigated. Theeffects of glutamate excitotoxicity wereinvestigated by exposing the cultures to0-01-10 mM glutamate for 60 minutes.Other cultures were additionally exposed tohypoxia, induced by placing cultures in anatmosphere saturated with 95%0,/5%CO2.After 60 minutes cultures were returned tonormal medium for 24 hours, after whichcell death was quantified using propidiumiodide (PI). Exposure to glutamate (0-3-10mM) or hypoxia alone did not produce PIfluorescence in the neuronal cell layers.However, 60 minutes exposure to combinedhypoxia and glutamate produced a signifi-cant increase in PI staining. PI fluorescencewas observed in 46-3 (8 9)% of CAl and41-7 (9 9)% of CA3 after simultaneousexposure to 0-3 mM glutamate and hypoxia.These data show that hippocampal neuronsin organotypic culture are remarkably resis-tant to glutamate toxicity up to 10 mMunder normal conditions. However, in con-ditions in which neuronal energy is compro-mised, very low concentrations of glutamatebecome toxic. Thus after cerebral ischaemia,a small increase in extracellular glutamatemay be sufficient to produce appreciableneuronal damage.

MI'I'OCHONDRIAL FUNCTION IN THE AGINGISCHAHMIC RAT BRAIN

M Davis, T Whiteley, DM Turnbull, ADMendelow. Departments of Surgery(Neurosurgery), Neurology, and Medicine(Geriatrics), University of Newcastle uponTyne, UK

Age related impairments of cerebral functionmay be in part secondary to structural andfunctional decline in brain mitochondria.Such oxidative damage to mitochondrialdeoxyribonucleic acid (DNA) and the sub-sequent defects in oxidative phosphorylationmight also be implicated in the pathogenesisof ischaemic neuronal damage and maythereby contribute to the age relatedincrease in infarct volume that has been doc-umented in a rodent model of focal cerebralischaemia. This hypothesis was evaluated byassessing mitochondrial function in bothischaemic and non-ischaemic brain tissue ofadult and aged male Wistar rats, six hoursafter occlusion of the left middle cerebralartery by thermocoagulation, according tothe technique of Tamura. Mitochondriawere harvested from the left and right cere-bral hemispheres of both age groups and theactivities of enzymes involved in catalysingoxidative phosphorylation, including theactivities of citrate synthase and the enzymecomplexes I, II, III, and IV were assessed ineach hemisphere. Data was analysed usingStudent's t test and the results are presentedas means with their standard errors.Complex I activity was lower in ischaemic

brain, with mean values of 91 1 (8 8)nmol/min/mg protein and 126-7 (14)nmol/min/mg protein in the left and righthemispheres respectively (P < 0 05, n = 13)and also declined with aging. The meanactivity in aged rats (n = 7) was 97-4 (15)nmol/min/mg protein compared with 160-9(18) nmol/min/mg protein in adults (n = 6,P < 0 05). The activities of complexes IIand IV were not significantly impaired inischaemic brain, but both declined withaging. The mean activity of complex II inaged rat brain was 222-1 (34) nmol/min/mgprotein, compared with 371-1 (39)nmol/min/mg protein in adults (P < 0 05),whereas mean values for complex IV were3-32 (0 52) K/s/mg protein and 5-41 (0-46)K/s/mg protein respectively (P < 0 05).Complex III and citrate synthase activitieswere not affected by aging or ischaemia.

Aging was associated with significantimpairments of cerebral mitochondrial func-tion, with decline in the activities of com-plexes I, II, and IV. The individualrespiratory chain complexes also exhibitedselective vulnerability to a focal cerebralischaemic lesion, with significant impair-ment of complex I activity in the lesionedhemisphere of both age groups. The agerelated decline in complex I activity may beimportant in the enhanced susceptibility ofthe aging brain to ischaemic neuronal dam-age.

BLOOD FLOW VELOCITY IN BASILAR ARTERYAND CEREBRAI CORTICALMICROCIRCULATION AFTER SYSTEMICADMINISTRATION OF I-NAME IN RABBITS

HK Richards, Ewa Kozniewska, MCzosnyka, JD Pickard. MRC CambridgeCentre for Brain Repair and AcademicNeurosurgery Unit, Addenbrookes Hospital,Cambridge, UK and Department of Clinical

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and Applied Physiology, School ofMedicine, Warsaw, Poland

Transcranial Doppler indices of blood flowvelocity (FV) pulsatility are becoming widelyused in clinical practice. To investigate theeffect of nitric oxide (NO) on FV pulsatility,the effect of inhibition of basal release ofNO on FV in the basilar artery and cerebro-cortical microcirculation was assessed usingan experimental model.

In 12 New Zealand White rabbits, FV,cortical laser Doppler flux (LDF), and arter-ial blood pressure (AP) were recorded for 60minutes after inhibition of basal release ofNO by systemic administration of NG nitro-L-arginine methyl ester, L-NAME (6 mg/kgintravenously).

After administration of L-NAME, APincreased and FV fell rapidly, both becom-ing significantly (P < 0-01) changed frombaseline values by the third minute andremained significantly raised or decreasedfor the remainder of the experiment. LDFexhibited a significant but slow decreasewith time. It reached a value which was sig-nificantly lower than baseline (P < 0-01) at40 minutes after L-NAME administration.L-NAME induced NOS inhibition in rab-

bits provokes a rapid reaction in FV in thebasilar artery and a slow reduction in corti-cal microcirculation. A gradual increase incerebrovascular resistance was therefore pre-ceded by a rapid decrease in the complianceof the large cerebral arteries.

DIABETES MELUIITJS ALTERS THEPATHOPHYSIOLOGY OF HAEMORRHAGICSTROKE: THE ROLE OF NITRIC OXIDEPATHWAYS

IP Fouyas, PAT Kelly, IM Ritchie, IRWhittle. Department of Clinical Neuro-sciences, Western General Hospital,Edinburgh, UK

Diabetes mellitus is associated with vasculardysfunction and impaired cerebrovascularresponsiveness. The role of diabetes in theevolution of ischaemia was considered in arodent model of intracerebral haemorrhage.

Arterial blood or silicon oil (50 p1) wasinjected into the striatum of both sponta-neously diabetic insulin-treated rats andnon-diabetic controls. After 24 hours, localcerebral blood flow (LCBF) was measuredusing ['4C]-iodoantipyrine autoradiography.LCBF was also measured in separate groupsof non-lesioned animals treated acutely withsaline, N--nitro-L-arginine methyl ester (L-NAME, 30 mg/kg intravenously), 7-nitroin-dazole (25 mg/kg intraperitoneally) or3-morpholinosydnonimine (SIN-1, 1-8 mg/kg/h intravenously).

In diabetic aniimals the volume of tissuesurrounding the haematoma in which LCBFwas between 15 and 35 ml/100 g/min (2-04(0A49) mm3; mean (SEM)) was significantlylarger than that found with oil injection(0-21 (0 08) mm3) and was also larger thanin control animals injected with either blood(0-27 (0-15) mm3) or oil (0-29 (0-07) mm3).As reported previously, basal LCBF was sig-nificantly reduced in the striatum of diabeticanimals and their response to L-NAME wasattenuated. By contrast, the response to 7-NI and SIN-1 was preserved in diabetic rats,indicating a specific perturbation ofendothelial nitric oxide (NO) activity butpreservation of neuronal NO in diabetes.

Diabetes mellitus influences the extent ofischaemia after haemorrhagic stroke. Theblood itself and not the "mass" effect isresponsible for the development of thepenumbra. Impaired endothelial NO activitymay be responsible for early exhaustion ofvasodilatory capacity in diabetes after strokeand subsequent development of ischaemia.

BRAIN DERIVED NEUROTROPHIC FACTORPREVENTS HYPOXIC/HYPOGLYCAEMICDAMAGE IN ORGANOTYPIC HIPPOCAMPALCULTURES

AK Pringle, LE Sundstrom, GJC Wilde, Flannotti. Clinical Neurological Sciences,University of Southampton, SouthamptonGeneral Hospital, Southampton, UK

Neurotrophins such as brain derived neu-rotrophic factor (BDNF) may form part ofan endogenous neuroprotective mechanismafter cerebral ischaemia. Although pretreat-ment with BDNF has been shown to pre-vent ischaemia neurodegeneration in vivo,this has not been replicated in vitro. Wehave investigated the effects of BDNF in amodel of ischaemia more representative ofthe in vivo situation. Organotypic hippocam-pal slice cultures were prepared from 8-10day old rat pups and maintained in vitro for14 days. Ischaemia was simulated by expo-sure of cultures to 95%N2/5%CO2 in glu-cose free medium for 60 minutes, afterwhich cultures were returned to normoxicconditions for 24 hours. Cell death as deter-mined by propidium iodide (PI) fluores-cence and quantified using NIH Image 1-5524 hours following 60 minutes ischaemia,significant PI fluorescence was presentthroughout CAl (68-7 (4 9)% of cell area).BDNF (0-1-100 ng/ml) produced a concen-tration dependent reduction in neuronaldamage when present in medium for 24hours before, during, and after the ischaemicepisode. Damage was reduced to 10-1(5 3)% by 100 ng/ml BDNF. Further stud-ies showed that 100 ng/ml BDNF was neu-roprotective only if present during the 24hours before ischaemia. These data suggestthat preincubation with BDNF is necessaryfor neuroprotection, implying that transcrip-tional changes are required such as upregu-lation of other neuroprotective proteins.

A COMPARISON OF DIFFERENT METHODS OFEMBRYONIC DISSECTION USED TO OBTAINSTRIATAL TISSUE FOR INTRACEREBRALTRANSPLANTATION IN THE RAT MODEL OFHUNTINGTON'S DISEASE

C Watts, A Rosser, SB Dunnett. MRCCentre for Brain Repair, CambridgeUniversity, UK

Huntington's disease (HD) is an inheritedprogressive neurodegenerative conditioncharacterised by movement, cognitive, andpsychiatric disturbances, and involves theloss of intrinsic striatal neurons as its promi-nent pathological feature. The clinical fea-tures are not susceptible to pharmacologicalmanipulation and neural transplantation isbeing intensively investigated as a possibletherapeutic alternative. In a rat model ofHD, foetal cells from the ganglionic emi-nence are transplanted into the lesionedstriatum. The ganglionic eminence, which is

divided into medial and lateral parts, givesrise to striatal primordium and adjacentstructures such as globus pallidus, amygdala,and piriform cortex. Grafts derived from thelateral part may contain a greater proportionof striatal tissue than grafts derived from themedial part or the standard dissection of thewhole eminence. A neuronal marker, micro-tubule associated protein (MAP-2) and astriatal specific marker, dopamine andadenosine 3:5 monophosphate-regulatedprotein (DARPP-32) in cell cultures havebeen used to compare the amount of striatalprimordial tissue obtained from the differentmethods of embryonic dissection. Ourresults indicate that, used in conjunction,MAP-2 and DARPP-32 accurately identifystriatal tissue obtained by different methodsof embryonic dissection. This will facilitatefurther refinement of intrastriatal striatalgrafts in the rat model of HD.

GENETIC DIFFERENCES BETWEEN FAMILIALAND SPORADIC GLIOMAS

Dan Fults. University of Utah, Salt LakeCity, Utah, USA

Tumours arising in cancer prone familiesresult from inherited, germ line mutations invarious genes controlling cell growth. Insome hereditary cancer syndromes thedefective gene has been identified, includingthe P53 gene in Li-Fraumeni syndrome,NF1 in von Recklinghausen's neurofibro-matosis, APC in familial polyposis, andMTS1 in familial melanoma. Although thefundamental cause of CNS cancer isbelieved to be genetic, few brain tumourcases are inherited. An important question iswhether brain tumours result from somaticmutations in the same genes that segregatein cancer families. To consider this ques-tion, DNA sequence analysis of four genesknown to cause hereditary cancer syndromes(P53, NFl, APC, MTS1) was carried out inpatients with sporadic gliomas. Varioustypes of gene mutations in tumour cells werefound but not in peripheral blood leucocytesfrom affected patients; mutation frequencieswere much lower in these sporadic tutorsthan reported in familial cases. These resultsindicate that most gliomas in adults resultfrom acquired, somatic mutations in cellgrowth control genes and not from inher-ited, germ line mutations.

FUNCTIONAL EXPRESSION OF A HUMANTUMOUR SUPPRESSOR GENE (P53) IN RATGLIOMA. AN EX VIVO MODEL

Victor CK Tse, Gerald D Silverberg.Molecular Neurosurgery Laboratory, Depart-ment of Neurosurgery, Stanford UniversitySchool of Medicine, Stanford, USA

The functional expression of the human p53gene leads to a reduction of tumour growth,both in vitro and in an ex vivo implantation.A retrovirus vector was used to insert p53into a rat glioma cell line (RT-2). A signifi-cant retardation of the in vitro growth curvewas seen and colony formation was signifi-cantly inhibited. Ex vivo implantation of theinfected cells showed the integration of thetransgene and its in situ expression resultingin a reduction of tumour volume. This studyshows the effectiveness of tumour suppres-

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sor genes in the treatment of a brain tumourmodel. The mechanisms of growth suppres-sion and the possible implications of adversein vivo tumour selection were discussed.

GENE EXPRESSION IN EXPERIMENTALISCHAEMIA: PARALLELS WITH GENEEXPRESSION AFTER SURGERY FOR

CONTUSIONS, INTRINSIC TUMOURS, ANI)EPILEPSY

PC Whitfield, VL Woodbum, JD Pickard.Academic Neurosurgical Unit and PDNRC,Addenbrooke's Hospital, Cambridge, UK

Adaptive cellular responses to external stim-uli, such as cerebral ischaemia, involve thetranscription and translation of DNA intoproteins. These include inducible transcrip-tion factors (ITFs) which are fundamentalto the stimulus-transcription response. ITFsmay influence the outcome of each individ-ual cell, and have been implicated in celldeath mechanisms. The ITF response toforebrain ischaemia in the gerbil has beenfully characterised. The pattern of ITFinduction differed according to ischaemicduration and reperfusion time. Transitoryinduction of hippocampal c-fos and c-junwas observed. Induction of J7unB was bipha-sic, with delayed expression evident in theselectively vulnerable CAl subfield 24 and72 hours after moderate ischaemia. NGFI-A expression was induced in surviving den-tate neurons. In addition, sustained glialactivation in response to moderateischaemia was seen throughout the hip-pocampus. Parallel studies on surgicallyresected tissue from patients with cerebralcontusions (n = 13), intrinsic tumours (n =8), and intractable epilepsy (n = 3) wereperformed. c-fos was expressed in eight(33%), and c-jun in 18 (75%) patients. Theinduction of ITFs may be a direct responseto the underlying pathology. Secondly, ITFsmay be important in the pathogenesis ofsecondary events in disease. Specific block-ade of ITF translation into proteins willhelp clarify the role of these factors in vivo.

FK-506 IMPROVEMENT IN RECOVERY AFTERSPINAI CORD INJURY: POSSIBLE ROIE OFGAP-43 EXPRESSION IN CALCINEURIN EFFECT

Joseph R Madsen, Paul MacDonald, LarryI Benowitz. Department of Neurosurgery,Children's Hospital, Boston, USA

Recent investigations have shown that FK-506, in wide use as an immunosuppressantdrug in transplantation, can stimulate neu-rite outgrowth in vitro, and can apparentlydiminish the size of experimental-cerebralinfarcts in rats. The previously puzzlingfindings that the specific receptors for FK-506 and similar drugs, calledimmunophilins, are more abundant in theCNS than in the immune system provide atheoretical mechanism for such activity.GAP-43, an intracellular phosphoproteinknown to be involved in growth cone activ-ity, is dephosphorylated by calcineurin, atarget of the FK/immunophilin system.However, as there is a negligible quantity ofGAP-43 in the uninjured spinal cord, signif-icant upregulation of this protein in neuronswould be necessary to implicate it in FK-506 neuroprotection.The effects of FK-506 given intra-

venously to rats 10 minutes after pho-tothrombotic thoracic spinal cord injury (1mg/kg), and intraperitoneally at 24 and 48hours after injury (0 5 mg/kg) were exam-ined. Clinical benefit in the FK-506 groupwas evident at 21 and 28 days postinjury,both by Tarlov scores (3-1 (0 2) v 2-3 (0 3),P = 0-024), and IP measurements (51-2(1 2) v 47 0 (1-3), P = 0-046, df = 44).We now report that tissue obtained from

similarly lesioned and treated animalsshowed scattered perilesional neuronsstrongly immunoreactive for GAP-43. ThusFK-506, an immunosuppressive agentwhich can promote neurite outgrowth invitro, significantly improves the recoveryafter photothrombotic spinal cord injury.Mechanisms of this effect may involvemodulation of the phosphorylation stateof GAP-43 expressed in perilesionalneurons.

CULTURE AND PRELIMINARYCHARACTERISATION OF EPIDERMAL GRO\X`THFACTOR GENERATED MOUSE CNS STEMCELLS

T Ryken, C Watts, A Rosser, C Svendsen.Department of Neurosurgery, StateUniversity of New York Health ScienceCentre at Syracuse, Syracuse, New York,USA and MRC Centre for Brain Repair,University of Cambridge, Cambridge, UK

Cultures derived from embryonic mousestriatal primordia (E18) were initially propa-gated in serum free culture conditions usingDMEM:F12 (1:1) supplemented with B27media supplement and epidermal growthfactor (20 ng/ml). After seven days the pri-mary cultures were centrifuged, resuspendedat a density of 20 000 cells per ml, andallowed to incubate an additional sevendays. This resulted in colonies of free float-ing spheres of cells which could be propa-gated for up to eight weeks by serialsubculture. These secondary cultures occa-sionally undergo spontaneous differentia-tion, adhere to the surface of the cultureflask, and display a variety of cellular mor-phologies. These morphological alterationsare enhanced by culturing the spheres overpoly-1-lysine coated glass coverslips and byremoving the EGF from the culture media.Immunofluorescent studies using antibodiesfor GFAP, MAP, Gal C, nestin, beta-tubu-lin, NCAM, CD-56, and CDS7, result in avariety of staining patterns. These findingsindicate that multiple phenotypes, both glialand neuronal, can result from prolongedculture of these primitive spheres. The con-tinued characterisation of this culture systemwill not only enhance the study of develop-mental neurobiology but suggests a potentialrenewable source of embryonic stem cellswhich may be of benefit in CNS transplanta-tion.

INTIRAOPERATIVE MRI: THE GENERAILELECTRIC MRT SYSTEM

Eban Alexander III. Department of Surgery(Neurosurgery), Brigham and Women's andthe Children's Hospitals, Harvard MedicalSchool, Boston, USA

The prototype General Electric (GE) MR/TIntraoperative Magnetic Resonance ImagingSystem was designed to enable real time

MRI while performing major open operativeprocedures. The design of the imaging mag-net was revised into two large tori, providingthe best arrangement for optimisation ofmanual access for the surgeon and an assis-tant. Combined with specially designed sur-face coils, the system offers excellent imageresolution.

High speed graphic computers are used tosegment and register MR data sets, using aPIXSYS triple charged couple device(CCD) imaging system to correlate MRIspatial information with the system's spatialenvironment. The MR/T (T for "therapy")holds tremendous promise for complex neu-rosurgical resections, especially for infiltra-tive tumours or those with intimateattachments to critical neural and vascularstructures, as well as for operative resectionelsewhere in the body.The ability of MR to analyse and quantify

thermal gradients with high resolutionenables the use of neodymium YAG laser,radiofrequency electrode, cryoprobe orfocused ultrasound lesioning, and tumourablation, carefully controlled through visual-isation in 3D space.The extent of tumour resection, lesioning

electrode position, degree of spinal decom-pression, etc can be confirmed intraopera-tively. The promise of such techniques asintraoperative functional brain imaging,image guided laser resection and focusedultrasound destruction of lesions emerge aspromising future applications. Sophisticatedvirtual reality, supported by a robust intra-operative MR imaging device, offers thepotential for a truly revolutionary surgicaltool. Entire new vistas in neurosurgicalintervention may open, mirroring the funda-mental quantum leap that was enabled bythe operating microscope a half century ago.

IMAGE DIRECTED PERCUTANEOUS SPINALSURGERY

Patricia Littlechild, NV Todd. NewcastleGeneral Hospital, Westgate Road,Newcastle upon Tyne, UK

There is currently no accurate method ofusing the technology of image guidedsurgery in minimally invasive spinal surgery.Previous attempts to develop a system havebeen hampered by the lack of a suitablemethod of registering the images to thepatient. A new method is under develop-ment, in which a percutaneously placedguide wire provides the basis for registration.This method involves the use of a purposebuilt surgical robot, guided by orthogonal xrays, to locate a surgical target within thespine. Preliminary trials are underway inphantoms, and show the system to be ableto locate a target with a mean error of 2-5mm. Further modifications to the robot areexpected to improve the accuracy. Proposedapplications for this method include spinalbiopsy, and placement of percutaneous lat-eral mass fixators in the cervical spine.

MORPHOMETRIC ANAIYSIS OF THE AXIS, WITHPARTICULAR REFERENCE TO POSTERIORSCREW FIXATIONS

G Solanki, AA Madawi, ATH Casey, HACrockard. Department of SurgicalNeurology, The National Hospital, QueenSquare, London, UK

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While C 1-2 transarticular screw providesthe most rigid fixation, there is a danger ofvertebral artery injury. The question arisesas to whether such injury is merely due tolack of technical experience or skills orbecause of specific anatomical variations.The osteometric study consisted of 50 dry

specimens of the second cervical vertebrae.Twenty one linear and five angular measure-ments were read using a PC linked elec-tronic calliper with direct data downloadcapabilities capable of 0-01 mm accuracyand a standard goniometer capable of 10accuracy.A significant number of anatomical varia-

tions were observed. Internal vertebralgroove erosions were noted in 22% of speci-mens and the height of the lateral massthinned to < 2-1 mm. Here clearly posteriorscrew insertions are an extreme risk to thevertebral artery, regardless of surgical skills.

In this study, the ideal drill angle for C1-C2 transarticular screw, was anatomicallybetween O° and 14-190, in the medial direc-tion, aiming at the anterior tubercle of atlas;similar safe angles for the transpedicularscrew were 32.39° in the medial directionand 24 06° in the superior direction fromthe point of insertion.Due to great variations in the axis mor-

phology and symmetry, failure to outlineanatomical safe bounds preoperatively, maylead to unexpected surgical complications.Careful CT at the appropriate angle to visu-alise asymmetry and erosions should bedone to exclude anatomical variations andhelp choose the right surgical approach foreach case.

THE MYELOPATHY FUNCTIONAL DISABILITYINDEX: FUTURE DIRECTIONS

ATH Casey, HA Crockard, M Bland. TheNational Hospital for Neurology andNeurosurgery, London, UK

The aim of the study was to measure disabil-ity caused by cervical myelopathy complicat-ing rheumatoid arthritis.The responses from 250 consecutive

patients to the Stanford Health AssessmentQuestionnaire were prospectively recorded.Using principal components analysis onthese results, the original questionnaire wasreduced from 20 questions to 10 questions,to create a myelopathy functional disabilityindex. In the second part of the study, theresponses to this abbreviated questionnaireby those patients undergoing surgery fromthe original group of 250 patients wereanalysed with respect to outcome, to assesscriterion related validity (predictive).

This method of data reduction resulted inno significant loss of infornation, reliability(internal consistency Cronbach's = 0 968)or sensitivity. The new scale, the myelopathydisability index, measures only one dimen-sion (Eigen value 6-97) and is more finelytuned to measuring disability in thesemyelopathic patients. When administered tothe 194 patients undergoing cervical spine(group 2) surgery the myelopathy disabilityindex was an accurate predictor of neurolog-ical and functional outcome, as well assurvival after surgery (P < 0-0001). Respon-siveness was also acceptable (standardisedresponse mean, 0 4 and the effect size,0 36).The myelopathy disability index provides

a user friendly, objective, and reliable meansof assessing disability in patients withrheumatoid involvement of the cervicalspine and also predicting outcome after sur-gical intervention. It also provides informa-tion for both the patient and surgeon alike,on what to realistically expect from surgery.Its adoption will facilitate comparisonsbetween different forms of surgical interven-tion for cervical myelopathy. Other possiblefuture uses will be discussed.

TREATMENT OF REFLEX SYMPATHETICDYSTROPHY WITH SPINAL CORD STIMULATION

R Segal, S Baser, BR Stacey. Departmentsof Neurological Surgery, Neurology andAnesthesiology, University of Pittsburgh andVeterans Affairs Medical Centre, Pittsburgh,USA

Six patients diagnosed with reflex sympa-thetic dystrophy (RSD) who were refractoryto conservative management underwentautonomic testing (quantitative sudomotoraxon reflex test (Q-SART) and thermogra-phy) preimplantation and postimplantationof a spinal cord stimulator (SCS). The SCSinduced reversal of the RSD syndrome withpatients reporting satisfactory pain relief andbeing tapered off narcotics, as well as havingresolution of swelling and discolouration ofthe involved limb. All the patients keep thestimulator turned on constantly; one patientrequired replacement of an exhausted bat-tery in 12 months. The Q-SART followingSCS demonstrated excessive resting outputin 316 patients resolving in 215 patientsstudied for more than three months afterimplantation. Excessive, persistent sweatproduction (volume 7-64 p1) in 3/6 patientsresolved (volume 2-17 Al), with normalisa-tion of Q-SART curve morphology, anddiminished active sweat production in 4/6patients improved in 2/5 patients afterimplantation. The thermography studiesdemonstrated the temperature asymmetry,ranging from 20 to 5°C decrease on thesymptomatic limb in 6/6 patients, clearlyimproved in all patients studied for morethan three months, with less temperatureasymmetry in two, no temperature asymme-try in one, and smaller area of temperatureasymmetry in two.

HRP RETROGRADE LABELLING OF ANTERIORHORN CELLS IN PERIPHERAL NERVE INJURY INTHE RAT

John Parker Mickle. Department ofNeurosurgery, University of Florida,Gainesville, USA

Various models have been proposed in ani-mals for the study of regeneration in periph-eral nerves: three types of injury are mostcommonly employed: transection; pinch;and clipping. These three models were stud-ied in three groups of rat sciatic nerve utilis-ing the retrograde transport of horseradishperoxidase (HRP) to the anterior horn cellcolumn as a measure of regeneration orinjury. The retrograde transport andlabelling of an anterior horn cell across anarea of manipulation (suture, pinch, clipapplication) was defined as direct evidenceof transport continuity from the peripheryacross the manipulated segment to the ante-

rior horn cell. Six animals were in eachgroup. Each animal had a four stitch repairof nerve transection, a 10 second pinch withjeweller's forceps, or a 30 second standardaneurysm clip application. Animals werethen subjected to HRP application, 0-5 cmdistal to the area of manipulation, on days 0through 5. After HRP application, the ani-mals were allowed to survive two days, afterwhich they were perfused through the car-diac ventricle with saline and a mixture ofparaformaldehyde and glutaraldehyde. Thelumbosacral spinal cords were removed andsectioned horizontally at 50 , intervals. Thecontralateral sciatic nerve was labelled withHRP at the same time that the experimentalside was labelled to have a control. Anteriorhorn cell labelling was then quantified bycounting individual cells on the control andthe experimental sides.

In the transection group of animals, ante-rior horn cell labelling did not appear on theexperimental side until day five and repre-sented only about 1% of control. HRP labelwas present in both the pinch and clip appli-cation groups on day 1. This rapidlyincreased to about 40% of control by day 5.These data suggest that the most commonmodels used in defining injury and regenera-tion in peripheral nerve are very differentsystems when compared with a retrogradelabelling technique used to define regenera-tion (pinch clip v transection). The pinchand clip application groups would appear torepresent not only regeneration, but alsoinjury expression, with some fibres remain-ing intact after manipulation. These datasuggest that a clearer definition of regenera-tion and peripheral nerve manipulation inexperimental animals should be developed.

KLIPPEL-FEIL SYNDROME REVISITED:DEVELOPMENTAL PATTERNS

Karoly M David, John M Stevens, H AlanCrockard. Department of SurgicalNeurology, The National Hospital forNeurology and Neurosurgery, QueenSquare, London, UK

The classic triad of Klippel-Feil syndrome isonly present in about 50% of patients withcongenital craniocervical junction anomalieswhich represent a wide variety in extent andclinical significance. To increase under-standing of these abnormalities thoroughretrospective analysis of plain x ray films,CT, CT-myelograms and MRI of patientswith congenital craniocervical junctionfusion anomalies were performed. Specialattention was given to fusion patterns andtheir possible embryological background.

In addition to the well known differencebetween fusion of ventral and dorsal parts ofvertebrae there was almost invariably a pro-nounced difference between the fusionpattern on the left and right side. Atlanto-occipital assimilation occurred with a widerange of subaxial vertebral and laminarfusions. Cervical split cord was always asso-ciated with extensive fusion of narrow andbroad vertebral bodies with or without pos-terior spina bifida. The vertebral canal wasusually very capacious similar to earlyembryological stages. Fusions involving theclivus, the odontoid, and long segments ofthe vertebral column are suspected to origi-nate from anomalies of the notochord.

Illustrative cases with their embryologicalbackground were discussed.

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PATHOPHYSIOLOGY OF CHIARIMALFORMATION IN RELA'I'ION TOSYRINGOMYELIA: A STUDY OF CSF DYNAMICS

WITH SPATIAL MODULATION OF

MAGNETISATION

DE Sakas, CM Tolias, SC Wayte, DJ Beale,B Williams. Walsgrave Hospital and TheMidlands Centre for Neurosurgery andNeurology, Birmingham, UK

Spatial modulation of magnetisation(SPAMM), an MRI technique used inassessing motion, was applied to the study ofCSF flow in patients with syringomyelia andin healthy volunteers. Quantitative CSF flowvelocity measurements were made in theanterior and posterior upper cervical sub-arachnoid space and inside the syrinx beforeand after craniocervical decompression. Inpatients the preoperative CSF velocitieswere found reduced at the upper cervicalsubarachnoid space by 26% ventral to and73% dorsal to the spinal cord when com-pared with those of healthy volunteers. Aftercraniocervical surgical decompression,SPAMM showed that CSF velocitiesincreased by 94% and 42%, ventral and dor-sal to the cord respectively. Normalisation ofCSF velocities in patients was highly predic-tive of clinical improvement. These resultsdo not support previously proposed theorieson the pathogenesis of syringomyelia, whichrely on displacement of CSF from the ven-tricles into the central spinal canal.Conversely, they are in agreement withrecent studies, which suggest that the injuryto the cord and expansion of the syrinx arecaused by displacement of CSF from theintracranial subarachnoid compartment tothe spinal subarachnoid compartment.

NORMAL PRESSURE HYDROCEPHALUS:

SPECIFIC PATTERNS OF COGNITIVE CHANGE

Joanna L Iddon, John D Pickard, Barbara JSahakian. Departments of Psychiatry andNeurosurgery, University of Cambridge,UK

In study I, 10 patients with normal pressurehydrocephalus (NPH) (shunted and non-demented) were assessed on standardisedneuropsychological measures including ver-bal fluency, the mini mental state examina-tion (MMSE), and on the computerisedCANTAB battery.

Results showed a specific pattern ofimpairment on tests of "executive function"including attentional set shifting and plan-ning.

In study II, 15 preshunt patients weresubdivided into demented (group 1, n = 7)and non-demented (group 2, n = 8) patientsas identified by the MMSE. Test sessionstook place preshunt and then again sixmonths postshunt. The same test batterywas given as in part I of the study, althoughgroup 1 patients were unable to completemost of these.

Group 1 showed a reversal of dementiapostshunt but remained globally cognitivelyimpaired. Group 2 showed a specific patternof executive impairment both preshunt andpostshunt, reflecting the same pattern ofimpairment as patients in study I. Subjectivereports from patients and relatives in group1 were of pronounced improvement in activ-ities of daily living postoperatively.

In conclusion, sensitive neuropsychologi-

cal tests can detect specific long term pat-terns of cognitive impairment in NPH.

ASSESSMENT SCALES ANI) THE COSTS OFSURGICAL, PREVENTION OF STROKE

M Davis, A Radstock, M Deverill, RPSengupta, AD Mendelow. RegionalNeurosciences Centre, Newcastle GeneralHospital and Department of HealthEconomics, University of York, UK

Cerebrovascular disease is a major cause ofdeath and disability and is responsible for asignificant proportion of National HealthService expenditure. Carotid endarterec-tomy (CE) prevents ischaemic stroke insymptomatic patients with severe carotidarterial disease and surgical intervention alsoreduces the morbidity and mortality fromaneurysmal subarachnoid haemorrhage(SAH). Analysis of the cost per qualityadjusted life year has shown that such surgi-cal intervention in SAH comparesfavourably with other surgical procedures.The risks and prognosis of surgical treat-ment may be related to clinical grading sys-tems. In patients with carotid stenosis, therisk of carotid endarterectomy may be pre-dicted by the Sundt risk classification, andin SAH, the World Federation ofNeurosurgical Societies (WFNS) has pro-posed a five point grading system. Thisstudy has evaluated the costs of the surgicaltreatment of carotid stenosis and SAH inrelation to these preoperative clinical grad-ing systems.The medical records of all patients who

were admitted after SAH and who had sub-sequent surgical intervention (1990-2), orwho underwent CE (1987-92), were exam-ined. Patients were assigned to a preopera-tive risk category according to the WFNS orSundt grading systems. The length of stayon the intensive care unit, high dependencyunit, and in a neurosurgical ward was docu-mented, along with the duration of timespent in neurosurgical theatres and the dura-tion of surgery. All investigations and med-ications were recorded. Outpatient visits(CE patients) and resource implicationsarising from complications, including re-admissions, repeat investigations, or repeatsurgical intervention, were recorded. Theduration of time spent with patients by med-ical personnel and other healthcare profes-sionals was documented. Costs were dividedinto direct, indirect, and overhead and costinformation was obtained for each wardtype, from the neurosurgical theatre suite,and from the outpatient department. Themean cost per episode of care was calculated

Hospital costs of stroke prevention

Carotid endarterectomy

Sundt grade Cost inC] (mean)I 2625II 2828III 4117IV 3243

Subarachnoid haemorrhage

WFNS grade Cost in a (mean)

I 4272I 5232III 7187IV 6825V 11546

and related to preoperative grade.Poorer preoperative grades were associ-

ated with higher mean costs.Preoperative grading may predict the sub-

sequent costs of surgery for stroke preven-tion and may be important in cost benefitanalysis.

RELIABILITY OF NEAR INFRAREDSPECTROSCOPY (NIRS) IN 'I'HE ASSESSMENT OF'CO, REAC'ITIVI'TY IN PATIEN'I'S WITHCEREBROVASCULAR DISEASE

P Smielewski, PJ Kirkpatrick, M Czosnyka,JD Pickard. Academic Neurosurgical Unit,Addenbrooke's Hospital, Cambridge, UK

The reliability of near infrared spectroscopy(NIRS) and reproducibility of the CO, reac-tivity test results have been studied inpatients with cerebrovascular disease.Twenty patients with symptomatic carotidstenosis were examined. Signals end tidalCO, arterial blood pressure (Finapress),flow velocity (FV) in the middle cerebralartery (transcranial Doppler (TCD)), SaO0(pulse oximeter), Hb, and HbO, (NIRS)and extracranial microcirculation (laserDoppler flux (LDF)) have been digitisedand recorded continuously. The protocolconsisted of two sets of 5% CO, chal-lenges-one on each side-with a break offive minutes between them. At the end ofeach recording two brief compressions of thesuperficial temporal artery were performed.Ten patients were re-examined within thenext two days using the same protocol.

Both TCD (FV) and NIRS showed somevariation in reactivity to CO2 (23% FV, 22%HbO, 31% Hb, 35% Hbt) between the twoconsecutive challenges. Higher differences inboth FV and NIRS reactivities were usuallyassociated with variation in ABP. Superficialtemporal artery compression confirmed thatwith a 6 cm interoptode distance HbO2 issome four times more sensitive to changes inCBF than extracranial circulation.The reliable assessment of CO, reactivity

using either TCD or NIRS should includerepeated CO2 challenge and careful analysisof the influence of change in ABP.

A PROSPECTIVE AUDIT OF ANEURYSMALSUBARACHNOID HAEMORRHAGE COMPARINGEARLY AND LA'I'E SURGERY

PJA Hutchinson, H Seeley, PC Whitfield, PJKirkpatrick. Academic Neurosurgical Unit,Addenbrooke's Hospital, Hills Road,Cambridge, UK

The results are reported for an ongoingprospective audit of outcome of patientswith aneurysmal subarachnoid haemorrhage(SAH). The effect of timing of surgery on(a) three month Glasgow outcome score(GOS) and (b) length of neurosurgical staywas sought.A standard proforma has been used since

September 1992 for recording the demo-graphic and clinical details of all patientswith SAH admitted to the East AnglianRegional Neurosurgical Unit. Data wereindependently collected by the ClinicalAudit Department.

Between September 1992 and December1995, 420 patients were admitted with SAH(mean age 53-1 years; range 16-89 years;59% female). The mean time from bleed tohospital admission was 2-4 days. 259

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patients underwent clipping of aneurysm atmean time 6-1 days postbleed.

Fifty nine per cent of the operatedpatients underwent early (0-4 days) surgery(mean 2-3 days) and 41% late (> 4 days)surgery (mean 10-0 days). Both groups werewell matched for demographic features andseverity of SAH. The outcome at threemonths was favourable (GOSI and GOS2)in 84% of the early group and 85% of thelate group. The operative mortality rate atthree months was 7% and 9% respectively.The length of stay was significantly shorter(95% CI P < 0-001) for those undergoingearly surgery (mean time 16-6 days) com-pared with those undergoing late surgery(23-2 days). In this unit this corresponds toa saving of 759 inpatient hospital days peryear.

Surgical outcome is independent of thetiming of aneurysm surgery, but those whoundergo late surgery have a longer inpatientstay.

TIMING OF ANEURYSMAL SURGERY INELDERLY PATIENTS

H Fernandes, A Jenkins, NV Todd, RPSengupta, PJ Crawford, AD Mendelow.Newcastle General Hospital, Newcastle-upon-Tyne, UK

There is a trend towards early clipping ofaneurysms after subarachnoid haemorrhage(SAH), especially in the good grade patient.Reluctance to extend this to elderly patients,however, still exists, with the expectationthat they will do worse.

Data were collected prospectively on allpatients admitted to the NeurosurgicalDepartment at Newcastle General, withSAH, from 1991-5.

Surgical clipping of an aneurysm was car-ried out in 416 patients. Early surgery (threedays or less from ictus) was carried out in209 patients under 65 years. One hundredand seventy eight (85-2%) made afavourable recovery (Glasgow outcomescore: good recovery or moderately disabledat six months). One hundred and thirty sixhad delayed surgery (4 to 79 days, mean10), 119 (87-5%) of whom made afavourable recovery.

Over the same period 27 patients, 65years of age or older, had aneurysmal clip-ping within three days, 20 made afavourable recovery. Of the 44 that haddelayed surgery (4 to 90 days, mean 12days), 32 made a favourable recovery. A X2test showed no significant differencebetween these observed frequencies (P =0 54 and 0 9). All four groups were compa-rable in terms of admission and preoperativeWFNS grade (t test admission grade, P =0-75, preoperative grade, P = 0 9).

These data would suggest that whereasthe rate of favourable recovery is not statisti-cally higher in the under 65 age group, themore elderly population do not fare worse ifoperated for aneurysmal rupture withinthree days.

ENDOTHELINS IN CEREBRAL VASOSPASM:EFFECT OF ORAL ANTAGONIST R047-0203 INPATIENTS

D Grosset, GM Teasdale, W Taylor, ADMendelow, A Wallnoeffer, R Jones. Instituteof Neurosurgical Sciences, Glasgow,Neurosurgery, Newcastle, UK and RochePharmaceuticals, Basle, Switzerland

Experimentally, endothelins cause severecerebral vasoconstriction and high concen-trations are found in the CSF of patientswith vasospasm after subarachnoid haemor-rhage. In a multicentre study we have inves-tigated the effect of Ro47-0203 (Bosentan),a competitive selective antagonist of endo-thelin I at A and B receptors in patients withDoppler evidence of vasospasm within 14days of subarachnoid haemorrhage.Twenty four patients were studied, each

had undergone operation for a rupturedaneurysm and had been shown by serialstudies with transcranial Doppler sonogra-phy (TCD) to have a recent pronouncedincrease in middle cerebral artery flow veloc-ities (MCAFV). Patients were randomisedto receive placebo (n = 6) or Ro47-0203 (n= 18) 500 mg intravenously over 30 min-utes. TCD measurements were made twohours before infusion, continuously fourhours afterwards, and serially for 24 hoursand blinded interpretation made accordingto predetermined criteria. Of 18 activelytreated patients only one patient showed acontinuing increase in MCAFV; in sevenpatients MCAFV remained stable. Sixpatients showed a probable and four a defi-nite decrease in velocity. In the five patientsin the placebo group three showed a furtherincrease in velocity, one showed stable val-ues; probable or definite decreases in veloc-ity were seen in only two.

These preliminary results encourage fur-ther studies of the role of endothelins incerebral vasospasm and exploration of thepotential of endothelin antagonists for clini-cal treatment.

INTRAOPERATIVE HYPOTHERMIC PROTECTIONDURING ANEURYSM SURGERY: A PILOTCLINICAL TRIAL

CM Loftus, MM Todd, JC Torner, A Gelb,R Craen, A Schubert, M Mahla. TheUniversity of Iowa College of Medicine, 200Hawkins Drive, Iowa City, USA

A multicentre randomised, prospective trialof intraoperative hypothermia in aneurysmpatients is presented. Candidates includedpatients in WFNS grades I-III, with pre-SAH Rankin scores of 0, 1, or 2. Pre-operative and postoperative neurologicalassessment employed the NIH stroke scale(blinded examiner), with examinations per-formed immediately before surgery, and at1, 3, and 7 days, and 6 and 12 weeks aftersurgery. Outcome at three months wasbased on the Glasgow outcome scale.The surgical team was blinded as to

group assignment. All patients underwentstandardised isoflurane/N2O/fentanyl anaes-thetic. Oesophageal temperature was con-trolled using forced air warming/cooling,water mattress, and heated humidification.Hypothermic arm patients were cooled to atarget of - 33-5°C at clip application, thenrewarmed as quickly as possible. Normo-thermic arm patients were maintained at36-50C.The trial began in January 1995; 70

patients had been entered at five centres byDecember 1995. Initial data survey indicatesthat target temperatures were reached in75% of hypothermic patients, with a groupmean temperature of 33-8°C. There were noobvious untoward effects of cooling.Additional preliminary data were presented.The pilot trial will be halted after 100patients have been entered and recruitment

of added international centres will be soughtto permit the design/completion of a larger,definitive trial (estimated size- 1500patients).

INTERNAL AND EXTERNAL CAROTIDCONTRIBUTION TO NEAR INFRAREDSPECTROSCOPY (NIRS) DURING CAROTIDENDARECTOMY (CE)

JMK Lam, PJ Kirkpatrick, P Al-Rawi, PSmielewski, JD Pickard. AcademicNeurosurgical Unit, University ofCambridge, Cambridge, UK

Sixteen patients undergoing CE were stud-ied. Transcranial Doppler monitoring mid-dle cerebral artery flow velocity,laser-Doppler flux (LDF) monitoring scalpblood flow, cerebral function monitor, andNIRS (Hamamatsu) were placed on the sideof operation. Data were recorded continu-ously.The external carotid artery (ECA) was

clamped for two minutes followed by inter-nal carotid (ICA) clamping. After CE, theECA and the common carotid artery clampswere released. It was followed by release ofICA in two minutes.

Interrupted time series analysis was usedto compare parameters before and afterclamping or release of an artery. Reductionin HBO2 and increase in HB as measured byNIRS were detected after clamping of ICAin 10 cases, ECA in 10 cases, and both inseven cases. The changes were inconsistentin three cases because of fluctuation inblood pressure. In six of the seven cases,where both ICA and ECA contributed toNIRS, ICA contributed more. Hence, NIRSdepended predominantly on ICA in 9/16cases and on ECA in 4/16 cases. ECAdependence had a strong association withipsilateral severe ICA stenosis and no severestenosis at the other ICA and ECAs.Changes in NIRS after clamping or releaseof ECA had a strong association with signifi-cant corresponding changes in LDF, butthere was no such association after clampingor release of ICA.

TRANSCUTANEOUS DETECTION OF CHANGESIN OXYHAEMOGLOBIN CONCENTRATION INRESPONSE TO INTERNAL CAROTID INJECTIONSOF RADIOCONTRAST MEDIA USING NEARINFRARED SPECTROSCOPY

TJ Germon, PD Evans, N Barnett, P Wall,TT Lewis, RJ Nelson. Department of Neuro-surgery, Frenchay Hospital, Bristol, UK

Near infrared spectroscopy (NIRS) may beused to monitor transcutaneously concentra-tions of oxy and deoxyhaemoglobin in a tis-sue volume, the size of which is thought to beproportional to the separation between theNIR light emitter and detector. Internalcarotid (IC) arteriography results in a tran-sient displacement of oxygenated haemoglo-bin from the arterial and capillary bed.Time-resolved, multichannel NIRS was usedto detect reduction in oxyhaemoglobin con-centrations in the frontal region after 10 ICinjections (10 patients five men, threewomen: mean age 42-5 years) undergoingelective IC arteriography before epilepsysurgery. We predicted greater reductions inoxyhaemoglobin concentration at increasingemitter-detector separations due to theincreasing proportion of cerebral tissue remit-

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ting NIR light to the mcre distal detectors.A significant reduction was found in oxy-

haemoglobin concentration in the 0-10 sec-onds after injection of the radiocontrastmedium at all emitter-detector separationsfrom 0 7-5 5 cm. However, when adjustedfor mean photon path length the magnitudeof the reduction was not dependent on emit-ter-detector separation.

These results differ from a similar studyusing intra-arterial indocyanine green dyewhich has been used to validate dual-channelNIRS. They suggest that a significant amountof radiocontrast passes into the extracerebraltissues during IC arteriography or that, dueto optical channelling, most photons detectedpass through extracerebral tissues.

NON-INVASIVE NEAR INFRAREDSPECTROSCOPY MEASUREMENTS OF HBO,CORRELATED WITH INVASIVE DYNAMICMICROPOLARGRAPHIC PO, VALUES INNON-TRAUMATIC HYDROCEPHALIC PA'I'IENTSAT DRAINAGE

GS Cruikshank, R Duckworth. Departmentsof Neurosurgery and Neuro-Anaesthesia,Institute of Neurological Sciences, SouthernGeneral Hospital, Glasgow, UK

The ability of non-invasive NIRS to reflectparenchymal brain tissue oxygenation is inquestion. The effect of scalp and skullattenuation may limit the NIRS signalderived from brain tissue. This study sets outto correlate the relation between direct tissuePO2 measurements and non-invasive NIRS data from patients with non-traumatic hydrocephalus recorded at the timeof pressure correction by ventricularpuncture. The major assumption in thismodel is that hydrocephalus exerts auniform effect of pressure on the par-enchymal substrate for NIRS and PO0recordings.Ten patients with hydrocephalus due to

congenital aqueduct stenosis (two), posteriorfossa tumours (three), or shunt malfunctions(five) were entered into this study. TheCritikon 2001 NIRS system was used to non-invasively evaluate the change in brain HbO.in the left frontal region. Invasive brain accesswas via a right frontal burr hole whichallowed a dynamic micropolarographic andventricular puncture pressure measurementsto be made during a continuous recording ofNIRS. With conditions otherwise unalteredthe effect of ventricular puncture and decom-pression was monitored.

Intraventricular pressure varied at punc-ture from 44 down to 10 mm Hg, and wasbrought down to a drainage height of 10 cmof water. There was an immediate improve-ment in monitored median tissue PO2 whichwas more pronounced at higher pressure lev-els. There was a good direct correlationbetween the median PO2 and change inHbO2. There was a close inverse correlationbetween these factors and ventricular pres-sure.

In all cases the effect of a decrease in pres-sure by ventricular puncture was to improvethe HbO2 and median tissue PO2 measure-ments. The response to dropping pressureseems to be due to a directpressure effect on microcirculation as theimprovement in oxygenation appears rapid.This study provides evidence that the correla-tion between HbO2 measured non-invasivelyand median tissue PO measured invasively isgood in such a circumscribed model.

ASSESSMENT OF CEREBRAI HAEMODYNAMICS

USING SPATIALLY RESOLVED SPECTROSCOPY

PG Al-Rawi, P Smielewski, H Hobbiger, GDhond, S Ghosh, PJ Kirkpatrick. UniversityDepartment of Neurosurgery, CambridgeUniversity, Cambridge, UK

Spatially resolved spectroscopy (SRS,Hamamatsu Photonics) is a new develop-ment for deriving a quantitative measure ofcerebral oxygen saturation non-invasively.SRS delivers near infrared light (four wave-lengths) via a common scalp optode. Backscattered light is detected at three closelyplaced scalp receivers which theoreticallysamples light that has followed a similar path.An algorithm is used to calculate absoluteconcentrations of haemoglobin (Hb) andoxyhaemoglobin (HbO2), and hence meancerebral haemoglobin saturation.

This machine has been incorporated into amultimodality monitoring system for the pur-pose of validating SRS% saturation againstjugular bulb oxygen saturation (NjO2), inpatients undergoing routine cardiopulmonarybypass (CPB) procedures (n = 24). Datawere digitised and recorded real time.

Correlation between SRS and SjO mea-surements varied from patient to patient (r =0-08-0 97). Overall the range of changes seenwith the SRS were not as great as those seenwith SjO2 measurements. SRS tended to givereadings that were 10-15% lower than SjO2readings.SRS provides a new means of assessment

of cerebral oxygenation; however, the resultsof this study suggest that SRS is not, as yet, areliable monitor of cerebral oxygen saturationduring CPB. Variables affecting transmissionof light into and through cerebral tissue arecomplex. Calibration of this technique is dif-ficult, and requires further investigation andadjustment, possibly using different clinicalscenarios.

LUMBAR CEREBROSPINAL FLUID PRESSURF

MONITORING USING THE NEW CODMAN

MICROSENSOR

H Femandes, E Bashir, A Jenkins. NewcastleGeneral Hospital, Newcastle-upon-Tyne,UK

Direct measurement of CSF is required onmany patients with hydrocephalus. The mostaccurate method, with an intraventricularcatheter, is invasive. Some lumbar methodsexist, but the new Codman intracranial pres-sure (ICP) monitoring system has yet to bevalidated in this role.The Codman MicroSensor ICP transducer

consists of a strain gauge pressure sensormounted at the tip of a flexible nyloncatheter.

Three patients, with differing pathologicalcauses of communicating hydrocephalus weremonitored using this device. Raised pressurewas demonstrated in two patients, and theirsymptoms settled with operative CSF diver-sion. One patient with normal pressures andheadaches settled with Pizotifen.The Codman catheter removes the need

for a CSF column and its inherent problems,and because it is flexible lends itself tointrathecal placement. It can be secured with-out risk of fracture, unlike fibreoptic devices.It has been validated as an accurate device inthe laboratory, and there is some preliminarydata to confirm ventricular accuracy. Wehave successfully used it in three patients for

the measurement of lumbar CSF pressure,with maximum patient comfort, and nobreakages. Although comparative readingsare not available, the satisfactory clinicalresults bear witness to its reliability.

STATISTICAL ISSUES IN COMPARISONS OFIN'I'RACRANIAL PRESSURE M14ONITORINGDElVICES

DF Signorini. Department of ClinicalNeurosciences, Western General Hospital,Edinburgh, UK

The comparison of two methods of measur-ing the same physical parameter when neithercan be considered a "gold standard" is arecurring problem in medical research.Typical analysis of the problem involves plot-ting one measurement against the other andcalculating the correlation coefficient. It hasbeen argued that it is more informative toplot the difference between measurementsagainst their average.The nature of intracranial pressure (ICP)

monitoring devices implies that comparisonstudies generally involve few patients, each ofwhom contributes many measurements. Thisimplies that not all of the paired measure-ments are statistically independent, and thatBland-Altman plots may not be adequate.

This paper aims to show that a more rigor-ous analysis which takes this non-indepen-dence into account can illustrate features ofthe physical processes which are not readilyapparent using "standard" methodology. Themotivating and illustrative example is an invivo comparison of an intraparenchymalCodman ICP monitoring device with bothintraparenchymal and intraventricularCamino devices, which is ultimately analysedusing a mixed effects ANOVA model.

CORREIATION BETWE'EN SLOW WVAVES ININTRACRANIAL, AND ARTERIAL PRESSURE: ANEW INDEX OF CEREBROVASCUIAR REAC'I'IVITY

M Czosnyka, P Kirkpatrick, P Smielewski, DMenon, JD Pickard. Academic NeurosurgicalUnit, Addenbrookes Hospital, Cambridge,UK

Association between changes in arterial pres-sure (AP) and intracranial pressure (ICP)depends on the cerebrovascular reactivityreserve. An index was developed for the con-tinuous monitoring of this association andverified in a group of 82 severely head injuredpatients. AP, ICP, and transcranial Dopplerblood flow velocity in MCA (FV) wasrecorded daily (20 minutes to two hour peri-ods). The slow waves response index (SWRx)was calculated as a moving correlation coeffi-cient between 30 consecutive samples ofaveraged (over six seconds) values of ICP andAP. Positive SWRx correlated significantlywith greater ICP (r = 0-496; P < 0-00001),lower CPP (r = 0-36; P < 0-001), and pooroutcome (at six months after injury: r = 0-46;P < 0-00001). Correlation of the SWRx withtranscranial Doppler index of autoregulation(correlation between time average FV andCPP) was very close: r = 0-63; P < 0-000001.SWRx was positive (P < 0 05) during the firsttwo days after injury, but only in patientswith an unfavourable outcome.

Computer analysis of slow waves inAP and ICP is able to provide continuousindex of absent (positive SWRx) or intact(zero or negative SWRx) vascular reactivity.Absent reactivity is predictive of pooroutcome.

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