University of Keele, 15-16 April 1993

74ournal ofNeurology, Neurosurgery, and Psychiatry 1993;56:724-732

Proceedings of the Association of British Neurologists,University of Keele, 15-16 April 1993

DETECTION OF CIRCULATING CEREBRALEMBOLIH Markus, A Loh, MM Brown. St George'sHospital Medical School, London, UK

Theoretically it should be possible to detectcirculating solid cerebral emboli as highintensity signals on a Doppler ultrasounddisplay, and recently such signals have beennoted in patients with potential embolicsources.An in vivo validation study was carried

out. Pathological emboli (atheroma, throm-bus and platelet aggregates) were intro-duced into the sheep proximal carotidartery while the ipsilateral distal carotidartery was insonated using a transcranialDoppler ultrasound machine. A total of 74emboli, with sizes as small as 0-2 mm, wereintroduced and all were detected as shortduration high intensity signals. Smalleremboli could not be made, but micro-spheres as small as 10 microns weredetected.A logarithmic correlation was found

between embolus size and amplitude of sig-nal (thrombus rho = 0-87, platelet 0-97,atheroma 089); the signal associated withplatelet emboli was significantly less intensethan that with thrombus (p < 0-05) oratheroma (p < 0 005). A significant linearcorrelation was found between embolus sizeand duration of high intensity signal(thrombus r = 0 91, platelet 0-82, atheroma0 82).

This new technique will allow detectionof circulating cerebral emboli in humans.Analysis of signal parameters will give infor-mation on the size, and possibly the nature,of such emboli. It may allow selection ofpatients with particularly high risk of subse-quent embolic stroke. Similar signals havebeen detected in subjects with carotidstenosis and cardiac valvular disease.

COMPARISON OF MAGNETIC RESONANCEANGIOGRAPHY, INTRA-ARTERIAL DIGITALSUBTRACTION ANGIOGRAPHY AND DUPLEXULTRASOUND IN THE ASSESSMENT OFEXTRACRANIAL CAROTID ARTERY STENOSISGR Young, PRD Humphrey, MDM Shaw,TE Nixon, ETS Smith. The Walton Centrefor Neurology and Neurosurgery,Liverpool, UK

The authors carried out a triple blind com-parison of duplex ultrasound (US), intra-arterial digital subtraction x-rayangiography (DSA) and 2D and 3D time-of-flight magnetic resonance angiography(MRA) in the assessment of the extracranialinternal carotid artery. Patients werescreened with US to exclude those with lessthan 30% stenosis of the symptomaticcarotid artery. A total of 70 consecutivepatients referred for angiography, withsymptoms of carotid territory ischaemia,had investigation.

Percentage stenosis values were groupedinto mild (0-30%), moderate (31-69%),severe (70-99%) or occluded categories.Analysis of the first 36 patients is complete.

Spearman's rank correlations were 0-92(MRA and DSA), 0 90 (MRA and US) and0 93 (DSA and US).

For clinically important differences thechance corrected proportional agreement orKappa (ic) statistic was used, whereK = 0-61-0-80 indicates good agreementand K = 0 81-1 00 indicates very goodagreement. K = 0-68 (MRA v DSA), 0-68(DSA v US) and 0 70 (MRA v US).Weighted kappa values wereKW = 0-80, 0-80, and 0-81 respectively.

Assuming DSA to indicate the true situa-tion (data will be presented to question this)the sensitivity and specificity for diagnosing70-99% stenosis by MRA were 85% and96% respectively, with positive predictivevalue 92% and negative predictive value91%.

Investigation with MRA together withUS will largely replace the need for DSAwhen assessing suitability for prophylacticcarotid endarterectomy.

COAGULATION ABNORMALITIES IN BENIGNINTRACRANIAL HYPERTENSION

JD Sussman, GAB Davies-Jones, MGreaves, M Leach. Royal HallamshireHospital, Sheffield, UK

Study of the pathophysiology of benignintracranial hypertension (BIH) suggeststhat either an increased resistance to CSFflow across the arachnoid villi, or anincreased pressure within the venous systemmay give rise to raised intracranial pressure.The similarity between the symptoms andsigns which arise in venous sinus throm-boses and BIH raises the possibility thatmicrovascular occlusion which is not visibleon conventional angiography might give riseto cases of BIH.

Thirty eight patients with BIH weretherefore investigated by measurement ofblood cell counts, fibrinogen levels, anticar-diolipin antibodies, lupus anticoagulantautoantibodies, protein C and S, andantithrombin III levels.Twenty three (60%) showed abnormali-

ties previously associated with thrombotictendencies. Twelve (32%) of the 38 hadlupus anticoagulants, ten (26%) had abnor-mally high fibrinogen levels. Some otherrare causes of hypercoagulability werefound.

These findings suggest that, as suspected,BIH is a symptom complex with a variety ofcauses and a new approach to treatment issuggested.

A STUDY OF HEREDITARY ESSENTIAL TREMORPG Bain, LJ Findley, CD Marsden. MRCHuman Movement and Balance Unit,London UK

Objective: To determine the phenotype ofhereditary essential tremor (HET).

Background: Clinical information onHET is scarce compared to that on "essen-tial tremor".

Methods: 20 index cases with incontro-vertible HET and their kindreds were stud-ied (51 ofwhom were affected).

Results: HET is autosomal dominant,with bimodal age of onset (median: 17years). Penetrance was virtually completeby the age of 65. The segregation ratio foraffected/total kin was 0-48. There were noexamples of the disease skipping a genera-tion. Men and women were equally affect-ed. The typical phenotype was a mildsymmetrical action tremor of the upperlimbs. No isolated tremors of the legs, head,face, voice, jaw and tongue were encoun-tered and no dystonic postures occurred.There was a strong association with classicalmigraine but none with Parkinson's disease.Primary writing tremor and primary ortho-static tremor did not occur. A total of 70%of head tremor was of a "no-no" variety.Fifty percent of cases were alcohol respon-sive but in 20% of families heterogeneity ofresponsiveness existed. Tremor severity anddisability increased with age and the dura-tion of tremor but age at onset had no pre-dictive value on outcome.

Conclusion: Hereditary essential tremordoes not produce dystonia and differs inmany respects from previous descriptions of"essential tremor".

HEMISPHERECTOMY; AN EFFECTIVETREATMENT FOR RASMUSSEN'S SYNDROMEZ Matkovic, JM Oxbury, CBT Adams, SMOxbury, J Morris, Z Zaiwalla. The RadcliffeInfirmary, and the Park Hospital, Oxford,UK

Seven patients with Rasmussen's syndromehad hemispherectomy (7 hemispherectomy,1 restricted corticectomy). Pathology con-firmed cortical damage (7), and inflamma-tion (5). Pre-operative features were: all hadonset with seizures (tonic/clonic 4, simplefocal 2, complex focal 1) at age 4-8 years;unilateral weakness developed 0-4-6 yearslater; 2 had dysphasia and 2 hemianopia.Electroencephalography showed excess slowactivity bilaterally (7), spikes (unilateral 5,bilateral-2). Neuroimaging showed unilat-eral cerebral atrophy (6). CSF examinationrevealed pleocytosis (1), oligoclonal band-ing (1). IQ ranged 54-105 (median 67).Clinical deterioration developed overmonths (5) or years (2). Control of seizureswas not achieved by: anticonvulsant drugs(7), restricted corticectomy (5), ketogenicdiet (2), steroids (2), gamma globulin (2).Hemispherectomy was performed 0-5-20years after onset (median, 3). Postoperativefollow up to 6 years has been with regularclinical and neuropsychological assessment.After a follow up period of at least 3

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months, six were walking independently,one with assistance and five were seizurefree. Psychosocial functioning was assessedby questionnaire. Parents have all describedhemispherectomy as "successful" and out-come as "very satisfactory".

It is concluded that hemispherectomy isthe only satisfactory treatment forRasmussen's syndrome.

EFFECT OF STRUCTURED BACKGROUNDS ONSMOOTH PURSUIT EYE MOVEMENTSMC Lawden, H Bagelmann, TJ Crawford,TD Matthews, C Kennard. Charing Crossand Westminster Medical School, London,UK

The oculomotor smooth pursuit system isdriven by the slip of the target image uponthe retina arising from errors in matchingeye and target velocities. Pursuit of an

object moving against a structured back-ground will result in retinal flow in thedirection opposite to target movement.Central mechanisms allow these distractingsignals to be overridden effortlessly. To iso-late the anatomical substrate of this capacitythe effect of the presence of a structuredbackground upon smooth pursuit in 27patients with focal cerebral lesions was

studied. Studies on normal subjects con-

firmed that a background has little effectupon pursuit.

Eye movements were recorded byinfrared oculography or the scleral searchcoil method. The target was a bright spotmoving horizontally in a triangular wave-

form of amplitude 22-5 deg visual angle, ateither 10, 20, 30, or 36 5 deg/s. Data were

collected in darkness and with a structuredbackground. Fourteen patients showed a

significant reduction of gain with a struc-tured background, while the remaining 13showed little or no effect. Comparison ofthe location of the cerebral lesions in thesetwo groups suggested that lesions in theinferior parietal cortex (area 40) result indisruption of pursuit in the presence of a

background.

ANTI-GANGLIOSIDE ANTIBODIES INPERIPHERAL NEUROPATHYHJ Willison, J Veitch, G Paterson, PGEKennedy. University of Glasgow, UK

Autoantibodies reactive with polysialylatedgangliosides are becoming increasinglyidentified in patients with acute and chronicperipheral neuropathies.

In Miller Fisher syndrome (MFS), it hasbeen observed that all (4/4) consecutivecases that have recently been seen had anti-GQlb IgG autoantibodies with titres rang-ing from 1/960 to 1/13500 and lower titreIgM anti-GQlb antibodies. These antibod-ies are absent in controls. 3/4 MFS cases

also showed reactivity with GDlb, GD3and GDla, mainly in the IgG fraction.These data concur with 2 other recentreports of similar findings.A patient has also recently been identified

with a chronic sensory demyelinatingneuropathy and an IgM paraproteinaemia

in whom the paraprotein reacts attitres in excess of 1/100,000 withNeuNAc(a2-8)NeuNAc(a2-3)Gal config-ured disialosyl groups present on the gan-gliosides GDlb, GTlb, GQlb and GD3.This patient is similar to 4 other reportedcases.

These data indicate that clinical pheno-types can be segregated serologically on thebasis of their pattern of anti-gangliosideantibody reactivities in that a) anti-GQlbIgG antibodies appear to be a highlyspecific and diagnostically useful marker forMFS and b) a large fibre predominantlysensory demyelinating neuropathy is partic-ularly associated with IgM anti-disialosylantibodies.

NERVE GROWTH FACTOR IN INJURED HUMANPERIPHERAL NERVE: IMPLICATIONS FORNERVE REPAIRP Anand, R Birch, P Foley, D Sinicropi, SPeroutka. The Royal London HospitalMedical College, London, the RoyalNational Orthopaedic Hospital, Stanmore,UK and Genentech Inc, San Francisco,USA

Animal models show that degenerativechanges in injured nerves, includingdecreased expression of sensory neuropep-

tides and neurofilaments, and axonal atro-phy, may be caused by deprivation of nervegrowth factor (NGF), and can be reversedby administration of exogenous NGF. Theimminent availability of recombinanthuman NGF for clinical use led to thisstudy of brachial plexus injury in obstetricand road traffic accident cases, wheredespite advances in reconstructive surgery,nerve degeneration and failure of regenera-

tion result in chronic pain and poor recov-

ery. NGF concentrations in sural nerves

used for grafting in these cases rangedbetween 2,000 and 6,000 pg/g, in accordwith previously reported levels of 2,400 ±

500 pg/g in post-mortem adult human sciat-ic nerve. The levels of NGF were lower(500-2,000 pg/g) in avulsed spinal roots ofboth adults and neonates 3 months post-injury. NGF levels were usually low butvariable in different cases just proximal anddistal to the site of injury, and in dorsal rootganglia related to avulsed roots: this may

partly explain the variable spontaneous andpost-surgical outcomes. As NGF concentra-tions in dorsal column and dorsal horn ofpost-mortem human spinal cord rangebetween 10,000 and 20,000 pg/g, localexogenous NGF administration appearsindicated in re-implantation of avulsed dor-sal roots and peripheral nerve repair.

MOLECULAR STUDIES IN SPINAL MUSCULARATROPHYKE Morrison, RJ Daniels, MJ Francis, KEDavies. Institute of Molecular Medicine,University of Oxford, UK

Childhood onset proximal spinal muscularatrophy (SMA) is a neuromuscular diseasecharacterised by selective loss of alphamotor neuron cell bodies. Three forms havebeen distinguished on the basis of severityof disability and age at onset. All three showautosomal recessive inheritance and havebeen mapped by linkage analysis to probesat 5ql 1-2-13-3.We have expanded the original linkage by

genotyping over 60 SMA pedigrees with

many novel microsatellites generated fromyeast artificial chromosomes (YACs) andcosmids which map within the candidateSMA interval. Multipoint mapping andanalysis of key recombinants has refined thedisease locus to a lcM region, flanked bymarkers D5S345 and 2a9-1. The novel

microsatellites that have been developed arenow being used in several laboratoriesworldwide to provide more accurate prena-tal prediction of SMA.YACs have been isolated for all relevant

markers and by generating end clones andsubsequent YAC walking, the entire candi-date region is now almost completelycloned. Genes from this region are beingisolated by directly screening fetal brain andspinal cord cDNA libraries with YACs andcosmid contigs. One expressed sequencecharacterised to date is of particular inter-est, as it shows homology to a portion of theandrogen receptor, the first exon of whichshows a trinucleotide expansion in spinalbulbar muscular atrophy.

SURGICAL TREATMENT OF NEUROGENICTHORACIC OUTLET SYNDROME: A FOLLOW UPSTUDYZ Matkovic, M Donaghy, PJ Morris.Radcliffe Infirmary, and John RadcliffeHospital, Oxford, UK

Twenty eight patients (23 f, 5 m; age 23-62years) were assessed from 3 months to 16years following 23 operations for suspectedneurogenic thoracic outlet syndrome.

Cervical ribs were demonstrated by plainx-rays (15) or MRI only (1). Cervical ribresection (17) produced resolution (9) orsignificant improvement of symptoms (7).Symptoms continued to progress in onepatient subsequently diagnosed as sufferingfrom syringomyelia.

Twelve patients had features of thoracicoutlet syndrome but no cervical ribs. In 4no definite operative abnormality wasfound, scalenus anterior was divided, andsymptoms improved in all 4. Brachialplexus was decompressed by first rib resec-tion in 7. Symptoms resolved in 2,improved in 2, resolved initially and after 3repeat operations for recurrences (due toregrowth of first rib, development of afibrous band, and fibrous tissue formationrespectively) in 1, and progressed in 2 inwhom chronic spinal muscular atrophy wasdiagnosed years later. Symptoms improvedin one patient following C7 transvexprocess resection.

Following surgery, pain (22/24 patients)and sensory disturbance (21/25 patients)diminished, and muscle power improved(10/21 patients). Surgical complicationswere transient: shoulder girdle pains (3),phrenic nerve palsy (2), neurological wors-ening (1).

It is concluded that surgical treatment ofneurogenic thoracic outlet syndrome iseffective and well-tolerated both in patientswith and without a cervical rib.

HOW SHOULD WE INVESTIGATE PATIENTSWITH SUSPECTED DEFECTS OF THEMITOCHONDRIAL RESPIRATORY CHAIN?MJ Jackson, LA Bindoff, DM Tumbull.University of Newcastle upon Tyne, UK

Respiratory chain disease (RCD) is animportant cause of neurological illness.RCD may present in a variety of ways andis therefore considered in many differentialdiagnoses. Detailed evaluation of RCD isdifficult, time-consuming and is only under-taken in specialist units. Since it is not pos-sible to investigate every patient in whomRCD is suspected in such detail, canpatients be selected for investigation byroutine clinical tests?

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The authors evaluated the results ofserum and CSF lactate, EMG, serum crea-tine kinase activity (CK) and muscle histol-ogy in 50 patients with RCD (establishedby biochemical and molecular analysis).

Serum lactate was found helpful but wasnot sufficiently sensitive for screening pur-poses in certain groups of RCD, for exam-ple, myopathy, elevated in all patients withFanconi/myopathy syndrome and of novalue in progressive external ophthalmople-gia. CSF lactate was consistently elevated inRCD that presented with CNS involve-ment. CK and EMG were normal or nearnormal in RCD even in patients withmyopathies, and the finding of unremark-able CK and EMG in a myopathy is animportant clue to metabolic muscle disease.

Muscle histology does not always showragged-red fibres, even in patients withRCD myopathy. We have foundcytochrome oxidase activity a better indica-tor of RCD.The data have been used to propose an

algorithm for the evaluation ofRCD.

PROTON SPECTROSCOPY IN DEMYELINATINGLESIONSCA Davie, CP Hawkins, WI McDonald,DH Miller. Institute of Neurology, London,UK

Magnetic resonance spectroscopy (MRS) isproviding useful information about chemi-cal pathology in an increasing number ofneurological diseases. In multiple sclerosisconsistent abnormalities have been reportedusing this technique. N-acetyl Aspartate, amarker of neuronal impairment and loss, isdecreased within MS plaques while Cholineand inositol show an increase in concentra-tion probably due to increased membraneturnover. Using short echo time protonspectroscopy of lOmsecs, six patients werefollowed at monthly intervals with sympto-matic or MRI evidence of acute demyelinat-ing lesions which displayed Gadoliniumenhancement.

Spectroscopy of these lesions showed anincrease in the Choline/Creatine ratio, anincrease in the Inositol/Creatine ratio and adecrease in the NAA/Cr. ratio compared tohealthy age matched controls and normalappearing white matter (NAWM). In addi-tion, spectra from the enhancing lesionsshowed large peaks relative to NAWM andhealthy controls at 0 9 and 1-3 ppm whichare likely to represent myelin breakdownproducts. Spectra from chronic plaquesshowed much smaller peaks in these regionssimilar to NAWM.MRS allows the in vivo detection of

myelin breakdown products in MS. Thismay prove useful in differential diagnosisand in monitoring patients involved infuture treatment trials.

HOW NEURONS INFLUENCE THE PATHWAY OFOLIGODENDROCYTE PROGENITORDEVELOPMENTJP Zajicek, DAS Compston. University ofCambridge, UK

For efficient myelination to occur in theCNS oligodendrocyte progenitors mustproliferate, migrate and differentiate in anordered sequence. To investigate theseprocesses in detail, the authors adopted anin vitro tissue culture model of myelinationusing purified embryonic rat dorsal root

ganglia upon which are plated purifiedoligodendrocyte progenitor cells. Analysis ofthese cultures has demonstrated an axonalsignal which stimulates mitosis in progeni-tors and this is mediated by platelet derivedgrowth factor (PDGF). Secondly, there isan alteration of cell surface molecules onprogenitors in co-cultures with axons sothat ganglioside expression is modified.Thirdly, there is a bias of the differentiationpathway seen in progenitors grown in serumfree medium which restricts the productionof oligodendrocytes and promotes differen-tiation into astrocytes. These findings arerelevant both to normal development ofstructures at the node of Ranvier and mayexplain the nature of astrocytosis whichcharacterises chronic demyelination.

QUANTITATIVE MRI IN PATIENTS WITHCLINICALLY ISOLATED SYNDROMESSUGGESTIVE OF MSM Filippi, MA Horsfield, WI McDonald,DH Miller. Institute of Neurology, London,UK and Scientific Institute S. Raffaele,Milan, Italy.

A semi-automated quantitative measure-ment of brain MRI abnormalities seen atpresentation and at five year follow up wasperformed in 84 patients presenting with aclinically isolated syndrome (CIS) of theoptic nerves, brainstem or spinal cord sug-gestive of multiple sclerosis (MS).

Patients who developed MS during fol-low up had a higher lesion load at presenta-tion compared to those who did not (p <0 0001). There was a strong correlation ofthe MRI lesion load at presentation withboth the increase in lesion load in the nextfive years (p < 0-0001) and disability at fol-low up (p < 0-0001). At follow up, disabili-ty and brain lesion load were stronglycorrelated in patients who developed MS (p= 0 0002).These results establish that MRI at pre-

sentation with CIS suggestive ofMS is use-ful in predicting the subsequent clinicalcourse, and the development of new MRIlesions. This suggests that quantitativebrain MRI will be helpful in selectingpatients with early clinical MS for treatmenttrials, and for subsequent monitoring oftheir response to treatment.

NERVE GROWTH FACTOR IN HUMAN SPINALCORD: CHANGES IN MOTOR NEURON DISEASEP Anand, P Foley, J Martin, M Swash, DSinicropi, S Peroutka. London HospitalMedical College, London, UK, andGenetech Inc, San Francisco, USA

Classical studies have shown that nervegrowth factor (NGF) is selectively trophicto peripheral sympathetic and sensory fibresand central cholinergic neurons. Using anassay based on recombinant human NGF,regional NGF levels were measured in post-mortem human spinal cord from patientswith motor neuron disease (MND) andmatched controls. Our findings extend theclassical view of NGF. High concentrationsof NGF were found in normal dorsal col-umn, dorsal horn, dorsolateral fasciculusand anterior white matter (range 10 to 20ng/g), which are several fold higher than inperipheral nerve, and include regions notthought to be dependent on NGF. As cervi-cal ventral horn provides limited tissue,studies are in progress to measure NGF in

this region. There was a significant decreaseof NGF in dorsal column and dorsal hornin MND cases, while an increase was foundin dorsolateral fasciculus. The low NGFlevels in dorsal cord may result partly fromdecreased uptake and transport from atro-phied peripheral tissues, and perhaps relateto the sensory abnormalities documented inMND. As there was evidence of corti-cospinal tract degeneration in the dorsolat-eral fasciculus in the MND specimens,reactive glial cells may be the source of theincreased NGF in this region. It is proposedthat NGF may play different primary andsecondary roles in neurodegeneration, thelatter akin to its role in inflammation.

THE SIGNIFICANCE OF THE CHANGE IN THEPROTON NMR SPECTRUM IN EAERE Brenner, PMG Munro, SCR Williams,GJ Barker, CP Hawkins, WI McDonald.Institute of Neurology, London, UK

Proton magnetic resonance spectroscopy(MRS) provides data about the relative con-centrations of compounds from chosen vol-umes down to 1 cm3 (the size of many MSlesions). Acute lesions show an elevation ofthe choline:creatine ratio, and some chroniclesions show a decrease in N-acetylaspartate(NAA). The former has been attributed todemyelination and the latter to neuronalloss, but conclusive evidence is lacking.The evolution of the spectra and histo-

logical appearances in 40 guinea pigs withacute experimental allergic encephalo-myelitis was studied (EAE) and comparedwith 26 controls. The increase in cholinecorrelated not with demyelination but withinflammation, and the reduction in NAAwas not accompanied by neuronal loss; it islikely that it results from neuronal dysfunc-tion. These findings have important impli-cations for the interpretation of MRS inpatients.

THE CONSEQUENCES OF "FRONTAL"IMPAIRMENT FOR REACTION TIMES INPARKINSON'S DISEASEJE Harrison, S Goodrich, C Kennard, LHenderson. Charing Cross & WestminsterMedical School, London, UK

Studies of normal subjects and patients withParkinson's disease (PD) have convergedon the idea that the processes underlyingchoice and simple reaction time (RT) aredissociable. In this regard, a key finding hasbeen a selective impairment of simple RT inpatients with PD. Unfortunately, recentstudies have not been able to reliably repli-cate this phenomenon.The authors present an experiment in

support of the selective impairment of sim-ple RT, showing it to be evident only in asub-population of PD patients. All PDpatients in this experiment were tested onthe Wisconsin Card Sorting Test, a neu-ropsychological test held to be sensitive tofrontal lobe dysfunction. According to per-formance, patients were allocated to either agroup showing signs of frontal dysfunction(n = 9), or a group (n = 9) showing nofrontal impairment.A comparison of mean reaction times for

PD patients with evidence of frontal dys-function, and those without, showed a sig-nificant interaction demonstrating "frontal"PDs to be significantly slower in simple RT,but not reliably so in choice RT

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(p < 0-01). The working hypothesis is thatthese patients suffer from a frontal-type syn-drome which disrupts the preparatoryprocess essential in normal simple RT per-

formance.

FAMILIAL ALZHEIMER'S DISEASE: THENEUROLOGY OF APP MUTATIONSAM Kennedy, SN Newman, J Ball, PRoques, EK Warrington, RSJ Frackowiak,MN Rossor. St Mary's Hospital, MRCCyclotron Unit, and The National Hospitalfor Neurology and Neurosurgery, London,UK

The description of four mutations in theamyloid precursor protein gene co-segregat-ing with the affected individuals withFamilial Alzheimer's disease provides evi-dence for allelic heterogeneity in this condi-tion. In order to assess for phenotypicheterogeneity, the 9 living affected individu-als from the three British pedigrees(F-l(,3,), F-2(cI-,) and F-3(,.l,,)) were

assessed and the case records of the otherdeceased individuals reviewed. Four indi-viduals were very severely affected. The

mean age at onset for each family was 52,55 and 52 years respectively. All individualspresented with cognitive impairment butwith little insight into their cognitive diffi-culties. Myoclonic jerks were observed in allliving individuals and seizures were a fre-quent manifestation. (5 out of 10 cases inAPP-3). Neuropsychological testing in 4cases showed severe global memory deficitsand widespread generalised cognitivedecline with preservation of object picturenaming skills. Positron EmissionTomography demonstrated bi parietal bi-temporal hypometabolism with additionalfrontal hypometabolism proportional to theseverity of dementia.

Despite the severity of dementia in theaffected cases studied, similar ages at onset,clinical and neuropsychological profiles are

apparent.

NEW APPROACHES TO DIAGNOSIS IN PRION

DISEASESJ Collinge, MS Palmer. St Mary's HospitalMedical School, London, UK.

The transmissible spongiform encephalo-pathies are now known to have a largerrange of phenotypic expression than was

hitherto realised and these conditions,which include cases in which the classicalpathological features of spongiformencephalopathies are absent, may now beclassified as prion diseases. The prion pro-tein (PrP) and its gene play a central role inthe aetiology of inherited, acquired and spo-radic prion diseases. The availability of bothprion protein gene analysis and the detec-tion of the disease related isoform of prionprotein by immunoblotting has enabled there-classification of a number of atypicalneurodegenerative cases as variants of priondisease. We have screened DNA from over

700 cases and controls for PrP mutationsand detected over 20 cases with pathogenic

mutations. Immunoblotting has beenapplied on cases where frozen tissue is avail-able. The authors here previously reportedthat normal polymorphisms of the PrP genecan affect both disease susceptibility andphenotype. We have recently identified 9individuals with deletions in the PrP gene.

These deletions constitute a new class ofPrP polymorphisms and appear, to date, tobe benign. In several of the cases in which a

pathogenic mutation was detected a familyhistory of neurodegenerative disease was

not initially apparent. PrP gene analysisshould be considered in all cases of pre-

senile dementia. In addition we are devel-oping a bioassay for infectivity of braintissue using transgenic mice. This combina-tion of DNA analysis, immunoblotting andtransgenic bioassay should allow greaterunderstanding of this group of conditionsand provide a useful adjunct to traditionalclinicopathological diagnostic criteria.

IS READING A SPARED ABILITY IN DEMENTIAOF ALZHEIMER'S TYPE (DAT)?J R Hodges, N Graham, K Patterson.University of Cambridge and MRC AppliedPsychology Unit, UK

It is often assumed that both whole-word(lexical) and sound-based (phonological)reading are preserved in DAT. Exceptionword pronunciation (for example, pint,island, naive) is used as a measure of pre-

morbid intelligence in the National AdultReading Test (NART). Yet it is well estab-lished that semantic memory is impaired inDAT which would be expected to produceselective impairment in exception wordreading (that is, surface dyslexia). To date,studies of reading in DAT are limited andhave yielded conflicting results.The authors assessed reading in 45

patients with DAT and 25 controls on 252regular and exception words in threematched frequency bands, and the NART.The DAT cases were divided into threegroups according to performance on theMini-Mental State Examination(MMSE)-minimal (> 23); mild (15-23);and moderate (< 15)-matched for age andeducation. Analysis of variance showed thatthere were significant effects of regularity,word frequency and disease severity as wellas a significant group X word type interac-tion (that is, a pattern of surface dyslexia).Impairment in exception, but not regularword, reading was highly correlated withmeasures of semantic memory (for example,naming, picture-pointing etc.).Furthermore, there was a significant drop inperformance on the NART with increasingdisease severity which would lead to an

erroneous underestimation of IQ by 15points (1 SD) in the moderate DAT group.

In conclusion, reading of exceptionwords is not spared in DAT; as predicted,features of surface dyslexia are present. Thisfinding casts doubt upon the reliability ofthe NART in predicting premorbid IQ inDAT.

CORTICAL VERSUS SUB-CORTICAL DEMENTIA:A REAL DISTINCTION?A Rosser, N Graham, JR Hodges.University of Cambridge, UK

The distinction between cortical and sub-

cortical dementia is disputed. Althoughthere is growing evidence that aetiologicallydistinct forms of dementing illness producequalitatively distinct patterns of cognitivedeficit, most previous comparative studieshave been methodologically flawed. Theauthors compared two patient groups with

predominantly subcortical disorders-pro-gressive supranuclear palsy (PSP, n = 10)and Huntington's disease (HD, n = 10)-and patients with the prototypic form ofcortical disease, dementia of Alzheimer'stype (DAT, n = 10), matched for overalllevel of dementia on the Mini-Mental StateExamination (MMSE) and DementiaRating Scale (DRS) on a comprehensiveneuropsychological test battery. In nopatient was the degree of dementia severe(MMSE range 18-30). Performance ontests of naming, word-picture matching,language comprehension and non-verbalsemantic knowledge was similar across thegroups. Patients with PSP and HD weresignificantly more impaired on tests ofvisuo-spatial ability and initiation; ADpatients were more impaired on tests of ver-bal episodic memory. Verbal fluency wasimpaired in all patient groups compared tocontrols, but letter fluency was relativelymore impaired than category fluency in thePSP and HD groups. A battery of testsdesigned to assess semantic knowledgeabout the same items, within and acrossmodalities, was given; performance wassimilar in the three patient groups, althoughthe nature of the deficit underlying theimpairment in the groups appears to bedifferent. The results offer support for thecortical-subcortical distinction.

SUBCLINICAL INVOLVEMENT OF THENERVOUS SYSTEM IN BEHCET'S DISEASE ANEUROPSYCHOLOGICAL STUDYF Ahmed, J Bamford, A Coughlan, MAChamberlain, B Noble. St James'sUniversity Hospital and The GeneralInfirmary, Leeds, UK.

A third of patients with Behget's disease(BD) will develop neurological symptoms(neuro-BD). They have a bad prognosisand the risks of more aggressive chemother-apy are considered justifiable. However, thefirst "clinical" event may leave severe neu-rological sequelae and methods of identify-ing patients with neuro-BD at an early"subclinical" stage are required. MRI hasshown "asymptomatic" cerebral lesions butremains scarce in the UK and there is insuf-ficient evidence to justify regular scanning.Simple neuropsychological assessmentshave been used to detect subtle deficits inconditions such as MS and would be apractical alternative if they predicted thedevelopment of neuro-BD. We report herethe results of the initial assessment of acohort of patients with BD who will be fol-lowed prospectively.We assessed 21 patients who fulfilled the

International Study Group (ISG) criteriafor BD and age, sex and IQ matchedhealthy controls. None had symptoms orsigns on routine examination to suggest cur-rent or previous involvement of the nervoussystem. Their disease activity was gradedaccording to ISG recommendations.

Although patients were more anxious(p < 0 02) and depressed (p < 0 01) thancontrols there was no correlation betweenmood and performance on other tests.Significant impairment (p < 0 05) inpatients with BD was found on the tests ofalertness, verbal and non-verbal memory,and naming. There was no correlationbetween the systemic disease activity andthe extent of neuropsychological impair-ment.

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TREMOR ASSESSMENT IN CLINICAL TRIALSPG Bain, LJ Findley, P Atchison, MBehari, M Vidailhet, JC Rothwell. MRCHuman Movement & Balance Unit,London, UK

We developed a clinical rating scale formeasuring the severity of essential tremor atspecific anatomical sites. Then using 4raters and 20 patients with essential tremor,the rating scale was assessed for both inter-and intra-rater reliability. The scale was

also validated against a disability self-questionnaire, accelerometry and the degreeof impairment found in patients' handwrit-ing and spirography.The rating scale proved to have substan-

tial inter- and intra-rater reliability (assessedusing Cohen's Kappa coefficients).Furthermore, the clinically rated scores forthe patients' right upper limb posturaltremors correlated well with the resultsobtained from the disability self-question-naires and assessments of spirography andhandwriting impairments (all significant atp < 0-01).The results of upper limb accelerometry

had no relationship with either disability or

spirography and writing impairment but didcorrelate with the raters' scores for upperlimb postural tremor (p < 0-01).

It is concluded that: 1) accelerometrydoes not provide a valid index of tremorinduced disability; 2) a clinical rating scalecan be reliable and is valid; 3) no othertremor rating scale has been assessed in thisway.

BIOENERGETICS OF THE GASTROCNEMIUSMUSCLE IN MYOTONIC DYSTROPHYPRJ Barnes, GJ Kemp, DJ Taylor, GKRadda. University of Oxford and MRCClinical and Biochemical MagneticResonance Unit, UK

The authors have used 31p magnetic reso-

nance spectroscopy to study bioenergeticsin the gastrocnemius muscle of 14 patientswith myotonic dystrophy (MyD). At rest,intracellular pH was higher in the patientgroup [705 ± 0-01 [SE] v 7-03 ± 0-01; p =

0-009, Mann-Whitney U statistic]. Theintracellular phosphocreatine (PCr) concen-tration was normal, but that of inorganicphosphate (Pi) was raised at 5-9 ± 11 mM(control 3-6 + 0-2; p = 0-004) and the cal-culated concentration of free ADP was alsoraised (33 ± 64M vs 20 ± 2pM; p = 0 04).During plantarflexion exercise the patientgroup exercised for a mean of 5-2 ± 1N1minutes compared with 10-7 ± 0 4 minutesin controls (p = 0-0004). The levels of pH,PCr, Pi and ADP at the end of exercisewere not different in the two groups, how-ever, and the relationship of pH and PCrutilisation was normal. The recovery halftimes for PCr, Pi and ADP and the appar-ent calculated mitochondrial V,, for ATPresynthesis following exercise were all nor-mal. These data contrast with those fromthe forearm flexor in patients with MyDwhere resting muscle showed normal pHbut there was an abnormal relationshipbetween pH and PCr utilisation duringexercise. One explanation is that changes inresting pH are related to regeneration notpresent within more severely affectedmuscle.

THE RELATIONSHIP BETWEEN Gd-ENHANCEMENT AND PROTON NMR SPECTRALCHANGES IN EAERE Brenner, SP Morrissey, EPGH DuBoulay, PMG Munro, SCR Williams, GJBarker, CP Hawkins, WI McDonald.Institute of Neurology, London, UK

The earliest detectable event in the develop-ment of the new lesion in MS, as in experi-mental allergic encephalomyelitis (EAE), isa breakdown in the blood-brain barrier inassociation with inflammation. The precisesequence of events is however uncertain.We have attempted to elucidate them inacute EAE in guinea pigs. In acute EAE asin MS magnetic resonance spectroscopy(MRS) there is an elevated choline:creatineratio which at least in the former is associat-ed with inflammation, reflecting increasedmetabolic turnover in the cellular infiltrate.In sequential studies in 14 animals withEAE compared with 8 controls, we

observed an increase in choline:creatinebefore the onset of Gd-enhancement. Thissuggests that perivenous inflammation pre-cedes blood-brain barrier breakdown tosolutes. Whether the same is true in MSawaits the results of serial MRS studies inpatients with much ongoing disease activity.

IMPROVING THE RECORDING OF CLINICAL

ASSESSMENT OF STROKE PATIENTS WITH A

CLERKING PROFORMARJ Davenport, MS Dennis. WesternGeneral Hospital, Edinburgh, UK

A thorough clinical assessment is essentialfor the accurate diagnosis, treatment, reha-bilitation, prediction of outcome and sec-

ondary prevention in patients with acutestroke. The aims of this study were to mea-sure the completeness of patients' assess-

ments by junior doctors and to determinewhether the introduction of a clerking pro-forma would improve this.The authors prospectively identified all

patients admitted with an acute stroke tothe Unit over an 8 month period. Using a

carefully constructed form and explicitlyworded standards two observers (RJD andMSD) audited the completeness of therecording of the patients' assessments in themedical records. Disappointing results (seetable) led to the introduction of a strokeclerking proforma which was followed by afurther audit. Although the inter rater relia-bility of our audit form was reasonable,equal proportions of the records were

assessed by each observer before and afterthe introduction of the proforma to min-imise bias. The numbers audited after theintroduction of the proforma were based onsimple power calculations.Our results (see table) show that a clerk-

ing proforma improves the completeness ofrecording of patients' assessments and facil-itates further audit which may improvepatient care.

THE REFERRED TRIGEMINAL SYNDROME: APOTENTIALLY IMPORTANT AETIOLOGICALCONCEPT CONCERNING THE GENESIS OFHEADACHECJF Davis. The Radcliffe Infirmary,Oxford, UK

Headache is by far the commonest singledisorder managed by the neurologist (30%of outpatients). A very large part of diagno-sis is descriptive rather than aetiologicallybased. The headaches of many patients failto fit either with traditional descriptive cate-gories or with the new InternationalHeadache Society classification.A series of sixty outpatients (Age 14-72

mean 39-4; Female:Male = 3:1) with con-

stantly lateralised anterior head pain is pre-sented. The pain was of 0 5 to 252 monthsduration (mean 24-6 months), locatedorbitally in 73%, right sided in 60%, inter-mittent or persistent equally often, andassociated with a relevant cervical history in54% or ipsilateral suboccipital tenderness inat least 55%. Of these a small number arediscussed in detail in particular respect offeatures which strongly imply that their painwas triggered from structures at the cranio-cervical junction without any complaint ofpain localised to this area. There is limitedbut indicative literature to suggest thatpotentially painful processes localised tothis area may, no doubt due to some inter-action with the spinal nucleus of the ipsilat-eral fifth cranial nerve, generate referredpain which is experienced entirely within its"cutaneous" territory. From this, it is spec-ulated that many or all of the larger groupof fifty eight patients with no overt or iden-tifiable cause for their symptoms may alsohave their pain triggered from the cranio-cervical junction. If this conclusion be cor-

rect, it may have wider implications inrespect of the mechanism of genesis ofheadache of a less clearly localised nature.

MRI OF PATIENTS WITH ISOLATEDIDIOPATHIC RETINAL VASCULITISA Gass, E Graham, IF Moseley, WIMcDonald, DH Miller. Institute ofNeurology, London, UK

Retinal involvement (for example, venous

sheathing, leakage on fluorescein angiogra-phy) in MS patients occurs in up to 40%,whereas only 10% of patients with retinalvasculitis go on to develop MS. We there-fore performed cranial MRI in IRV patientsto look for further evidence of multifocaldisease suggestive of CNS demyelination.Ten patients with isolated IRV under theage of 50 had MRI of the brain (axial PD,T2, pre- and post Gadolinium) and opticnerves (coronal STIR). MRI was performed2 to 12 years after the first manifestation ofretinal disease.

Seven of 10 brain examinations were nor-

mal. 3 patients showed brain abnormalities:1 had a single white matter lesion, 1 showedextensive white matter disease suggestive of

Before (n = 160) After (n = 66) Difference ofProportion

Recordedl Recorded! (with 95%Examples ofAudit Items Standard % Standard % confidence intervals)

Symptoms from wimess 88/100 88% 31/33 94% 6% (-16,4%)Peripheral vascular disease 23/144 16% 60/65 92% 76% (68,85%)Cervical Bruit 79/160 49% 65/66 99% 50% (41,57%)Conscious level 105/160 66% 66/66 100% 34% (27,42%)Swallowing 32/122 26% 63/66 96% 70% (60,79%)Driving 7/92 8% 55/61 90% 82% (73,92%)

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ischaemia and 1 had multiple lesions indis-tinguishable from MS. After Gd-DTPAinjection no pathological enhancement was

observed. Only two patients showed abnor-mal high signal in the optic nerve, one ofwhom also had multiple white matterlesions. Our MRI findings support previousclinical data which show that the risk ofdeveloping MS with idiopathic retinal vas-

culitis is low. This contrasts sharply withclinical and MRI studies in isolated opticneuritis.

COMPARISON OF FAST SPIN ECHO (FSE) ANDSHORT INVERSION TIME INVERSIONRECOVERY (STIR) IMAGING IN OPTICNEURITIS (ON)A Gass, IF Moseley, D MacManus, DHMiller, WI McDonald. Institute ofNeurology, London, UK

FSE is a new technique with scan times thatare up to 16 times shorter than thoseobtained with conventional sequences,

which allows very high resolution images ofthe optic nerve in 11 minutes. Optic nerveMRI was performed in 18 patients with ONand in 10 normal controls. Two sequenceswere obtained coronally: FSE (in plane res-

olution 0 5 mm, slice thickness 3mm) andSTIR (in plane resolution lmm, slice thick-ness 5mm), a sequence sensitive for demon-stration of optic nerve lesions.FSE demonstrated much more anatomi-

cal detail than STIR (for example, distinc-tion of optic nerve and sheath). In ON,STIR and FSE were equally sensitive tolesion detection in 10 nerves, FSE appearedsuperior to STIR in 9 and only STIRdetected a lesion in 2 cases. Two sympto-matic nerves revealed no abnormality inboth sequences. In several cases FSE alonedemonstrated nerve swelling, atrophy or

partial cross-sectional involvement of thenerves by lesions. In conclusion, FSE imag-ing of the optic nerve improves anatomicaldefinition and increases lesion detection inON.

CHRONIC INFLAMMATORY DEMYELINATINGPOLYNEUROPATHY MIMICKING A SPINALSTENOSIS SYNDROMEL Ginsberg, RHM King, J Workman, PKThomas. Royal Free Hospital School ofMedicine, London, UK

The authors report a patient with chronicinflammatory demyelinating polyneuropa-thy (CIDP) who developed cauda equinasymptoms due to swelling of the nerve rootsin the lumbar spinal canal. A 44 year oldwoman presented with a 13 year history offluctuating back pain radiating to the legsexacerbated by exercise. She had mild distalsensory symptoms in the limbs.Examination revealed tendon areflexia andslight distal sensory loss. Electrodiagnosticstudies indicated a demyelinating polyneu-ropathy. Sural nerve fascicular biopsyshowed evidence of chronic demyelinationwith hypertrophic changes and the presence

of inflammatory infiltrates. MRI of the lum-bar spine revealed markedly thickenednerve roots from the level of the conus

medullaris, filling the distal thecal sac. Thiscase shows that spinal compressive syn-dromes may occur in acquired hypertrophicneuropathies as well as in hereditary motor

and sensory neuropathy and expands thespectrum of the clinical presentation ofCIDP.

ACCURACY, REPRODUCIBILITY ANDVARIABILITY OF QUANTITATIVE ASSESSMENTSOF BULBAR AND RESPIRATORY FUNCTION INMOTOR NEURON DISEASE (MND)A Goonetilleke, RJ Guiloff. WestminsterHospital, London, UK

Several drugs are being tested in MND.Survival studies require large numbers, are

protracted and expensive. Anotherapproach is to screen drugs eligible for sur-

vival studies by assessing deterioration ofbulbar and respiratory function (whichrelate to survival in MND) over a period, insmaller samples. The validity of quantitativetests of these functions is studied.

Five raters timed repeated stimuli gener-ated by a metronome simulating bulbartests. For all raters, mean error-rate was

5 1%, correlation coefficient 0-89 and %difference 1-5 (readings 3 hours apart).Coefficient of variation (CV) of 10 readingswas 3-2%.The experienced rater obtained more

reproducible and less variable readings, andperformed timed bulbar (tongue, speech,jaw, swallowing) and respiratory tests (vitalcapacity, chest circumference) on 26 MNDand 21 age and sex-matched controls over 5days. Learning effects were eliminated. Forall subjects and tests, mean correlation coef-ficient was 0-98 and % difference 2-3 (read-ings 3 hours apart), with CV 8-8% (10readings over 3 days); MND and controlsubjects behaved similarly. Composite bul-bar scores improved reproducibility andvariability. The estimated rater contributionto this variability was 17%.

These tests are suitable for assessingdeterioration of bulbar and respiratory func-tion in small samples ofMND patients.

ACCURACY, REPRODUCIBILITY ANDVARIABILITY OF HAND-HELD DYNAMOMETRYIN MOTOR NEURON DISEASE (MND)A Goonetilleke, RJ Guiloff. WestminsterHospital, London, UK

The limitations of manual testing of musclestrength are recognised. More objective andaccurate methods are preferable in monitor-ing longitudinal changes, as required inclinical trials. The validity of readingsobtained by hand-held dynamometry were

investigated.A spring-loaded device designed to

"break" at preset forces was used to assess

accuracy, reproducibility and variability ofreadings obtained by three raters with vary-

ing experience in the method. Accuracy(mean error-rate of 3 0%), but not repro-ducibility or variability, was improved bygreater experience.The rater with intermediate experience

tested strength in 9 muscle groups of 19patients with MND. For all patients andmuscles, mean correlation coefficient was

0-98 and % difference 13-2 (readings 6 daysapart), with mean coefficient of variation(CV) of 9 9% (10 readings over 6 days).Use of a global composite muscle score

resulted in improvements in reproducibilityand variability, with mean correlation coef-ficient 0-98 (% difference 6 7) and CV

5-8%. The rater was estimated to contribute40% of the total variability of readingsobtained whilst testing patients.

Hand-held dynamometry is a suitablemethod for assessing muscle strength inMND patients undergoing clinical trials.

MYORHYTHMIA AND OVERLAP SYNDROMESNJ Gutowski, JR Heron. NorthStaffordshire Royal Infirmary, UK

Five patients showing forms of an unusualtremor, myorhythmia, are presented. In allcases the palate and eye movements werenot affected. The first two are cases ofessential myorhythmia. The other casesshow an overlap between myorhythmia andother tremors originating in the brainstemand cerebellar regions. Myorhythmia is atremor which is present at rest and absentduring sleep. It can be synchronous or asyn-chronous in different muscle groups andcan have a variable rate in each musclestudied. It may be influenced by cough,stress, sustained posture, voluntary move-ment or peripheral stimulation. Thepatients presented demonstrate firstly thatin essential cases of myorhythmia palataltremor is absent. Secondly, that myorhyth-mia has a wide frequency range (at least 0 4Hz to 6 Hz). Thirdly, it can occur in associ-ation with other tremors originating in thebrainstem, cerebellar and extrapyramidalpathways and fourthly there is commonly afamilial history of tremor. To study themechanisms underlying myorhythmia maxi-mum information will be obtained fromessential cases. It should be realised thatmyorhythmia can occur in the context ofother tremors involving the brain stem,cerebellar and extrapyramidal circuits.

THE FUNCTIONAL LIMITATIONS PROFILE IS AVALID, RELIABLE AND SENSITIVE MEASURE OFDISABILITY IN MULTIPLE SCLEROSISJ Hutchinson, M Hutchinson. St Vincent'sHospital and University College, Dublin,Eire

The standard measure of disability in multi-ple sclerosis (MS), the Kurtzke ExpandedDisability Status Scale (EDSS), is an ordi-nal scale subject to inter- and intraratervariability with a bimodal distribution inMS populations. The Illness Severity Score(ISS), is an interval score derived from theEDSS. The Functional Limitations Profile(FLP) is a validated interval measure ofpatient report of disability.On two occasions over six months 34 MS

patients were assessed prospectively by aneurologist and a psychologist, using theabove measures. The FLP PhysicalDimension and its sub-scale Ambulation,correlated significantly with the EDSS forboth visits (at visit 1: r = 0 74 and 0-81respectively, at visit 2: r = 0-76 and 0-82).The reliability of FLP was assessed by com-paring scores in the 23 patients who had notchanged clinically (EDSS change <1-0, ISSchange < 3 7). The 99 7% confidence limits(CL) were, for FLP Physical Dimension-4-5 to +6-1, Ambulation -8-2 to + 8-7.For sensitivity of the FLP the 11 MS clini-cally changed patients (EDSS > 1-0, ISS >3 7) were assessed; 99 7% CL were, forFLP Physical Dimension -26-3 to -0-1,Ambulation -26-5 to + 6-4.

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70Proceedings of the Association ofBritish Neurologists

The FLP in this pilot study is a valid,reliable and sensitive measure of MS dis-ability. If confirmed by larger studies itwould be useful in prospective studies oftreatments of MS.

THE INFLUENCE OF HLA-DR AND -DQALLELES ON PROGRESSION TO MULTIPLESCLEROSIS FOLLOWING A CLINICALLYISOLATED LESIONMA Kelly, DA Cavan, MA Penny, CHMijovic, D Jenkins, S Morrissey, DHMiller, AH Barnett, DA Francis. Universityof Birmingham and Institute of Neurology,London, UK

A five year follow up study was performedon 70 white patients presenting with isolat-ed neurological syndromes of the opticnerve, brainstem or spinal cord to assess therisk of progression to multiple sclerosis(MS). The influence on patient prognosis ofHLA-DR and -DQ alleles and presentationwith disseminated brain lesions, demon-strated by MRI scanning, was determined.Clinical progression to MS was observed in60% of optic neuritis patients, 50% ofpatients with a brainstem syndrome and35% of patients with a spinal cord distur-bance.

Multiple sclerosis and the isolated clinicalsyndromes were positively associated withDR15, DQA1*0102 and DQB1*0602 thefrequency of the alleles in the latter groupwas intermediate between that seen in MSpatients and healthy controls. Conversion toMS was positively associated with theDR15.DQA1*0102.DQB1*0602 haplotypebut the influence ofHLA was only apparentin patients with disseminated brain lesionsat presentation (MRI-positive)-MS devel-oped in 86% of MRI-positive, DRI 5-posi-tive patients compared with 55% ofMRI-positive, DR1 5-negative patients (p <0 025). The data suggest that these HLAalleles are involved in susceptibility to initialdemyelinating lesion formation and areimportant in the subsequent developmentof MS in MRI-positive patients.

BENIGN MS: MRI EVIDENCE FOR A LESSINFLAMMATORY DISEASED Kidd, AJ Thompson, DG MacManus,BE Kendall, WI McDonald. Institute ofNeurology, London, UK

The development of disability in multiplesclerosis is highly variable, approximatelyone third of patients having a benigncourse. The reasons for this are not clear.Two longitudinal studies involving 11patients with early relapsing/remitting dis-ease and 11 with benign MS have been car-ried out. Patients had a clinical examinationand a Gadolinium-DTPA enhanced MRIscan of brain at monthly intervals for sixmonths. There was no difference in disabili-ty between the two groups. Mean MRIlesion loads were 41 and 48 respectively.Over the study period a mean of 0 5 relaps-es per relapsing/remitting patient and 0A2relapses per benign patient occurred. Therewere 6-6 new lesions per relapsing/remittingpatient and 1-9 new lesions per benignpatient (p < 0.03). The number of newlesions per relapse was significantly less inthe benign group (2-25 v 6-0, p < 0-03).Enhancement occurred in 80% and 38% of

new lesions in relapsing/remitting andbenign groups respectively.Thus patients with benign MS appear to

have fewer new MRI lesions per relapse andless evidence of blood-brain barrier break-down and inflammation. This may result inless axonal damage and consequently lessclinical disability.

INTEROBSERVER VARIATION IN THECLASSIFICATION OF SUBTYPES OF CEREBRALINFARCTIONRI Lindley, MS Dennis, J Wardlaw, JSlattery, PAG Sandercock, CP Warlow.University of Edinburgh, UK

The classification of subtypes of cerebralinfarction (total and partial anterior circula-tion infarction, lacunar infarction, and pos-terior circulation infarction) predicts: earlymortality; functional outcome; and whetherthe infarct was due to large- or small-vesselocclusion. The reliability of the classifica-tion in clinical practice was examined.Two clinicians independently assessed

consecutive patients admitted to hospitalwith an acute stroke. Neurological historyand signs, and the subtype of infarct wererecorded.

Eighty five patients were assessed.Interobserver agreement for the classifica-tion was good (kappa 0 59; 95% confidenceinterval 0 43-0 74). Disagreement in theassessment of the commonly elicited neuro-logical signs explained many of the misclas-sifications: interobserver agreement wasgood for some signs (hemiparesis kappa0 77, dysphasia 0 70), moderate for some(hemianopia 0 39) and poor for others (sen-sory loss 0-1 5).The level of interobserver agreement is

satisfactory. The classification can helpidentify priorities for investigation andresearch studies and is simple and practica-ble enough for use in routine clinical prac-tice.

THE ANALYSIS OF THE PREDICTIVELOCALISING VALUE OF CLINICAL SEIZUREPATTERNS DEFINED WITH THE ASSISTANCEOF CLUSTER ANALYSISM Manford, DR Fish, SD Shorvon.Institute of Neurology and Charing CrossHospital, London, UK

Localisation of clinical seizure patterns iscurrently defined by the "gold standard" ofremission of seizures after resective surgery.This method is highly selective and intro-duces substantial bias. A novel approach isdescribed.A total of 252 cases were selected with

focal abnormality of interictal EEG, ictalEEG, imaging or clinical pattern. Witnessedseizure histories were taken and sequence ofseizure manifestations was encoded. Datawere entered into a statistical cluster analy-sis and 25 groups identified, which wererefined to 14 groupings by hand, each cor-responding to a clinical seizure type.Location of lesions on imaging was analysedby a template technique and the involve-ment of different regions coded 0-3. Therelation between seizure type and regionalcortical involvement was assessed, usingchi-square analysis. Ictal and interictal EEGpatterns were also assessed for each seizuretype.

Well recognised seizure patterns wereidentified by this technique, for example,Jacksonian motor, which was strongly asso-ciated with perirolandic lesional involve-ment. Less familiar seizure types, forexample, tonic posturing were also definedand this type was significantly associatedwith lateral premotor lesions (p < 0-001). Inthese groups, however, there were impor-tant minorities, with different associationson investigation. This analysis is less biasedthan in previous series and reflects the limi-tations of clinical seizure localisation.

EARLY RECOVERY SCALE FOR SEVERETRAUMATIC BRAIN INJURYDLMcLellan, BAWilson, S Home, MWatson. Southampton University, UK

Chartering the recovery of patients withsevere brain injury is difficult because cur-rent outcome scales are too crude. Eightyseven patients recovering from severe trau-matic brain injury have been studied toestablish the pattern and sequence of recov-ery of physical and psychological functions.The methodology required for this work iscomplex and will be discussed. An initialscale of 50 items has been identified cover-ing the segment of recovery from coma toemergence from post-traumatic amnesia.These fifty items will be presented andshow that the pattern of recovery is broadlysimilar to the sequence of normal functionaldevelopment, but differs from it in someimportant respects. This scale and develop-ments from it should prove helpful in theclinical assessment of patients and in defin-ing objectives for rehabilitation.

A PROSPECTIVE STUDY OF THE CAUSES OFSPASTIC PARAPARESIS AND QUADRIPARESIS IN585 PATIENTSAP Moore, LD Blumhardt. University ofLiverpool, UK

In a three year period between 1986-89 aprospective study was carried out of thecauses of non-traumatic spastic paraparesisand quadriparesis in a regional centre in theUK. A total of 585 patients were selectedby intention to investigate by myelography.Patients under 15 years old or who had pre-viously been investigated for myelopathywere excluded. One year after recruitmentwas halted the case notes were reviewed toascertain the diagnosis.The final diagnosis remained uncertain in

27-4%, falling to 18-6% after MRI in aselected group. The commonest diagnoseswere cervical spondylotic myelopathy(23 6%), extrinsic tumour (16-4%), multi-ple sclerosis (9-1% rising to 17-8% afterMRI) and motor neuron disease (4-1%).

Ninety six patients had extrinsic com-pressive neoplasms, of which 41% were car-cinomas, 20% were of nervous systemorigin, 17% haemopoeitic, 7% were cysts,7% were mesenchymal. There were 41/585patients with previously known malignancy.In only 2 of these was an independent non-cancerous pathology identified.

Reasons for an uncertain diagnosisincluded multiple pathology and insufficientevidence of causation. Others in this groupmay have multiple sclerosis or motor-neurone disease.

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AMNESIC SYNDROME FOLLOWINGTHEOPHYLLINE ASSOCIATED SEIZURES:IATROGENIC BRAIN INJURYJI O'Riordan, J Hutchinson, MXFitzgerald, M Hutchinson. St Vincent'sHospital and University College, Dublin,Eire

Theophylline associated seizures usuallyoccur with high theophylline serum levelsand are often benign in nature. In some cir-cumstances epileptic activity may be pro-

longed, focal in nature, resistant to therapyand with a poor outcome. The possibilitythat seizures associated with chronic theo-phylline therapy may cause brain injury isnot generally recognised.Two patients without a history of epilep-

sy, a 68 year old man with emphysema anda 16 year old girl with cystic fibrosis, devel-oped status epilepticus when on chronicoral theophylline therapy. Although seizureactivity was quickly controlled, bothpatients remained confused. Both have an

amnesic syndrome confirmed by detailedneuropsychological testing. Anterogradeamnesia persists six months after presenta-tion and results in significant disability.MRI (T2 weighted) in one showed a highsignal lesion in the left hypothalamus.Serum theophylline in one patient was inthe mildly toxic range.

Theophylline associated seizures may

result in severe brain injury and death.Various factors may predispose certainpatients to develop seizures; these includeadvanced age, pre-existing neurological dis-ease, low serum albumin and the concomi-tant use of cimetidine, ciprofloxacin and theerythromycin group of antibiotics.

SIDE OF NEUROLOGICAL SYMPTOMSPREDICTS RESULTS OF INVESTIGATIONPM Rothwell. Western General Hospital,Edinburgh, UK

Eighty two patients, under 60 years of age,

who had undergone inpatient neurologicalinvestigation during the last 4 years, for uni-lateral sensory symptoms and/or weakness,in the absence of "hard" neurological signs,were identified by review of discharge sum-

maries. Positive investigations, defined as

those which explained the symptoms, were

found in 22 cases [27%]. Investigation was

more frequently positive for right-sided thanleft-sided symptoms [54% vs 13%, p <

0.01] and in males than females [42% v

19%, p = 0 05]. The number of investiga-tions performed was not influenced by theside of symptoms or the sex of the patient(table).Seventeen patients were described as anx-

ious or hyperventilators at initial consulta-tion, ofwhom 16 subsequently had negativeinvestigations. Ten patients were seen by a

psychiatrist during their in-patient stay anddiagnosed to be depressed, of whom 9 hadnegative investigations. In patients with nor-

mal investigations, anxiety was associatedwith left-sided symptoms [94%] anddepression with right-sided symptoms[89%, p < 0-001].

In patients with unilateral symptoms andno "hard" signs the side of symptoms pre-dicts the result of investigation. The oppo-site lateralisation of symptoms in anxietyand depression is consistent with experi-mental evidence of functional hemisphericasymmetry with altered mood.

FAMILIAL BENIGN FASCICULATIONIK Saadeh, TK Banerjee, PJ Hughes, LSIllis. Wessex Neurological Centre,Southampton, UK

Fasciculations may occur as part of abenign syndrome. Fasciculations in 3 familymembers are described. The father andelder son were symptomatic, whereas theyounger son was asymptomatic. Theauthors have been unable to find any previ-ous report of several affected memberswithin one family.

Patients with fasciculations or musclecramps without the presence of wasting orweakness or EMG evidence of denervationare unlikely to develop motor neuron dis-ease. Fasciculations, have been described inotherwise normal individuals, peripheralneuropathies and a variety of toxic, druginduced and metabolic disturbances.Differentiation between malignant andbenign fasciculation of healthy peopleremains uncertain.

Electrophysiological findings are proba-bly not helpful in distinguishing betweenmalignant and benign fasciculation,although some differences have beendescribed. Although 3 cases of benign fasci-culation occurring in 2 generations of onefamily have been identified, the pathogene-sis of this disorder is uncertain.

POSSIBLE PREFERENTIAL EFFECT OFDEMYELINATION ON THE MAGNOCELLULARPATHWAYR Sehdev, DH Foster, JR Heron. Universityof Keele and North Staffordshire RoyalInfirmary, UK

Psychophysical investigation of patientswith optic neuritis and multiple sclerosishas revealed conflicting evidence supportingselective and non-selective losses in variouscomponents (spatial, temporal, luminanceand colour) of visual function. On the basisof anatomical, physiological, and psy-chophysical studies in humans and otherprimates, two major pathways of visualprocessing have been identified, the magno-cellular pathway and the parvocellular path-way. These pathways may provide aframework for explaining the different pat-terns of visual loss in demyelinating disease.

Symptoms Sex Mentul stateSide of PositiveSymptomls investigations Sensory All M F Anxious Depressed

Right yes 8 15 9 6 1 0Right no 8 13 3 10 1 8Left yes 4 7 2 5 0 1Left no 27 47 12 35 15 1Total 47 82 26 56 17 10

Measurements were made in a group ofsix patients with previous optic neuritis withrelatively mild residual impairment follow-ing their last episode of optic neuritis, andin a group of five healthy, age- and sex-matched controls. Three kinds of flickeringstimuli, with different spatial configurations,were used to obtain a measure of temporalmodulation sensitivity at different temporalfrequencies, in the form of de Lange attenu-ation characteristics. Patients showed lossesin modulation sensitivity in all conditions,but most strongly for stimuli with relativelylow effective spatial frequency, independentof temporal frequency, and for one condi-tion of relatively high spatial frequency. Apossible interpretation of these findings isthat there is a preferential effect of demyeli-nation on the magnocellular pathway.

NON-VACUOLAR MYELOPATHIES IN HIVINFECTIONSV Tan, RJ Guiloff, F Scaravilli, NHarcourt-Webster, BG Gazzard.Westminster Hospital and Institute ofNeurology, London UK

Non-vacuolar myelopathies in HIV infec-tion have not been well documented. Thirtyeight patients with myelopathy seen overeighteen months were drawn from a popu-lation of 488 patients with AIDS, 1015symptomatic non-AIDS/PGL, 407 wellseropositives, 10 with seroconversion ill-ness, and 21 of undetermined status.

Eighteen patients had clinical, radiologi-cal and/or pathological data incompatiblewith a diagnosis of vacuolar myelopathy(VM). All were male homosexuals; medianage 34 years (range 21-61), median CD4count 49 cells/ml, (2-520). Seven had acutemyelopathies (H.zoster 2, probable CMV 2,extradural lymphomatous deposits 1, cordcontusion 1, undetermined 1). Five hadacute myeloradiculopathies (H.zoster 1,CMV 4). Four* had chronic myelopathies(cervical spondylosis 2, undetermined 2).One, with intellectual impairment andmyelopathy mimicking VM, recoveredspontaneously. One had a hysterical para-paresis. The diagnosis was confirmedpathologically in 2 (H.zoster myelitis, CMVradiculomyelitis).The annual incidence of non-vacuolar

myelopathies in our population was 1-4% inAIDS, 0-5% in symptomatic non-AIDS/PGL, and 0-2% in well seropositives.Potentially treatable causes included cervi-cal spondylosis, CMV myelitis/myeloradi-culitis and H.zoster myelitis.Subacute/chronic myelopathies should notbe diagnosed as VM without adequateinvestigation. CMV infection was commonin acute myelopathy/myeloradiculopathy;concomitant retinitis should be sought.*One had a subacute myeloradiculopathy(CHV).

HERPES SIMPLEX TYPE-I ENCEPHALiTIS INAIDSSV Tan, RJ Guiloff, F Scaravilli, PEKlapper, GM Cleator, BG Gazzard.Westminster Hospital and Institute ofNeurology, London and University ofManchester UK

Classical HSV-1 encephalitis has not beendescribed in AIDS. It has been suggestedthat severely immunocompromised AIDSpatients may be unable to mount the necro-

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tising immune reaction responsible for theclassical clinicopathological picture.An AIDS patient is presented with a

CD4 count of 161 cells/pl and clinicallytypical acute HSV-1 encephalitis withsevere cerebral necrosis in the distributionseen in immunocompetent subjects. CTscan and EEG showed bitemporal abnor-malities. Serum viral titres, CSF antigen-specific oligoclonal studies and PCR forHSV were negative. He died 4 weeks fromthe onset of illness.

There was swelling of both temporallobes, bilateral uncal herniation and bilater-al extensive necrotic change in the hip-pocampi, insulae, and parahippocampal andcingulate gyri. Unlike HSV encephalitis inimmunocompetent patients, where viralantigen is rarely demonstrable after 3 weeksof illness or after antiviral treatment, viralinclusions were abundant and easily visibleon H + E and with immunostaining, asdescribed in one previous anergic non-HIVpatient. PCR of brain tissue identified thevirus as HSV-1.The severe acute necrotising immune

reaction appeared to be largely macrophageand/or monokine mediated; poor viral clear-ance may have been due to impaired T-cellfunction.

SERUM OLIGOCLONAL BANDS IN MULTIPLESCLEROSISAZJ Zeman, G Keir, EJ Thompson, WI

McDonald. Institute of Neurology,London, UK

The detection of oligoclonal bands of IgGin CSF, in their absence from serum, hasproved a robust and sensitive method fordemonstrating an intrathecal immuneresponse in the investigation of multiplesclerosis. The presence of oligoclonal bandsin the serum in multiple sclerosis has beennoted in the past, but there has been con-siderable disagreement over their incidenceand significance. We have examined CSFand serum pairs from 50 consecutivepatients with CSF oligoclonal bands,undergoing investigation for multiple scle-rosis, using the sensitive technique of iso-electric focusing followed byimmunodetection. Serum oligoclonal bandswere present in 46% of cases. There areboth: 1) qualitative and 2) quantitative rea-sons for concluding that these oligoclonalbands reflect systemic synthesis of oligo-clonal IgG which is independent of theintrathecal immune response: 1) the serumpattem is discordant with the CSF patternin 87% of patients with serum oligoclonalbands, indicating independent synthesis inthe two compartments; 2) quantitative mea-surement of intrathecal IgG production inthese patients, combined with dilutionexperiments, indicate that clones synthe-sised intrathecally will very rarely achieve asufficient concentration in serum to bedetected. These findings support the viewthat systemic immune activation is commonin multiple sclerosis.

OLIGOCLONAL BAND NEGATIVE MULTIPLESCLEROSISAZJ Zeman, D Kidd, B McLean, EThompson, WI McDonald. Institute ofNeurology, London, UK

The demonstration of intrathecal synthesisof oligoclonal IgG has diagnostic and prog-nostic implications in suspected multiplesclerosis, and the oligoclonal IgG may play apart in the pathogenesis of the disease.Oligoclonal bands are absent from about10% of cases of clinically definite multiplesclerosis, but this group of patients has sel-dom been studied. Twenty five suchpatients have been identified among 247patients with clinically definite multiple scle-rosis (10-1%). On detailed review of these25 cases the laboratory results proved to beequivocal or technically unsatisfactory in 12(48%), and 5 patients had plausible alterna-tive explanations for their symptoms (25%).Ten oligoclonal band negative patients withunequivocal laboratory results and clinicaldiagnosis were matched for age, sex, diseaseduration and type with 10 oligoclonal bandpositive controls. Disability was assessed onthe Kurtzke scale by an examiner blind tothe CSF findings. In 7 of the 10 pairs thepositive control was more severely disabled,while in only 2 pairs was the negative patientmore severely affected (p = 0-01). Absenceof oligoclonal bands in putative clinicallydefinite multiple sclerosis should raise suspi-cion of misdiagnosis or laboratory error, butundoubted cases of oligoclonal and negativemultiple sclerosis do occur, and may have arelatively benign prognosis.

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University of Keele, 15-16 April 1993

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